Professional Documents
Culture Documents
PLANT ALKALOIDS
BY
THOMAS ANDERSON
HENRY
D.Sc.(Lond.),
Formerly Director, Wellcome Chemical Research
Laboratories and Superintendent of Laboratories,
Imperial Institute, I Minion.
FOURTH
EDITION
THE BLAKISTON
COMPANY
Philadelphia T o r o n t o
1949
First edition .
Second edition
Third edition .
Fourth edition
1913
1924
1939
1949
vl
CONTENTS
PAGE
1X
Introduction
Pyridine Group. Piperine, Piperovatine, Leueenol, Mimosine,
Alkaloids of Ricinus communis, Fcenugrec, Areca Nut, Hemlock,
Lobelia, Tobacco (Nicotiana spp.), Anabasis aphylla, Pomegranate Root Bark
.
.
.
.
.
.
.
.
64
116
viii
CONTENTS
PAGE
413
415
418
484
488
498
500
517
539
553
Pyrrolidine Group
599
Pyrrolidine Group
601
Quinazoline Group
617
Glyoxaline Group
621
Alkaloidal Amines
630
661
716
Minor Alkaloids
771
779
Index
784
PLANT ALKALOIDS
INTRODUCTION
THE literature of alkaloids can conveniently be divided into five
sections, dealing with (1) the occurrence and distribution of these substances
in plants ; (2) biogenesis, or the methods by which alkaloids are produced
in the course of plant metabolism; (3) analysis, ranging from the commercial and industrial estimation of particular alkaloids to the separation,
purification and description of the individual components of the natural
mixture of alkaloids, which normally occurs in plants ; (4) determination
of structure ; and (5) pharmacological action.
In the period that has elapsed since the third edition of this book was
published there have been additions to each of these sections, and to
some of them the new contributions have been numerous and important.
Many new alkaloids have been described and new occurrences recorded.
An interesting feature of this section of work is the operation of a number
of what may be called alkaloidal surveys, ranging from searches for
alkaloidal plants to investigations of plants of a particular botanical
order, or of a selected botanical genus, or of geographical or other variants
of a single species. In Soviet Russia, Massagetov 1 has made a preliminary
examination of 113 species collected in Central Asia, out of which he has
found promising materials among lichens, mosses and liverworts, some
varieties of maize, cotton and beans, certain species of Picea and Pinus,
and a specially rich source in Dipsacus azureus belonging to the Dipsacaceae,
a botanical family which like the allied Composite, has not been a frequent
source of alkaloids. In the same country, in 1939, Lazur'evskii and
Sadikov 2 examined over 200 plants collected by various expeditions in
Central Asia and recorded alkaloids in a number of species, including
Aconitum talassicum and Convolvulus hamadce, the alkaloids of which have
since then been investigated in detail as described later. Mention may
also be made of the comprehensive volume on " The Poison Plants of New
South Wales," compiled by Evelyn Hurst under the direction of the
Poison Plants Committee of the University of Sydney. It includes numerous
monographs on plants containing toxic alkaloids and should be of great
value to research workers concerned with plant chemistry.
In the course of the intensive campaign carried on in the United
States of America during the war for the discovery of effective antimalarial drugs, a team of workers 3 made anti-malarial tests on 600 different
plants belonging to 123 families of phanerogams and three families of
cryptogams, and it is recorded that the suppressive activity shown by
some of these plants appeared to be associated with alkaloidal fractions
of their extracts.
ix
INTRODUCTION
INTRODUCTION
XI
series of papers on the alkaloids of the Leguminosae, White points out that
although this order has been investigated perhaps more than any other
for alkaloids, there is still uncertainty regarding the nature and distribution
of alkaloids even in some common species, that little is known of the alkaloid content of common European plants grown under new conditions, for
example in the Southern Hemisphere, that a large number of factors are
capable of altering the alkaloidal content in quantity and nature, and that
in much of the older European literature there is uncertainty due to
incomplete chemical investigation.
Although the number of alkaloids still in use in medicine is small,
serious difficulty was caused by the war, due to the cutting-off of the
usual sources of supply of the natural drugs which yield essential alkaloids,
such as atropine, cocaine, hyoscine, morphine, emetine and ergometrine.
Shortages were met as far as possible by new sources of supply and by
local cultivation of the opium poppy, belladonna and other necessary
drugs. This necessity provided new opportunities for the collection of
experimental data regarding the possibility of plant selection and ot the
effects of environment and of changes in cultural conditions on yield of
alkaloids. An interesting account of the kind of work this involves will
be found in the paper by W. O. James referred to below. One outcome
of this work is the observation by workers in several countries that in
solanaceous plants the tropane alkaloids are formed mainly in the roots. 7
The plants generally used were belladonna, stramonium and Duboisia spp.,
and the necessary cultivation experiments were similar to those briefly
described under the alkaloids of tobacco. The problem is, however, more
complex than the results of these special observations seem to imply,
and W. O. James, 8 in the course of an account of work done by the Oxford
Medicinal Plants Scheme on the biosynthesis of the belladonna alkaloids,
states that alkaloids are first formed in the meristem of the radicle and
can be detected when the radicles are 3 mm. long, but also shows that
detached belladonna leaves can be induced to increase their alkaloidal
content. He concludes that on the evidence available it is possible that the
leaf alkaloids have a dual origin : by synthesis in situ and by translocation
from the root.
A curious observation, first made by Barnard and Finnemore 9 in the
course of a systematic examination of Duboisia myoporoides in the whole
range of its distribution in Australia, is that in this plant the relative
proportions of the two main alkaloids is extremely variable, hyoscine being
predominant in plants of the northern area and hyoscyamine in those of
the southern region. Hills, Trautner and Rodwell,9 continuing this work,
confirmed this general result, but in the course of selection trials found
that individual trees could exhibit the same variation ; the leaves of one
specimen at Nambour, Queensland, contained in October about 3 per
cent, of almost pure hyoscyamine and in April about the same amount of
almost pure hyoscine. Trautner, 10 in a paper dealing with these anomalies,
and also discussing the possible modes of origin of the various aminoalcohols, tropine, 0-tropine, scopine, etc., and of the acids, tropic, benzoic,
xii
INTRODUCTION
INTRODUCTION
xiii
belladonna plants, significant increases in alkaloidal content were produced only by arginine, N H 2 . C(NH). NH . (CH2)S . CH(NH2)COOH
with glucose, putrescine, N H 2 . (CH 2 ) 4 . NH 2 , alone or with glucose,
hexamine with glucose, and " formamol" (hexamethylenetetramineanhydromethylene citrate) with glucose. It is known that by bacterial
action arginine can be converted via ornithine,
N H 2 . (CH 2 ) 3 . CH(NH2) . COOH,
into putrescine, and Cromwell has been able to demonstrate the presence
of both arginine and putrescine in belladonna. He has also shown that
belladonna extracts are capable of oxidising added putrescine to ammonia
and a product, reacting with 2 : 4-dinitrophenylhydrazine as an aldehyde
and estimated colorimetrically by that means, which is assumed to be
either succinaldehyde or 8-aminobutyraldehyde, or a mixture of the two,
though neither could be isolated and identified. Quite recently James and
Beevers,14 in a preliminary announcement, record the isolation from
belladonna leaves and roots of a polyphenolase which under specified
conditions oxidises /-ornithine to a-keto-8-aminovaleric acid. In the
simplest form of Robinson's tropinone synthesis, as described in the
atropine section, succinaldehyde was condensed with methylamine and
acetone, so that if Cromwell's assumption is correct that succinaldehyde is
formed in the experiment he describes, a further confirmation of Robinson's
theory is provided and an interesting first step has been taken towards at
least indirect observation of such a synthesis in plant material.
One of the most attractive features of Robinson's theory is that it
makes understandable, on the basis of a slight change in either a primary
material or in the metabolic process, the fact that a plant may produce
more than one type of alkaloid, or that two closely related plants may
each form alkaloids of distinct types. Thus, still keeping to the Solanacese,
which seem to be popular as material for biogenetic experiments, the two
Duboisia species D. myoporoides and D. Leichhardtii always produce
hyoscine or hyoscyamine or both, while a third species, D. Hopwoodii,
produces nicotine or nomicotine, 15 or both. The two latter alkaloids are
characteristic of all the species, so far examined, of another solanaceous
genus, Nicotiana. For the biogenesis of nicotine Robinson suggested
(1917) 12 the initial formation from ornithine by the methylating and
oxidising action of formaldehyde of a pyrrolidylcarbinol-amine. This by
condensation with a molecule of acetonedicarboxylic acid could furnish
a product, which with formaldehyde and ammonia could yield a y-ketopiperidine ring. From this stage, by steps that are easy to imagine,
involving, in succession, reduction of a carbonyl to a secondary carbinol
group, elimination of water and finally dehydrogenation to pyridyl,
nicotine could be formed. In a later paper (1934) 12 lysine,
NH 2 (CH 2 ) 4 . CH(NH2) . C0 2 H,
the next higher homologue of ornithine, is considered as a possible source of
the pyridine ring, but this raises the difficulty of explaining the attachment
of the pyrrolidine nucleus in the /J-position, though it is suggested that the
INTRODUCTION
xiv
NHg.CHjj.CHg.CHg.CHtNHgKCOgH
CH 2 0
=CHlOH)
2
^;NMe
CH2CH2
NHMe.CHg.CHg.CHg.CHO
CO,H
CO
\NMe
CHrCH=-CH
CHg.COgH
CH-CH
8
CH 2 0
CH 2 0
COCH
NMe '
CHgCH2
NE,
CH5
,2
CCH
\
CH
CHgNHCH2
CH
,2
CH
/
NMe
Nicotine
y-ketopiperidine nucleus m a y be regarded as an oxidised lysine or protolysine derivative.
Of t h e remaining types of solanaceous alkaloids, the nor- bases, such
as norhyoscyamine, could be provided for b y an alternative suggestion,
based on t h e observation t h a t a m i x t u r e of the a m m o n i u m salts of
oca'-diaminoadipic and citric acids could be oxidised by hydrogen peroxide
to nortropinone.
,CH(NH2).C02H
CH
-CH.OH
fa
CH
NH
CHo
CH(NH2).C0gH
X3H.0H
qq'-Dlamlnoadlplo a c i d
NH
CH_.C0oH
2
CH, .C0 2 H
ClOH).COgH
CO
CHg.COgH
CHg.CO^
CHo CH
CO
CHn
norTropinone
C i t r i c acid
Teloidine, t h e basic hydrolytic p r o d u c t of meteloidine, has been
synthesised recently under physiological conditions b y Schopf and
Arnold, 1 6 on the lines of the tropinone synthesis, mesotartaric aldehyde
(CHOH . CHO) 2 , being condensed a t 25 with acetonedicarboxylic acid
&nd methylamine hydrochloride t o teloidinone (5-keto-l : 2-dihydroxytropane) which on catalytic hydrogenation yielded teloidine ( 1 : 2 : 5 trihydroxytropane).
INTRODUCTION
xv
NH2
HN:C.NH 8
Arglnine
CH5CH- -CH
NMe CO
CH.,CHo CH.CCUH
CH 2 CH 2 CHO
CHgNH2
CHNHMe
NH2
Ornithine
CH5CH
CHo
' I
Ajnlnoaldehyde
CHgCH- -CHo
NMe
CO
NMe CO
CHgCH
CH2
Troplnone
I n t h e l a r g e g r o u p of i s o q u i n o l i n e a l k a l o i d s a c o n s i d e r a b l e n u m b e r
of t r a n s f o r m a t i o n s f r o m o n e t y p e t o a n o t h e r a r e d e s c r i b e d l a t e r i n t h e
a p p r o p r i a t a sections ; for example, from p a p a v e r i n e t h r o u g h laudanosine
to glaucine a n d from t h e berberine t o t h e cryptopine t y p e , a n d t h e possib i l i t y of s u c h c h a n g e s m a y a c c o u n t f o r t h e a s s o c i a t i o n i n t h e s a m e p l a n t
of a l k a l o i d s of m a r k e d l y d i f f e r e n t t y p e s . W i n t e r s t e i n a n d T r i e r first
s u g g e s t e d t h e p o s s i b l e f o r m a t i o n o f i s o q u i n o l i n e a l k a l o i d s f r o m 2 m o l s . of
d i h y d r o x y p h e n y l a l a n i n e , a c c o r d i n g t o t h e following scheme, leading t o
norlaudanosine, from which laudanosine is obtainable b y m e t h y l a t i o n a n d
papaverine by methylation a n d dehydrogenation.
norLaudanosine
12
Robinson
(1934) h a s elaborated this into a scheme e m b r a c i n g
hydrastine, berberine, e^icryptopine, corydaline, sanguinarine
and
homochelidonine, t h o u g h he points o u t t h a t d i h y d r o x y p h e n y l a l a n i n e is
labile and too easily convertible into indole derivatives t o be capable of
xvi
INTRODUCTION
CH 2
CH 2
UBO
LaudanoBlnt
Identical Formulae
Claucln
protoSlnonanlM
INTRODUCTION
xvii
xviii
INTRODUCTION
INTRODUCTION
xir
experiments on a known mixture of hyoscine and hyoscyamine, to determine conditions for separation, applied a form of partition chromatography to the total alkaloids of Datura ferox, D. Stramonium and Atropa
Belladonna. In the case of the two latter plants the graph of eluate
fractions showed only two peaks corresponding to hyoscine and hyoscyamine, as shown by the constants of the related fractions isolated, and
the sum of the two fractions was close to the amount of total alkaloids
as previously determined. The graph for D. ferox was more complex
but the fractions corresponding to the two main peaks were proved to be
hyoscine and meteloidine respectively and the sum of the fractions representing the remaining peaks amounted to only 0-08 out of 0-610 per cent,
total alkaloids, calculated as hyoscyamine. Meteloidine had previously
been recorded only from D. meteloides. The results show that partition
chromatography provides a simple method of isolating separately hyoscine
and hyoscyamine from small quantities of solanaceous drugs. The
Datura ferox used was grown in England from seed collected in Rhodesia.
Previous analyses by Barnard and Finnemore 9 of Australian-grown plants
of this species and by Libizov 27 of Crimean plants, recorded hyoscyamine
as the chief alkaloid. This seems therefore to be an addition to the
solanaceous plants referred to above, which are liable to change the
nature of their alkaloidal components.
According to Rowson, 28 polyploids of solanaceous plants, induced by
the action of colchicine, show an increased content of alkaloids, but the
relative proportions of hyoscine and hyoscyamine remain the same and
are characteristic for the species.
A notable change in methods of isolating alkaloids from plant materials
has been described by Applezweig,29 depending on the use of a suitable
ion-exchange material and capable of application on a semi-micro scale or
for industrial use. It has been applied to the preparation of the total
alkaloids of cinchona bark (totaquina) and according to Sussman, Mindler
and Wood, is also used industrially for the recovery of hyoscine.
Many alkaloids are obtained in such small quantities that it is not
possible to describe them in detail, and recourse must be had to giving
characteristics for picrates, aurichlorides and similar compounds. The
reineckates, first used by Christensen and later by Rosenthaler, 30 are a
useful addition to such compounds, and have been so used recently by
Evans and Partridge 26 for the characterisation of solanaceous alkaloids.
In spite of their importance, basicity constants rarely figure in descriptions of alkaloids. Figures for a series of alkaloids and related substances
were published by Kolthoff in 1925 and have been extensively used.
Recently a few more have been added by Schoorl, and Adams and Mahan
have provided figures for the whole group of necines, the amino-alcohols
resulting from the hydrolysis of the pyrrolizidine group of alkaloids.31
For the purposes of this book, an alkaloid is regarded as a relatively
complex, organic base, occurring naturally in a plant and usually possessing
marked pharmacological activity. This excludes simple, naturally
occurring bases and the biological amines, which are adequately dealt with
XX
INTRODUCTION
elsewhere.32 The purines are also omitted, as these are now well described
in text-books of organic chemistry for advanced students and recent
interest in them is centred chiefly on derivatives, which are more appropriately dealt with in a text-book of biochemistry than in a work on
alkaloids.
The material is arranged, as in previous editions, primarily on the basis
of nuclear structure, which it must be admitted is arbitrary, for most of
the more complex alkaloids could be dealt with under more than one
structural heading. Most of these structural groups are, however, almost
traditional in alkaloidal literature and seem to have arisen usually from
the nature of the products obtained in early, drastic degradation experiments. Two new groups have been added, the components of which
formerly occupied considerable space among " alkaloids of undetermined
constitution." The p y r r o l i d i n e group consists so far, only of the
" necylnecines," characteristic of the genus Senecio, but also found less
extensively in other genera. The steroidal alkaloid group is so named
because there is reason to believe it consists mainly of alkaloids containing
a tetracyclic system identical with, or closely related to, that of the steroids :
it includes the extensive series of alkaloids found in Aconitum, Delphinium
and Veratrum species and the glucosidal alkaloids of Solanum spp. A
preliminary statement by Haworth et al.33 published after the section on
Holarrhena alkaloids had been passed for press, indicates that the carbon
atoms of conessine are accounted for by the aWopregnane structure, but
the position of the ethylenic linkage and the points of attachment of the
three N-methyl groups are still uncertain. On this basis conessine also
belongs to the steroidal alkaloid group and as several of its associates are
convertible by simple reactions into conessine, the nature of an important
fraction of the sixteen Holarrhena alkaloids is becoming clear.
In future a third new group will be required, according to another
preliminary statement published quite recently by a team of Australian
chemists, Messrs. Hughes, Lahey, Price and Webb. They have isolated
six alkaloids from three rutaceous species of that country, five of which
have been definitely shown to be acridine derivatives. This appears to be
the first-fruits of a survey of the type referred to above, which is being
carried out on the Australian flora under the auspices of the Council for
Scientific and Industrial Research and several of the Australian Universities.34
Within the alkaloidal groups there have been a considerable number
of additions, notably, as might be expected, in the already large isoquinoline group.
Under the heading " Alkaloids of Undetermined Constitution," have
been included bases about which a good deal of information is available,
though they cannot yet be allocated to sturctural groups, either because
sufficient, definite information is not available, or because such data are
available only about one or two members of an extensive series found in
one plant or one genus. The Dichroa bases are probably quinazolines.
Of the Erythrophloeum alkaloids some might be placed in the group of
INTRODUCTION
xxi
alkaloidal amines as they are esters of alkylamino- alcohols, but they have
several associates about which little is yet known. Similarly in the
Gelsemium bases, sempervirine is now known to be closely related to
yohimbine and there are indications that gelsemine may also be an indole
alkaloid, but there are several associates, including gelsemicine, the most
potent of the set about which there is little chemical information.
The section " Minor Alkaloids " covers plants arranged in alphabetical
order of their botanical names, from which well-defined alkaloids have
been isolated but which have not yet been examined in detail or for some
reason do not readily fit into preceding groups. Following "Minor
Alkaloids " is a list, also arranged alphabetically under botanical names,
of plants in which the presence of alkaloids has been recorded but from
which well-defined and recognisable alkaloids have not yet been isolated,
although in some cases names and empirical formulae have been assigned to
amorphous products. Information is apt to arise rapidly and unexpectedly
in these days and too late for transfer to its appropriate section one of the
plants in this list, Talauma mexicana, has been shown to contain an
alkaloid aztequine, belonging to the iwbenzylwoquinoline series.
Comparatively few alterations have been made since 1939 in the
structures accepted for well-known alkaloids. A slight but important
change has been adopted in the formula of strychnine and contributions
to the chemistry of that alkaloid and its associates are still being made,35
though the formula seems now so well established that Woodward has
recently suggested and discussed a scheme for the biogenesis of strychnine
on which Robinson has commented favourably.36 Robinson has also
proposed a scheme for the biogenesis of emetine. This involves a modification in the formula of that alkaloid, which is supported by Dewar's interpretation of the results of recent chemical work on emetine by Rarrer
et al., by Spath and by Pailer.37
Another alteration is the proposed 7-membered ring in the formula
of colchicine which receives substantial support from a preliminary
announcement just made by Buchanan, Cook, Loudon and MacMillan 38
that they have synthesised 9 : 12 :18 :14-tetramethoxy-3 : 4 : 5 : 6-dibenzj i : 3:5.. c^cfoheptatriene-7-one and shown it to be identical with the
a/3-unsaturated ketone obtained by oxidation of deaminocolchinol methyl
ether.
The chemistry of yohimbine is also under active discussion and new
papers have appeared, or are promised, dealing with the structure and
synthesis of ketoyobyrine. 59
A modification of the formula of oc-fagarine just announced establishes
its close relationship to the alkaloids of cusparia bark, which like Fagara
is derived from a rutaceous genus.40
The advent of the sulphanilamide group of drugs and the
development of the biological products known as anti-biotics, presented
biochemists and pharmacologists with many interesting problems and
m view of these and other like attractions, it is not surprising that
the pharmacology of alkaloids seems to be receiving less attention
INTRODUCTION
xxii
now than a t one time it attracted. Much work has been done in
determining details of the pharmacological activity of the many new
alkaloids, such as those of the pyrrolizidine group, that have been
described in the last ten years, but the most striking development is
probably the number of synthetic replacement products for alkaloids made
available, and the remarkable variation in structure shown both as regards
the prototype to be replaced and among the substitutes themselves. As
shown in the appropriate sections, much research has been expended on
modifying the tropane and cinchona alkaloids, but in both cases effective
synthetic drugs have been found in substances structurally different from
the prototypes. There is, for example, little or no structural similarity
between quinine, mepacrine and paludrine, though all three are in use as
anti-malarial drugs. A like absence of structural similarity is found in
the new synthetic replacements for quinidine in the control of auricular
fibrillation. These substances are also local anaesthetics and spasmolytics.
Similarly, as pointed out in connection with-physostigmine, a considerable
number of alkaloids and other substances share with this alkaloid the
capacity to inhibit the action of choline-esterase on acetylcholine, and it is
beginning to be suggested that the action of many chemical substances,
including alkaloids, in the body is to be accounted for by modification of,
or interference with, the production or action of potent biological amines
such as acetylcholine, histamine or epinephrine.
Burn 41 has pointed out that the grouping together of many properties
as fundamentally the same, brings into some sort of order the long list of
apparently pharmacologically unrelated alkaloids, and that the similarity
in many properties of atropine, papaverine and quinine, and of conessine
and quinine, suggests points of biochemical similarity.
REFERENCES
(The simple page references are to pages in this volume)
(1) Farmatsiya, 1946, 9, No. 3, 22 (Chem. Abstr., 1948, 42, 2728). (2) Trad.. Uzbekskogo Gosudarst. Univ. Sbornik Trudov Khim., 1939, 15, 182 (Chem. Abstr., 1941, 35,
41S4). (3) SPENCER, KONIUSZY, R O G E R S , SHAVEL, EASTON, KACZKA, K U E H L , P H I L L I P S ,
W A L T I , F O L K E R S , MALANGA a n d S E E L E R , Lloydia, 1947, 10, N o . 3, p . 145. (4) Rev.
Bot. appi. Agric. trop., 1939, 19, 564. (5) A. de CANDOLLE, " L a Phytographie," Paris,
1880, p . 174. (6) Ann. Rev. Biochem., 1944, 13, 543. (7) See, for example, KRAEVOI
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Proc Lenin. Acad. Agr. Sci. U.R.S.S., 1944, No. 10, 24 (Chem. Abstr., 1947, 41, 4197);
SHMUK, ibid., 1945, Nos. 1-2, 3 (Chem. Abstr., 1947, 41, 4198) ; PEACOCK, L E Y E R L E
Austr.,
(10) J .
Proc. Austr. Chem. Inst., 1947, 14, 411. (11) See p p . 65-6. (12) ROBINSON, J. Chem.
Soc, 1917, 111, 876 ; I X Congreso Internacional de Quimica, Madrid, 1934, Vol. V,
Group IV, p . 17 ; J. Chem. Soc, 1936,1079; (with SUGASAWA), ibid., 1931, 3163 ; 1932,
INTRODUCTION
789 ; 1933, 280.
1948'
xxm
(13) Biochem. J., 1937, 31, 551 ; 1943, 37, 717, 722.
43, No. 1, x i .
(14) Ibid.,
Exp.
Biol Med. Sci., 1947, 25, 191 (Chem. Abstr., 1948, 42, 2399). (16) See p. 84 and SCHOPF
and ARNOLD, Annalen, 1947, 558, 109 (Chem. Abstr., 1948, 42, 2602). (17) Brit. Assoc.
Reports, 1929, 51 ; IX Congreso International de Quimica, Madrid, 1934, Vol. IV,
Group I I I , p . 97. (18) SCHOPF, IX Congreso International de Quimica, Madrid, 1934,
Vol. V, Group IV, p . 189 ; Annalen, 1935, 518, 1 ; Angew. Chem., 1937, 50, 779, 797 ;
(with BAYERLE), Annalen, 1934, 512, 190 ; (with LEHMANN), ibid., 1935, 518, 1 ; (with
SALZER), ibid., 1940, 544, 1 ; (with THIERFELDER), ibid., 1932, 497, 22. (19) See
pp. 170-1. (20) Austr. Chem. Inst. J. and Proc, 1945, 12, 232, 405. (21) Quart. J.
Pharm. Pharmacol., 1945, 18, 245, 338 ; 1946, 19, 8, 127, 526 ; 1947, 20, 87. (22)
VALENTIN, Pharm. Zeit., 1935, 80, 469 ; (with FRANCK), ibid., 1936, 81, 943 ; MERZ
and FRANCK, Arch. Pharm., 1937, 275, 345. (23) BROWNLEE, Quart. J. Pharm.
Pharmacol.,
Pharm.
Assoc.,
REIMERS,
GOTTLIEB
and
(24) Quart.
CHRISTENSEN,
J. Pharmcol.,
ibid..
Amer.
Dansk.
Tids. Farm., 1943, 17, 5 4 ; 1945, 19, 129, 1 6 7 ; GOTTLIEB, ibid., 1947, 21, 92
J. Amer. Chem. Soc, 1948, 70, 423. (26) EVANS and PARTRIDGE, Quart. J. Pharm.
Pharmacol., 1948, 21, 126 ; see also TRAUTNER and ROBERTS, Analyst, 1948, 73,140.
(27) LIBIZOV, Proc. Lenin. Acad. Sci. (Biochem.), 1941, 3, 23. (28) ROWSON, Quart. J.
Pharm. Pharmacol., 1945, 18, 175, 185 ; cf. BEESLEY and FOSTER, Nature, 1948, 161.
561. (29) APPLEZWEIG, Ind. Eng. Chem. (Anal), 1946, 18, 82 ; J. Amer. Chem. Soc,
1944, 66, 1990 ; (with RONZONE), Ind. Eng. Chem., 1946, 38, 576 ; SUSSMAN, MINDLER
1892, [2], 45, 213, 356 ; ROSENTHALER, Arch. Pharm., 1927, 265, 684.
(31) KOLTHOFF,
Biochem. Zeit., 1925, 162, 289 ; SCHOORL, Pharm. Weekbl., 1939, 76, 1497 ; ADAMS
and MAHAN, J . Amer. Chem. Soc, 1942, 64, 2588. (32) See, for example, " Die biogenen
Amine," M. GUGGENHEIM, 1940 ; Verlag von S. Karger, Basle and New York. (33)
HAWORTH, M C K E N N A a n d SINGH, Nature, 1948, 162, 22 ; Chem. and Ind., 1948, 716.
(34) Nature, 1948, 162, 223. (35) ROBINSON (with BAILEY), J. Chem. Soc, 1948, 703 ;
(with PAUSACKER), ibid., p . 951 ; WOODWARD and BREHM, J. Amer. Chem. Soc, 1948,
70, 2107 ; PRELOG (with KOCOR), Helv. Chim. Acta, 1948, 31, 237 ; (with VEJDELEK),
ibid., p . 1178. (36) WOODWARD, Nature, 1948, 162, 155 ; ROBINSON, ibid., p . 156.
(37) ROBINSON, Nature,
K A R R E R , EUGSTER and R U T T N E R ,
Helv.
Chim. Acta, 1948, 31, 1219 ; SPATH, Monats., 1948, 78, 348 ; PAILER, ibid., 1948, 79,
127.
this
volume, p . 654. (39) WOODWARD and WITKOP, J. Amer. Chem. Soc, 1948, 70, 2409 ;
SCHLITTLER and SPEITEL, Helv. Chim. Acta, 1948, 31, 1199 ; CLEMO and SWAN, Nature,
1948,
162, 693.
PLANT ALKALOIDS
PYRIDINE GROUP
ALTHOUGH pyridine has been recorded as occurring in plants, the evidence
does not as a rule amount to more than a pyridine-like odour, though more
definite evidence has been provided by Goris and Larsonneau 1 for its
occurrence in belladonna leaves and by Kuhn and Schafer 2 for its presence
in the roots of the same plant. 3-Methoxypyridine, b.p. 40/l mm.
characterised as picrate, m.p. 139, mercurichloride, m.p. 120, aurichloride,
m.p. 176, and platinichloride, m.p. 194, has been found by Manske 3 in
Thermopsis rhombifolia (Nutt) Richards, and in Equisetum arvense L.
Piperidine has been obtained from pepper, 4 from Psilocaulon absimile
N.E.Br (Aizoacese) in which it occurs to the extent of 4-5 per cent.,5 and in
Petrosimonia monandra.6 N-Methylpiperidine has been recorded in
Girgensohnia spp.
REFERENCES
(1) Bull. Sci. Pharmacol., 1921, 28, 497, 499.
(2) D3Ul. Apoth. Zcit., 1938, 53, 405,
424.
(3)
J.
Can.
Res.,
1942,
B,
20,
265.
(4)
SPATH and
E N G L A E N D E R , Ber.,
68, 2218 ; cf. PICTET and PICTET, Helv. Chim. Acta, 1927, 10, 593.
S.
Afr.
J.
Sci.,
1934,
31,
184.
(6)
JURASCHEVSKI and
1935,
(5) RIMINGTON,
STEPANOV, J.
Gen.
Chem.,
PYRIDINE
GROUP
NELSON, J. Amer. Chem. Soc, 1919, 4 1 , 1115 ; SPATH and DARLING, Ber., 1930, 63,
737.
(11) ASAHINA and A S A N 6 , J. Pharm. Soc. Japan, 1920, 5 0 3 ; 1922, 8 5 ; ASANO
a n d KANEMATSU, ibid., 1927, 521 ; Ber., 1932, 65, 1602 ; GOKHALE and B H I D E , J.
Ind.
THOMS and TH&MEN, Ber., 1911, 44, 3 7 1 7 ; GOODSON, Biochem. J., 1921, 15, 123.
(14) A C R E E , JACOBSEN a n d H A L L E R , J. Org. Chem., 1945, 10, 236, 4 4 9 ; 1947, 12,
731.
Inst.,
1944, p . 253 ;
(with SYNERHOLM a n d ARTHUR, ibid., 1945, p . 433) ; (with HARVILL and ARTHUR,
1943, p . 87).
LEUCENOL
^i/
N
(I)
C H
C-OMe
HCf^CO
C-OMe
HCf^Nc-OH
H c U / C H , HC k ^ C H
NMeOH
(H) (N-MeCl)
JJJ;
CO
HCITSCOH
HC
\s
CH
NMe
{w)
PYRIDINE
GROUP
product of this action is hydrolysed by the alkali, to a hydroxymethoxypyridine which adds on a molecule of methyl alcohol to form (II). This,
as the methochloride, in losing a molecule of methyl chloride must, at the
high temperature involved, undergo further rearrangement to give the
N-methylhydroxypyridone (IV) via the supposed intermediate (III).
This explanation has been revised recently by Bickel,5 who has shown
that the product, C 7 H u 0 3 N, first formed in this reaction, is the
monohydrate of iV-methyl-3-methoxypyridone-4, MeO . C5H3ONMe, H 2 0,
the "chloride," C7H10O2NCl, is the hydrochloride, MeO . C-H3ONMe, HC1
of the same base, and the substance formed when the " chloride " is
heated is N-methyl-3-hydroxypyridone-4. The constitution of the latter
had already been established by Wibaut and Kleipol,3 who had synthesised
it by the action of methylamine on meconic acid (V) and decarboxylation
of the resulting product (VI) to the desired substance (VII = IV).
RICININE
Chem.,
ibid., 1937, 250, 80. (3) Rec. Trav. Chim. Pays-Bas, 1946, 65, 319 ; 1947, 66, 93 ;
Nat. Tijds. Ned. Ind., 1940 (for a comment on this paper see WIBAUT, Rec. Trav. Chim.
Pays-Bas, 1946, 65, 392).
PYRIDINE
GROUP
C.OH
CH C.CN
CH C.CN
II
io
CH
II
CH CO
N.CH 3
Ricinine
CH
H C.COOH
CH C.OH
N
2 -Hydroxy'pyridine3-carboxylic acid
N.CH 3
Ricinidine
N.CH 3
Ricininic acid
CH
C.COOH
CH CO
CH CO
dH
H
C.CONH,
CH CO
N.CH 3
N.CH 3
TS-methyl-2-pyridone- T$-methyl-2-pyridoneS-carboxylic acid
3-carboxylie acid amide
the hydrolysis of a CN group, so t h a t the acid appeared to be a iV-methyl2-pyridonecarbOxylic acid. I t was synthesised by t h e action of methyl
iodide on the di-silver salt of 2-hydroxypyridine-3-carboxylic acid and
hydrolysis of the resulting ester to iV-methyl-2-pyridone-3-carboxylic acid.
The latter was then converted to the amide which, on dehydration, yielded
ricinidine. The steps in the formation of ricinidine from ricinine and b y
synthesis are shown in the foregoing set of formulae.
The validity of this formula for ricinine was established by the same
a u t h o r s ' synthesis 10 of t h e alkaloid from 4-chloroquinoIine (I). The
Cl.C
C.C1
CH
N
HC
CH
HC
C.COOH
HC
II
CH
(I)
HC
Wei
\
X
C.C1
HC
C.CO.NHj
I
CCl
HC
\
(17)
II
C.OCH,
N
HC
C.COOH
II
HC
*N
(n)
C.OCH,
3
S
C.CN
HC
\
C.CO.HH
CCl
/ \
(V)
/
HC
I
HC
C.OH
(III)
C.OCH,
3
\
C.CN
I
CO
N.CH 3 (VI)
TRIGONELLINE
ALKALOID OF FffiNUGREC
Trigonelline, C 7 H 7 0 2 N. This base occurs in plants belonging to a
number of botanical families. It was isolated by Jahns 1 from
fcenugrec seeds (Trigonella Fcenumgrcecum) and has also been found in
garden peas, 2 hemp seed,2 oats, 2 potatoes, Stachys spp., dahlia, 3
Strophanthus spp., 4 coffee,5 and Dichapetalum cymosum.* Holtz, Kutscher
and Theilmann ' have recorded its presence in a number of animals.
The fact that nicotinic acid (vitamin PP *) is excreted as trigonelline 8 has
stimulated interest in the latter ; its development has been studied by
de Almeida,9 reactions for its detection have been suggested by Raffaele 10
PYRIDINE
GROUP
and methods for its estimation in foodstuffs and in urine by Kodicek and
Wang and other authors. 11
Trigonelline crystallises as a monohydrate from alcohol in hygroscopic
prisms, m.p. 130 or 218 {dry, dec). It is readily soluble in water
or warm alcohol, less so in cold alcohol and slightly so in chloroform
or ether. The salts crystallise well, the hydrochloride, B . HC1, in leaflets,
m.p. 260 {dec), sparingly soluble in dry alcohol. The picrate forms shining
prisms, m.p. 198-200, soluble in water, but sparingly soluble in dry alcohol
or ether. The platinichloride is soluble in water, but scarcely so in
dry alcohol. The alkaloid forms several aurichlorides : the normal salt,
B . HC1 . AuCl3, is precipitated when excess of gold chloride is added to the
hydrochloride, and after crystallisation from dilute hydrochloric acid
containing some gold chloride has m.p. 198. Crystallised from water or
very dilute hydrochloric acid, slender needles, B 4 . 3HAuCl4, m.p. 186, are
obtained. 1
When trigonelline is heated in closed tubes with baryta water at 120,
it gives rise to methylamine, whilst similar treatment
a s.
with hydrochloric acid at 260 furnishes methyl chloride
an
CH
C .CO
d nicotinic acid (pyridine-3-carboxylic acid), indicating
|
||
that it is the methylbetaine of nicotinic acid.
CH
CH
Hantzsch 12 prepared this betaine by treating nicotinic
\ /
acid methiodide with silver hydroxide and Jahns 13 subse3
quently identified trigonelline with Hantzsch's synthetic
Trigonelline b a s e Trigonelline appears to exert no marked physiological
action. 11 Ackermann 15 first observed that nicotinic acid administered
to dogs appears in the urine as trigonelline.
REFERENCES
(1) Ber.,
1885,
18,
2518.
(2) SCHULZE
and
FRANKFURT,
ibid.,
1894,
27,
709.
(5) GORTER, Annalen, 1910, 372, 237 ; cf. POLSTORFF, Chem. Soc. Abslr.,
1910, ii, 234 ; PALLADINO, ibid , 1894, ii, 214 ; 1895, i, 629 ; GRAF, ibid., 1904, i, 915 ;
NOTTBOHM and MAYER, Zeit. Vnters. Lebensmitt, 1931, 61, 429. (6) RIMINGTON,
Onderstepoort J., 1935, 5, 81. (7) Zeit. Biol., 1924, 81, 57. (8) SARETT, PEKLZWEIG
and LEVY, J. Biol. Chem., 1940, 135, 483 ; KUIINAU, Vitamine u Hormone, 1942, 3, 74
(see also H U F F , J. Biol. Chem., 1946, 166, 581 ; 1947, 171, 639). (9) Agron. Lusit.,
1940, 2, 307 (Chem. Abslr., 1943, 37, 410). (10) Ann. Chim. farm, (ital.), 1939, 7, 46
(Chem. Abslr., 1941, 35, 5643). (11) Nature, 1941, 148, 2 3 ; cf. F o x , M C N E I L and
F I E L D , J. Biol. Chem., 1943,147, 445; SLOTTA and NEISSER, Ber., 1938, 71, 1987 ; CIUSA
and D E S S I , Ann. chim. appl., 1947, 37, 88. (12) Ber., 1886, 19, 31, see also ref. (8).
(13) Ibid., 1887, 20, 2840 ; cf. WEIJLARD et ah, J. Amer. Chem. Soc, 1944, 66, 1319.
(14) For recent observation see VOLMER and FURST, Bull. Acad. Med., 1939, 122, 241
(Chem. Abstr., 1940, 34, 4805). (15) Zeit. Biol., 1912, 59, 17 ; cf. KOHLRAUSCH, ibid.,
1911, 57, 273 and ref. (8).
ARECA
NUT
ALKALOIDS
the seeds are employed as a masticatory. In India and China ground areca
nut is used as a vermifuge, and it is also so employed in Europe in veterinary
medicine. After preliminary work by Bombelon, 1 Jahns 2 isolated, in
addition to choline, the alkaloids arecoline, arecaidine, arecaine and
guvacine, of which the second and third are identical. Emde 3 added
arecolidine and K. Hess 4 guvacoline. A sixth alkaloid, whose existence
was first indicated by Jahns, was named isoguvacine by Trier,5 and was
examined by Winterstein and Weinhagen.6 Methods for the isolation of
the alkaloids are given by Jahns 2 and by Chemnitius 7 and for their
recovery from technical areca residues by von Euler et al.1
Arecoline is usually stated to be present to the extent of 0-1 per cent.,
but Chemnitius ' gives the yield of hydrobromide as 0-35 to 0-4 per cent.
Arecaidine and guvacine occur in smaller quantities, whilst guvacoline and
arecolidine are found only in minute amounts. Alkaloidal assay processes
for areca nuts have been published by Bourcet,8 and the National
Formulary Committee,8 and Bond 8 has described a method of estimation
for arecoline hydrobromide. A microchemical test for the identification
of arecoline has been devised by Gornyi.9
Guvacine, C 6 H 9 0 2 N. This, the simplest of the areca nut alkaloids,
forms small lustrous prisms, m.p. 271-2 (J. 2 ), 293-5 (W. and W. 6 ),
[a]D 0, is neutral to litmus, and moderately soluble in water or dilute
alcohol, but almost insoluble in other solvents. The hydrochloride,
B . HC1, crystallises in prisms, m.p. 316 (Freudenberg 10 ), sparingly soluble
in dilute hydrochloric acid ; the platinichloride, B 2 . H 2 PtCl 6 . 4H 2 0,
separates from water in hexagonal prisms, m.p. 211 (J.}, 233 (W. and W.),
220-1 (F.), and the aurichloride, B . HAuCl4, in broad, flattened prisms,
m.p. 197-9 (F.). The base and its salts decompose on melting.
Guvacine behaves as a secondary amine furnishing an acetyl derivative,
m.p. 189-90, and a nitroso-derivative, m.p. 167-8, the methyl ester of
which on treatment with liquid ammonia forms iV-nitroso-4-aminopiperidine-3-carboxylamide, m.p. 172 (von Euler et al.1). On distillation
with zinc dust guvacine yields j8-picoline (3-methylpyridine). On treatment
with sodium methoxide and potassium methyl sulphate, Jahns obtained
arecaine (arecaidine, p. 10) and an isomeride of the latter, and since he was
unable to prove the presence of a carboxyl group, assigned to guvacine and
arecaine formulae different in type from those attributed to arecaidine and
arecoline. Though Trier 5 first suggested that guvacine might be
J 1 -tetrahydropyridine-3-carboxylic acid, it was Freudenberg 10 who first
called attention to the similarity of guvacine and 4 3 -tetrahydropyridine3-carboxylic acid (synthesised by Wohl and Losanitsch), 11 and subsequently
demonstrated their identity. The same author showed that guvacine,
contrary to Jahn's experience, does yield a methyl ester, which was
subsequently accepted by K. Hess 12 as identical with guvacoline (p. 10).
The latter on treatment with methyl iodide gives a mixture of arecoline
methiodide and hydriodide. Arecoline on hydrolysis furnishes arecaidine,
so that this series of reactions demonstrates the relationship of the four
chief alkaloids of areca nut.
10
PYRIDINE
GROUP
Guvacine, C 6 H 9 0 2 N
== J 3 -tetrahydropyridine-3-carboxylic acid
Guvacoline, C 7 H n 0 2 N = guvacine methyl ester
Arecaidine, C 7 H u 0 2 N = N-methylguvacine
Arecoline, C 8 H 13 0 2 N
= A7-methylguvacine methyl ester
Guvacoline, C 7 H u 0 2 N. K. Hess 13 assigned this name to an alkaloid,
obtained by E. Merck from areca nut, which yields a hydrobromide, short
prisms, m.p. 144-5, that he identified with guvacine methyl ester
hydrobromide (see above). The base 10 is a colourless oil, b.p. 114/13 mm.,
which yields a hydrochloride, m.p. 121-2, a platinichloride, m.p. 211,
and on methylation furnishes a mixture of arecoline methiodide and
hydriodide (p. 12).
isoGuvaane. Along with guvacine, Jahns obtained a small fraction
of another crystalline alkaloid which Trier 5 named isoguvacine and
regarded as J 2 -tetrahydropyridine-3-carboxylic acid. According to
Winterstein and Weinhagen,6 the base has m.p. 220, [a] D 0, is faintly
acid to litmus and yields crystalline salts : hydrochloride, m.p. 231 ;
platinichloride, m.p. 235; and aurichloride, m.p. 198-200. It gives a
dimethyl derivative, the platinichloride of which melts at 252. These
melting-points indicate that the substance may be mainly arecaidine, but
as it yields, on distillation with zinc dust, a substance giving a pyrrole
reaction, the authors suggested that it is a simple pyrrole derivative
isomeric with guvacine.
Arecaidine (Arecaine), C 7 H n 0 2 N . H 2 0. This alkaloid forms colourless
four- or six-sided tablets, m.p. 222-3 (J.), 2 232 (H. and L.), 12 is soluble in
water, but not in most organic solvents. The hydrochloride, B . HC1, forms
slender, colourless needles, m.p. 261 (dec), the hydrobromide has m.p.
242-3 ; the platinichloride B 2 . H 2 PtCl 6 crystallises in octahedra, m.p.
225-6 (dec.), and the aurichloride, B . HAuCl4, in prisms, m.p. 197-8
(dec.), from hot, dilute hydrochloric acid.
The fact that arecaidine furnishes a methyl ester (arecoline), and must
therefore contain a carboxyl group, led Jahns to attempt its synthesis by
methylating the potassium salt of nicotinic acid (pyridine-3-carboxylic
acid) and reducing, and incidentally hydrolysing, the methyl ester
methochloride so formed. The product was a mixture of arecaidine and
dihydroarecaidine, so that the former must be a 1-methyltetrahydropyridine-3-carboxylic acid. Since natural arecaidine is optically inactive
and the synthetic product could not be resolved, Mayer 14 suggested that
it must be l-methyl-J 3 -tetrahydropyridine-3-carboxylic acid, and this
was confirmed by Wohl and Johnson's 1S synthesis of the alkaloid from
acrolein (I).The latter was converted into /3-chloropropaldehyde
acetal (II), and this condensed with methylamine to j8-methyliminodipropaldehyde tetraethylacetal (III), which on treatment with
hydrochloric acid gave l-methyl-J 3 -tetrahydropyridine-3-aIdehyde (IV),
from the oxime of which was obtained by the action of thionyl chloride,
3-cyano-l-methyl-J 3 -tetrahydropyridine (V). This, on hydrolysis, gave
the corresponding carboxylic acid, which is arecaidine, and this, on
esterification with methyl alcohol, yielded arecoline (see p. 12). Hess and
ARECA
NUT
ALKALOIDS
11
CH
II
CH
CH.;
HMe
C.COOR
2CX
H,
HC
/ * *
>
CH5
-H 2 C
-Mile
(IV
->
CH.
/
NMe
2 \
C.COCR
/
NMe
NH
Guvaclne (R = H)
Guvacoline (R = Me)
Arecaidine (R = H)
Arecoline (R = Me)
(VI)
CHO
CH
.CH
.CH
HPC
2|
<?H 2 CH-
(III)
(II)
(I)
HC
2
->
CH
CI 2C1
CH2
(EtO)-CH
CH(OEt),
EtO.CH.OEt
HC:0
H2C
\ . C N
HPC
CH,
NUe
(V)
N0H 3 CH 2
3t02C.CH2
OHg.COgEt
1
CHKMeCH
CHgCO
II
CH.C0 2 Et
CHgHMeCHg
CH 2 CHOH.CH.COgEt
III
CHgCH^CH.C00R
IV
12
PYRIDINE
GROUP
HEMLOCK
13
ALKALOIDS
J. Amer. Pharm. Assoc, 1945, 34, 45 ; BOND, J. Assoc. Off. Agr. Chem., 1941, 24, 817 ;
1942, 25, 817. (9) FARMATSIYA, 1939, No. 5, p. 13 (Chem. Abstr., 1940, 34, 7064).
(10) Ber., 1918, 51, 976, 1669. (11) Ibid., 1907, 40, 4701. (12) Ibid., 1918, 51, 806 ;
1919,52,206. (13) Ibid., 1918, 51, 1004. (14) Monats., 1902, 23, 22. (15) Ber., 1907,
40, 4712 ; MANNICH, ibid., 1942, 75, 1480. (16) J. Gen. Chem. U.S.S.R., 1941, 11, 140
(Chem. Abstr. 1941, 35, 5505). (17) D.R.P., 485, 139 ; cf. MCELVAIN, J . Amer. Chem.
Soc, 1924, 46, 1721 ; (with STORK), ibid., 1946, 68, 1049. (18) Ber., 1935, 68, 506.
(19) Compt. rend. Acad. Sci. U.S.S.R., 1940, 29, 48 ; J. Gen. Chem. U.S.S.R., 1941,
11, 829 ; 1944,
14,
997.
(20)
Ibid.,
1941,
11, 934.
(21)
K A R R E R and
RUCKSTUHX,
Ilelv. Chim. Acta, 1944, 27, 1698. (22) DIXON, Ileffter's Handb., 1924, 2, 813 ; ZUNZ,
Ele'm. Pharmacodyn. spec, 1932, 329 ; EULEU and DOMEIJ, Acta Pharm. Toxicol., 1945,
1, 263. (23) Folia Pharmacol. Jap., 1938, 26, 44 ; 1940, 28, 72. (24) SCHXEGEL, Arch,
exp. Path. Pharm., 1939, 192, 389 ; FINGER, Rev. Med. Vet. Buenos Aires, 1944, 26, 6
BATHAM, Parasitology, 1946, 37, 185. (25) Trop. Agr., 1941, 96, 187. (26) Bull, mens
Sue. linnienne Lyon, 1944, 13, 28, 46, 58.
ALKALOIDS OF HEMLOCK
The common hemlock, Conium maculatum, contains five alkaloids.
Power and Tutin found a similar mixture in fool's parsley, 1 and a volatile
alkaloid resembling coniine is stated to occur in certain aroids.2 According
to Svagr,3 " water hemlock " (Cicuta virosa) owes its poisonous properties
to toxins and not to " cicutine," a name sometimes used as a synonym for
coniine. The toxic properties of hemlock juice have been known from very
early times ; thus it was the chief ingredient in the poison administered to
criminals by the Greeks. The leaves and the unripe fruits are the parts
used in medicine. The following are the names and formulae of the
alkaloids :
d- and l-Coniine, C8H17N
Conhydrine, C8H17ON
d- and l-N-Methylconiine, C8H16N . CH 3
ip-Conhydrine, C8H17ON
y-Coniceine, C8H15N
Madaus and Schindler 4 have investigated the changes in alkaloidal
content occurring in hemlock during the vegetative period.
Farr and Wright, who devised processes for the estimation of the total
alkaloids as hydrochlorides, give the following percentages for the various
parts of the plant : stem, 0-01-0-06 ; leaves, 0-03-0-18 ; flowers, 0-09-0-24 ;
green fruit, 0-73-0-98. The same authors quote 0-096-0-83 as the range of
variation found in commercial samples of the fruit in 1904 and 1-05-3-6 as
the range in fruits collected in England. 5 The British Pharmaceutical
Codex, 1934, quotes 0-2 per cent, for the leaves and 2-5 per cent, for the
fruits. In British Columbia, where the plant has a larger habit than in
England, Clark and Offord 6 found 0-025 per cent, in the stems and 0-92
per cent, in the fruits. An assay process for the fruits was given in the
Eighth Revision of the United States Pharmacopoeia and 0-5 per cent, of
total alkaloids was specified as a minimum.
Dilling "> has provided a scheme for distinguishing between the hemlock
bases and other alkaloids, such as sparteine, nicotine and lobeline.
Of the total alkaloids of hemlock isolated by the method of Chemnitius 8
and fractionally distilled, the portion boiling up to 190 contains most of
the coniine, y-coniceine and N-methylconiine, the conhydrine and
14
PYRIDINE
GROUP
is
CONIINE
CH
HC
CH 3 .[CH 2 ] 6 .CH 3
/K.
CH
( I ) Conyrlce
( I I ) n-Octane
CH.CH,
3 7
KH
( I I I ) Coniine
CHO.[CH2]3.CH(C3H7)NH
(IV) Amlno-H-^propylvaleraldehyde
5HC
?H
<r
CHCH 2 MH
(VI)
SH
CH
CH
I
CH
-CH;>
CHC1
CH,
1
CH
-CHa
CH0H
iH
N
(V)
CH C
CH-,
CHN
(VIII)
(VII)
16
PYRIDINE
GROUP
In 1893 Laden burg found t h a t when coniine is distilled with zinc dust
there is produced along with conyrine a substance only distinguishable
from cZ-coniine b y its higher specific rotation. This substance, isoconiine,
was a subject of discussion for m a n y years. 2 5 I t was also found in his
synthetic coniine, the d-coniine isolated from the latter having [<x]D + 19,
which was reduced to t h a t of d-coniine by heating the product a t 290 for
ten hours. The modified synthetic method adopted by Ladenburg in 1907
designed to avoid t h e possible presence of propenylpiperidine, as suggested
by Loffler, in the finished product also yielded a d-coniine of high rotation,
+ 17-85. This method, in the hands of Hess and Weltzien, 2 5 gave similar
results, b u t these authors found t h a t if Ladenburg's second process is
modified b y catalytic hydrogenation of methyl-2-picolylalkine (VII) to the
corresponding piperidine derivative, which is then reduced b y hydriodic
acid and phosphorus, followed b y zinc and sulphuric acid, the 2-propylpiperidine (VI) formed is dZ-coniine and yields d-coniine, [a]1^" -f- 14-96 on
deracemisation, and t h e y suggest t h a t " isoconiine " is cZ-coniine containing
a n impurity of higher optical rotation.
A n u m b e r of other syntheses of coniine have been effected, 26 of which
t h a t of Diels and Alder is of special interest. The initial adduct of pyridine
and methyl acetylenedicarboxylate, viz., tetramethylquinolizine-1 : 2 : 3 :
4-tetracarboxylate (IX) on oxidation with dilute nitric acid is converted
into methyl indolizine tricarboxylate (X). This, on hydrolysis and
decarboxylation, furnishes indolizine, the octahydro-derivative (XI) of
which, also known as octahydropyrrocoline, 2 7 is converted by the cyanogen
bromide method (as applied by Winterfeld and Holschneider to lupinane,
p . 123) successively into the bromocyanoamide ( X I I ) , cyanoamide ( X I I I )
a n d tZZ-coniine (XIV). A synthesis of the alkaloid, starting from indolizine
(pyrrocoline) is described by Ochiai and Tsuda. 2 8
CHCHC.CO^Me
C.COgMe
CH
C.CC^Me
CH2
CH
J
CH
CH2
-C.COgHe
CHH-
CHCC.CO^e
CH^j
CH
CHo
3H2Br
I
CHo
-CHCH,
CH-
CH-
CH3
CH,
CH2
N*CN
(XII)
N.CN
(XIII)
-CH2
CH 2 -
C.C02Me
(XI)
(X)
CHp
CH2
CH2
(IX)
CH2
CH,
C.C02Me
I
CHN
CH
CHp
CH "~CHpGHpBCH-?
CH2
CHo:
(nv)
CONHYDRINE
17
18
PYRIDINE
GROUP
the production of pip2ridyl-2-propionic acid on oxidation. 2-jS-Hydroxypropylpiperidine (XVI) suggested by Willstatter 33 seemed to be excluded,
since neither of the two forms of this product prepared by Loftier and
Tschunke 4 1 resembled conhydrine, and these authors suggested the
alternative (XV) as probably representing the alkaloid. Support for this
view was provided by Hess and collaborators,42 who showed that
dZ-iV-methylconhydrinone is iV-methyl-2-piperidyI ethyl ketone (XVII).
that dZ-conhydrine (m.p. 69-70), produced by a somewhat indirect
method, is identical with the product, m.p. 69-5-71-5, prepared by Engler
and Bauer ** by the reduction with sodium in ethyl alcohol of 2-pyridyl
ethyl ketone, and that conhydrine on dehydrogenation over platinised or
palladised asbestos gives rise to a mixture of tetrahydropyridyl-2-ethyl
ketone and 2-a-hydroxypropyIpyridine. Spath and Adler 4 0 have shown
that conhydrine can be degraded in two stages (XIX) by exhaustive
methylation to trimethylamine and a mixture of two products, an oil,
C 8 H 14 0, b.p. 157-9/744 mm., and a crystalline substance, C 8 H 16 0 2 ,
m.p. 75-6. The oil, when heated with water at 170 is converted, by
addition of a molecule of water, into the crystalline substance. The
latter contains two active hydrogen atoms (Zerewitinoff estimation), and
on exposure to hydrogen over palladised charcoal absorbs enough to
saturate one ethylenic linkage producing a new substance, m.p. 94-6.
On oxidation with permanganate in dilute sulphuric acid, propionaldehyde
and succinic acid are produced, whilst the saturated substance, m.p. 94-6,
is oxidised to w-valeric acid. These results indicate that the substance of
m.p. 75-6 is e-dihydroxy-ida-n-octene (XXI), that the oil, C 8 H l 4 0, is the
corresponding oxide (XX), and that the representation of conhydrine
as 2-a-hydroxypropylpiperidine (XV) accounts for their production.
A
H2C
HC
\
(W)
A
^H 2
CH.CH(0H)Kt
NH
(XVI)
,CH.
CH2
CH.CH.CH( OH )Me
/
NH
H2C
H,C
(XVII)
\X
CH 2
CH^CH.Et
(XIX) NMe 3 I
HC
HC
(XX)
\az
CH^;CH.Et
CH 2
CH.C0.Et
NMe
CHo
H2C
2C\
HC
H,C
CH
HC
H?C
CH(OH)
(XXI)
19
j-CONHYDRINE
A0*
H2<j!5
H2C6
3CH2
2 CH.Pr
/
NH (XXXI)
H2C
HO.HC
CH2
CH.Pr a
HO.HC
HC
/
KH (XXCII)
\
46
CH 2
CH.Pr 0
/
HH (XXIV)
This has been confirmed by Spath and Lorenz, who have shown that
dihydro-i/f-conhydrinemethine
must be <x-dimethylamino-octan-/?-ol,
Me2N . CH2 . CHOH . CH2 . (CH 2 ) 4 . CH3, since it is oxidised by chromic
acid in acetic acid to a-dimethylamino-octan-/3-one, which has been
synthesised from w-heptoylchloride by the action of diazomethane in ether,
and treatment of the resulting <x-chloro-w-octan-/3-one with dimethylamine.
y-Coniceine, C8H15N. This base may b3 isolated by Wolffenstein's
method (p. 14), or recovered from the benzoyl-S-aminobutyl propyl ketone,
into which it is converted in von Braun's process, by heating with
PYRIDINE
20
GROUP
Name
o-Coniceine
/3-Coniceine
-y-Coniceino
i-5-Coniceine
i-5-Coniceine
t-Coniceine
composed of
f2-raethylconiJ dine and
1 o-2-methyl\ conidine
i^-Coniceine
Boiling-point
Meltingpoint of
aurichloride
158
190
/
168
}
122-5
\(m.p. 41)
171-172
69
158
207
Specific
rotation,
(!o
+ 18-4
161
150-151
192
178
- 52-99
inactive
lsevorotatory
inactive
+ 42-34
151-154
167-168
143-145
19S-199
171-172
(oily)
Relative
density
Aminocharacter
0-8930 at 15 Tertiary
0-8519 at 50 Secondary
0-8825 at 22-5 Secondary
0-896 a t 23 Tertiary
0-904 at 15
0-8836 a t 15
Tertiary
Tertiary
+ 67-4
0-8856 at 15
Tertiary
- 87-34
0-8624 at 15
Tertiary
+ 122-6
0-8776 at 15
Secondary
21
CONICEINES
CH .CH .CH
| 2
2j
CH JSH. C . P r
(I)
(VI)
CHo
CHg.CHgJJCHMa
CHg.CHgJJ
I I
(II)
CH
n f
MBC:CH.H
CHp.CH
2 .CH.CH 2
2
Q H C
CH
CH:CHN
CH:CH-
CHg
CHg
r
CH
CH
-CH
N
IV)
IV)
(iy)
QH : CH
CH
CH
CH_CH p
CH2
I *
I **
CH
?H2
CH.COJJ
"'2'
CH
(IV)
22
PYRIDINE
GROUP
REFERENCES
(1) J. Amer. Chem. Soc, 1905, 27, 1461. (2) H E B E R T and H E I M , Bull. Soc. chim.,
1898, [iii], 17, 664. (3) Chem. Listy, 1923, 17, 166. (4) Arch. Pharm., 1938, 276, 280.
(5) Pharm. J., 1887-8, [iii], 18, 13, 511 ; 1891, [iii], 21, 857, 936 ; 1895-6, [iv], 1, 89 ;
1904, [iv], 18,185. (6) Trans. Roy. Soc. Canada, 1926, [iii], 20, 111, 153. (7) Pharm. J.,
1909, [iv], 29, 34, 70, 102. (8) J. pr. Chem., 1928, 118, 25. (9) Ber., 1894, 27, 2615 ;
1895, 28, 302. (10) Ibid., 1905, 38, 3108 ; 1917, 50, 1477. (11) Arch. Pharm., 1827,
20, 97. (12) Annalen, 1849, 70, 7 3 . (13) Ber., 1881, 14, 705. (14) Ibid., 1933,
66, 596. (15) MELZER, Arch. Pharm., 1898, 236, 701 ; cf. DILLING, loc. cit.'' (16)
GABUTTI, Chem. Soc. Abstr., 1906, [ii], 711. (17) AHRENS, Ber., 1902, 35, 1330 ; cf,
LOFFLER and F R I E D R I C H , ibid., 1909, 42, 107. (18) HOFMANN, ibid., 1884, 17, 825.
(19) TAFEL, ibid., 1892, 25, 1619. (20) LADENBURG, ibid., 1885, 18, 1587. (21) Ibid.,
1881, 14, 705 ; 1882, 15, 2313 ; 1883, 16, 558 ; 1884, 17, 825 ; 1885, 18, 5, 109. (22)
Ibid., 1895, 28, 1459. (23) Ibid., 1906, 39, 4365. (24) Ibid., 1886, 19, 439,
2579. (25) Ibid., 1893, 26, 8 5 4 ; 1 8 9 4 , 2 7 , 8 5 3 , 8 5 9 , 3 0 6 3 ; 1 8 9 6 , 2 9 , 2 7 0 6 ; 1901,
34, 3416 ; 1906, 39, 2486 ; 1907, 40, 3734 ; cf. WOLFFENSTEIN, ibid., 1894, 27, 2611,
2615 ; 1896, 29, 1956 ; SIMON, Bull. Soc. chim., 1894, [iii], 9, 949 ; LANDOLT, Ber.,
1894, 27, 1362 ; H E S S and W E L T Z I E N , ibid., 1920, 53, 139.
(26) E N G L E R a n d B A U R ,
ibid., 1891, 24, 2530 ; 1894, 27, 1775 ; LAUTENSCHLAGER and ONSAGER, ibid., 1918,
51, 602 ; KOLLER, Monats., 1926, 47, 393 ; D I E L S and ADLER, Annalen, 1932, 498, 16.
(27) CLEMO and RAMAGE, J. Chem. Soc, 1932, 2969. (28) Ber., 1934, 67, 1011. (29)
I&id., 1909,42,107. (30)Ibid., 1917, 50,1192,1386. (31)Ibid., 1932,65, 927. (32)Compare CLOUGH, J. Chem. Soc, 1918, 113 526. (33) WILLSTATTER, Ber., 1901, 34, 3166.
(34) L O F F L E R a n d F R I E D R I C H , ibid., 1909, 42, 107.
(35) Cf. P L A N T A a n d K E K U L E ,
Annalen, 1854, 89, 150. (36) Ber., 1891, 24, 1678. (37) Ibid., 1917, 50, 1386 ; 1919,
52, 1622 ; 1920, 53, 129. (38) Annalen, 1856, 100, 1329. (39) HOFMANN, Ber., 1885,
18, 5 ; LELLMANN, Annalen, 1890, 259, 1 9 3 ; L O F F L E R a n d F R I E D R I C H , Ber., 1909,
42, 107. (40) SPATH and A D L E R , Monats., 1933, 63, 127. (41) Ber., 1909, 42, 929.
(42) Ibid., 1917, 50, 1386 ; 1919, 52, 964 ; 1920, 53, 119 ; Annalen, 1925, 441, 101 ;
cf. MEISENHEIMER a n d MAHLER, ibid., 1928, 462, 301. (43) Ibid., 1891, 24, 2530;
1894, 27, 1775. (44) Ibid., 1891, 24, 1071. (45) Ibid., 1909, 42, 116, 960. (46) SPATH,
K U F F N E R and E N S F E L L N E R , Ber., 1933, 66, 591 ; SPATH and LORENZ, ibid., 1941, 74,
599.
(47) Ibid., 1885, 18, 109. (48) Ibid., 1890, 23, 680. (49) Ibid., 1909, 42, 4059.
(53) LELLMANN, 5 1
also Annalen, 1890, 259, 197 ; LOFFLER, (with KAIM), Ber., 1909, 42, 94 ; (withFLUGEL)
ibid., p . 3420. (54) Gazzelta, 1890, 20, 761 ; Ber., 1890, 23, 1793, 2154. (55) Ibid.,
1912, 45, 734 ; 1913, 46, 1089. (56) Ibid., 1927, 60, 1607. (57) Annalen, 1932, 498,
16. (58) J. Chem. Soc, 1931, 49 ; 1932, 2969 ; cf. TULLOCK and MCELVAIN, J. Amer.
Chem. Soc, 1939, 61, 961. (59) PRELOGandBALENOVIC, Ber., 1941, 74,1508.
(60)Ibid.,
1909, 42, 948. (61) LOFFLER, ibid., p . 122 ; SPATH et al." (62) Pharmacographia,
1879, 299. (63) Compt. rend., 1908, 147, 996. (64) See also H U N T and FOSBINDER,
Anesthesiology, 1940, 1, 305.
ALKALOIDS OF LOBELIA
The presence of alkaloids in Lobelia injlata, Linn., was first recorded
by Proctor. 1 Lobeline was prepared by Lewis 2 as a basic oil from which
Siebert 3 made and analysed a series of salts and proposed the formula,
C 18 H 23 0 2 N. In 1921 Bohringer and Sohne 4 protected a process for the
isolation and separation of three alkaloids, a-, /} and y-lobelines. In the
same year Wieland published the first 5 of a series of papers in which is
described the isolation of several 'groups of alkaloids, to most of which
constitutional formulae have been assigned and, in some cases, confirmed
LOBELIA
ALKALOIDS
23
by synthesis. These alkaloids are remarkable for their close inter-relationship and the fact t h a t three of t h e m can be synthesised 6 b y a v a r i a n t of
Robinson's general process which is a possible phytochemical method.
Lobelia is recognised in several pharmacopoeias, but standards are not
usually prescribed for its alkaloidal content, which should.be from 0-3 to
0-4 per cent.
Numerous methods for the alkaloidal assay of lobelia and its galenical
preparations have been published a n d two recent critical surveys, b y a
sDecial committee of the Society of Public Analysts 7 and b y Caulkin, 8
indicate t h a t the process of Markwell 8 is satisfactory. Processes for the
isolation and separation of the various alkaloids have been protected b y
patent. 9 Balandin 9(a) states t h a t Lobelia sessiliflora contains less alkaloid
t h a n L. inflata b u t yields a high-quality lobeline.
According to Wieland, the typical lobelia alkaloids so far isolated and
examined belong to three groups (Table A), all of which can be represented
by the general Formula I .
T A B L E A. Lobeline Group
norLobelanine. C 2 1 H 2 3 0 2 N. R = H ; R 1 and R 2 = C 6 H 5 . CO
Lobelanine. C 2 2 H 2 5 0 2 N. R = Me ; R 1 and R 2 = C 6 H 6 . CO
^Lobeline } C ^ H 2 N - R = M e ; R*=C6H5.CO; R2=C6H5.CHOH
norLobelanidine. C 2 1 H 2 7 0 2 N. R = H ; R 1 and R 2 = C 6 II 5 . C H O H
Lobelanidine. C ^ H ^ N . R = Me ; R 1 and R 2 = C 6 H 5 . C H O H
Lelobine Group
norLelobanidine.
C 1 7 H 2 7 0 2 N. R = H ; R 1 = C H 3 . C H 2 . C H O H ; R 2 = C 6 H 5 . C H O H
Lelobanidine.
C 1 8 H 2 9 02N. R = Me ; R 1 = C H 3 . C H 2 . C H O H ; R 2 = C 6 H 5 . C H O H
Lobinine Group
Lobinine. C 1 8 H 2 5 0 2 N. R = M e ; R ! = C H 3 . C H 2 . C H O H ; R 2 = C c H 5 . C O .
Ethylenic linkage from C 3 to C 4 .
isoLobinine. C 1 8 H 2 5 0 2 N. Possibly stereoisomeric with lobinine, or with
ethylenic linkage C 4 to C 6 instead of a t C 3 t o C 4 , or with
R 1 = . C H 2 . C H O H . C H 3 instead of C H 3 . C H 2 . C H O H
Lobinanidine. C 1 8 H 2 7 0 2 N. R = Me ; R 1 = C H 3 . C H 2 . C H O H ; R 2 =
C 6 H 5 . CHOH. Ethylenic linkage C 3 to C 4 .
woLobinanidine. C 1 8 H 2 7 0 2 N. As lobinanidine for R . RJ.R 2 , but source
of difference undetermined.
There are also present a t least four subsidiary, unnamed alkaloids,
which have not been fully characterised.
B A S E . C 1 9 H 2 6 0 3 N 2 , m.p. 232 (dec), B . HCI, m.p. 299-300 (dec.) ;
B . H I , m.p. 279 ; B . HC10 4 , m.p. 254-5 ; B . Mel, m.p. 244 (dec.).
Monobenzoyl derivative, m.p. 220. Bromo-compound, m.p. 288
(dec.).
BASE. C ] 4 H 2 1 ON, m.p. 103; oxalate, m . p . 176 (dec).
24
PYRIDINE
GROUP
CH2
0H
lAgC-HC
CH-CI^R 1
Bz-H z 0(VIII)
(I)
(Yi
(VI)
(VII)
C 6 H 5 -CH0H-[CH 2 ]7-CH0H-C 6 H 5
CH-C%Bz
H-CH3
CH
I
CH-
H2C
-CH
I
OH,
0(OH1-
HI)
Bz - CO-OJHJ-
CH.0H 2 .C00H
HSOC-HC
(III)
N.CH3
(VIII) - L o b e l a n i n e , or w i t h one Bz
(IV)
0H 2
0H-000H
N-CHj
CgHg.CHOH. l o b e l i n e
LOBELIA
ALKALOIDS
25
26
PYRIDINE
GROUP
/ \
OH
o-o
0-0
C-0H
n
OH-Hi
HC-C
II
Ph'OH
Ph-C
HO
HC
(CH2)2-Ph
Th- (CH 2 ) 2
N
(II)
(DC)
(X)
X2
CH 2
H,0 /
HpO-0
Bz
H 2 0-HCl
C-CHo
I *
Ph-0H0H \ ^ /
NH
Bz
IXII)
10H.0H 2
CHOH-Ph
H0:0
CH 2
C:CH
Ph-0HOH
0H0H-Ph
NH
(XIII)
(XVI) |
0H2
HgO
(XIV)
Bz-OHg-OO-CHg-OHg-OHg-OO-OHg-Bz
Bz-0H:0
Bz = .CO-OgHg
(XV)
mis
3
C00H
MH;,
Ph-00-OH,
OHO
0BC
OH.2
^OHg
OHj-CO-Ph
Rl-00-OH 2 -Ho/
\oH-CH2-00-Ph
Hjpl
JcB2
\ /
OHg
*zatf>,zcoe
LOBELIA
ALKALOIDS
27
28
PYRIDINE
GROUP
TABLE B.
Lelobine Group
Melting point of
Natural Alkaloid
Derivative
MD
Base
norLelobanidine, C 1 7 H 2 7 0 2 N
methylated to
oxidised t o
rf-Ielobanidine
d- reorlelobanine
dZ-Lelobanidine,
resolved to
oxidised t o
(i-lelobanidine
dZ-lelobanine, C 1 8 H 2 5 0 2 N
C18H290 N
Z-Lelobanidine I .
oxidised t o
Z-lelobanine
B . HC104
193
86
174
190
171
141
176
68
79
86
142
159
171
152
176
136
86
(dihydrate)
186
171c
176
102-5
(1-5 H 2 0 )
186
165
158
4- 0
+ 20*
41*
Z-lelobanine
B . HI
90
41*
Z-Lelobanidine I I
oxidised to
63t
+ 41*
+ Ll-5*
0
+ 41*
B . IIC1
+ 20*
to
30
PYRIDINE
GROUP
All forms have not been fully examined but dZ-lelobanidine is probably
typical. It contains two hydroxyl groups (dibenzoyl derivative m.p. 178)
and is a tertiary base (methiodide m.p. 162-4). On mild chromic acid
oxidation it yields dMelobanine (XVIII) and on vigorous oxidation,
benzoic (Ph . CHOH . side-chain), acetic and propionic ( E t . CHOH
side-chain) acids, while the methylpiperidine nucleus survives in the forms
of l-methylpiperidine-2 : 6-diacetic (scopolinic acid, IV, p. 24) and
l-methyl-2-carboxylic-6-acetic (methylgranatic) acids, the latter being
identical with that obtained from methylgranatoline (p. 59), whence it is
concluded that the configuration of rfZ-lelobanidine and methylgranatoline
includes both m-forms and that Z-lelobanidine I which is oxidised to
Z-lelobanine and Z-methylgranatic acid is an optically active cis-iorm..
As Z-lelobanidine II also yields Z-lelobanine on oxidation the difference
between the I and I I forms must be stereochemical and lie in one of the
side-chains, in spite of the quantitative identity of their specific rotations.
The four asymmetric centres might have the following individual directional
effects 1.1. d . d . and d . I. d . I. in the two forms, but the total effect
might be identical.
It should be noted that rf-norlelobanidine, [a]D -f- 62-8(EtOH), on
oxidation yields (Z-norlelobanine, of which the hydrochloride has
[a]D - 11-5.
Lelobanines, C 18 H 25 0 2 N (Formula XVIII). These are diketo-bases
resulting from the chromic acid oxidation of the corresponding
lelobanidines. Those recorded in Table B are Z- and <ZZ-forms, derived from
ZI and ZII, and dl forms of lelobanidine respectively, dZ-lelobanine is the
best known of these products. The methiodide, not isolated, on treatment
with silver oxide yields dimethylamine and a neutral, deep-yellow oil
convertible by hydrogenation into a glycol, C 17 H 28 0 2 , b.p. H7-8/0-03 mm.,
which was oxidised by chromic acid to l-benzoyI-7-propionyl-w-heptane
(XIX), m.p. 51, semicarbazone, m.p. 186 (dec), the identity of which was
established by synthesis.
LOBININES, C 18 H 25 0 2 N (Table C). These are keto-alcohol bases.
Lobinine, and probably isolobinine, differ from the lelobanidines (XVII)
in having (1) a side-chain, .CH 2 . CO . Ph in place of .CH 2 . CHOH. Ph,
and (2) an ethylenic linkage in the heterocyclic nucleus probably at
C 3 C4 in lobinine (XX) and possibly at C* C5 in isolobinine. On
mild oxidation by chromic acid they yield the diketo-bases, lobinanines,
C i g H ^ O ^ (XXIII), and are reduced by sodium amalgam in acetic acid to
lobinanidines, CjgH^OaN (XXII). On hydrogenation they are converted
into lelobanidines (XVII).
Lobinine, C 18 H 25 0 2 N. First isolated by Wieland, Ishimasa and
Koschara 17 who, on the evidence then available, regarded it as 2-phenacyll-methyl-7-)3-hydroxypropylhexamethyIeneimine, C^H^OaN (XXI), which
was modified to (XX) in 1939.1S It furnishes an oxime (B . HC1, m.p.
182) and a benzoyl derivative (B . HC1, m.p. 146-7). On reduction by
sodium in acetic acid it is converted into the unsaturated dihydric alcohol
for which th* original name " lobinol " has been changed to /Mobinanidine,
T A B L E C.
Lobinine Group
Melting point of
Derivative
Ml>
Base
Lobinine, C 18 H 25 0 2 N .
130*
106+
Reduced to .
Hydrogenated to
Oxidised to .
Lobinanidine, C 18 H ?7 02N
Hydrogenated to
Oxidised t o .
j8-lobinanidine, C 18 H 27 0 2 N
/Melobanidine, C 18 H 29 0 2 N
lobinanine, C 18 H 2S 0 2 N
.
a-lelobanidine.
lobinanine
B . HC1
B.HI
B . HC104
144
130
146
181
152
133
180
39-2t
65*
120*
37t
94
95
169
94
200
174
142
133
171
176
164
171
169
176
65*
isoLobinine
Reduced to .
Hydrogenated to
Oxidised to .
j8-isolobinanidine
Melobanidine I
wolobinanine .
isoLobinanidine
Hydrogenated to
Z-lelobanidine I
76$
41*
11*
28 t
41*
78
154(dry)
161 "
86
150
111
86
PYRIDINE
32
GROUP
CH 2
CH 2 .CH 2
CH-CH 2
CHOH
CHOH
I
Et
(XVII).
HMe
Pb
Lelobanidine
(XVIII)
Lelobanine
CH
,H,C
HcG-HC
2
I
HCOH
I
Ph.
(XXII).
/ \
CH
CH
HCOH
CH
H2C HC lb
CH-CH,
I d
CO
NMe
I
Ph
Ph
Lob i n a n i d i n e
CHOH
I
Et
(XX).
CH,
Lobinine
CH
HoC
H2C
CH
CH-CH2
HMe
(IH).
l-Benzoyl-7propionyl-n-heptane
(1939)
H2C-HC
I
CO
I
Et
(XXIII).
CH-CH 2
I
CO
HMe
Ph
Lobinanine
-CH 2
CH 2
CH,
I
CHo-CH
CH.CHI A I \tlM
a
CO
NMe
CHOH
I
Ph
CH3
(XXI).
Lobinine
(1931)
LOBELIA
1B
ALKALOIDS
33
PYRIDINE
34
GROUP
(7) Analyst, 1939, 64, 581. For a study of t h e polarographic method with lobeline see
NYMAN, Svensk. Farm. Tid., 1943, 47, 401, 429. (8) Quart. J. Pharm., 1939, 12, 438 ;
MARKWEIX, Pharm. J., 1936, 136, 617 ; see also UFFELIC, Pharm. Weekbl., 1946, 81,
41. (9) E.g., Brit. Pat. 145,621-2; 156,190; 314,532. Ger. Pat. 336,335; 340,116;
362,380 ; 389,816 ;1 532,535. Buss. Pat. 54,334. (9a) Farmatsiya,
1946, 9, 17.
(10) Annalen, 1925, 444, 40 ; SCHOPF a n d BOETTCHER, ibid., 1926, 448, 1. (11)
W I E L A N D a n d DRAGENDORFF, ibid.,
(12) W I E L A N D a n d D R I S H A U S ,
idem., p . 102. (13) Idem., p . 126 ; cf. Brit. Pat. 312,919 ; 314,019.
Ber., 1892, 25, 2398.
Annalen,
(14) SCHUSTER,
1929, 473, 118.
DRESBACH, J. Pharm Exp. Ther., 1928, 32 241 ; WHITEHEAD, Univ. Colorado Studies,
1942, 27, 1 (Analeptic action). (20) STANOJEVIC and DJORDJEVIC, C. R. SOC. Biol.,
1938, 127, 1362 ; V O N E U L E R , LILJESTRAND a n d ZOTTERMANN, Vpsala
Lakarefdren
Forh., 1939, 45, 373 ; BERLINER, Arch. int. Med., 1940, 65, 896 ; (with LILIENFELD),
ibid., 1942, 69,739 ; Amer. J. Med. Sci., 1942,203,349 ; ROTOR, DAMIAN and AUSTRIA,
Ada Med. Philippina, 1941, 2, 435 ; PICCIONE and B O Y D , J. Lab. Clin. Med., 1941,
26, 766. (21) RICHTER, Arch. exp. Path. Pharm., 1938, 190, 280 ; 1939, 193, 117, 256.
(22) Verh. Kon. VI. Acad. Geneesk Belg., 1945, 7, 1 ; see also LENQLLE and R U P P E R T ,
ibid., 1942,199, 478, 497 ; D E BACKER, C. R. Soc. Biol, 1944, 138, 901. (23) China
J. Physiol., 1929, 3, 279. (24) Curr. Set., 1945,14, 198. (25) Chem. Abslr., 1945, 39,
3814.
(26) J. Org. Chem., 1944, 9, 537 ; see also FOSTER, MOENCH a n d CLARK, J . ,
TOBACCO
ALKALOIDS
35
36
PYRIDINE
GROUP
TOBACCO
37
ALKALOIDS
the neutral d-tartrate, m.p. 68-5 (hydrated), [aj2 -f- 29-5 (dry salt), both
crystallise from alcohol on addition of ether.
The dipicrate,
B . 2C6H2(N02)3OH, short yellow prisms, m.p. 224, and the tetrachloriodide,22 C 10 H 14 N 2 .2(HIC1 4 ), orange prisms, m.p. 150 (dec), are
characteristic. The ^j-toluenesulphonamide has m.p. 212-3 and is soluble
(20 per cent.) in water. On exposure to ultra-violet light nicotine is
converted to nicotine oxide (picrate, m.p. 169), nicotinic acid and
methylamine. 23
By the action of sodamide on nicotine Tschitschibabin 23w obtained
2-aminonicotine, m.p. 124-5 (dipicrate, m.p. 223-5) and 6-aminonicotine,
m.p. 60, b.p. 300 (dipicrate, m.p. 225 (dec.)). The interaction of these
substances with alkyl halides has been investigated by Goldfarb and
Kondakova and with chloroacetone by Goldfarb and Katrenko. The
analogous 2-aminonicotyrine, C 10 H U N 3 , m.p. 77-8, picrate, m.p. 189-190
and 6-aminonicotyrine, m.p. 97-8, monopicrate, m.p. 257 (dec.) have
been prepared by Clemo and Swan 23a) by the action of sodamide on
nicotyrine and also by the dehydrogenation of the 2- and 6-aminonicotines
respectively.
Nicotine may be detected by the colourless, crystalline mercurichloride
obtained when an aqueous solution is added to a solution of mercuric
chloride, by the black precipitate formed under similar conditions with
potassium platinic iodide and the characteristic crystalline periodide,
B I 2 . HI, m.p. 123, produced on'admixture, under specified conditions, 24
of ethereal solutions of nicotine and iodine (cf Anabasine, p. 43). A
polarographic study of nicotine has been made by Kirkpatrick. 24 '"'
norNicotine, C9H12N2. The base was first obtained by M. and
M. Polonovski 25 and was subsequently prepared by von Braun and
Weissbach 26 along with metanicotine by the action of boiling benzoic acid
on nicotine. The isolation of Z-nomicotine from tobacco by Ehrenstein 10
and of d-womicotine from Duboisia Hopwoodii by Spath, Hicks and Zajic x
has been referred to already. The chief constants of von Braun's
wornicotine are given in the following table with those of the natural d- and
/-forms as first isolated.
norMicotlne from
Boiling point
Specific Gravity
Nicotine
(von Braun)
Tobacco
(Enrenstein)
139-140 A a n t .
130.5-131.3Al
DjO
1.044
Befractive Index
Specific rotation
[] "5.5
1>5378
Mf-17.7
D. Hopwoodii
(SpSth e t a l . )
117/3.6
D$
m.
1.0797
Melting points of
Dipicrate
188-190
191-1*
191-19*
Wplorolonate
283 - 823
250-258
858-853
38
PYRIDINE
GROUP
TOBACCO
39
ALKALOIDS
colourless prisms, m.p. 125, was recovered. This cannot be acylated and
gives neither an oxime nor a phenylhydrazone. When heated with
sulphurous and sulphuric acids at 130-140 it yields methylamine, oxalic
acid and 3-acetylpyridine (see diagram below).
By the action of bromine on nicotine in hydrobromic acid, dibromoticonine (Formula B), C10H8O2N2Br2, nodular crystals, m.p. 196, is
obtained. This with zinc dust in warm alkali yields methylamine and
pyridyl-/S : y-dihydroxybutyric acid,
C 5 H 4 N . CHOH . CHOH . CH 2 . COOH,
and when heated with barium hydroxide in a sealed tube at 100
decomposes into methylamine and malonic and nicotinic acids, probably
via the intermediate product C.
These reactions indicate that the residue C5H10N includes a series of
three primary carbon atoms ending in a group . NCH 3 thus :
. CH 2 . CH 2 . CH 2 . NCH 3 .
and, since difficulty is experienced in reducing nicotine beyond
hexahydronicotine, this residue must
be cyclic, i.e., it is Nmethylpyrrolidine as in (A). On this view these series of changes may be
represented thus :
CH 2
HO
NMe
CH,
(A)
A
VJ
OH
CBtfl
OH
(B)
00-
00-OH
MeN
(0)
I
Mlootinlc a c i d , CjajH-COOH
Malonic aoid, COOH-0H2-0OOH
Methylamine, CHj-NHo
AcH
HO
V
OH
OEECEEr
3 - A c e t y l p y r i d i n e , C5H4N-CO-CH3
O x a l i c a c i d , H000-000H.
M e t h y l a m i n e , CK3-NH2-
CBrC
(D)
Me
00
The objection that Formula (A) for nicotine does not provide for the
benzoyl derivative of nicotine obtained by FJtard 34 was overcome when
Pinner 35 showed that in this reaction the pyrrolidine ring is opened,
giving rise to metonicotine (isonicotine), and that the supposed
benzoylnicotine is benzoylwietanicotine,
C a H 4 N . CH : CH . CH 2 . CH 2 . NCH 3 . CO . C 6 H 5 ,
from which metanicotine (b.p. 275-8; picrate, m.p. 163 (dry)) can be
recovered by heating with hydrochloric acid under pressure at 100.
Confirmation of this constitution for mctonicotine is provided by its
conversion by hydriodic acid into iododihydrojwetanicotine, which is
reduced by zinc and hydrochloric acid to dihydromrfanicotine, of which a
40
PYRIDINE
GROUP
TOBACCO
41
ALKALOIDS
N-Mel
HO
HO
HO
(II)
(71) CH
CHg
OH?
KMe
CH 2
CH
(V)
CH
HC
NH
(III)
f)
V
(IV)
CH
CH
CH
CH
CH
o cS
NMe
NJJa
;H
CH
PYRIDINE
42
sat
GROUP
OH.CH_
CH
CO
X
Ethyl nlootlnate
CH
/\
I
CH
CH
CH
\
N.CH3
CH,
L
C
C-OO-CH
-> i
JSH
CO
1-Methylpyrrolldone
CHp
CH
6H2
!H
CH
CK,
r
CH 2
H.CH,
(II)
C 5 H 4 N.CO.(CH E ) 3 .HHCH 3
(III)
C^N.CHOHlCHjjlgJJHCHg
(IV)
C 5 H 4 N.CHI.(CH 2 ) 3 .NHCH 3
\ /
N
CH.
dl-Niootlne
Craig's Synthesis.
CH
CHg
y \
CH
-CH
C-
CHg
(V)
(VI)
Y
CgH^I.C.CHg.C^.CHg.OC^g
CH,
H
HOH
y
norNleotine
-<-
H2cHOOC.HC
N.CH 3
(VIM) Methylnlcotono
-CH,
CH
\ N N.CHg
/
(IX) Hygrinlc add
HC
^GH
H.C
* l
CH
I
H.CH,
(X) a-Nlcotlne
ANABASINE
43
fc
Product described by
Ehrenstein
Orekhov
Boiling point
Specific rotation
S m i t h : Pictet
145-6/14 m m .
137-5-8-5/10-5 m m .
Smith, 280-l/775 m m .
276/760 m m .
155/19 m m .
P i c t e t , 250-5
81 * (base)
72-9 (base)
Specific g r a v i t y
D* 1-0455
D;:" 1 0 7 6 1
Refractive index
n'jf 1-5430
nf/*
Dipicrate, m . p .
200-5
201-4
1-5423
Smith, 213
P i c t e t , 163
Dipicrolonate, m . p .
235-7
233-5
* According t o Norkina et aZ.58 the specific rotation varies with t h e solvent and racemisation is a p t to occur during extraction.
Values much lower than 81 have been given by Smith. 5 9 The salts are dextrorotatory.
ANABASINE
45
46
PYRIDINE
GROUP
TOBACCO
ALKALOIDS
47
48
PYRIDINE
GROUP
have little effect on the yield of alkaloid, but does affect its distribution
in the plant. Of more fundamental interest are the effects on the nature
and distribution of alkaloid produced in grafting 71 and hybridisation 72
experiments. Dawson 71 found that when tomato plants were grafted on
tobacco, nicotine was found in the leaves, stems and fruit of the scion,
whereas in the reverse grafts no appreciable amount of nicotine appeared
in the tobacco scions. Similarly, Shmuk, Smirnov and Ilyin 71 found that
when Solatium nigrum, stramonium or tomato was grafted on N. tabacum
or N. rustica, nicotine appeared throughout stock and scion, but when
tobacco was used as the scion on the same three species nicotine could not
be detected in stock or scion. Shmuk, Kostov and Borozdina on the other
hand grafted JV. glauca (yielding anabasine) on JV. tabacum and found that
stock and scion then contained a mixture of nicotine and anabasine, the
latter predominating, and when the grafting was reversed anabasine
replaced nicotine entirely in stock and scion. In hybrids of JV. rustica
(yielding nicotine) with JV. glauca, the influence of the latter seemed to
predominate and the crosses contained anabasine only, but progeny of the
back cross (JV. rustica X JV. glauca X JV. rustica) included plants in which
anabasine or nicotine might occur alone and others containing a mixture
of the two. Results of such experiments are influenced to some extent by
external factors and it is not surprising that the results of workers in
different countries do not always agree. Dawson 7 1 (1945), after an
interesting and comprehensive analysis of the accumulation patterns in
graft combinations involving JV. tabacum, JV. glauca, JV. glutinosa and
tomato and in the hybrid JV. tabacum X JV. glauca, has come to the conclusion that nomicotine is produced only in the leaf, and at the expense of
nicotine formed in the root. This is taken to mean that of the three major
alkaloids, nicotine, anabasine and nomicotine, only the first two are formed
by total synthesis in situ, and the third is a secondary product. Contrary
to previous findings, anabasine does not predominate over nicotine in the
hybrid JV. tabacum x JV. glauca. Nicotine is formed in the roots and
translocated to the leaves, where it is converted into nomicotine, by a
transmethylation reaction. Nicotine is produced in the roots of all three
species. Anabasine is produced in both root and shoot of JV. glauca.
norNicotine is produced in the leaves of JV. glutinosa and in the leaves of
some strains of JV. glauca and JV. tabacum, but always at the expense of
preformed nicotine. Either nomicotine or nicotine may be a normal
constituent of JV. glauca, depending on the strain examined. Dawson has
also shown 73 that excised tobacco root tips grown in vitro in sterile culture
synthesise nicotine, which accumulates in the surrounding tissue and
synthesis in the roots seems also to be supported by results obtained in the
investigation of the distribution of alkaloid in various organs of the
tobacco plant.7*
Efforts are still being made to estimate that elusive notion " quality in
smoking tobacco " by chemical analysis 7 6 ; it does at least seem to be
clearly established that a low content of protein and of nicotine is desirable,
and in that connection the isolation by Bucherer76 of several species of
TOBACCO
ALKALOIDS
49
50
PYRIDINE
GROUP
see also H I C K S , Aust. J. exp. Biol., 1936, 14, 39 ; WENUSCH, Pharm. Zeit., 1936, 77,
141 ;
B O W E N , J.
Econ. Entom.,
BOTTOMLEY, N O T T L E and
WHITE,
Austr. J. Set., 1945, 8, 18. For early work see LIVERSIDCJE on " piturine," Chem. News,
1881, 43, 124 ; PETIT, Pharm. J . , 1879, [iii], 9, 819 ; ROTHERA, Biochem. J., 1910, 5,193.
(2) J. Amer. Chem. Soc, 1931, 53, 277 ; 1935, 57, 959 ; NELSON, ibid., 1934, 56, 1989 ;
KIIMUEA, J. Appl. Chem. U.S.S.R.,1938,11,
109. (3) Compt.rend., 1929,189, 945; (with
MENSCHIKOV),
1934, 67, 1845. (4) J. Ind. Chem. Soc., 1943, 20, 181 ; cf. Pharmacographia Indica,
London, 1891, Vol. I I , p . 266. (5) Can. J. Res., 1939, 17, B , 21 ; 1945, 23, 165.
(6) NOGA, Fachl. Mitt. 0?t. Tabakregie, 1914 (Chem. Soc. Abstr., 1915, i, 711); cf. SPATH
and BINIECKI, Ber., 1939, 72, 1809. (7) Compt. rend. Acad. Sci. U.S.S.R., 1941, 32, 62 ;
J. Appl. Chem. Russ., 1939, 12, 1582 ; _1940, 13, 776 ; 1941, 14, 864 ; see also SHMUK
and KHMURA, Bull. Appl. Bot. U.S.S.R., 1935, A, 111 (Chem. Abstr., 1937, 31, 5513) ;
MARKWOOD a n d BARTHEL, J., Assoc. Off. Agric. Chem., 1943, 26, 280; BOWEN and
BARTHEL, Ind. Eng. Chem., 1944, 36, 475 ; Anal. Edit., 1943, 15, 740 ; 1944, 16, 377.
(8) J. Assoc. Off. Agric. Chem. (U.S.A.), 1943, 26, 2 8 3 ; MARKWOOD, Science, 1940,
92,204. (9) Ber., 1901, 34, 696. (10) Arch. Pharm., 1931, 269, 627. (11) Osterr. Bot.
Zeit.,
RAVENNA, Atti. Accad. Lincei, 1911, 20, i, 614 ; SPATH and ZAJIC, Ber., 1936, 69, 2448 ;
SPATH and K U F F N E R , Fortsch. Chem. Org. Naturstoffe, 1939, i i , 248. (13) See, for
example : K A N and L I N , J. Chin. Chem. Soc, 1941, 8, 1 ; ASKEW, N.Z. J. Sci. Tech.,
1942.24B,41 ; FRITZSCHE, Syracuse Chem., 1942,35, No. 7, 3, 6 ; BOWEN and BARTHEL,
J. Assoc. Off. Agric. Chem., 1944, 27, 224 ; t h e following U.S. Patents : GARNER,
2,128,043 ; MCCOY, 2,162,738 ; R A D E R , 2,235,589 ; EDWARDS, 2,251,041 ; T I G E R and
D E A N , 2,293,954, and Russian Patents : SHMUK et al., 54,879 ; SAFRONOV, 57, 144 ;
MEDRIKOV, 58,981. SUBRAMANIAN and VARIYAR, J. Sci. Ind. Res. (India),
1944,3,143.
(14) SEKA, Klein's " Handbuch der Pflanzenanalyse," 1933, 4, P t . 3, p . 544 ; TONKIN,
" A l l e n ' s Commercial Organic Analysis," Edit. 5, Vol. 7, 6 2 5 ; D 6 R R , Z. Unters.
Lebensm., 1934, 67, 1 1 3 ; P Y R I K I , ibid., 1943, 86, 8 9 ; SCHWEITZER, Lands.
Jahr.,
1943, 93, 331. The Pfyl-Schmitt pierate process (ibid., 1927, 54, 60) is modified b y
various authors in Tabak, 1940, 3, 93-123 and by SPAIKOV 1VaJ and RASMUSSEN and
K O T O E D . 1 6 ^ . (15) HOFMANN, Biochem. Zeit., 1933, 260, 26 ; Mikrochem., 1935,18, 24 ;
BODNAR and NAGY, Z. Unters Lebensmitt, 1937, 73, 191 ; WENUSCH, ibid., 74, 43, 46 ;
RIPAN-TILICI and CBISTEA, ibid., 1938, 76, 44 ; Dent. Zeit. ges. gericht Med., 1938-9,
61
TOBACCO ALKALOIDS
30, 231 ; SPIES, Ind. Eng. Chem. Anal,
1943,15, 596 ; SUTHERLAND, DAROGA and POLXARD, J. Soc. Chem. Ind., 1939, 58, 284 ;
DAWSON, Proc. Indiana Acad. Sci., 1939, 49, 91 ; CORCORAN, H E L M E R a n d P A G E ,
1940,
23, 792, 800, 804 ; 1942, 25, 474 ; B O W E N , ibid., 1947, 30, 315 ; R A P P , WOODMANSEE
and M C H A R G U E , ibid., 1942, 25, 760 ; B O W E N , ibid., 1945, 28, 578 ; AVENS a n d P I E R C E ,
Ind. Eng. Chem., 1939, 31, 505 ; SPAIKOV, Ann. Univ. Sofia. Fac. Agron. Sylv., 1941-2,
20, 415 (Chem. Abstr., 1945, 39, 3627) ; RASMUSSEN and KOFOED, Dansk. Tids. Pharm.,
1944, 18, 233 ; TRAUTNER and N E U F E L D , Aust. Chem. Inst. Journ. Proc, 1946, 13, 70.
(166) SHMUK et aW ; MARKWOOD 8 ; KHMURA, Vsesoyuz. Nauch. Issledovated Inst.
Tabach Makhoroch Prom., 1939, No. 140, 97 (Chem. Abstr., 1940, 34, 4862); C. R .
SMITH, Ind. Eng. Chem., 1942, 34, 251 ; LARSON and HAAG, ibid. (Anal Edit.), 1944,
16, 86 ; E D W A R D S , J. Soc. Chem. Ind., 1944, 63, 186. (16c) COPLEY, E S K E W a n d
WILLAMAN, Chem. Eng. News, 1942, 20, 1 2 2 0 ; MCMURTRAY, BACON a n d R E A D Y ,
U.S. Dept. Agric. Tech. Bull., 1942, No. 820 ; SHMUK, Tabachm. Prom., 1933, No. 3 ,
pp. 4-6. (16d) JACKSON, Chem. Rev., 1941, 29, 123 ; MARION, Rev. trimestr. Can.,
1938, 24, 1 7 0 ; SPATH a n d K U F F N E R . 1 2
(17) JEPHCOTT, J. Chem. Soc, 1919, 115,
105 ; PATTERSON a n d F U L T O N , ibid., 1925, 127, 2435 ; PATTERSON, LAMBERTON and
CUNNINGHAM, ibid., 1932, 962 ; LOWRY a n d L L O Y D , ibid., 1929, 1376, 1771 ; T A T E and
WARREN, Chem. and Ind., 1937, 56, 39T. (18) RATZ, Monats., 1905, 26, 1241.
(19) J E P H C O T T 1 7 ; HUDSON, Zeit. Phys. Chem., 1904, 47, 113; TSAKALATOS, Bull. Soc.
Chim., 1909, [iv], 5, 3 9 7 ; K E L L Y , O'CONNOR a n d R E I L L Y , Nature,
J. Chem. Soc, 1941, 275 ; 1942, 511 ; cf. C R . SMITH, 1 6 'W A S K E W , 1 3 NORTON, BIGELOW
and VINCENT, J. Amer. Chem. Soc, 1940, 62, 261. For behaviour in salt solutions see
FITZGERALD, J. Council Sci. Ind. Res. Auslr., 1945, 18, 266. (20) See, for example,
LIQUIER, Compt. rend., 1924,179, 269 ; LOWRY, Nature, 1926,117, 417 ; (with Lloyd). 17
(21) P I C T E T a n d ROTSCHY, Ber., 1900, 33, 2 5 3 3 ; cf. SPATH and BOBENBERGER, Ber.,
1944, 77, 362. (22) CHATTAWAY and P A R K E S , J. Chem. Soc, 1929,1314. (23) RAYBURN,
HARLAN and HAMMER, J. Amer. Chem. Soc, 1941, 63, 115. (23a) TSCHITSCHIBABIN
(with BUCHHOLZ), J. Russ. Phys. Chem. Soc, 1920, 50, 5 4 8 ; (with KIRSSANOV),
Ber., 1924, 57, 1163 ; GOLDFARB (with KONDAKOVA), C. R. Acad. Sci. U.S.S.R., 1945,
48, 484 ; 49, 421 ; (with KATRENKO), ibid., 1940, 27, 673 ; CLEMO a n d SWAN, J. Chem.
Soc, 1946, 603. (24) KIPPENBERGER, Zeit. Anal. Chem., 1903, 42, 275 ; KATZ, ibid.,
1937, 108, 408 ; SHAIKOVA, Pharm. it. Pharmakol., 1938, 10 ; see also F U K S , J. Appl.
Chem. U.S.S.R., 1946, 19, 102. (24a) Quart. J. Pharm., 1946, 19, 530. (25) Compt.
rend., 1927, 184, 331, 1333. (26) Ber., 1930, 63, 2018. (27) Ger. P a t . 80,520;
Ber., 1905, 38, 880, 882 ; cf. SPATH and ZAJIC, 1935. 1 (28) U.S. Dept. Agric. Bur.
Entom., E561, 1942. (29) H U B E R , Annalen, 1867, 141, 271 ; W E I D E L , ibid., 1873,
165, 328 ; LAIBLIN, Ber., 1877,10, 2136. For recent industrial methods see WOODWARD
et al.,Ind. Eng. Chem., 1944, 36, Indust. Edit., pp. 540, 544 ; VASIUNINA, J. Appl. Chim.
Russ., 1943, 16, 206. (30) Ber., 1886, 19, 2587. (31) Annalen, 1879, 196, 172.
(32) Ber., 1891, 24, 326 ; 1893, 26, 628, 1029. (33) Ibid., 1892, 25, 2807 ; 1893, 26,
292, 765. (34) Compt. rend., 1893, 117, 170, 278. (35) Ber., 1894, 27, 1053, 2861 ;
1895, 28, 456. (36) Ibid., 1942, 75, 522. (37) LOFFLER and KOBER, ibid., 1909, 42,
3431. (38) Ibid., 1893, 26, 628, 1029 ; cf. HARLAN and H I X O N , J. Amer. Chem. Soc,
1930, 52, 3385. (39) MAASS et al., Ber., 1905, 38, 1831 ; 1906, 39, 3697 ; 1914, 47,
1164. (40) Ibid., 1897, 30, 2117. (41) Ibid., 1895, 2 8 , 1904. (42) Ibid., 1885,18,
1828 ; 1887, 20, 698 ; 1889, 22, 659, 2518. (43) P I C T E T a n d ROTSCHY, ibid., 1904, 37,
1225 ; cf. SPATH a n d K A I N R A T H , 1938, 7 1 , 1276 ; see also W I B A U T (with DINGEMANSE),
Rec. Trav. Chim., 1923, 42, 1033 ; (with GITSELS), ibid., 1938, 57, 755 ; 1941, 60, 176,
and LIONS and RITCHIE, Proc. Roy. Soc. N.S. Wales, 1940,74,110. (44) Biochem. Zeit.,
1935, 275, 361 ; SPATH and KESZTLER, Ber., 1937, 70, 2450. (45) Bull. Soc. Chim.,
1880, [ii], 34, 449 ; cf. B L A U , Ber., 1894, 27, 2535 ; T A F E L , ibid., 1892, 25, 1619 ; see
also MORTON and HORVITZ, J. Amer. Chem. Soc, 1935, 57, 1860. (46) Ber., 1895, 28,
52
PYRIDINE GROUP
1904 ; 1898, 3 1 , 2018 ; 1900, 33, 2355. (47) Rec. trav. Chim., 1928, 47, 935 ; see also
FBANK, HOLLEY and WIKHOLM, J. Amer. Chem. Soc., 1942, 64, 2835. (48) Ibid., 1932,
51, 1157 ; SPATH, W I B A U T a n d KESZTLER, Ber., 1938, 7 1 , 100.
(49) Z E L I N S H I ,
ibid.,
1925, 58, 185 ; cf. ZELINSKI a n d JURGEV, ibid., 1931, 64, 101. (50) Ibid., 1935, 68,
494, 1125. (51) Ibid., 1928, 6 1 , 327. (52) J. Amer. Chem. Soc., 1933, 55, 2854.
(53) GOUGH a n d K I N G , J. Chem. Soc., 1931, 2968 ; 1932, 2768 ; 1933, 350 ; L U N D ,
ibid., 1933, 686 ; 1935, 418 ; a n d CLEMO a n d HOLMES, ibid., 1934, 1739. (54) Helv.
Chim. Acta, 1925, 8, 3 6 4 ; K A R R E R a n d TAKAHASHI, ibid., 1926, 9, 458.
(55) TSCHITSCHIBABIN a n d B Y L I N K I N , Ber., 1923, 56, 1745 ; W I B A U T a n d DINGEMANSE,
Rec. trav. Chim., 1923, 42, 1033 ; 1926, 45, 657, 671. (56) Ibid., 1933, 52, 941.
(57) J. Amer. Chem. Soc, 1934, 56, 1144. (S8) Compt. rend., 1929, 189, 9 4 5 ; Ber.,
1931, 64, 2 6 6 ; (with NORKINA and NARKUZIEV), J. Gen. Chem. Russ., 1937, 7, 951.
(59) J. Amer. Chem. Soc, 1931, 53, 277 ; 1935, 57, 959 ; NELSON, ibid., 1934, 56, 1989.
(60) SPATH a n d KESZTLER, Ber., 1937, 70, 239, 704.
(61) OREKHOV a n d N O R K I N A ,
ibid., 1932, 65, 742, 1126 ; ZDANOVICH and MENSHIKOV, J. Gen. Chem. V.S.S.R., 1945,
15, 116 ; SADYKON, ibid., 1947, 17, 1710 ; SMITH, J. Amer. Chem. Soc, 1932, 54, 397.
(61a)
1933, 66, 466 ; cf. WENUSCH (with SCHOELLEB) ibid., 1934, 67, 1 3 4 4 ; (with
BILOWITZKI) Biochem. Zeit., 1934, 270, 15 ; F U K S , Lab. Prakt. U.R.S.S., 1941, 16, 23.
(63) KABATSCHNIK and KATZNELSON, Bull. Soc. Chim., 1935, [v], 2, 521, 5 7 6 ; Ber.,
1935, 68, 399, 1247 ; cf. Compt. rend. Acad. Sci. U.R.S.S., 1934, 1, 406 ; 4, 47 ; 1935,
3, 1 6 9 ; also OREKHOV a n d NORKINA, Ber., 1932, 65, 1 1 2 6 ; a n d MENSCHIKOV,
GRIGOROVITCH a n d OREKHOV, ibid., 1934, 67, 289, 1157, 1398. (63a) VILJAMS a n d
MAVLEIRNOV, J. Appl. Chem. Russ., 1944, 17, 228. (64) SPATH (with MAMOLI), Ber.,
1936, 69, 1082 ; (with KESZTLER), ibid., 1937, 70, 70. (64a) U.S. Dept. Agric. Bur.
Entom., E537 (1941). (65) Arch. Pharm., 1906, 244, 388. (66) Fachl. Mitt. ost.
Tabakregie, (1914) (Cftem. Soc. Abstr., 1915,[i], 711). (67) Quoted by SPATH, WENUscnand
Z A J I C , B C T . , 1 9 3 6 , 6 9 , 393. (68) Ibid., 1936, 69, 757. (69) GREBINSKY, Compt.rend. Acad.
Sci. V.S.S.R., 1941, 32, No. 4 (Nature, 1944,151, 338). (70) VLADESCU and DIMOFTE, Bui.
cult, ferment. Tulunului, 1940, 29, 153 ; 1941, 30, 115, 226 ; 1942, 31, 32 (Chem. Abstr.,
1942, 36, 6578 ; 1943, 37, 3473, 3566 ; 1941, 38, 145). (71) DAWSON, Amer. J. Bot.,
1942, 29, 6 6 ; 1914, 31, 351 ; 1945, 32, 4 1 6 ; J. Amer. Chem. Soc, 1945, 67, 5 0 3 ;
SHMUK (with SMIRNOV and ILYIN), Compt. rend. Acad. Sci. U.S.S.R., 1941, 32, 365 ;
(with KOSTOV and BOROZDINA), ibid., 1939, 25, 477.
J. Sci. Tech.,
Ind.
Eng. Chem. (Ind. edit.), 1944, 36, 556 ; WENUSCH, Wien. Chem. Zeit., 1943, 46, 178 ;
P Y R I K I , Z. Unters. Lebensm., 1942,84,36. (76) Zentr. Bakl. Parasitenk., 1942, Abt. I I ,
105, 166 ; 1943, Abt. I I , 105, 445 ; ENDERS and GLAWE, Biochem. Zeit., 1944, 312,
277. (77) F o r anabasine, see especially SMITH, RICHARDSON a n d SHEPARD, J. Econ.
Entom., 1930, 23, 863 ; GINSBERG, SCHMITT a n d GRANETT, J. Agric. Res., 1935, 5 1 ,
349 ; ROABK *<*> ; NABOKOV, Amer. Rev. Soviet Med., 1945, 2, 449. (77a) BEALL,
Ann. Repl. Entom. Soc. Ontario, 1941, 72, 32. (776) Nicotine aerosols, SMITH a n d
GOODHUE, J. Econ. Entom., 1943, 36, 904 ; review of nicotine as insecticide, MCINDOO,
ibid., p . 473. (78) J. Amer. Chem. Soc, 1942, 64, 2835. (79) Nature, 1944, 153, 448.
. (80) " A Survey of Insecticidal Materials of Vegetable Origin," Imperial Institute,
London, 1940. (81) Inst. Biochem. Acad. Sci. U.S.S.R., 1940, 1-203. (82) W I I A M A N
and BAKER, Cornell Vet., 1943, 33, 365. (83) F o r useful bibliographies see ZUNZ,
" Elements de Pharmacodynamic speciale," 1,1932,268 ; CUSHNY, " Pharmacology and
Therapeutics," London, 1934, 335 ; for a recent survey of information see HAAG and
LARSON, Virg. Med. Monthly, 1944, 7 1 , 235. (84) J. Pharm. Exp. Ther., 1943, 77, 107.
(85) J. Chem. Soc., 1939, 1365. (86) For a n informative article on this subject see Sir
ANABASIS
ALKALOIDS
53
Humphrey ROLLESTON, Lancet, 1926, 210, 961 ; CORTE, " A History of Smoking,"
English translation by England, New York, 1932. For information on the development
of tolerance to nicotine in animals, see BEHBEND and T H I E N E S , J. Pharm. Exp. Ther.,
1933, 48, 317 ; PEAKL, Science, 1938, 87, 216. (87) STRAUB and AMANN, Klin. Woch.,
1940,19,169; L.*SSING, Med. Well., 1938, 12, 1485 ; COON and ROTHMAN, Proc
Soc.
Exp. Biol. Med., 1939, 42, 231 ; J. Pharm. Exp. Ther. Proc, 1941, 72, 9 ; "HUEPER,
Arch. Path., 1943, 35, 8 4 6 ; R O T H , MCDONALD and SHEARD, J. Amer. Med. Assoc,
1944, 125, 761 ; Med. Clin. N. America, 1945, 29, 949 ; B U R N , TRUELOVE and B U R N ,
Brit. Med. J., 1945, i, 403. (88) PERLMAN, DANNESBORG and SOKOLOFF, J. Amer. Med.
Assoc, 1942, 120, 1 0 0 3 ; HAAG and LARSON, Fed. Proc, 1942, I I , 1, 1 4 2 ; Science,
1943, 97, 187; J. Pharm. Exp. Ther., 1942, 76, 235, 240 ; 1943, 77, 343 (with NEALE),
ibid., 1940, 69, 289 ; (with FINNEGAN), ibid., 1945, 85, 356 ; 1946, 86, 239 ; 1947, 91,
357 ; (with SCHWARTZ), 1946, 88, 82 ; P Y R I K I , Zeit. Physiol. Chem., 1943, 277, 233 ; Z .
Unters Lebensm., 1943, 85, 3 3 7 ; LOCKETT, J. Physiol., 1944, 103, 68, 185. (89)
Biochem. Zeit., 1938, 298, 2 6 8 ; (with MULLER), ibid., 1941, 308, 355; (with BECKER),
ibid., 1943, 313, 182. (90) Arch. int. Pharmacodyn., 1935, 51, 335 ; HICKS and SINCLAIR,
Aust. J. Exp. Biol. Med., 1947, 25, 83 ; cf. LARSON, HAAG and FINNEGAN, Proc. Soc.
Exptl. Biol. Med., 1945, 58, 231. (91) J. Pharm. exp. Ther., 1934, 50, 9 3 ; cf.
MAYER, Arch. Sci. phys. nat., 1904, 17, 418 ; OOSTERHUIS and WATERMAN, J. Pharm.
Exp. Ther., 1938, 63, 318 ; HEYMANS and BOCCKAERT, Arch. int. Pharmacodyn., 1941,
65,196. (92) KARREU etal.,Helv. Chim. Acta, 1926, 9, 458, 461. (93) HAAG, J. Pharm.
exp. Ther., 1933, 48, 9 5 ; see also ROARK sl/a> and for aminoanabasines, PPLUEKTOV,
Farmakol Toksikol., 1939, 2, 49 (Chem. Abslr., 1940, 34, 3818) ; KABATSCHNIK and
ZITZER, J. Gen. Chem. Russ., 1940, 10, 1007 (Chem. Abstr., 1941, 35, 3640) (94)
MKNSCHIKOV et al., Ber., 1934, 67, 1157 ; for methylanabasine see SAKSONOV, Farmakol.
Toksikol., 1946, 9, 13. (95) Proc Soc Expt. Biol. Med., 1946, 63, 423.
54
PYBIDINE
GROUP
U.R.S.S.,
59, 807 ;
SADYKOV and SPASOKUKOTSKI, J. Gen. Chem. U.R.S.S., 1943,13, 830; SADYKOV, ibid.,
1945, 15, 252. (2) DASHKKVICH, Trudy Leningrad Inst. Sovet Torgovli, 1939, No. 2,
p. 8 (Chem. Abstr., 1943, 37, 3228). (3) J. Amer. Chem. Soc., 1932, 54, 397. (4) Ber.,
1932, 65, 724. (5) Compt. rend., 1929, 189, 945 ; (with MENSCHIKOV), Ber., 1931, 64,
206;
1932,
65,
234;
MAXIMOVA), 1934,
Chem. Russ., 1937,7, 2048 (Brit. Chem. Abstr., 1938, A, ii, 74).
67,
1845.
(6) J.
Gen.
PELLETIERINE
55
PYRIDINE
GROUP
H2C|
|CH2
CH2
Via oxime
H2C\/CH.CH2.CH2.COOH
NH
fi-2-piperidylpropionic acid
H2C|
CH2
H 2 C \ JcH.CH2.CH2.CHO
NH
Pelletierine
|CH2
POMEGRANATE
BARK
ALKALOIDS
57
Spielman et al. record b.p. 128/8 mm. and n|5 1-5070 for the 0-(2pyridyI)-propionaldehyde they hydrogenated using Raney nickel as
catalyst in alcohol at 150 and 170 atm. pressure. The pelletierine acetal
produced had b.p. 91-2/l mm. and nf 1-4568 and yielded a benzoyl
derivative, b.p. 177-8, nf 1-5229, from which by hydrolysis JV-benzoylpelletierine, m.p. 74-6, was obtained; by similar procedure Nacetylpelletierine, b.p. 174/18 mm., n|6 1-4908, and pelletierine
cthylurethane, b.p. 119-21/1 mm., nf 1-4771, the constants recorded
being in satisfactory accord with those given by Hess 3 for these
pelletierine derivatives. No method has yet been found of recovering
pelletierine from the acetal.
woPelletierine, C8H15ON. This name, originally applied by Tanret to
a base, now regarded as dZ-pelletierine, has been adopted by K. Hess 13 for
a different alkaloid. This is an oily liquid having b.p. 102-7/H mm.,
[a]x, + 0; the hydrobromide melts at 149 and the picrate at 147-8.
MoPelletierine is also obtained by demethylation of methyKsopelletierine
and is convertible into the latter by methylation. Its constitution is
discussed below.
Methyh'sopelletierine, C9H17ON. This base, isolated by Piccinini 2
under the name isomethylpelletierine, was re-examined by K. Hess 15 et al.
It is an oily alkaline liquid, b.p. 114-7/26 mm., miscible with water and
optically inactive. The hydrochloride has m.p. 156, hydrobromide,
m.p. 151-2 ; the picrate melts at 158 and the aurichloride forms orangeyellow rosettes, m.p. 115-7. The base can be resolved into d- and
/-forms having b.p. 109/24 mm., and specific rotations [<x]J,8 of 6-7 and
9-9 in dilute sulphuric and hydrochloric acids respectively. rf-Methyljsopelletierine d-hydrogen tartrate has m.p. 133^ and [a]u + 22-7, and
the antipode has m.p. 132-4 and [a]Jf 20-83, whilst the two
hydrochlorides have [a]Jf + 11-08 and 10-64 respectively.
Constitution. The alkaloid yields a crystalline semicarbazone, m.p.
169, a liquid hydrazone, b.p. 154-5/29 mm., and a liquid oxime, b.p.
160/12 mm., from which a crystalline picrate, m.p. 106, can be prepared.
The methiodide crystallises in cubes, m.p. 156. On oxidation with
chromic acid in sulphuric acid solution the base yields iV-methylpiperdine2-carboxylic acid, and the hydrazone on reduction with sodium in alcohol
at 150-70 forms iV-methylconiine (p. 17).
In view of these reactions methyk'^opelletierine must be Nmethylpiperidine with one of the following side-chains in position 2 :
(a) CH2. CH 2 . CHO; (b) CO . CH2 . CH 3 ; (c) CH 2 . CO . CH 3 . If the
side-chain were (a) methyKsopelletierine should be formed
by
N-methylation of pelletierine, which is not the case. Decision between
(b) and (c) proved difficult. If the side-chain were (c) the alkaloid should
be a-iy-methylpiperidyl-2-propan-/?-one (I).
This substance was
synthesised by Hess and Eichel 3 and appeared not to be identical with
methylwopelletierine, and Hess was, therefore, led to the conclusion that
the side-chain must be (b), which would make methykVopelletierine
structurally identical with methylconhydrinone. The difficulty was
PYRIDINE
58
GROUP
solved by Meisenheimer and Mahler,5 who found that the synthetic product
of the earlier workers was a mixture and devised the following new
synthesis. 2-/3-Hydroxy-n-propylpyridine (II) as the methosulphate was
hydrogenated, with platinum-platinum oxide as catalyst, to 2V-methyl-2j3-hydroxy-n-propylpiperidine, b.p. 110-20/22 mm., which on oxidation
with chromic anhydride in acetic acid gave methylwopelletierine (I).
Catalytic hydrogenation of 2-/?-hydroxy-n-propylpyridine (II) gave
2-j8-hydroxypropylpiperidine, m.p. 69-70 (not 45-7 as stated by
Ladenburg). This, on oxidation with chromic anhydride in acetic acid,
gave isopelletierine (III) (a-piperidyl-2-propan-/J-one), which on
methylation by formaldehyde yielded methywopelletierine (I).
CH
OH
H/
\H2
H2C
<
CH.CH 2 .C0.CH 3
^NMe
(I) Mfithgllsopelletlerlne
CH
HC
C.CHg.CHOH.CHg
HgC
N
(II)
I*2
CH.CHg.CO.CHg
NH
(III)
IsoPelletlerlne
POMEGRANATE
BARK
59
ALKALOIDS
12^
N.CH,
>N.CH,
, N .CHC
CHV n 12*
C 0
c^
^s
6 10\
N-methylgranatoline
^N.CH-7
C6H 10 ;
^C0
C6H 10
Tropinone
C6H10
CC
Tropins
N-methylgranatenine
M-methylgranatyliodide
N.CH:
->
|
CH
^0H
-Pelletierine
N , C H
^>N.CH3
-^CcHSCH
5
\llCH
Tropidlne
Iodotropine
HMe:C 6 H 1 0 :(C00H) 2
(IX)
KMe:C 5 H 8 :(C00H) 2
(VII)
NHiCgHj^CHg
This has led to the adoption for i/i-pelletierine of formula; based on those
suggested at various times for tropinone 18 ; thus Piccinini found that the
alkaloid reacts with amyl nitrite to form a dmonitroso-derivative, and with
benzaldehyde to give a dibenzylidene compound (yellow prisms, m.p. 200)19
and on that ground suggested that the alkaloid must contain two reactive
methylene groups thus : CH2 . CO . CH2. The same author proposed
the formula finally adopted as the result of a study of the exhaustive
methylation > of the dimethyl ester of iV-methylgranatic acid (VIII),
(methiodide, m.p. 167) which yielded in the first stage of the degradation,
dimethyl iV-di-methylgranatenate, C 6 H 9 (NMe 2 ): (COOMe)2, an oil yielding
a crystalline, methiodide, m.p. 143-4, which on boiling with alkali,
decomposed into trimethylamine and fto/nopiperylenedicarboxylic acid (X):
the latter on reduction furnishes suberic acid (XI). Under like conditions
60
PYRIDINE
GROUP
f a }H2
/ \
fa~ f
CH
CH
CHCH2
CH,
CH2
CH
COgH
CO^
COgH
CC>2H
COgH
(x)
OH
CH
(xi)
/ \
I
CH
2
CH
I 3
COCH
C00H
CO^
tni)
(xni)
CH
CH
J.
v I
C.H2
NMs
CO
^ CH2
MJe
>
CH2
NH
CH2
CH.CH2.C00H
CH 2 CH
CHr
CE 2
CH2
(XIV) y P e l l e t i e r l n e
CH2
CH2
CH?
CH?
>CH 9
I I
CHp-
CH
(XVII)
C00H
Clk
CH.CH2.C00H
(XV) N-ffiethylgranatie a c i d
NMej.OH
V
CH 2 CH
NMep.OH
CH
CH2
CH2
CH
C00H
(XVI) G r a n a t i c
CH2
CH=CH
CH2
CH,
CH5
CHo
I
CH=CH
(XVIII)
CH
CH2
acid
I
CH===CH
(XIX)
POMEGRANATE
BABK
ALKALOIDS
61
dide, m.p. 170-1 (dec), which with silver oxide gives cj/cZooctatetraene
CH.C0.0
CH
CH
CH.G0.O
1^
NMe
CO
Ca
0H
+ NHJJe +
CO
Ga
1^
CH,.CH0
> - CH
CH.C0.0
<3
CH
CH.C0J3
CH 2
Me
CO
III
(XX)
CH CH
CH*
>-
CH.C0.0
CH.j
> CH?
CH
CH,
NMe
CO
I ! '
(XXI)
CHo.CHo.CHNHe
CO
(XXII)
62
PYRIDINE GROUP
CHCH?
NMe CO
I
I
CH=CHCCH2CH2-CHCH2
C H 2 _ C H CH 2
3
NMe
CH2CH
CO
I
CH2
(XXIII)
(XXIV)
Biol.,
(7) T A N R E T
; H E S S , Ber.,
1005.
(8) E W E R S , Arch. Pharm., 1899, 237, 4 9 ; S T 6 D E R , Pharm., Zeit., 1902, 46,
4 5 1 ; cf. VAN ITALLIE, Pharm. Weekbl., 1916, 53, 1661; TANRET, J. Pharm.
Chim.,
1928, [viii], 8, 112. (9) Ber., 1918, 51, 741 ; cf. H E S S a n d W E L T Z I E N , ibid., 1920, 53,
63
(12) (a)
Bee. Trav. Chim., 1940, 59, 653 ; 1941, 60, 905 ; B E E T S , ibid., 1943, 62, 5 5 3 ; (6) J.
Org. Chem., 1941, 6, 780 ; (c) (with KLOPPENBURG and B E E T S ) , Rec. Trav. Chim., 1944,
6 3 , 1 3 4 ; (with KLOPPENBURG), 1946, 65,100. (13) Ibid., 1919, 52,1005. (14) Compt.
rend., 1880, 90, 696 ; 1920, 170, 1118. (15) Ber., 1917, 50, 344, 1386 ; 1918, 51, 741 ;
1919, 52, 964, 1005. (16) MENZIES and ROBINSON, J. Chem. Soc., 1924, 2163. (17)
CIAMICIAN a n d SILBER, Ber., 1892, 25, 1601 ; 1893, 26, 156, 2740. (18) CIAMICIAN and
SILBER, ibid., 1894, 27, 1851, 2860 ; 1896, 29, 482. (19) Gazzetta, 1899, 29, i, 408 ; i i ,
115. (20) Ibid., 1899, 29, i i , 104. (21) Real. Accad. Lincei, 1899, [v], ii, 219. (22)
CIAMICIAN a n d SILBER, Ber., 1893, 26, 2738 ; PICCININI, Gazzetta, 1902, 32, i, 260.
ibid.,
TROPANE GROUP
DERIVATIVES OF TROPINE AND ALLIED AMINO-ALCOHOLS
THE names, formulae and structures of these alkaloids are given in the
following table. The esters of tropine or 0-tropine are known as tropeines
or 0-tropeines respectively. The first eleven items in the table are sometimes called the " solanaceous alkaloids," but they are not the only
alkaloids, or even the only type of alkaloid, found in the botanical family
Solanacese. They are also sometimes referred to as the " mydriatic
alkaloids " though other alkaloids also exert this action.
TABLE A
Structure
No.
Name of Alkaloid
Formula
Amino-alcoliol
1
2
3
4
5
6
7
8
9
10
11
12
apoAtropine
Belladonnine
Atropine
Hyoscyamine
worAtropine
norHyoscyamine
Benzoyltropine
Tropacocaine
Hyoscine
Meteloidine
Tigloidine
Valeroidine
C17H2102N
13
14
Poroidine
isoPoroidine
C12H2102N
C12H2102N
15
16
17
Convolvine
Convolamine
Convolvidine
C16H2104N
C17H2304N
18
Convolvioine
C34H4204N2
C17H2303N
C17H2303N
CuH2103N
C16H2103N
Cl5H1902N
C16H1902N
C17H2104N
C13Hal04N
C 13 H 21 0 2 N
C13H2303N
*-32-H 42 0 8 N 2
Tropine
Tropine
Tropine
Tropine
worTropine
norTropine
Tropine
tp -Tropine
Scopine
Teloidine
i/p -Tropine
Dihydroxytropane
norTropine
MorTropine
norTropine
Tropine
Alkamine,
m.p. 274-6
Eaterifying Acid
Atropic acid
(3-Isatropic acid
dZ-Tropic acid
Z-Tropic acid
cZZ-Tropic acid
Z-Tropic acid
Benzoic acid
Benzoic acid
Z-Tropic acid
Tiglic acid
Tiglic acid
isovaleric acid
isovaleric acid
d-a-Methylbutyric acid
Veratric acid
Veratric acid
Veratric acid
SOLANACEOUS
ALKALOIDS
65
sources of supply were devised, e.g., from Duboisia spp. by Ralph et al.,7
from Indian belladonna root by Srivastava and Basu 8 and from local
plants in Hungary by Zalav. 1 The extraction of hyoscyamine and its
conversion to atropine is, for some purposes, the replacement of a potent
by a less active alkaloid and also inevitably entails the loss of some valuable
alkaloid by hydrolysis. A device adopted in England to avoid these losses
was the preparation and use of the total alkaloids of Egyptian henbane
(Hyoscyamus muticus)9 in the form of the mixed sulphates containing
80 per cent, of hyoscyamine.
Atropa acuminata Royle ex Lindl. (A. lutescens Jacquemont.) " Indian
belladonna." Whole plant, grown from Indian seed in the United
States, 5 0-32 to 0-38; large stems, 0-14. According to Corfield,
Kassner and Collins,10 the leaves and roots, as imported from India,
contain on the average 0-45 and 0-47 of non-volatile alkaloid,
respectively. Much volatile alkaloid (Markwell11). Recognised in
the British Pharmacopoeia 1932, Addendum V.
Atropa Belladonna Linn. Leaves, 0-4 ; roots, 0-5; seeds, 0-8; whole
plant, 0-2 to 1-0 ; hyoscyamine with some hyoscine ; atropine has
been found but may have resulted from racemisation during
extraction ; opoatropine and possibly belladonnine (Kreitmair 1 2 ).
Atropa bwtica. Leaves, 0-82-1 -06; roots, 0-94 ; fruit, 1-09 ; hyoscyamine
and atropine. 13
Datura alba Nees. Pericarps, leaves, stems ; hyoscine. Seeds, hyoscine
with a little hyoscyamine.14
Datura arborea. Leaves, 0-44; seeds, 0-23; hyoscine; with some
hyoscyamine in young stems and roots (Kircher 1 5 ). Roots, 0-16 ;
leaves, 0-15 ; flowers or seeds, 0-12; alkaloid described as " datu-ine "
(Montesinos 15) which should be atropine.
Datura fastuosa. Variety " niger " ; fruits, 0-2; leaves and stems, 0 1 2 ;
roots, 0-1. Variety "flor ccerul. plen" ; seeds, 0-25. Variety "flor
alb. plen " ; seeds, 0-22. In all three varieties, hyoscine alone, or
with hyoscyamine.16
Datura Metel. Fruits, 0-12; leaves, 0-2 to 0-5; roots, 0-1 to 0-2; seeds,
0-2 to 0-5. Usually mainly hyoscine ; occasionally a little atropine
or hyoscyamine.18 norHyoscyamine has also been found.17 No
hyoscine (Libizov 1 6 ).
Datura meteloides. Whole plant, 0-4. Hyoscine, atropine, meteloidine 18 ;
norhyoscyamine.17
D. quercifolia.l s Leaves, 0-42 ; seeds, 0-29. Hyoscine and hyoscyamine
(Kircher ) .
O. Stramonium Linn. Leaves, 0-2 to 0-45 ; seeds, 0-2 to 0-5 (chiefly
hyoscyamine " ) ; roots, 0-21 to 0-25 (hyoscyamine and hyoscine) ;
leaves and tops, 0-6 to 0-7.s
uboisia Leichhardtii von Muell. Leaves examined by Mitchell 20 yielded
^nyoscyamine, 1-97;
Z-hyoscine, 0-06;
dZ-hyoscine, 0-05;
^wrnyoscyamine, 001 and a new alkaloid, D, 006 (C^H^O^HBr,
8
66
TROPANE
GROUP
SOLANACEOUS
67
ALKALOIDS
68
TBOPANE
GROUP
During the war years much more attention seems to have been given
to biological research on Solanaceous spp. than to chemical research on the
solanaceous alkaloids. With extension of the range of supply of these
drugs the attention of pharmacognosists has naturally been given to the
diagnostic characters of possible substitutes for the official drugs. George 36
has determined the palisade ratio values of Atropa Belladonna and its
Indian replacement product A. acuminata and Melville 37 has made a
detailed, histological study of the roots of both species. In Hungary,
Halmai 38 has dealt with the detection of Scopolia carniolica in belladonna
leaves. The allied species, S. japonica, was the subject of histological
examination by Fujita and Higashi 39 in 1937. On the cultivation side
Prasad 40 has investigated the effects of mineral deficiency on Datura alba
Nees and Hyoscyamus niger L. and other points of cultivation interest with
regard to Datura spp. are dealt with by Ramstad and Fretheim 41 and for
belladonna by Brewer and Laurie 42 and by Sievers, Lowman and Kelly. 5
Procter 43 has described a virus disease of Hyoscyamus niger in New Zealand.
REFERENCES
(1) ZALAV, J. Hung. Chem. Soc., 1941,2,13. (2) Bulletin No. 1 2 1 , " The Cultivation
of Medicinal P l a n t s . " H.M. Stationery Office ; MELVILLE, Pharm. J., 1942, 149, 202.
(3) ASHBY, J. Roy. Soc. Arts, 1942, p . 138 ; Ann. Repts. Council Sci. Ind. Res. Austr.,
1941-2, p . 11 ; 1942-3, p . 11. (4) ALLAN, J. New ZealandDept. Sci. Ind. Res., 1940-1,
15, 15. (5) SIEVERS and LOWMAN, J. Amer. Pharm. Assoc, 1944, 33, 45 ; (with
KELLY), 1945, 34, 28 ; WoLFRED,"^lmer. J. Pharm., 1943, 115, 108. (5a) Econ. Rot.,
1947, 1, 306. (6) Rept. Sci. Advis. Board Indian Res. Fund Assoc, 1943, 103. (7)
R A L P H (with L E A N a n d W I L L I S ) , J. Proc. Roy. Soc. N.S.W.,
ROSENBLUM, Aust.
J. Pharm.,
(10)
Ibid.,
1943, 16, 108. (11) Pharm. J., 1941, 146, 259. (12) For recent work on alkaloids in
belladonna, see SZENTGALI, Magyar Gyog. Tars. Ert., 1937, 13, 6 1 9 ; K U H N a n d
SCHAFER, Pharm. Zenlr., 1939, 80, 151, 163 ; Deut. Apoth. Zeit., 1938, 53, 405, 424 ;
POTLOG, Heil u. Gewilrz Pflanzen, 1940,19, 55 ; ALLAN 4 ; D E CONNO, Bull, Ort Rot. Univ.
Napoli, 1941,15,73 ; LAURIE and STILLINGS, Chemurgic Digest, 1943,2, 29 ; SIEVERS and
LOWMAN, 6 CORFIELD et al.10 The following are concerned with Bulgarian belladonna, for
which special virtues have been claimed : KREITMAIR, Merck's Jahresb., 1938, 52, 39 ;
K I N G and W A R E , J. Chem. Soc, 1941, 331 ; MARKI, Pharm. Acta Helv., 1943, 18, 229.
(13) CABALLERON and R O Y O , Farm Nueva, 1936, 4, 82 ; MUGICA, Anal. Fis. Quim., 1936,
34, 100. (14) PRADISH and SANTOS, Rev. filipina med. farm., 1939, 30, 170 ; 1940,
31, 1. (15) KIRCHER, Arch. Pharm., 1905, 243, 309 ; 1906, 244, 66 ; MONTESINOS,
Bol. Soc. Quim. Peru, 1939, 5, 99 ; VILLABA et al., Anales. Soc biol. (Bogota), 1945, 1,
189. (16) ANDREWS, J. Chem. Soc, 1911, 99, 1876; SCHMIDT, Arch. Pharm., 1906,
244, 66 ; 1910, 248, 6 4 1 ; b u t cf. LIBIZOV, Farmatsiya, 1939, No. 9, p . 17 and Sov A,ibid.,
1946, N o . 6, p . 27. (17) CARR a n d R E Y N O L D S , J. Chem. Soc, 1912, 101, 946. (18)
PYMAN a n d R E Y N O L D S , ibid., 1908, 9 3 , 2077. (19) A N D R E W S 1 6 ; C H E N a n d K A O , J .
Chin. Pharm. Assoc, 1936, 1, 38 ; SANDFORTH, Angew. Botan., 1940, 22, 1 ; ALLAN 4 ;
E B Y , SCHOLL and PHILLIPS, J. Amer. Pharm. Assoc, 1938, 27, 474 ; YOUNGKEN and
F I S C H E R , ibid., 1942, 3 1 , 257 ; JOHNSTON a n d N U N E Z - M E L E N D E Z , ibid., p . 166 ; D Y S O N
and COETZEE, S. African J. Sci., 1943, 40, 162. (20) J. Chem. Soc, 1944, p . 480.
(21) J. Council Sci. Ind. Res. (Austr.), 1945,18, 234. (22) MERCK, Arch. Pharm., 1893,
231, 117.
(24) Council Sci. Ind. Res. (Austr.) Rept., 1941-2, p . 1 1 . (25) GADAMER, Arch.
Pharm., 1898, 236, 7 0 4 ; DUNSTAN a n d BROWN, ./. Chem. Soc, 1899, 75, 7 2 ;
1901, 79, 71 ; see also AMOR et al.* (26) Bull. Imp. Inst., 1911, 9, 115 ; KONOVALOVA
SOLANACEOUS
69
ALKALOIDS
and MAGIDSON, Arch. Pharm., 1928, 266, 449. (27) AHRENS, Annalen,
CHASTON, Pharm. J., 1889, pii], 20, 461 ; RANSOM, ibid., p . 462 ; JERMSTAD, Medd.
Norsk Farm. Selsk., 1942, 4, 93 (Chem. Abstr., 1944, 38, 1075). (29) SCHMIDT and
HENSCHKE, Arch. Pharm., 1888, pii], 26, 185 ; WATANABE, Chem. Soc. Abstr., 1911
pi], 427 ; CARR and R E Y N O L D S . 1 7 (30) Farmatsiya, 1939, No. 10, 21 (Chem. Abstr.,
1942,36, 3910), cf. SIEBEKT, Arch. Pharm., 1890,228,145. (30a) J. Gen. Chem. U.S.S.R.,
1946, 16, 2121. (31) P E T R I E , Proc. Linn. So:., N.S.W., 1907, 32, 789; 1917, 4 1 ,
118, 137. (32) Trudy Uzbekskogo Gosudarst Univ. Sbornik Rabot Khim., 1939, 15,
43 (Chem. Abstr., 1941, 35, 4029). (33) OREKHOV and KONOVALOVA, Arch.
Pharm.,
1933, 271, 145 ; Ber., 1934, 67, 1153 ; 1935, 68, 814 ; J. Gen. Cliem. Russ., 1937, 7,
646, 673.
(35)
Bull. Sci. Pharmacol., 1921, 28, 499. (36) Quart. J. Pharm., 1946,19,144. (37) Ibid.,
1944, 17, 201, 2 1 3 ; 1945, 18, 331. (38) Ber. Ungar. pharm. Ges., 1943, 19, 132, cf.
MARKOVIC, Deut. Heilpflanze, 1944, 10, 9. (39) J. Pharm. Soc. Jap., 1937, 57, 158.
(40) Ind. J. Pharm., 1944, 6, 13 ; J. Amer. Pharm. Assoc, 1946, 35, 121 ; 1947, 36,
180 ; JAMES, Econ. Bot., 1947, 1, 230. (41) Medd. Norsk. Farm. Selsk., 1942, 4, 177
(Chem. Abstr., 1944, 38, 3780). (42) Chemurg. Digest, 1944, 3, 65. (43) N. Z. Journ.
Sci. Tech., 1944, 26A, 83.
ANALYTICAL METHODS.
Methods for the isolation of individual
solanaceous alkaloids from plants have been greatly improved and typical
examples will be found in the references given under the various plants
listed above. For quantitative analysis for commercial purposes, it is
usually sufficient to determine the total, non-volatile alkaloids, the results
being expressed as hyoscyamine. Methods of assay are provided in the
British Pharmacopoeia 1932, Addendum VII, and the United States
Pharmacopoeia, XIII. Useful critical reviews of processes both for the
crude drugs and galenical preparations have been published by various
authors. 1 A colorimetric method has been described by Allport and
Wilson 3 depending on the Vitali-Morin reaction of which a study of the
nature and limits of applicability has been made by James and Roberts. 8
Precipitation as silicotungstate has been proposed by Vallery,4 while for
quaternary atropine compounds Reimers 5 has suggested estimation of
the tropic acid produced on hydrolysis, a method extended later to tropic
acid esters of the atropine series in general. Kirkpatrick 6 has investigated
the suitability of polarographic methods for the estimation of individual
alkaloids, and Rrownlee 7 has found the chromatographic process
satisfactory with preparations of solanaceous drugs. In connection with
work on the biogenesis of these alkaloids it has become necessary to
estimate quantitatively at least the three chief solanaceous alkaloids,
hyoscine, hyoscyamine and atropine, and Rowson 8 has made a critical
survey of methods available for this purpose. All these processes are
chemical and some attention has been given to biological methods since
so far as total, non-volatile alkaloids are concerned, the results may
include atropine, hyoscyamine and hyoscine of which atropine is in some
pharmacological activities less potent than either of the other two. Gunn,
who uses as a biological test the antagonistic action of belladonna alkaloids
agamst the effect of carbamylcholine on isolated mammalian intestine,
has found that the alkaloids from Atropa Belladonna and from A. acuminata
70
TROPANE
GROUP
are identical in their biological action and twice as active in the biological
test as atropine sulphate, but that is only true when the chemical process
of estimation used, eliminates the volatile alkaloids, which have no
atropine-like action. A similar biological method has been used by Levy 10
for the assay of galenical preparations of belladonna and various kinds of
pharmacological tests have been used by other authors. 10
For the detection and microchemical estimation of these alkaloids, the
precipitation, crystalline form and melting-points of the perbromides,
periodides, aurichlorides or picrates and the mydriatic test have been
used. 11
Atropine, C 17 H 23 0 3 N. This alkaloid does not normally occur in more
than traces in solanaceous plants and in its preparation by Mein 12 and by
Geiger and Hesse, 13 the hyoscyamine originally present in the plant was
probably converted into atropine in the process of extraction. The present
formula is due to Liebig, and von Planta 14 showed that atropine was
identical with " daturine " obtained from stramonium. Commercially the
alkaloid is prepared by racemisation of Z-hyoscyamine with dilute alkali or
by heating in chloroform solution. Methods for the preparation of
atropine and its salts have been described by Chemnitius 15 and by Duilius. 15
The alkaloid crystallises from alcohol on addition of water, or from
chloroform on addition of light petroleum, or from acetone, in long prisms,
m.p. 118, sublimes unchanged when heated rapidly, is readily soluble in
alcohol or chloroform, less soluble in ether or hot water, sparingly so in
cold water (1 in 450 at 25), and almost insoluble in light petroleum.
The aqueous solution is bitter to the taste and alkaline to litmus. Atropine
is optically inactive, but the commercial alkaloid may contain hyoscyamine
and be slightly la^vorotatory.
Atropine causes dilation of the pupil of the eye. A drop or two of an
aqueous solution, containing 1 part in 130,000 parts of water, introduced
into the eye of a cat is sufficient to produce this effect. When warmed with
sulphuric acid and a small crystal of potassium dichromate, atropine
develops a bitter almond odour. Evaporated to dryness on a water-bath
with concentrated nitric acid, it gives a residue which becomes violet on
adding a drop of sodium hydroxide solution in alcohol (Vitali's test).
With a solution of mercuric chloride atropine gives a yellow to red
precipitate of mercuric oxide.
Of the salts of atropine the sulphate, B 2 . H 2 S0 4 . H 2 0, is that usually
employed in medicine. It occurs as a colourless, crystalline powder,
m.p. 195-6, when dried at 130, soluble in water (1 in 0-38) or alcohol
(1 in 3-7), and sparingly so in chloroform (1 in 620) or ether (1 in 2,140).
It can be reerystallised by adding acetone to its solution in alcohol. The
hydrobromide, B . HBr, m.p. 163-4, forms slender needles, and the
oxalate, B 2 . H 2 C 2 0 4 , opaque warty masses of minute prisms, m.p. 198.
The platinichloride, B 2 . H 2 PtCl 6 , being soluble in dilute hydrochloric acid,
is not precipitated when atropine hydrochloride is added to platinic
chloride solution containing free hydrochloric acid. On evaporation it is
obtained in monoclinic crystals, m.p. 207-8.
The aurichloride;
ATROPINE
71
72
TROPANE
GROUP
ATROPINE
73
hydrochloric acid into atropic acid (V), and this in turn on addition of
hypochlorous acid gave chlorotropic acid (VI), which on reduction
with zinc dust and iron filings in alkaline solution passed into tropic
acid (VII).
(I)
Ph.CO.Me> (II)
(IV)
Ph.(C0OH)C(0Et).Me
Ph.OCl2.Me
>
>(III)
(VI)
Ph.tCOOlOCCl.CHgOH
> (VII)
(V)
Ph.(CN)C(OEt).He
Ph.fCOOHjCtC^
Ph.(COOH)CH.Ci^OH
Ph.(OH)C(CN) Me
(XII) Ph.C(C00H):CHg
>>
(XI)
(XIII)
Ph.(OH)C(COOH).Me
>
Ph.CH(C00H).CH20H.
74
TROPANE
GROUP
16
ATBOPINE
Tropica, CgE-jOH
by action of HgSO^-
Tropinone. CgE^^CH
dl-Troplnlc a d d , OgHj^jQ^
Tropleenlne. (^E^^ON
Oxidation by chromic aeld
nortroplnone, CfHjjCH
Tropidlne. CgH, Jl
_l
\
Eihydrozytropl dine, CgB^jOg"
Tropidlne methlodlde
Tropilene. 0 ? H, 0 0
By "exhaustive methylation"
amalgam, tropinone forms, not tropine, but ^r-tropine (p. 100), identical
with that obtained by the hydrolysis of benzoyl-^r-tropine (tropacocaine),
found in coca leaves. When reduced electrolytically or by zinc dust
in hydriodic acid, a mixture of tropine and ^-tropine is produced,
which can be separated by fractional precipitation of the picrates, tropine
picrate being the less soluble (0-46 per cent, in water at 16). It is possible
in this way to convert i/r-tropine into tropine by oxidising the former to
tropinone and reducing the latter electrolytically. 45 Some tropane (p. 87)
is also formed in this reduction.
dl-Tropinic acid, C 8 H 13 0 4 N. This oxidation product of tropine and
0-tropine, is a substance of great importance in this group, and its constitution and relation to tropine gave rise to much discussion.46 It
crystallises in small needles, m.p. 248 (dec), is soluble in water and almost
insoluble in other media. It is a dibasic acid and yields salts, both with
bases and acids. Its formation by the oxidation of tropine is not explicable
in any simple manner by Ladenburg's tropine formula, and it was this
difficulty which led Merling to propose his formula for this base. By
crystallisation of the cinchonine salt, ^-tropinic acid can be resolved into
d- and Z-forms.
Tropigenine (nortropine), C7H13ON. This product of the action of
potassium permanganate on tropine is a strong base, which crystallises
worn ether in colourless needles, m.p. 161; b.p. 233 (picrate, m.p. 170-1' :
TkOPANE GROUP
76
CH
CHg
IH
-CH
2-
CH,
CMe
-CH,
2
CHOH
CH,
CEOH
CHOH
CH,
2
I
I
(XVIa) HMe C H
CH
(XVIb) M t e CH
CH
(XVII) NH
-CMe,
CHCH2
CH,
CHOH
(XVIlDMIto C H C H g
.CH CH
CHJJ- - C H -
We
(HXJCiigv.n
CHOH
CH,
v-ng
/ \
Nils
(XX)
IU,
I
CH,
CHOH
Ov~
to-CH
g.
11
ATROPINE
51
CHg.CHg.GOOH
(XH)
CHj.CH.COOB
(mi) cHg.ci^.cBj.cooH
CH:CH.CHg.000H
(mil)
CH.OH.OI^.OOOH
I
(XXIV)
CSg-CH
CH.-CK-
-CH
CO
I
CHg
CH-CHgCH 2
CH
HMa
CH
(XXV) CH 2 -CH
CO
(XXVI)
CHg
CT^-CHCH
CHg
-CO-
CH = -CH
CH,
-CHBrCH3r
CHg-CHg-
CH
CH,
CH
CHg CHg
CHg-CH.,-CHg
eyaloHeptone
Suberone
cycloHepteoe dlbromlde
N(CH,
3'8
C H . CH
2
CHg CHg
CH
CH
CHg
Plane thylagdnog
&-cyclohaptena
CH =
-CH-
CHErCH '
-CH
= CH
CHBr
CH
C H
2-0H2
2 cycloHeptsdlem
(Dlhydrotropl 11 dace)
-CHg-CHg
C H
cycloHeptadiene dlbromlde
(DUrydrotropllldene d l b r o a l d e ]
H(CH3)2
CH-
CH'
-CH
i
OH
C H , CHBr C H .
2
T 2
CH
CHgCH
cycloHepjtatrleno
ttropllldtne)
CHCH- -CH
2
i
3CH
CH
CH" C H -
I
-CH
Bromocycloheptadlene
(Tro-pllldene hydrobromlda)
CHg
CH-
--L
g-Methyltropldlna
TROPANE GROUP
78
CH
CH,
BrJJ^
CH.,
CH=
fc
CH
oi-Methyldlhydrotropldlne
CH
CHj,
CH_
I^CHg
CH-
CH
CHBr
Bromodlhydrotropidine
methobromide.
CHj>CH
CHp
N.CH CH
CHgCH
S
CH
Tropidine
ATROPINE
TO
undergoes spontaneous isomerisation into, bromo-^-tropine-methylammonium bromide, and this on reduction with zinc dust and hydriodic
acid yielded, not, as was expected, tropine (or ^-tropine), but, by elimination of water and bromine, tropidine methiodide, from which tropidine
can be obtained as already stated.
CH -CH " C H 2
CH-- CH(HMe2) CH 2
72
jCHOH
N JJe I
NMeBr
CHDH
2
J-CSBr
CH -CH-
CH,-OHCH
-CHBr
0HMethyl-ty-tropine
dlbromlde
I
CHBr
CH
-CH-
CH
3Hg
Tropidine methiodide
CHzCHN.CH *
CH.0.C0
^CHgOH
-CHc
-CH
iH
28
Atropine (dl-tropyltropeine) and Hyoscyamine (1-tropyltropeine).
3H
* In norhyoscyamine and moratropine (p. 83) this -CH, group is replaced by -H.
TBOPANE
80
CH 3
2
Vn2
CHO
_|-
(XXVTI)
NMe
(XXVTII)
GROUP
CHgCHfjCH 2
We
CO .
Ti i I
CH,
CHgCHfr-CHg
(XXIX)
(XXX)
CHgCH- -CH-COgEt
NMe
CHCH
CO
CH2
(XXXIV)
t
CIfeC.CH 2 .C0 2 Et
CH 2 .C0.CH 2 .C0 2 Et
+ NHgMe
CHg.CO.CHg.COgEt
(XXXI)
HMe
I
CH^C.CEg.COgEt
(XXXII)
CHgCH.CH2.C02Et
HMe
CHg-CH.CHg.COgEt
(XXXIII)
81
ATROPINE
C H u ON, m.p. 40-40-5, giving a picrate, m.p. 191-191-5 and a dipiperonylidene derivative, m.p. 206-206-5.
Though the dialdehyde-tropinone synthesis does not succeed when the
dialdehyde is replaced by a diketone, Blount and Robinson 59 have shown
that 1-methyltropinone (XXXV) can be obtained by the interaction of the
keto-aldehyde,
Isevulinaldehyde,
Me . CO . CH 2 . CH2 . CHO,
with
methylamine and calcium acetonedicarboxylate, and from this by reduction
to 1 -methyl- ^-tropine and benzoylation, 1-methyltropacocaine (b.p.
210/15 mm. ; picrate, m.p. 163-4) has been prepared.
W*--CMe
CHo
* *\ '\
(XXXV)
S'.CH
CH.C02R
Ul
NMe ,C0
l l
CHg!CH
"CH 2 (XXXVI)
Me.CH-C(C0 JJe)-CH 2
I 8 I'
NR CO
Me.N, CO
3JJMe
l l
I
I
R' .CH
CH.C02R ( X X m i j M e . C H - C C C O j H e ) ^
J.,
1926, 117, 1 7 9 ;
1930, 3, 3 4 2 ;
E X L E B , Pharm. Wcekbl., 1928, 65, 1152 ; EVANS and GOODRICH, J. Amer. Pharm.
Assoc,
1933, 22, 824 ; FRICKE and KAUFMAN, ibid., 1939, .""8, 215 ; MARKWELL, Pharm.
J.,
1941, 166, 2 5 9 ; CORFIELD, et al., Quart. J. Pharm., 1943, 16, 1 0 8 ; OHBLOM, Farm.
Notesbl., 1940, 42, 191 (Quart. J. Pharm. Abf.tr., 1941, 14, 188); GILLILAND, KAUFMAN
and BANG, J. Amer. Pharm. Assoc, 1943, 32, 326 ; E D E R and RUCKSTUHL, Pharm. Acta
Helv., 1943, 18, 605. (2) Quart. J. Pharm , 1C39, 1? L99. (3) Ibid., 1945, 18, 29 ;
1947, 20, 1. (4) Compt. rend., 1942, 214, 171, cj H A ; ARD, Bull. Soc Chim., 1939, [v],
6, 1077. (5) Arch. Pharm., 1940, 278, 1 3 0 ; D:insk. Tids. Farm., 1944, 18, 217.
(6) Quart. J. Pharm., 1945,18, 245 ; 1946,19, 526. (7) Ibid., 1945,18,163 ; cf. REIMEHS
and GOTTLIEB, Dansk.
Tids. Farm.,
. Amer. Pharm. Assoc, 1948, 37, 24. (8) Quart. J. Pharm., 1944,17, 226, 224. (9) Ibid.,
1944,18, 7. (10) Bull. Soc. chim. Biol, 1945,27,431. For other biological methods see,
* e x a m p l e , NOLLE, Arch. exp. Path. Pharm., 1929,143, 184 ; JENDRASSIK and W I L L ,
16S a n ^ 3 0 ' 1 5 3 , 4 ' F E R N A N D E Z > Md: 1928,127, 197, 204, and P U L E W K A , ibid., 1932,
w,307; K E I L and KLUGE.iWd., 1934,174,493; W A T S O N , H E A R D and J A M E S , Quart. J.
i > * ^ m " , 9 4 1 ' 1 4 , 2 5 3 : G u N N > Md-' 1 9 4 4 > 1 7 ' 7 - ( " ) Se*' f o r example, WAGENAAK,
812r eem-' 1 9 2 8 > 65 > 1 9 7 > 54> 1 2 2 6 ; FULTON, J. Assoc. Off. Agric. Chem., 1929,12,
. I - A M , Allen's " Organic Analysis," 5th edition, 7,819. (12) Annalen, 1888,6,67.
82
TROPANE
OBOVP
ibid., 1829 ; cf. GADAMER, Arch. Pharm., 1901, 239, 294 ; CHEMNITIUS, J. pr. chem.,
1927, [ii], 116, 276 ; DUILIUS, Chem. Zeit., 1930, 54, 182. (16) Gazzetta, 1881,11, 538 ;
1882, 12, 60. (17) Arch. Pharm., 1891, 229, 1 3 4 ; 1893, 231, 110. (18) Annalen,
1891, 261, 8 7 ; 1892, 271, 1 2 4 ; 1893, 277, 290. (19) Ibid., 1883, 217, 102. (20)
Jahresb, 1858, 376. (21) Ber., 1880,13,165. (22) Ber., 1884,17, 381. (23) KUSSNER,
Arch. Pharm., 1938, 276, 617. (24) Bull. Soc. chim., 1929, [iv], 45, 304. (25) Annalen,
1833, 7, 270. (26) Ibid., 1871, 157, 98. (27) Ibid., 1880, 206, 282. (28) CAKR a n d
REYNOLDS, J. Chem. Soc, 1910, 97, 1329 ; cf. GORIS and COSTY, Bull. Sci. Pharmacol.,
1922, 29, 113 ; K I N G and W A R E , J. Chem. Soc, 1941, 331.
(29) F o r suggestions as t o
mechanism of racemisation, see GADAMER, J. pr. Chem., 1913, [ii], 87, 312, and FRANKLAND, J. Chem. Soc, 1913, 103, 722. (30) Arch. Pharm., 1902, 240, 498. (31) Ber.,
1889, 22, 2590. (32) J. Chem. Soc, 1909, 95, 1969. (33) GADAMER, Arch. Pharm.,
1901, 239, 294. (34) KRAUT, Annalen, 1863, 128, 280 ; 1865, 133, 87 ; 1868, 148, 236 ;
LOSSEN, ibid., 1864,131, 43 ; 1866,138, 230. (35) Ber., 1880, 13, 376, 2041 ; 1889, 22,
2590 ; cf. MACKENZIE and STRATHERN, J. Chem. Soc, 1925,127, 82 ; K E R B , ibid., 1927
1943.
ibid., 1237 ; cf. VON BRAUN, ibid., 1920, 53, 1409. (38) Compt. rend., 1928, 186, 1630.
(39) J. Chem. Soc, 1919, 115, 828. (40) Ibid., 1919, 115, 490 ; cf. LADENBURG and
H U N D T , Ber., 1889, 22, 2591 ; GADAMER, Arch. Pharm., 1892, 230, 207 ; AMENOMIYA,
ibid., 1902, 240, 501. (41) -See especially, JOWETT and PYMAN, J. Chem. Soc, 1909, 95,
1020 ; JOWETT, PYMAN and D A L E , Seventh Internal. Cong. Applied Chem., 1909, IV, A,
1335 ; and PYMAN, J. Chem. Soc, 1917, 111, 1104. (42) LADENBURG, Annalen, 1883,
217, 117 ; Ber., 1887, 20, 1647.
ibid., 490.
(44) Cf. WILLSTATTER, Ber., 1896, 29, 393 ; MERLING, ibid., 1891, 24, 3108 ;
29, 1581, 1638 ; M. and M. POLONOVSKI, Bull. Soc chim., 1927, [iv], 41, 1190 ; 1928,
[iv], 43, 364. (49) Ber., 1883, 16, 1604. (50) Ibid., 1897, 30, 731, 2679. (51)
CIAMICIAN and SILBER, ibid., 1896, 29, 481.
1898, 31, 1535, 2498. For tropilene, cf. KOTZ and ROSENBUSCH, ibid., 1911, 44, 464.
(53) Ibid., 1901, 34, 129, 3163 ; Annalen, 1901, 317, 204, 267, 307 ; 1903, 326, 1, 23 ;
cf. LADENBURG, Ber., 1902, 35, 1159. (54) Annalen, 1891, 264, 310. (55) J. Chem.
Soc,
(56) Annalen,
1921, 422, 1.
ibid., 1921, 422, 15 ; KARRER et ah, Helv. Chim. Acta, 1947, 30, 1776.
Pat.
2,366,760.
(57a) U.S.
Russ.
Phys. Chem. Ges., 1915, 47, 1126. (61) MANNICH a n d MOHS, Ber., 1930, 63, 608 ;
MANNICH a n d V E I T , ibid., 1935, 68, 506.
MINOR
TBOPANE
83
ALKALOIDS
C6H5
NH CH-0-C0-CH
OHg-CH CH
CH2-0H
CHg-CHCH2
CgHg
HMo CH-0-C0-CH
CHg-CH -1B
CHg
GHg.OH
84
TSOPANE
GROUP
forms short yellow needles, m.p. 149-50; the picrate has m.p. 177-80.
Meteloidine is physiologically inactive.
On hydrolysis by baryta the alkaloid is resolved into tiglic acid,
CH3CH : C(CH 3 ). COOH, and a base, TELOIDINE, C 8 H 15 0 3 N, H 2 0, which
crystallises from boiling acetone diluted with a little water in chisel-shaped
needles, m.p. 168-9 (dry). It is not volatile ; the hydrochloride, m.p.
above 300, hydrobromide, m.p. 295, and aurichloride, B . HAuCl 4 . H 2 0,
m.p. 225, are all crystalline.
King 1 0 has suggested that tropine,
C8H15ON, oscine, C 8 H 13 0 2 N, and teloidine, C 8 H 15 0 3 N, are related to each
other in the following way :
|
CHCH
CHj,
H.CH CHOH
I
CH CH
3
I-
CH-
(4)
CH-CH.-CH
NMe
CHOHCH
CHCH.OHfc)
WCH.OH NMe
OH-
(i)
CH.
I I
CH
2
fe>
CH_
<>
CH
CH.0H W
(7)
Tropins
Osaiae
Teloidine (King)
Hyoscine (Scopolamine, Atroscine), C 17 H 21 0 4 N. The name hyoscine
was first used by Hohn and Reichardt 1 J for the basic hydrolytic product
of hyoscyamine, now known as tropine. It was subsequently used by
Ladenburg 12 for a supposed isomeride of atropine, C 17 H 23 0 3 N, isolated
from the mother liquors of hyoscyamine. This was found by Schmidt,
Hesse and others 13 to be identical with scopolamine, C 17 H 21 0 4 N, obtained
by Schmidt from Scopolia japonica.u
The name hyoscine has priority
and is in use, but scopolamine is also employed, especially in Germany.
The alkaloid can usually be obtained from the mother liquors of
hyoscyamine, but Datura Metel, in which hyoscine is the chief constituent,
was the better primary source but may now prove less valuable than
selected Duboisia spp. (p. 66). A process of manufacture has been
described by Chemnitius, 15 and a method for the recovery of Mvyoscine
from racemised base by Schukina et al.15 A method for its estimation in
presence of opium alkaloids has been devised by Wallen and Callback.15(a'
The free base is a syrup, soluble in ordinary solvents, least readily in
light petroleum or benzene. It is laevorotatory [a]| 18 (EtOH),
28 (H 2 0). The hydrobromide, B . HBr . 3H 2 0, m.p. 193-4 (dry),
[a] 15-72 (EtOH), 25-93 (anhydrous salt: H 2 0), 1 6 forms rhombic
tablets, is readily soluble in water or alcohol, sparingly in chloroform,
insoluble in ether. It is bitter and acrid to the taste, and is slightly acid
to litmus. This salt is that mostly used in medicine. The aurichloride,
B . HAuCl4, m.p. 208-9 (dec.) crystallises in needle-shaped growths
serrated on both edges. The auribromide, B . HAuBr 4 , m.p. 191-2,
forms long, rectangular, chocolate-red leaflets from boiling 2-5 per cent,
hydrochloric acid. The picrate crystallises in slender, primrose-yellow
needles, m.p. 187-8 ; but on recrystallisation from boiling water, forms
flat irregular six-sided scales, m.p. 187-5-188-5 (191-2 corr.).
Hyoscine, like hyoscyamine, is readily racemised by dilute alkalis, and
HYOSCINE
85
l^Hyo s e i n e
Base
Character
Hydrobromide
Character
M.p. {dry
salt)
Piorate
Character
M.p.
Aarlchloride
Charaetar
M.p.
Auribromide
Character
M.p.
Rhombie
t a b l e t s with
3^0
183-194
197-198
{corr.)
-25.9
Slender
netted
needle s .
187-188
191-192
(oorr.}23
Syrup
Rhomb i o
t a b l e t s with
3H0
2
193-194
197-198
dl-Hyosclne
Prisma c o n t a i n i n g
2H 0 , m.p. 36-40
( c o r r . ) . Anhydrous
substance, s y r u p 2 2 .
Rhombic t a b l e t s with
3H 0 , e f f l o r e s c e n t .
181-182
185-186
(corr.)
(OCBT.)
+26.3
III
M B (dry
s a l t In
water).
Syrup
d-Hyosclne
Readies.
187-188
173.5-174.8
177.5-178.5
Heedles,
both edges
serrated
204-305
208-209
(corr.)8*
Heedles,
both edges
serrated
204-205
208-209
(corr.)84
Chocolatered l e a f l e t s
187-188
191-192
(corr.)88
Chocolate-red
213-214
(corr.)
N e e d l e s , one edge
serrated.
214-S15"
,,
218-219 ( o o r r . )
leaflets
(corr.)83
86
TROPANE
GROUP
alkaloid and some of their chief derivatives (see table on p. 85). The
reactions of hyoscine are for the most part similar to those of atropine and
hyoscyamine, but it gives a white precipitate with mercuric chloride. I t
may best be distinguished from these alkaloids by means of its aurichloride
or picrate.
When warmed with barium hydroxide, dilute alkalis or acids, hyoscine
is hydrolysed, yielding tropic acid and a new base, CgH^OgN, oscine or
scopoline. Depending on the conditions of experiment, the tropic acid
obtained may be either the pure Z-form or the partially racemised acid ;
but the oscine obtained is invariably inactive.
It appeared to follow from this that the three known forms of hyoscine
are respectively Z-tropyl-cZZ-oscine, <Z-tropyl-<2Z-oscine and <ZZ-tropyl-dZ-oscine,
the optical activity of the first two being conditioned solely by the activity
of the tropyl radicle. This subject was discussed by King, 21 who confirmed
(I) Ph-CH-OOg-C^gON
( I I ) Ph,CH-C02-CQH120N
( I I I ) Pb-C-COg-CgH^ON
87
HTOSCINE
Derivative
Base
Plorate
Characteristics
L-0 seine
-0seine
Crystalline
form.
M.p.
WJJ In water
Needles
Needles
Needles or t a b l e t s .
109.5
-52.4
109.5
+54.8
109-110
Crystalline
form.
Dimorphous:
rhombs and
needles
237-238
Dimorphous:
rhombs and
needles
237-238
Prisms i n
warty masses
Deliquescent
273-274
281-282
(corr.)
Prisms i n warty
Prisms in
warty masses
masses (anhydrous)
Deliquescent
Tablets (hydrated)
273-274
273-274
U.p.
Hydrochloride
Crystalline
form.
M.p.
Mj, (basie ion)
i n water
-2471
dl>-0 s e i n e
Flattened rhombs
237-238
+24.0
?=2
mil)
Nile
CH
,8
CH, NMe
CH
r i
-CH
CH
,/
CHg NMe
(IX) CHgCHCH.0H
' 1 /
CH MeN 0
(XI) CH,[ 8
CH,CH 'CH-
CHgCH.C00H
CH,
CH_ CHCH.OH
CH.0H
<r
Hlte
(X) CHg-^H - C H 2
CH,CH
CH
*2
HO.CH
NMe
(XIII) CHg-CHCH g
88
TROPANE
GROUP
between positions 5 and 7 (XI), to account for its rupture in the first stage
of the operations. Gadamer and Hammer, 37 repeating this work with the
optically active forms of oscine, found that their results could be better
explained by an oxygen bridge between positions 3 and 7 (XII), a suggestion
first made by King 21 and subsequently accepted by Hess and Wahl, 37 who
provided an explanation of the course of the Hofmann degradation on this
basis. This formula makes one attachment of the second oxygen atom in
scopoline similar to that of tropine (XIII).
These results left unexplained the observation that while oscine and
benzoyloscine can each be resolved into two optically active forms,
cZZ-hyoscine can only be resolved into two forms, the optical activities of
which are conditioned by the tropyl radicle. King suggested 21 that this
might be due to the basic residue in hyoscine having a symmetrical and,
therefore, different configuration from that of oscine and capable of
yielding the latter on hydrolysis, but preferred to regard the d- and
Z-hyoscines as partial racemates. Hess and Wahl 3 7 were unable to
synthesise either Z-hyoscine (from Z-tropic acid and dZ-oscine) or apohyoscine
(from atropic acid and oscine), but did prepare by reduction of a^ohyoscine,
a deoxyhyoscine, which occurred in only one racemic form, although on
hydrolysis it furnished dZ-oscine and deoxytropic acid (phenylpropionic
acid). On the other hand, they found that esterification of dZ-oscine with
dZ-deoxytropic acid produced two racemic alkaloids (deoxytropylscopoleines) neither of which was identical with deoxyscopolamine. To
explain these facts, they adopted King's first view that in hyoscine the
amino-alcohol is symmetrical and is converted into oscine during hydrolysis.
This idea was shown to be correct by Willstatter and Berner, 38 who found
that hyoscine is slowly hydrolysed by pancreatic lipase, in presence of
ammonia-ammonium chloride as a buffer, to SCOPINE, C 8 H 13 0 2 N (with
partial conversion of the latter into oscine), which is the real basic component of hyoscine. Scopine crystallises in long needles, m.p. 76, is
optically inactive and is readily converted, by heat or by the action of
acids or especially of alkalis, into oscine. The hydrochloride crystallises
in leaflets, and the picrate in thin leaflets, m.p. 231. Scopine is clearly
distinguished from oscine by the characters of its platinichloride and
aurichloride.
Platinichloride
Scopine B 2 . H 2 P t C l 6 . 2 H ? 0
Long, domatic prisms, m.p. 219.
Oscine B 2 . H 2 PtCl 6 . H a O
Plates, m.p. 203.
Aurichloride
B . HAuCl 4 . i H 2 0
Small prisms, m.p. 216 (dec).
B . HAuCl 4 . H 2 0
Prismatic plates, m . p . 220 (dec).
89
HYOSCINE
m.p.
,CH CHCH
CH-
/
o
\
NMe
CHC3
CHCHCHp
CHO.Tr
CH-
NMe
CHOH
Hyoscine
I I
CHCH
CHCHCH
CH 2
MeN(Br)O.CH
'CHCH-
CH,
CH,
Scopine and
y"-3Coplne
Scopinium Bromide
CH.OHCHCH9
7
I'
NMe CH.OH
is a
CH.OHCHCH 2
NMe
CH;,CH
CH.OH
CH 2
Teloidine
(<W-worScopolamine),
dl-norHyoscine
C 16 H 19 0 4 N. This alkaloid was
found in the residual liquors from the manufacture of hyoscine.40 It
forms silvery filaments, m.p. 101-3, [a]D J: 0, is converted by methyl
bromide to hyoscine methobromide, m.p. 216-7 and hydrolyses to
dZ-tropic acid and noroscine (reorscopoline), the latter characterised as the
aurichloride, m.p. 242.
ALKALOIDS OF DUBOISIA
MYOPOROIDES
The variations in alkaloids recorded for this species have been stated
already (p. 66). The following account refers to four alkaloids (Barger
et al., ref. 23, p. 68) which have so far been observed only in this species
Tigloidine, C13H2102N. The hydrobromide of this syrupy base forms
tabular crystals, m.p. 234-5, [<x]D 0 ; picrate rectangular plates,
m.p. 239 from dilute alcohol; the aurichloride, golden-yellow plates,
m.p. 213-5-214 and the methiodide, square plates, m.p. 244-5. The
base is unsaturated;
the hydrobromide on hydrogenation yields
dihydrotigloidine (picrate, m.p. 134-5), and on treatment with bromine in
chloroform produces dibromodihydrotigloidine, m.p. 187 (dec). On
hydrolysis by boiling with barium hydroxide in water, tigloidine furnishes
tighc acid and 0-tropine (p. 100), and this evidence that it is tiglyl-^tropeine, was confirmed by synthesis of the latter. Tiglyltropeine
hydrobromide, prepared for comparison, had m.p. 207; the picrate
melted at 200.
TROPANE
90
GROUP
MINOR
TROPANE
ALKALOIDS
91
II
(XIV) C H _ CH=C-CH=CMe2
CH CH CH,
|
| 2
NMe CE-0-C0
(XV) CHgCH
CH C-Oteg
92
TROPANE
GROUP
1776. (19) Arch. Pharm., 1898,236, 9,47. (20) Ibid., 1898,236, 382; cf. H E S S E , Annalen,
1899,309,75; J.pr. Chem., 1901, [ii], 64, 353 ; 1902, [ii], 66, 194; and KUNZ-KRAUSE,
i6id.,1901,[ii],64,569. (21) J. Chem. Soc, 1919,115,476. (22) Cf. H E S S E , Ber., 1896,
29, 1776 ; GADAMER, Arch. Pharm.,
Chem. Soc, 1912, 101, 949 ; SCHMIDT, Arch. Pharm., 1894, 232, 409 ; FINNEMORE and
BRAITHWAITE, Pharm. J., 1912, 89, 136. (24) Cf. SCHMIDT, Arch Pharm., 1910, 248,
641 ; H E S S E , J. pr. Chem., 1901, [ii], 64, 274 ; THOMS and W E N T Z E L , ' ;
FINNEMORE
and BRAITHWAITE. 2 3 (25) Cf. JOWETT, J. Chem. Soc, 1897, 71, 680. (26) Ibid., 1919,
115, 974 ; cf. WILLSTATTER and H U G , Zeit. physiol. Chem., 1912, 79,146. (27) J. Chem.
Soc, 1910, 97, 1793. (28) Annalen, 1892, 271, 1 1 4 ; 1893, 276, 84. (29) Arch.
Pharm., 1898, 236, 11. (30) Apolh. Zeit., 1902, 17, 592 (Chem. Soc. Abstr., 1903, [i],
51); Arch. Pharm., 1905, 243, 559. (31) Arch. Pharm., 1909, 247, 79. (32) Ibid.,
1916, 253, 497 ; cf. H E S S and WISSING, Ber., 1915, 48, 1907.
(34) Ibid., 1915, 48, 1907, 2057. (35) Ibid., 1918, 51, 1013; cf. WILLSTATTER and
IGLAUER, ibid., 1900, 33,1175. (35a) Proc. Iowa. Acad. Sci., 1942, 49, 288. (36) Ber.,
1919, 52, 1947 ; cf. GADAMER and HAMMER, Arch. Pharm., 1921, 259, 110. (37) Ber.,
1922, 55, 1972; cf. GADAMER, ibid., 1923, 56, 130. (38) Ibid., 1923, 56, 1079. (39)
Compt. rend., 1925,180, 1755 ; 1928, 186, 147 ; Bull. Soc. Chim., 1928, [iv], 43, 79, 590.
(40) GMELIN, Arch. Pharm., 1941, 279, 112. (41) NOLLE, Khim. Farm Prom., 1934,
No. 5, 39 ; AWRUTOWA, Chem. Zentr., 1938, [i], 496. (42) Meded. uit's Lands Plant,
1894, 13. (43) Chem. Zentr., 1897, [ii], 130. (44) Ann. Jard. Bot. Buit., 1909, [ii],
Suppl., 3, 385. (45) Bee. trav. Chim., 1911, 30, 161. (46) J. Phil. Isl. Med. Assoc,
1937, 17, 349.
ALKALOIDS OF ERYTHROXYLON
COCA
The habitat of Erythroxylon spp. is principally the western side of South
America, and although indigenous species occur in India, Africa and
Australia, they have no economic value. Two kinds of coca leaves are
available in commerce, Bolivian or Huanuco leaves derived from E. coca
Lam. and Peruvian or Truxillo leaves obtained from E. truxillense Rusby ;
both are cultivated in Java. In South America coca leaves are chewed
with lime by the Indians as a stimulant, and are exported to Europe for
use in medicine and for the preparation of cocaine, but the principal source
of coca leaves is Java. Crude cocaine is manufactured in South America
and exported for refining and some aspects of this industry have been
discussed recently. 1
The alkaloids of coca leaves belong to six groups :
COCAINE
93
94
TROPANE
GROUP
COCAINE
95
96
TROPANE
GROUP
COCAINE
97
98
TROPANE
GROUP
Ecgonine C 9 H 15 0 3 N
> Anhydroecgonine C s H 13 O a N
OXIDATION : (a) Chromic acid
Tropine C 8 H 15 ON
Tropinone
' Tropinic acid
Ecgoninic acid
Ecgonine C B H 1B O g N' - *' C 8 H 13 ON ~* C 8 H 13 0 4 N ""*" C 7 H u 0 3 N
(b) Permanganate
Tropine C 8 H 15 ON > Tropigenine C 7 H 13 ON
Ecgonine C9H15OaN > norEcgonine C 8 H 13 0 3 N
EXHAUSTIVE METHYLATION :
-CH,
CHuCHCH.OH
ig-CH
i!Hg CH
CH.COOH
CH, OH
Nile
CH.COOH
NMe CH.OH
f%
(I)
(COOH)CH2
(II)CHg CH
CH2
( I I I ) CHgCHCH2
COCAINE
99
-CHCE.i!B,
C3.C0.H
I
3
CH-
Mile OH.SU
H.CH,
HMe CH,
I I I 8
(IV)CHCH CH
' 1
(W)CHCH-
[7)CHCHCH.,
!
.
NH
CH.OH
(IX)CH>~CH CH
2
a
-CH
CH-CHCH.OOoH
! 2 I
I
"
I
HMe CH.OH
CH CHCH.OO-H
2
CH?
jH-CH-OH.CC.3H
*.
( V m ) C H CH-CH
B,
B
ma
CH
II
IVII!CH_~CH
*
CH
P H ^ - C H CH.CO.OCH,
NMa
CH.O.CO.C.H.
(X)CBCHOH,
Cocaine
46
(BsthylbenzoylOBgcniaol
100
TROPANE
GROUP
CH20H GH 2
Kite
00
(XDGHgCKCH2
(XIIlOHgOHCHg
-CHCH.
UeH
CH.0H
(HII)CH(OH)CHCHJJ
HYGRINES
101
(p. 73)- I* crystallises in colourless tablets or prisms, m.p. 108, b.p. 240,
is miscible with water, ether or alcohol, alkaline in reaction and optically
inactive. The hydrochloride forms hygroscopic needles ; the aurichloride
crystallises in brilliant yellow plates, m.p. 225 (dec), and the picrate in
long needles, m.p. 258-9 (dec). ^r-Tropine esterifies with organic acids,
furnishing a series of derivatives, which from their analogy with the
tropeines have been called 0-tropeines, but unlike the former exert little or
no mydriatic action.
Mandelyl->/)-tropeine (0-homatropine), C 16 H 21 0 3 N, is a thick
uncrystallisable oil.
Tropyl-t/i-tropeine, C 17 H 23 0 3 N, crystallises in
colourless needles, m.p. 86.
Tropine and ^-tropine are mutually convertible as already described.
Mixtures of tropine and ^-tropine can be separated by means of
the picrates, that of ifi-tropine being the more soluble in water 57 (1-48
per cent, in water at 16). By the action of sodium amyloxide on tropine,
Willstatter has shown that i/r-tropine is produced 68 and this has been
confirmed by Barrowcliff and Tutin, 59 who also support Willstatter's view
that both bases are internally compensated, the relation being that of
cis-trans-isomerism.60 The synthesis of ^-tropine has been described
already (p. 77).
Troger and Schwarzenberg 61 have isolated a base (m.p. 53, b.p.
225-30; picrate, m.p. 237 (dec.) ) isomeric with tropine and ^r-tropine,
from coca leaves.
HYGRINES. This group of coca alkaloids was discovered by Lossen 63
in an ethereal extract of a slightly alkaline percolate of Peruvian coca
leaves. Liebermann and his pupils 63 re-investigated Lossen's supposed
homogeneous base, and observed that by distillation under reduced
pressure it could be separated into two products, hygrine and j8-hygrine.
Hygrine has also been found in Convolvulus kamadce (p. 67).
Hygrine, C8H15ON, b.p. 92-4/20 mm., lll-3/50 mm. or 193-5/
760 mm., D417 0-940, [a]D 1-3, is a colourless, strongly alkaline liquid
which absorbs carbon dioxide from the air and decomposes on exposure to
light. It forms an aurichloride and a characteristic picrate, yellow needles,
m.p. 158, dl-form, 149-50. On oxidation by chromic acid hygrine
yields hygric acid, C 6 H u 0 2 N, m.p. 164, which heated alone or with
strong sulphuric acid loses carbon dioxide, giving iV-methylpyrrolidine,
^sHuN. Both hygric acid and hygrine are tertiary amines and hygrine
gives a crystalline oxime, m.p. 116-20 (dZ-form, m.p. 125).
Hygric acid was synthesised by Willstatter by the following
method. 64 Ethyl bromopropylmalonate, CH 2 Br. CH 2 . CH 2 . CH(C0 2 Et) 2 ,
obtained by condensation of trimethylene bromide with ethyl sodiomalonate, on bromination yielded ethyl aS-dibromopropylmalonate,
^H 2 Br . CH2 . CH 2 . CBr(C0 2 . C2H5)2. This reacts with methylamine
terming two products both derived from iV-methylpyrrolidire-2:2dicarboxylic acid, viz., the dimethylamide (XIV) and the diethyl ester.
A hei former on heating with hydrochloric acid at 125, and the diethyl ester
with water at 160, both undergo hydrolysis and partial decarboxylation
102
TROPANE
GROUP
-me
NHS
"-
CH.G00H
>c(cojjmi9)r
(XV)CHg
; X I V ) O H CB;.
CH
2
NMe
1H
N
CH
2-
-NM8
CH.CH .CO.CHg
>0H.C0.0H2.CH3
(XVI)CHg
CEr
CH^
(XVII )CH-
CH2
CHg-HMe s
Jttte
>CH.CH^.CH0H.CH3
CHg
(XIX)OH^
CH
103
HYGRINES
215/50 mm. and has specific gravity 0-982 at 18. It gives an aurichloride,
C 14 H 24 ON 2 . 2HAuCl4, and forms a colourless crystalline dimethiodide.
When oxidised by chromic acid, it yields a small quantity of hygric acid.
Cuscohygrine, C13H24ON2 (Cuskhygrine). This third hygrine, first
recognised in "cusco " leaves by Liebermann and Cybulski,67 was
characterised by these authors and by Hess and Bappert. 68 It has now
been found in Convolvulus hamadce. It boils at 169-70/23 mm., has
specific gravity 0-9767 at 17, is optically inactive, absorbs carbon dioxide
forming an unstable carbonate, is miscible with water and gives a crystalline
hydrate, B . 3|H 2 0, m.p. 40. The alkaloid forms crystalline salts with
acids ; hydrobromide, m.p. 234, nitrate, m.p. 209 (dec), and yields a
methiodide, m.p. 244, and a crystalline oxime, m.p. 53-4. It contains
two tertiary nitrogen atoms and, on oxidation with chromic acid, furnishes
hygric acid. Liebermann assigned to it formula (XX), which Hess and
Fink 69 modified to (XXI) mainly on the following evidence. On long
standing in ethereal solution over potassium hydroxide, the alkaloid is
partly converted into dZ-hygrinc. It does not condense with benzaldehyde
as it should if it contained the chain CH 2 . CO . CH2. Cuscohygrine
yields two hydrazones, regarded as stereoisomeric, which on reduction
furnish di-iV-methyl-2-pyrrolidylmethane (XXII) and oca-di-jV-methylpyrrolidylpropane (XXIII). On treatment with nitric oxide in presence
of sodium ethoxide, 70 the alkaloid yields homohygric acid (2V-methyl-2pyrrolidylacetic acid (XXV)) and a mixture of bases believed to be of the
type (XXIV), since on reduction they furnish di-iV-methyl-2-pyrrolidylmethane (XXII). Sohl and Shriner 71 have confirmed the formation of
iV-methyl-2-pvrrolidylacetic acid from cuscohygrine and have synthesised
the acid. The latter has also been prepared by King, Clifton and Openshaw 72 but the acid has not yet been converted into substance (XXII).
The identity of the di-iV-methylpyrrolidylmethane (XXII) formed in these
reactions remains in doubt, since the synthetic product, which exists in two
stereoisomeric forms, subsequently prepared by Hess and Anselm 73
proved not to be identical with the substance derived from cuscohygrine.
Hess and Bappert 88 found that, although cuscohygrine could not be
exhaustively methylated, it yielded on reduction two stereoisomeric
CH^CHg-OH-CHg-CO-CHg-CH-CHg-CI^
(XX)CHg
sue
HMe
CTg-CHjj-OH-CHg-CH-C^-C^
(xni)cBjj
me
me^
C^
CH2-CB2-CH-0H (CO-Ciy-CH-CHg-CHg
(XJCDCH^
NMe
NUe
(xnn)o^
sue
rateCH8
/
?VCV?B-CK=?-0V?Ha
|
|
-
OB^
CHo-0B_-CH-CHo-C00H
!
104
TBOPANE
GROUP
1903,
[iv], 17, 784 ; cf. D E JONG, Rec. trav. Chim., 1906, 25, 1. For a review of this subject
and a process, see Bull. Health Org. League of Nations, 1938, 7, 429 a n d cf. D E J O N G ,
Bee. trav. Chim., 1938, 57, 1218; 1940, 59, 2 7 ; VAN ITALLIE, Pharm. Weekbl., 1938,
75, 909 ; VAN HULSSEN, Berg cultures, 1940, 14, 1444 (Chem. Abstr., 1941, 35, 3035);
E D E R and RUCKSTUHL, Pharm. Acta Helv., 1943, 18, 687. (7) Pharm. Weekbl., 1907,
44, 961 ; DE JONG, ibid., 1908, 45, 42 ; Rec. trav. Chim., 1906, 25, 1 ; 1911, 30, 204 ;
1923, 42, 980 ; 1940, 59, 687 ; Indische Mercuur, 1923, 46, 305 ; GORIS, CHALMETA and
CHALMETA 3 ; TORRICELLI, Mitt. Lebensm. Hyg., 1938, 29, 48. Detection of ecgonine,
see AMELINK, Pharm. Weekbl., 1938, 75, 861.
Bull. Sci. Pharmacol., 1920, 27, 359 (Chem. andDrugg., 1920, 394). CHEMNITIUS, J.pr.
Chem., 1927, [ii], 116, 276 ; SQUIBB, J. Soc. Chem. Ind., 1899, 8, 724, 1013. (9) D E
J O N G , Rec. trav. Chim., 1906, 25, 311 ; 1923, 42, 980 ; DUILIUS, Chem. Zeit., 1930, 54,
31.
KLEIN,
ibid., 3 3 3 5 ; D E J O N G , Rec. trav. Chim., 1940, 59, 2 7 ; 1942, 61, 5 4 ; 1947, 66,
544. (11) Ibid., 1885, 18, 2953. (12) Ibid., 1894, 27, 1523. (13) ALLEN'S
" Commercial Organic Analysis," 5th Edition, Vol. 7, p. 513, London, J . and A. Churchill:
Philadelphia, P . Blakiston's Sons & Co. I n c . ; cf. PESEZ, J. Pharm. Chim., 1939, [viii],
30, 2 0 0 ; MARTINI a n d GRAF, Mikrochemie,
J.
Pharm., 1911, 83, 195, 2 6 5 ; HANKIN, Analyst, 1911, 35, 2 ; CECCONI, Ann. Chim.
Applic.,1936,26,
2 1 8 ; GAUTIER, Ann. Chim. Anal., 1943,25,172. (15) (a) WAGENAAR
Pharm. Weekbl., 1930, 67, 229 ; MARTINI, Mikrochem., 1932,12, 111 ; VAN Z I J P , Pharm.
Weekbl, 1933, 70, 606 ; (6) ROSENTHALER, Mikrochem., 1924, 2, 121 ; FERRARIS, Boll,
chim. Farm., 1927, 66, 577 ; (c) W E I S S , Apoth. Zeit., 1930, 45, 724 ; E M D E , Chem. Zeit.,
1931,55,537; PASSARELLI, Boll. Chim.Farm., 1931,70, 891 ; FULTON, Amer. J. Pharm.,
1933, 105, 326 ;
Weekbl., 1933-1935 ;
NICHOLLS,
Analyst, 1936, 61, 155 ; BAGCHI et al., Ind. Med. Gaz., 1939, 74, 29 ; BERISSO, Chem.
Abstr., 1942, 36, 370 ; MILOS, Amer. J. Pharm., 1940,112, 403 ; FLORENTIN and H E R O S
Chem. Abstr., 1943, 37, 5550; BRUNING, Zeit. Vnters. Lebens., 1940, 79, 9 3 . (16)
STRAIT, A I R D a n d W E I S S , J. Pharmacol. Exp. Ther., 1941, 73, 363.
23,
508, 926.
(19)
Ber.,
1901, 34, 1457 ; Annalen, 1903, 326, 42 ; 1923, 434, 111 ; Munch, med. Woch., 1924,
71, 849 ; E . MERCK, Brit. P a t . 210,050. (20) Pharm. Zeit., 1889, 34, 5 1 6 ; cf. P A U L ,
Pharm. J., 1889 [iii], 20, 166. (21) Ber., 1888, 21, 3372 ; 1889, 22, 2661. (22) Ibid.,
1891, 24, 7. (23) Pharm. Zeit, 1887, 407, 668 ; Ber., 1889, 22, 665. (24) Ibid.,
1888, 21, 2342. (25) LIEBERMANN and DRORY, ibid., 1889, 22, 682. (26) Chem. Soc.
Abstr., 1899, [i], 9 6 3 ; cf. LIEBERMANN a n d G I E S E L , Ber., 1890, 23, 508, and E I N H O R N
and MARQUARDT, ibid., 979. (27) MERCK, ibid., 1885,18, 2954 ; EINHORN, ibid., 1888,
21, 48. (28) D E JONG, Rec. Trav. chim., 1939, 58, 1 0 7 ; 1940, 59, 687, (28a) PAUL,
Pharm. J., 1887-88, [iii], 18, 781. (29) Ber., 1888, 21, 3196. (30) Annalen, 1865,133,
351.
trav. Chim., 1947, 66, 99. (32) Ibid., 1901, 34, 1457.
(88) Annalen,
1921, 422,
PHARMACOLOGICAL
ACTION
105
15. (34) Ber., 1887, 20, 1221 ; UGRIUMOV, J. Gen. Chem. Buss., 1944, 14, 997.
(35) LIEBERMANN, ibid., 1907, 40, 3602; MATCHETT a n d L E V I N E , J. Amer. Chem.
Soc,
ibid'., 1890,
23,
2518;
24,
606;
WILLSTATTER
and
(37) LIEBERMANN,
MULLER,
1898,
31,
178.' (38) Ibid., 1901, 34, 519. (39) Ibid., 1 8 1 8 ; see also RUGGLI a n d
MAEDER, Helv. Chim. Acta, 1942, 25, 936. (40) EINHORN, ibid., 1888, 21, 3031. (41)
EINHORN and FRIEDLANDER, ibid., 1893, 26,1482 ; cf. WILLSTATTER and MOLLER, ibid.,
1170 ; cf. LADENBURG, ibid., 1902, 35, 1159. (58) Ibid., 1896, 29, 936. (59) J. Chem.
Soc, 1909, 95, 1970. (60) Cf. WILLSTATTER, Annalen, 1901, 317, 204 ; 1903, 326, 1 ;
1921, 422, 15. (61) Arch. Pharm., 1921, 259, 207. (62) Annalen, 1862, 121, 374.
(63) Ber., 1889, 22, 675 ; 1891, 24, 407 ; 1893, 26, 851 ; 1895, 28, 578 ; 1898, 29, 2050 ;
1897, 30, 1113. (64) Ibid., 1900, 33, 1160 ; Annalen, 1903, 326, 91 ; cf. KARRER and
WIDMER, Ilelv. Chim. Acta, 1925, 8, 364 ; H E S S , Ber., 1913, 46, 3114, (footnote) H E S S ,
EICHEL and UIBRIG, ibid., 1917, 50, 355. (65) Ibid., 1913, 46, 3113, 4104; SORM, Coll.
Czechoslov. Chem. Comm., 1947, 12, 245 (Chem. Abstr., 1948, 42, 558). (65a) Ber.,
1943, 76, 942. (66) Ibid., 1889, 22, 6 7 5 ; 1895, 28, 580. (67) Ibid., 1895, 28, 5 7 8 ;
1896, 29, 2050. (68) Annalen, 1925, 441, 137. (69) Ber., 1920, 53, 781. (70)
TRAUBE, Annalen, 1898, 300, 81. (71) J. Amer. Chem. Soc, 1933, 55, 3828. (72)
J. Chem. Soc, 1942, 422. (73) Ber., 1921, 54, 2310.
106
TBOPANE
GROUP
PHARMACOLOGICAL ACflOti
101
it has been observed that the blood of some rabbits contains an enzyme,
atropinesterase, which hydrolyses atropine, and presumably hyoscyamine,
into the relatively harmless tropine and tropic acid. 3 According to
Denys and Levy, genatropine (atropine iV-oxide) is not hydrolysed by this
esterase.3(a) A similar enzyme has been found by Bernheim and Bernheim
in guinea-pig liver.3
Effect of Change in Structure on Pharmacological Action. More effort
has been expended in attempts to correlate pharmacological action with
chemical constitution in this than in any other group of alkaloids, probably
because the types of action most characteristic of the two sub-sections of the
group, local anaesthesia, and mydriasis, are relatively easy to observe and
can be at least roughly measured. Recently attention has also been given
to the investigation of spasmolytic action in this group.
These investigations have followed three main lines, (1) alterations in
the amino-alcohol nucleus, (2) variation in the alkyl or acyl side-chains,
(3) influence of stereoisomerism. Tropine and ecgonine, the basic components of atropine and cocaine, lend themselves to such investigations,
but scopine, the amino-alcohol of hyoscine is so labile that systematic
modification of this alkaloid has not yet been possible.
Of the proximate derivatives of atropine, the methobromide and the
methonitrate are in use for much the same purposes as atropine, but the
methonitrate has received special attention for the treatment of pyloric
stenosis.4 apoAtropine has been found by Mancini to retain the same
type of action as atropine but to be less potent in peripheral and more
active in central nervous action. 5
According to Nyman 5fa) the pharmacological action of hyoscine is
considerably modified in the quaternary compounds of the alkaloid, e.g.,
the inhibiting action on salivary secretion is greatly increased in the
methonitrate, as is also the spasmolytic activity, but the mydriatic action
is unchanged and the central sedative activity disappears.
Whilst tropyltropine (atropine) is mydriatic, this property is of a low
order in benzoyltropine and is absent in benzoyl-^-tropine. The former
is a weak and the latter a potent local anaesthetic. This parallelism in the
influence of the tropyl and benzoyl radicals in developing mydriatic and
local anaesthetic action respectively, has been shown by von Braun and
his co-workers to occur through an extensive series of hydroxyalkylamines
in addition to tropine. Considerable modification may be made in the
structure of tropine without impairing its capacity for yielding mydriatics
and local anaesthetics. Thus von Braun, Muller and Rath 6 found that
the tropyl- and benzoyl-esters respectively of homotroTpine (I) and of
iV-hydroxyalkylnortropanes (III) are comparable with atropine and
tropacocaine (derived from tropine (II) and ^-tropine (II)), respectively
SHg OH OH.CH^)H
NUa
0];H
(I)CH 2 -OHCB a
C E j - OH
CH
K.CH. OBOH
(IIJOHgCH
CHg
CHg OH
HWH^OH
(111)08,,OH
CBg
CH,
108
TROPANE
GROUP
as mydriatics and local anaesthetics, while Rao 6 found that 1-methyltropacocaine (p. 81) has a general effect similar to that of tropacocaine.
In the case of the ^-hydroxyalkylnortropanes (III) anaesthetic action
is at its maximum when the hydroxyl group (in the chain of n-carbon atoms
attached to the nitrogen atom) is in the y-position, whilst the /}-position
is the most favoured for the development of mydriatic action, the esterifying acyl group being benzoyl- and tropyl- respectively. This relationship
holds throughout a series of similar substances, prepared from aliphatic
amines, piperidine, pyrrolidine, coniine, woquinoline and isoindole.8 For
example, in the substances represented by the following formulas, (IV) is
more active as a mydriatic than (V), and (V) more potent as a local
anaesthetic than (IV), when the tropyl group (Tr) is replaced by benzoyl
(Bz).
}H 2
H2C
H20
CH 2
\ CH
H2C
CH 2
HEC
V 2 .0Tr
^ CH
H2C
N CH2
JcHPr01
H2C
H(CH2)3.0Tr
M(CI
(IV)
CH 2
(V)
N(CH2)2.0Bz
(VI)
CH
CH,
CHCHCH.
I *
CH, Nile CO
(7II)CH 2 CH CHJJ
NMe
( U ) CHiCH.C.Cflg.CHg.CH
CH.O.Bz
CH2
PHARMACOLOGICAL
ACTION
109
(1) and (2) were potent mydriatics while (3) and (4) were inactive and,
110
TROPANE
GROUP
PHARMACOLOOIGAL
Z-Hyoscyamine
d-Hyoscyamine
dZ-Hyoscyamine
Methylatropine
d-Tartryltropine
Z-Homatropine
d-Homatropine
.
.
.
.
600
15
300
450
0
14
7
111
ACTION
dZ-Homatropine 10
Phenylacetyltropine
1
Benzoyltropine
1
o-Hydroxybenzoyltropine.
1
wi-Hydroxybenzoyltropine < 1
^-Hydroxybenzoyltropine < i
CH2.KMe2,HCl
(I)
HMe-j.CHg
CgH5
.O.CO.C6H5
N
CH2.NMe2,HCl
(II)
CH.O.CO.C.Hc
6 5
/ \
CH
2 1
Me.HC
CMe2
(III)^NH.HCl
saligenin, and the esters of aminoaromatic acids ; such as the ethyl and
diethylamjnoethyl esters of 4-aminobenzoic acid.
Several of these cocaine substitutes contain asymmetric carbon atoms,
and King has shown 17 that in the case of benzamine (III) there is no
difference in the anaesthetic action of the d- and Z- forms, but that the
Z-form is twice as toxic as the d-iovm.
Enterprise in the synthesis of new local anaesthetics shows no sign of
diminution and several useful reviews 17<a> dealing with the correlation
of structure and local anaesthetic action have been published of
which that by Moore deals generally with the subject, while Gilman,
Goodman, Thomas, Hahn and Priitting discuss structure and activity in
112
TROPANE
GROUP
PHARMACOLOGICAL
113
ACTION
1
2
3
4
5
6
7
8
9
10
11
12
Atropine (<W-tropyltropine)
.
.
.
.
l-Methyl-4-hydroxypiperidyI diphenylacetate
/3-Diethylaminoethyl <M-tropate
,,
a-phenyltropate
,,
benzilate
,,
diphenylacetate
,
fluorene-9-carboxylate
y-Diethylaminopropyl
,,
/3-Diethylaminopropyl
,,
,,
/J-isoButylaminoethyl
,,
,,
^-Di-n-butylaminoethyl
,,
y-Diethylamino-;8/J-dimethylpropyl di-tropate as
Acetylcholine
Histamine
014
1-8
10
50
0-7
60
10
4-0
>100
50
>12-0
4
0-5
200
20
0-7
1-5
10
50
4-5
2-5
90
150
30 0
TROPANE GROUP
114
1939, 9,
41 (Brit. Chem. Phys. Abstr., 1939, A i i , 349) ; SAKUSOV, J. Physiol. U.S.S.R., 1938, 24,
1150 ; RAYMOND-HAMET, C. R. Soc. biol., 1943, 137, 44. (2a) " Tropanol et pseudotropanol." Masson et Cie., Paris, 1937. (3) GLICK, J. Biol^ Chem., 1940, 134, 617 ;
SAWIN and GLICK, Proc. Nat. Acad. Sci., U.S.A., 1943, 29, 55 ; BLASCHKO, CHOU a n d
W A J D A , Brit. J. Pharmacol., 1947, 2, 108 ; E L L I S , ibid., p. 370. BERNHEIM and B E R N -
HEIM, J. Pharm. Exp. Ther., 1938, 64, 209 ; LEVY and MICHEL, Bull. Soc. Chim. biol.,
1945, 27, 570 ; L E V Y , C. R. SOC. biol., 1946, 140, 813.
(3a) D E N Y S and L E V Y ,
Bull.
Soc chim. biol., 1947, 29, 273. (4) DOBBS, Lancet, 1939, 236, 1 2 ; GRAHAM and
LAZARUS, Journ. Pharm. Exp. Ther., 1940, 70, 165. (5) Boll. Soc. ital. Biol.
Sper., 1939, 14, 273 ; DUENSING, Klin. Woch., 1938, 17, 1550 ; KREITMAIR a n d
W O L F E S , ibid., p . 1547. (5a) Acta. Physiol. Scand., 1943, 6, 2 5 6 ; Acta. med.
Scand., 1944, 118, 466. (6) Ber., 1918, 5 1 , 2 3 5 ; 1920, 53, 6 0 1 ; 1932, 65, 888.
(7) Quart. J. Pharm.,
1922, 55, 1666 ; cf. LAUNOY and FUJIMORI, Compt. rend. Soc. Biol., 1919, 82, 732.
(9) GRAY and T R E V A N , J. Chem. Soc,
Arch. exp. Path. Pharm., 1925, 105, 58. (10) J. Amer. Chem. Soc, 1918, 40, 669 ; cf.
TANRET, Compt. rend., 1923, 176, 1659 ; ELPHICK and GUNN, Quart. J. Pharm., 1932,
5, 220 ; R A O , ibid., 1934, 7, 46. (11) J. Amer. Chem. Soc, 1923, 45, 2738. (12)
BLICKE (with MAXWELL), ibid., 1942, 64, 428, 431 ; (with KAPLAN), ibid., 1943, 65, 1967.
(13) Proc. 7th Int. Cong. Appl. Chem., London, 1909 ; PYMAN, J. Chem. Soc, 1917, 91,
1104. See also ibid., 1906, 89, 357 ; 1907, 91, 92 ; 1909, 95, 1020. (14) GOTTLIEB,
Zeit. Physiol. Chem., 1923, 130, 374 ; WAGNER, Arch. exp. Path. Pharm., 1925, 109, 64 ;
GRUHN, ibid., 1925, 106, 115 ; MERCIER and R E G N I E R , Compt. rend., 1929, 189, 872 ;
Bull. Sci. Pharmacol., 1930, 65, 219. (15) J. Pharm. exp. Ther., 1920, 15, 1 0 5 ; cf.
J. Physiol., 1904, 30, 176 ; see also GRAHAM and GUNN
exp. Path. Pharm., 1939, 192, 405. (16) J. Pharm. exp. Ther., 1921, 17, 41 ; 1926, 29,
5 ; cf. J. Physiol, 1905, 32, 501 ; Arch. exp. Path. Pharm., 1912, 70, 433 ; H U G , ibid.,
1912, 69, 45. See also NYMAN, Acta. Physiol. Scand. Suppl., 1942, 10, 127. (17) J.
Chem. Soc, 1924, 125, 46. (17a) MOORE, Journ. Amer. Pharm. Assoc, 1944, 33, 193 ;
GILMAN et al., J. Pharm. exp. Ther., 1942, 74, 290 ; DAWES, Brit. Med. J., 1946, i, 43 ;
Brit. J. Pharmacol., 1946, 1, 90. (176) Brit. Med. Bull., 1946, 4, 82 ; see also CHANCE
and LOBSTEIN, J. Pharm. exp. Ther., 1944, 82, 203 ; BULBRING and W A J D A , ibid., 1945,
(17c) GUTIERREZ,
Arch. Exp. Path. Pharm., 1933, 173, 8 6 ; Klin. Woch., 1934, 13, 6 ; J. Pharm.
Exp. Ther., 1937, 60, 1 ; KREITMAIR, Klin. Woch., 1936, 15, 6 7 6 ; K R O N E B ,
ibid., p . 6 7 8 ; LEHMANN and KNOEFEL, J. Pharm. Exp. Ther., 1942, 74, 217, 274.
(19) Compt. rend. Soc. Biol, 1937, 126, 678 ; Arch, inter. Pharmacodyn, 1938, 59, 149 ;
cf. W A G N E R - J A U R E G G et al.,
Ber.,
(20) W O L F E S and
HROMATKA,
KREITMAIR18;
BASLE, 8 0 B . P . 448,181 (1934) ; 483,258 (1937) ; M E I E R , Klin. Woch., 1936, 15, 1408,
cf. W A G N E R J A U R E G G et al.11;
B U R T N E R a n d Cusic " ;
Pharm. exp. Ther., 1940, 69, 331; NECHELES, NEUWELT et al., Amer. J. Digest. Dis.,
1939, 6, 39, 3 8 7 ; HOFFMANN, Helv. Chim. Acta, 1941, 24, 86E ; (with MIESCHBB),
ibid., 1941, 24, 458 ; (with M E I E R ) , Helv. Med. Acta, 1040-1, 7, Suppl. VI, 106. (28)
TROPANE GROUP
115
BUBTNEB and Cusic, J. Amer. Chem. Soc, 1943, 65, 262 ; BTIRTNER, U.S.P. 2,334,310 ;
see also LEHMAN and K N O E F E L . 1 8
Soc,
1942, 64, 970 ; BLICKE and FELDKAMF, ibid., 1944, 66, 1087. (24) J. Amer. Pharm.
Assoc, 1943, 32, 2 4 9 ; BLICKE, Ann. Rev. Biochem., 1944, 13, 5 4 9 ; L O E W , Physiol.
Rev., 1947, 27, 542. (25) Amer. J. Digest. Dis., 1943, 10, 241. (26) Proc. Soc Biol.
Med., 1943, 53, 164 ; Arch. Ophthalmol, 1944, 31, 289 ; 1945, 33, 16 ; J. Pharmacol,
exp. Ther., 1944, 80, 2 8 5 ; FEATHEBSTONE and W H I T E , ibid., 1945, 84, 1 0 5 ; PETEKSON
and PETEKSON, ibid., p . 236. (27) Ibid., 1945, 85, 85 ; BOLBRING a n d D A W E S , ibid.,
1945, 84, 177 ; ING, Brit. Med. Bull., 1946, 4, 91 ; MANN, Brit. J. Ophthalmol., 1946,
3 0 , 8 ; L A W , Pharm. J., 1946, 157, 2 1 5 ; FORD-MOOKE and I N G , J. Chem. Soc,
1947, 55.
LUPINANE GROUP
ALKALOIDS OF THE
PAPILIONACEJE
PAPILIONACEOUS
ALKALOIDS
117
118
LUPINANE
GROUP
CHENOPODIACE^E
Lupinine and other bases (p. 53).
BERBERIDACE^
(41) Caulophyllum thalictroides. Methylcytisine (caulophylline).21
LUPIN
119
ALKALOIDS
PAPAVERACE^E
Z-Sparteine.22
Osterr. bot. Zeit., 1930, 79, 1 0 7 ; (c) JARETZKY a n d A X E R , Arch, Pharm., 1934, 272,
164; (d) W H I T E , N. Z. J. Sci. Tech., 1943, B . 25, 93-114; 1944, B . 25, 137-162;
1946, B . 27, 335, 339, 474, 478.
Parts I t o X I I I issued as a reprint (Govt.
Printer, Wellington, N.Z.) ; MARION et al., J. Amer. Chem. Soc, 1948, 70, 6 9 1 ;
(e) WINTERFELD and NITZSCHE, Arch. Pharm., 1940, 278, 393 ; ( / ) MERCK'S Jahresb,
1936, 50, 111.
Bull.
Soc.
Chim., 1938, [v], 5, 29. (2a) SADYKOV and PROSKURNINA, J. Gen. Chem. Russ., 1943,
13, 314. (3) I N G , J. Chem. Soc, 1935, 1053. (4) OREKHOV et al., Arch. Pharm., 1935,
273, 369 ; J. Gen. Chem. Russ., 1937, 7, 743, 853 (Genista), 906 (Brit. Chem. Abstr.,
1937, A, i i , 311). (4a) COUCH, J. Amer. Chem. Soc., 1940, 63, 986. (5) SCHMIDT,
Arch. Pharm., 1897, 235, 1 9 2 ; DAVIS, ibid., p . 199, 218 ; BECKEL, ibid., 1911, 249,
333 ; 1912, 250, 691 ; U E N O , J. Pharm. Soc. Jap., 1930, 50, 68. (6) COUCH, J. Amer.
Chem. Soc, 1932, 54, 1691 ; 1936, 58, 686, 1296 ; SOINE and J E N K I N S , Pharm. Arch.,
1941, 12, 65. (7) COUCH, J. Amer. Chem. Soc, 1934, 56, 155 ; 1937, 59, 1469 (7a)
DEULOFEU and GATTI, J. Org. Chem., 1945, 10, 179. (76) COUCH, J. Amer. Chem. Soc,
1939, 61, 3327. (8) Ibid., 1925, 47, 2584. (9) SCHMIDT 6 ; GERHARD, Arch. Pharm.,
1897, 235, 342, 355 ; B E R G H , ibid., 1904, 242, 416 ; WILLSTATTER a n d M A R X , Ber., 1904,
37, 2351. (9a) MARION, J. Amer. Chem. Soc, 1946, 68, 759. (10) COUCH, J. Amer.
Chem. Soc, 1934, 56, 2434. (11) Ibid., 1924, 46, 2507 ; (a) ibid., 1940, 62, 5 5 4 ; (b)
ibid., 1939, 61, 1523. (12) CLEMO a n d LEITCH, J. Chem. Soc, 1928, 1812. (12a)
RIBAS et al., Anales fis. y quim., Madrid, 1946, 42, 516. (13) OREKHOV et al.,
Ber., 1935, 68, 429. (13a) KONDO et al, Arch. Pharm., 1937, 275, 493. (14)
OREKHOV et al., Ber., 1933, 66, 948 ; 1935, 68, 431 ; Arch. Pharm., 1934, 272, 673 ;
(14a) BRIGGS (with RUSSELL), J. Chem. Soc, 1942, 507, 555.
ibid., 1937, 1795 ; 1942, 555 ; (14c) (with TAYLOR), ibid., 1938, 1206.
et al., Ber., 1933, 66, 621 ;
Applic,
(15) OREKHOV
Chim.
1941, 35,
1394; TSAREV, C. R. Acad. Sci. U.R.S.S., 1944, 42, 1 2 2 ; 45, 191 ; SAI MOISEEVA,
Trudy Vostock Sibirsk. Gosud. Univ., 1940, No. 4, 158. (19) MANSKE and MARION,
Can. J. Res., 1942, B . 20, 265 ; 1943, B . 2 1 , 144. (20) CLEMO a n d R A T E R , J. Chem.
Soc, 1935, 10. (21) P O W E R a n d SALWAY, ibid., 1913, 191. (22) SPATH a n d K U F F N E R ,
Ber., 1931, 64, 1127. (23) Soviet Plant Ind. Rec, 1940, No. 2, 68. (24) Rec. trav. bot.
Neerland., 1940, 37, 78. See also MOTHES and KBETSCHNEB, Naturwiss., 1946, 33, 26.
(25) Mi&jB, Rev. bot. appl. agr. trop., 1940, 20, 16 ; SENG-BUSCH, Landw. Jahr., 1942
91
710; BRAHM and ANDRESEN, Z. angew. Chem., 1926, 39, 1848. For some recent
120
LUPINANE
GROUP
LUPININE
121
122
LUPINANE
GROUP
first with zinc permanganate and then with chromic anhydride and
sulphuric acid, there was formed a lactone, CjHjeO^ b.p. 253-5, probably
/3-hydroxymethyloctoic acid lactone, CH 3 . [CHJ 4 . CH(CH 2 ). CH 2 . CO . O,
indicating the presence of S-hydroxymethyl-/l"-nonene (I) in the mixture
of unsaturated alcohols.
On reduction the latter furnished the
corresponding saturated alcohol, C10H22O, (II), b.p. 95-103/10-ll mm.,
aD + 0-32 to + 0-39 (0-25 dcm. tube). The validity of this formulation
of the main component (I) of the unsaturated alcohols was established by
the results of a series of reactions represented as follows, the residue
C H 3 . CH 2 . CH 2 . CH 2 . CH2 being indicated by C 6 H n . Products (I)
to (IV) were optically active, but this property disappeared in the
unsaturated hydrocarbon (V).
(I)
(II)
(III)
(IV)
(V)
(VI)
(VII)
(VIII)
(IX)
C^^.CHlCHgOHl.CHg.CHrCHg, by hydrogenation
>
.GHlCHgBrJ.GHg.CHg.CHg, by a c t i o n of t r i m a t h y l a n i n e
>
>
CgRj^.CO.CHg.CHg.CHg, by oximation
>
>
>
>-
H00C.CH2.CHg.GH3
n-amylamlne
n-butyrlo acid
II
CH2
I
CH2
( I I ) CH-j
CH
CH-j CH.CHp.OH
l\
CHp
CHX
I2
CH9
I\
CHg
CHj
I2
CH2\
(X) CHg
CH2
N
CH2
CH-jOHCH.CHo.OH
II
CHp
I
CH2
( H ) CH2N
CHP
6H2
CH2
123
LUPININE
into wolupinine (m.p. 76-8; [a] + 38-17), which is also produced by the
reduction of Z-lupininic acid instead of the expected Z-lupinine. They
suggested that lupinine and wolupinine are related to each other as cis- and
trans-forms respectively, the latter being the more stable.
The same authors have investigated the degradation of lupinane (XIII),
cf. (XIV), by the cyanogen bromide process, the steps and products being
as follows :
Lupinine Cj^BjigON
^-
>
H
10
>
>
>
i^-
The nature of the base, C10H15N, varies. When produced from pure
Mupinine, m.p. 68-9, it furnishes on oxidation only 3-methylpyridine-2carboxylic acid (XV) and pyridine-2 : 3-dicarboxylic acid. If, however,
lupinine, m.p. 63-5, is used, the resulting pyridine base on oxidation
furnishes in addition 2-w-butylpyridine-6-carboxylic acid (XVI) and
6-methylpyridine-2-carboxylic acid (XVII). The conclusion is drawn that
lupinine, m.p. 63-5, is a mixture of Z-lupinine (XI) with aZZolupinine (XII),
each of these components furnishing its own lupinane (XIII and XIV),
and that these two lupinanes contribute to the final degradation product,
" t h e tertiary pyridine base, C 10 H 15 N," the two isomerides 2-n-butyl-3methylpyridine (XVIII) and 2-w-butyl-6-methylpyridine (XIX) respectively. These interrelationships are shown by the following scheme :
CHp *"" CH~* CHp
GHg-CH-CHg
CH,
ft
CH,
0H
CH.
CH
CH
CHg- N CH.CHgOH
Lupinane
ex
alloLupinlne
(XII)
Bu.C=CH
CH
CH
CH
N-CMe
(nx)
CBg NCHg
1-luplnine
(XIII)
Bu.C=CH
Lupinane
ex
alloluplnlne
12YJ
CHgCHCHMe
I
CH
H-C.COOH
(xvi)
COOH.C-CH
and
r
CH
COOH.C-.CMe
r*.
HCHS
CH
H-CH
(ivu)
(CT)
Cfr .CCMe
CH
KCH
(XVIII)
LUPINANE
124
GROUP
CHo~ CH0:CH
y*z
?H2
CHo
CHc
?*%
CHr
CH2N C H a
CH2N CH 2
9 fV
e9 H 2
79%
fz
CHg.COgEt
1
CH
CH=N
CHo
CHo
CHp
?2
CH.COgEt
CHg-N CH2
(XXIV)
CHg-NCHg
(XXV)
CHo"~-CH"*~ CHo
fk
CHa
CH
CHo
CH
CH,2
COgEt
CHg NH BrCHg
(XXVI)
CHg-CHCO
(XXIII)
CH=CCH,
CHg CH-CO
>
CHg-NCHg
CH9
(XXII)
CH
CH
(XXI)
CHgCHCOgEt
H
3<f 2
CH2N
6
(XX)
;CH
(XXVII)
LUPIN INE
125
>
>
T h i s on h y d r o l y s i s and d e c a r b o x y l a t i o n g i v e s *
EtO(CH2)x
)CH-C0H.
which by th.i C u r t i u s - S c h m i d t r e a c t i o n , f o l l o w e d by
2
EtO(CH2NT
t r e a t m e n t w i t h hydrogen bromlds y i e l d s *
CH
Br(CH)*v
/
\
\
^CH.NHc2 and t h i 3 by t h e a c t i o n of d i l u t e a l k a l i g i v e s (CH 2 )x
(CHgiy
Br(CHg)tj'
N, |
Js
LUPINANE GROUP
126
0H=CC(0H) J i e
CHg
CH
GH
CHgCHCH.CHg
1
CH
CH
CH S
CB-N
CHc
CH.2
CH,
CHjj.OEt
CHgN CHg
fi-Lupinane
(XXVIII)
(XXIX)
(XXX)
127
LUPININE
co2st
CH
CHpCHCH.CH^P
?fe
fe
fz
fi
i 2
CHg-HH Br.CH
(XXXI)
CH
CH 2 N
(XXXII)
Lupinine
*.
and
iaoLuplnlna
(H)
fa
CH2
(XXXIII)
CHOH
CH 2 CHBr
H2C/ Y H CH2__^
H,C
\J
CH 2
(ixiiv)
~*
CHOH
CH 2 0Et
H2C/
H2C
V\.CH
kA/
CHg
CH2and
CH.CH 2 0Et
(xxzv)
UII)
CHg CH.CHgOEt
(xxevi)
128
LUPINANE
and L I E B E S C H E B ;
GROUP
Bet., 1881, 14, 1159, 1321, 1880, 1882; 1882, 15, 631, 1951).
(3)
416 ; (BECKEL) 1912, 250, 691. (5) Helv. Chim. Acta, 1928. 11, 1062 ; see also COUCH,
J. Amer. Chem. Soc, 1934, 56, 2434; SADYKOV (with LAZUR'EVSKII), J. Gen. Chem.
U.R.S.S., 1943,13, 319 ; (with SPASOKUKOTSKI), ibid., p. 830. (6) J. Chem. Soc, 1929,
1927 ; for general information see also CLEMO, R A P E R a n d TENNISWOOD, 1931, 429
(with RAMAGE), 1932, 2963 ; cf. K A R R E R and VOGT, Helv. Chim. Acta, 1930, 13, 1073.
(7) Ber., 1902, 35, 1910.
(8) Annalen,
Diss.,
J. Pharm. Soc. Jap., 1921, 659. (10) SCHOPF and SCHMIDT, Annalen, 1928, 465, 117.
(11) Helv. Chim. Acta, 1928, 11, 1062. (12) Ber., 1931, 64, 137,692; Arch. Pharm.,
1939, 277, 192. (13) Inaug. Diss. Marburg, 1928, cf. Bied. Zent., 1932, 3, A. 51. (14)
See, for example, KARRER and VOGT
; SCHOPF et al8
(1931).
RAMAGE), J. Chem. Soc, 1931, 437 ; (with R A P E R ) , 3190. F o r a third synthesis see
CLEMO, MORGAN and R A P E R ,
1935, 1743.
1932,
OCHIAI et al., Ber., 1935, 68, 2 2 9 1 ; SUGASAWA and L E E , J. Pharm. Soc. Jap.,
1939, 59,
113. (17a) Ber., 1943, 76B, 1034. (18) Annalen, 1932, 499, 109 ; Arch. Pharm., 1935,
273, 305. (19) CLEMO et al. refs. (15), (17) and J. Chem. Soc, 1931, 3185 ; 1932, 2969 ;
1937, 1518 ; 1938, 1183, 1318. (20) Ber., 1939, 72, 1103. (21) OESTERLIN, Angcw.
Chem., 1932, 45, 530. (22) Ber., 1939, 72, 1038. (23) Ibid., 1933, 66, 1751 ; Arch.
Pharm., 1935, 273, 315. (23a) J. Amer. Chem. Soc, 1947, 69, 3146. (24) J. Chem.
Soc,
Arch.
Pharm., 1940, 278, 70. (25) Ibid., 1939, 277, 192, 221.
129
LUPANINE
130
LUPINANE
GROUP
CHCH
CH2
CH2
CH
CH2N
CH
CH NCH
2 GH-CHGO
.N - = C5H9
CH2-CH2 CH2-CH-CH2
(I) Thorns and Bergerhoff
CH2
^2
9*2
CHgNCHg
(II) Winterfeld and Kneuer
LUPANINE
CH C C H
CH
I
CH
CO N C H
CHgCH C H C H .8
CB2
I I
CBj> N
I I
C E CH
I I
131
OHMe
CH
2
CHCH
CO N
CH2 CH CHg
CB2OH2
^CH-CH-CHg
C H = C C H CH
I
CH
' '
I (X)
I
CH
CHCH
CH2
2
C O N CHg
CHgCHg
C0H C H
,2CH2-CH2
3
2 1
.CH 2 CO . N : - (VII). CH 2 . COOH N H :
(XI). CH 2 . CHR . N
132
LUPINANE
GROUP
Couch 14 has suggested that dilupine and trilupine (see below) are near
relatives of lupanine.
MINOR ALKALOIDS OF Lupinus spp.
In the following account the numbers in brackets after the name and
formula of the alkaloid are the numbers of the plants in which it occurs as
given in the list (p. 117).
Monolupine. C16H22ON2, | H 2 0 (No. 13). Amorphous, b.p. 257-8/
4 mm. ; nf 1-569, [x]f 40-8 (EtOH). Salts. B . 2HC1, 2H 2 0,
m.p. 115-6 ; passes on drying into B . HC1, m.p. 280. B, 2HAuCl4, 3H 2 0,
m.p. 167-8.
B . M e l . H 2 0, m.p. 259. Monolupine may be a
C -methylanagyrine. *3
Dilupine. C16H2602N2 (No. 12). Oil, [a]f,6 + 65-6 (H 2 0). Derivatives have one oxygen less than the base. Methiodide, C16H26ON2, Mel,
m.p. 253 ; hydrobromide, C16H26ON2, HBr, m.p. 233-4. Regarded as
a C-methyllupanine N-oxide. 14
Trilupine. C 15 H 24 0 3 N 2 , 2H 2 0 (Nos. 12, 17). Needles, m.p. 127 or
252 (dry); [a]f + 63-8 (H 2 0). Hydrochloric acid in acetone converts
it into lupanine dihydrochloride, C15H24ON2, 2HC1, H 2 0, m.p. 163-4.
Methyl iodide gives lupanine iV-oxide methiodide, C 15 H 24 0 2 N 2 , Mel,
m.p. 127. B, H 2 PtCl 6 , 4H 2 0, m.p. 224 (dec.) ; B, 2HAuCl4, 4H 2 0,
m.p. 188-9 (dec). The base can be prepared by the action of calcium
peroxide on dMupanine and is regarded as lupanine di-N-oxide.14
Tetralupine. C10H19ON (No. 19). M.p. 81-3; Df 1-0194; nf
1-5128, [<x]f + 4-63. d-Camphorsulphonate, m.p. 164-5. Identity
with wolupinine uncertain. 15
Pentalupine. C16H30ON2 (No. 19). B.p. 175-182/2 mm. ;
nf
1-5155 ; [a] f 3-197.15
Hexalupins.
C15H20ON2, | H 2 0 (No. 14). M.p. 197-8; [a]?f +
126-1 (EtOH). Salts. B, 2HC1 . 3H 2 0, m.p. 116, passes into B,HC1,
m.p. 304-5, on slow heating. The aurichloride B 2 , 2HAuCl4, 5H 2 0, melts
at 204 (dec.) and the picrate at 245-6. 16
Octalupine. C 15 H 22 0 2 N 2 (No. 23). M.p. 167-5-169-5; b.p. 27080/6 mm. ; [a] f + 52-3 (EtOH). Salts. B, 2HC1, 1-5H20, m.p.
298-9; [a]?,5" + 36-3 (H 2 0). B . HAuCl4, m.p. 208-9; B . M e l . ,
m.p. 259. Reduced electrolytically to d-lupanine (p. 128) and Z-sparteine
(p. 133) and regarded as 2 :10-diketosparteine (formula V or VI, p. 131)
withCH2atC10->CO.).17
Nonalupine. C15H24ON2, 2H 2 0 (Nos. 10, 22). M.p. 91-5-92-5 or
235 (dry); b.p. 260-270/18 mm. ; [a]|5 21-3 (EtOH). Aurichloride,
m.p. 177-5-178 (dec), picrate, m.p. 185-6. No salts with mineral acids.
No .N-oxide group. Oxidised by permanganate to oxynonalupine,
C 15 H 24 0 3 N 2 , m.p. 168-5-170-5 ; aurichloride, m.p. 238-9 0 . 18
Spathulatine. C 32 H 64 0 5 N 4 , 4-5H 2 0 (Nos. 22, 24). M.p. 227; [oc]D
1-88 (CHC13). The mercuriodide, B, 3HgI 2 , m.p. 164, is characteristic.
The picrate melts at 182-4 and the methiodide at 250-2. Three oxygen
atoms are stated to be present as iST-oxide groups. Boiling dilute
SPARTEINE
133
1925, 263, 4.
(2) THOMS
J. Chem. Soc, 1931, 432 ; cf. DAVIS, Arch. Pharm., 1897, 235, 211, and COUCH, J. Amer.
Chem. Soc, 1934, 56, 1423. (4) J. Chem. Soc., 1928, 1 8 1 3 ; cf. WINTERFELD (with
K N E U E R ) , Ber., 1931, 64, 150; (with HOLZSCHNEIDER), ibid., p . 2415.
77B, 132. (5) SIEBEBT, Arch. Pharm., 1891, 229, 544 ; CALLSEN, ref. (1); BECKEL, ibid.,
1912,250,691; cf. SOLDAINI, Gazzetta, 1903, 33, 428. (6) J. Chem. Soc, 1933, 504. (7)
CLEMO and R A P E R , ibid., 1933, 644. (8) (With RONSBERG), Arch. Pharm., 1935, 273,
521 ; 1936, 274, 40, 48 ; (with HOFFMANN and HOLSCHNEIDER), ibid., 1937, 275, 65 ;
(with HOFFMANN), ibid., 5, 526 ; (with SCHIBM), ibid., 630. (9) J. Chem. Soc, 1936,
1025. (10) Arch. Pharm., 1904, 242, 4 1 6 ; cf. SCHMIDT, loc cit., 409. (11) Ibid.,
1910, 248, 451 ; 1912, 250, 691. (12) J. Pharm. Soc Japan, 1930, 50, 68. The
following references are t o papers by J . F . COUCH in the Journal of the American Chemical
Society. (13) 1936, 58, 686. (14) 1936, 58, 1296 ; 1937, 59, 1471. (15) 1934, 56,
2434. (16) 1934, 56, 155. (17) 1939, 61, 1523. (18) 1940, 62, 554, 986. (19) 1924,
46, 2507 ; 1940, 62, 554.
LUPINANE
134
GROUP
neither has a methyl group attached to it, and, since the alkaloid is
unaffected by reducing agents or permanganate, Wackernagel and
Wolffenstein suggested that it was a saturated bicyclic system based on
pyridine and pyrrolidine. 2 The first insight into the constitution of
sparteine is due to Moureu and Valeur's investigation of the " exhaustive
methylation " of the alkaloid. It forms two monomethiodides, (m.p.
240 (dec.); [a]D 22-75; hydriodide [a]D 17-15) and a' ([a]D
47-2 ; hydriodide [a]D 40-3).3 The a-methiodide subsequently prepared
by Schopf and Braun 4 had m.p. 243-^1, [a]^" 24-8. It yields two
methylsparteines (de-JV-methylsparteines). The a-derivative has m.p.
30-1, b.p. 178-9/ll mm., [a] D 55-4 (M. and V.), 172-5-173/10 mm.
(S. and B.); [OC]D 47-6 (S. and B.), whilst the /J-isomeride is a liquid
(b.p. 180-2/16-5 mm., [<x]D + 9-9). Schopf and Braun obtained, in
addition to the a-base, a third methylsparteine and a base, C16HSoON2,
which has the composition of a methylsparteine monohydrate, whilst
Clemo and Raper got still another methylsparteine (b.p. 135-6/l mm. ;
[oc]D 16-3 (EtOH); methiodide, m.p. 247).4 a-De-iV-methylsparteine
by a variety of processes is convertible into z'sosparteine, a saturated,
ditertiary base containing no methylimino-group, 5 and which in turn
furnishes two methiodides reconvertible through their methohydroxides
into a-de-iV-methylsparteine.6 In the subsequent stages of exhaustive
.CH
CH-
P1^
-CH
CH,
CH,
CH
CH2
CH,
OH.
1
CH
<ft^
|
CHg
CH
JN
Sparteine
NMe
ot -Me thylspartelne
JJ
tl
,CH
.0gH14N
CH
fH2
C .CoH, JJMe
I I I
C
CH,
CH
,CH
CHMe I
C
?2
NMe
ft -Methylsparteine
Methylheml apartellene
.CH
CH
C -
I f I
CH
2
OIL
0H
2
CH,
CH,
-CH2
CH
I" I
SPARTEINE
135
fV"^
CHo CH,
2
CH,
CH,
fz fz
CH,
l\
CH N -
-CH
CHOHCH
CH,
- C H - -CH3
r
CH-
CH - C H - CH
CHo
CH,
CH,
fa
CH
-CH
-CH C H g C H 2
CH,-N -
I
CH,
Z
CH-
I8
CH-N-
<jH2
-CH
CHg, C H -
fz
-CH,,
(III)
CH
CH,
CHg-
fz
'CH2
N - CHg CHg
(IV)
(ID
136
LUPINANE
QROUP
SPARTEINE
CHjj-CHCHCH;
I
I
-CHke
CH 2
CHgNI
I
CH-CH-CHg-CHg
<jH2
CHy.CHjr.0H8
-CMe
CH 2
CH-CH-CH
I
I
CHo
CH 2
I 2
CH
CHP
I 2
CHg-N
CHC = C-COgKt
II
CH
1
CH
II
(V)
CH2-CH2-CH2
N
I
CH=CH
CH2-CH- CH = CH20H
I
CH2
CH 2 NH
CH 2
I
I
I
I
CHP
CHCH
CH2
I
I
I
CH 2 -N CO
CH2-CH2
CHp
C H 2 - N CH 2
(VI)
N CH
II
It
CH
ce
1
I
i
(II)
CH 2
I
CH-CH-CH
I
9H2
1
CH
II
CH-NCO
JJHE-rfJH-yCH-!^
4 CH 2
I
CH 2 -N
2
1
(VIII)
(VII)
CH 2 -NCH 2
MeC
CH2
137
i 2
+ CH 2
3<k
"l
CK2 CH 2 -CH 2
1 0 1 2 1 3
6
s
i 2
17 2 & - i o C H 2
I
I
I
tfjH-uCH
UCH2
i
CH
I
CHP - N CH? CHo-CHo
2 ^ 1
16 ^ 15
12 "
(Villa)
CH2-CHCO
CH2
I
CH 2
COOH N
CH 2
'..
I
l
l
CH2
^)HCH
CH2
CHg^J'CH2 C H 2 - C H 2
(xi)
25
In 1933 I n g
showed t h a t anagyrine (p. 140), on catalytic
hydrogenation, was converted into Z-tetrahydroanagyrine, C 1 5 H 2 4 ON 2
(which proved to be identical with Z-lupanine), whilst on electrolytic
reduction it furnished hexahydrodeoxyanagyrine, C 1 5 H 2 6 N 2 , identical with
cZ-sparteine, with the exception t h a t it had [a]J,9 -j- 10-9, instead of -f- 15'9,
recorded b y Clemo, R a p e r a n d Tenniswood. I n g therefore suggested
formula (VII) for sparteine based on his proposed formula for anagyrine.
On this basis the pentadecane (p. 135) obtained by Karrer el al.11 from
sparteine should be 6 : 8-dimethyltridecane,
Me . ( C H 2 ) 4 . CHMe . C H 2 . CHMe . (CH 2 ) 4 Me
and Schirm and Besendorf l x have synthesised the latter and identified it
with the sparteine hydrocarbon. Clemo and Raper 26 have modified Ing's
formula t o (VIII). The l a t t e r provides a n explanation of t h e fact t h a t
sparteine yields two monomethiodides, which appear t o be stereoisomerides, but does not yield a dimethiodide. Examination of a space
model of (VIII) shows t h a t if the two octahydropyridocoline systems are
both trans and if the C 7 C9 bridge is cis with respect to the hydrogen
atoms attached t o C 6 a n d C 1 1 the system is fairly rigid a n d t h e nitrogen
atoms are so close to each other t h a t t h e formation of a dimethiodide is
impossible. C o u c h 2 6 has proposed a n e w numbering system for t h e
sparteine formula as shown in ( V i l l a ) .
Support for (VIII) has been provided b y Clemo, Morgan a n d R a p e r ' s
LUPINANE
138
GROUP
10
PAPILIONACEOUS
ALKALOIDS
13d
Genisteine, C16H28N2, is a volatile base, m.p. 60-5, b.p, 139-5140-5/5 mm. ; forms a hydrate, B . H 2 0, m.p. 117, [a]D 52-3 (EtOH),
a picrate, B . 2C6H2(N02)3OH, m.p. 215, and a platinichloride,
B . H 2 PtCl 6 . 2iH 2 0.
Retamine, C15H26ON2 (No. 26, table, p. 118). This alkaloid, isolated
by Battandier and Malosse,28 is isomeric with oxysparteine and gives
colour reactions suggesting relationship to sparteine. I t is a strongly
alkaline diacidic base, m.p. 168, [<xD] -f 43-15 (EtOH), yields crystalline
salts and derivatives of which Ribas, Sanchez and Primo 28 have prepared
the following : B . HC1, m.p. 272-3, picrate, m.p. 165-6 ; acetyl derivative, hygroscopic, m.p. 60 (approx.), phenylurethane, m.p. 190-1. I t
behaves as a tertiary alcohol on oxidation and when heated under pressure
with hydriodic acid and red phosphorus forms an isomeride. The same
authors suggest for retamine a provisional formula, which is (VIII) of
p. 137, with . C6H . >. C6(OH) . and they regard retamine as a hydroxy derivative of an isomeride of sparteine. The hydrochloride is stated to
have no action on the frog heart.
Ammodendrine, C12H20ON2, H 2 0 (No. 1, table, p. 116). The base has
m.p. 731, becomes anhydrous at 70-80, and then melts at 50-60,
[a]D 0. The salts are amorphous and deliquescent except the hydriodide
B . HI, which forms a crystalline precipitate, m.p. 218-20, from alcohol,
and the perchlorate, m.p. 199-200. An amorphous iV-benzoyl derivative
was obtained. With methyl iodide ammodendrine behaves as a secondary
base, yielding first iV-methylammodendrine hydriodide (a crystalline
precipitate, m.p. 183-5, from a mixture of alcohol and acetone), and at
the second stage Ar-methylammodendrine methiodide, m.p. 163-5. On
hydrogenation ammodendrine furnishes a dihydro-base, which is
hydrolysed into acetic acid and 2 : 3'-dipiperidyl, C10H20N2, and must
be dZ-iV-acetyl-S-a-piperidylpiperidine. Ammodendrine should therefore
be acetyltetrahydroanabasine and is of biological interest as the first
recorded occurrence of this type of alkaloid in the Leguminosae.29
REFERENCES
(1) J. Pharm. Chim., 1911, [vii], 4, 251. F o r other special tests, see GRANT, J.
Amer. Pharm. Assoc, 1920, 9, 704 ; COUCH, Amer. J. Pharm., 1925, 97, 38 ; WAGENAAR,
Pharm. Weekbl., 1929, 66, 809 ; JARETZKY and AXER, Arch. Pharm., 1934, 272, 152.
(la) Bull. Sci. Pharmacol., 1938, 45, 255. (16) Quart. J. Pharm., 1946, 19, 532.
(2) Ber., 1904, 37, 3238 ; cf. WILLSTATTER and MARX, ibid., 1904, 37, 2351, and
MOUREU and VALEUR, Compt. rend., 1903, 137, 194. (3) Compt. rend., 1905,
140, 1601, 1 6 4 5 ; 1905, 141, 4 9 ; Bull. Soc. Chim., 1908, [iv], 3, 6 7 4 ; cf.
BAMBERGER, Annalen,
1904, 242, 5 1 3 ;
387.
Pharm.,
(4) Compt. rend., 1907, 145, 929 ; cf. SCHOPF and BRAUN, Annalen,
1928,
J. Chem. Soc, 1929, 1931 ; SPATH and GALINOVSKY, Ber., 1938, 71, 1282.
(5) Compt.
rend., 1907, 145, 1184, 1343 ; 1908, 146, 79 ; 1911, 152, 386. (6) VALEUR, ibid., 1908,
147, 127 ; Bull. Soc. Chim., 1909, [iv], 5, 31, 37, 40. (7) Bull. Soc. Chim., 1905, [iii],
33, 1271. (8) Compt. rend., 1907, 145, 815. (9) Ibid., 1912, 154, 161. (10) Ibid.,
1912, 154, 309. (11) Helv. Chim. Acta, 1930, 13, 1292; cf. SCHIRM and BASENDORF,
Arch. Pharm., 1942, 280, 64. (12) Ibid., 1928, 11, 1062. (13) Ber., 1905, 38, 1772 ;
WPiNANE CtnOVP
140
cf. WACKRRNAGEL and WOLTFENSTEIN, ibid., 1904, 37, 3238. (14) Ibid., 1887, 20,
2218 ; 1891, 24, 1095 ; 1892, 25, 3607 ; 1897, 30, 195 ; 1905, 38, 3268. (14a) Bar.,
1944, 77, B . , 132.
(16) CLEMO
and RAPEK, J. Chem. Soc, 1929, 1931. (17) WINTERFELD el al., Arch. Pharm., 1928,
266, 299 ; 1929, 267, 433 ; 1930, 268, 372 ; 1934, 272, 273. (18) Biochem. Zeit., 1927,
186, 269. See also WINTERFELD and SCHIRM, Arch. Pharm., 1938, 276, 544. (19)
Gazzetta, 1912, 42, [ii], 447 ; (Chem. Soc. Abstr., 1912, i, 579). (20) Helv. Chim. Acta,
1926, 9, 886.
(21) Ber., 1931, 64, 150 (with HOLSCHNEIDER), ibid., 2415 ; cf. W I N T E R -
FELD and R.AUCH, Arch. Pharm., 1934, 272, 273. (22) J. Chem. Soc, 1928, 1811.
(23) Ibid., 1931, 429. (24) Ber., 1931, 64, 1520 ; cf. however, WINTERFELD and
HOLSCHNEIDER, ibid., 1934, 67, 778. (25) J. Chem. Soc, 1933, 504. (26) Ibid., 644 ;
CLEMO, MORGAN and R A P E R , ibid., 1936, 1025 ; cf. W I N T E R F E L D and SCHIRM,
Arch.
Pharm., 1937, 275, 630 ; COUCH, J. Amer. Chem. Soc, 1936, 58, 688 ; see also K I N G ,
Ann. Repts. Chem. Soc, 1933, 30, 238. (26a) C. R. Acad. Sci., U.R.S.S., 1941, 3 1 ,
335 ; see also refs. (14), (15) and (16). (27) VALEUR, Compt. rend., 1918, 167, 26,
163 ; J. Pharm. Chim., 1913, 8, 573 ; WINTERFELD a n d NITZSCHE, Arch. Pharm.,
1940, 278, 393. (28) Compt. rend., 1897, 125, 360, 450 ; cf. WUNSCHENDORF and
VALIER, Bull. Sci. Pharmacol., 1933, 40, 601, and RIBAS et al, Anales fis. y. quim.
Madrid,
i. Toksikol,
Bull.
ANAOYBINE
141
CH=C
CH-CH,
CH
CH
CH, N-
CHOH,
-GH
(I) C y t i s i n e
CH
CH N
CHCH
CH
0 0 - N GH 2
t%
CON-
-OH,
(VI) L u p l n l n e
(Karrer
0E
s>
Anasylne
CH
N -
-CH
CO-N-CH
2
(III)
CHCH.
(Ing)
C H CH C H C H ,
I 2
i
I Z
CH GH CH
CH,
C&j-CHj,
(ID
CH CHCH.CHg0H
CH=GCHCH_
GH2
OHg
CH
CH
(V) Lupaaine
{Cleioo and RaperJ
CH,
CH,
z
CH, N -
GH
-CH 2
OHg
CH
GHg
CH 2 -<;H 2
(IT) Spartelna
(Clemo and Raper)
142
LVPINANE
GROUP
From cytisine
COOH . CHMe . CH 2 . CHMe . COOH
From anagyrine COOH. C H ^ H ^ ) . CH 2 . CHMe . COOH
Ing also found that anagyrine, on catalytic hydrogenation above 80,
yielded a tetrahydro-derivative, C15H24ON2 (b.p. 186-190/1 mm., [a]|
61-45 (acetone)), identical with Mupanine (V) (b.p. 186-8/l mm.;
[a]D 61-0 (acetone)), and on electrolytic reduction furnished hexahydroanagyrine, C15H26N2 (b.p. 130-5/l mm., [a]},9 + 10-9), identical* with
d-sparteine (IV) (b.p. 133-5/l mm.; [a] D + 15-9), with the exception of a
difference in the degree of rotation. Galinovsky and Stern 12 have confirmed, by hydrogenation, the reduction of anagyrine to ^-sparteine,
identified by oxidation to d-oxysparteine, m.p. 87, [<x]D -f 10-27, which
with J-oxysparteine (p. 136) gave the dl-form, m.p. 112-3 (cf. p. 138).
They also found that the catalytic hydrogenation of anagyramide led only
to the reduction of the pyridone ring the product being d-oxysparteine.
The interesting relationships between the five most important alkaloids
in this group, which have been made clear by these investigations, are
shown by formula? (I) to (VI) on p. 141. The synthesis of oxysparteine
by Clemo, Morgan and Raper (p. 138) supports formula (II) for anagyrine.
REFERENCES
(1) GERRARD, Pharm, J . , 1886, 17, 109, 2 2 7 ; 1888, 19, 1029; 1889, 20, 1017.
(2) For bibliography see CLEMO and R A P E R . 4 (3) Oslerr. Pot. Zeit., 1930, 79, 107.
(4) J. Chem. Soc, 1935, 10. (5) Apoth. Zeit., 1895, 10, 903. (6) Arch. Pharm., 1900,
238, 227. (7) Ibid., 1900, 238, 191, 2 3 0 ; cf. GOESSMANN, ibid., 190G, 244, 20. (8)
J. Chem. Soc., 1933, 504; cf. R Y D O N , ibid., 1936, 1445. (9) Ibid., 1942, 507. (10)
J. Amer. Chem. Soc, 1939, 61, 3327. (11) OREKHOV et al., Ber., 1934, 67, 1394. (12)
Per., 1944, 77, 132.
CYTISINE
143
/v\
N
CH
CH 2
CH/Ny^CHjs
CH
CH 2
CH
/
X> \ CH
CH 3 .CIK
CH.OH
CH,
CO
CH
JCH2
NHCH,
GNH
CH 2 v
I (Ewins)
NH
II (Freund and Gauff)
in (Spath)
the latter stating t h a t cytisine gives van de Moer's reaction with ferric
chloride and hydrogen peroxide indicating the presence of an a-pyridone
ring, t h a t the oxygen a t o m in cytisine is not present as either a hydroxyl
or a normal carbonyl group, and t h a t , as the alkaloid shows marked
resistance to reduction, t h e two ethylenic linkages must be present as a
conjugated pair in a single ring.
In 1931 Ing 8 pointed out t h a t formulae (II) and (III) do not contain
methyl or potential methyl groups in positions 6 and 8 which t h e y occupy
in cytisoline. Further, a partially reduced quinoline ought to oxidise
easily to a benzenecarboxylic acid and so far the only simple oxidation,
products recorded from cytisine were ammonia, oxalic acid and isovaleric
acid. Distillation of cytisine w i t h zinc dust or soda-lime yields pyrrole
and pyridine, but no quinoline. On these grounds Ing suggested t h a t
cytisine should be formulated without a quinoline nucleus, and t h a t t h e
reactions which indicate the presence of an aromatic nucleus in the alkaloid
can be accounted for by an a-pyridone ring. This a-pyridone nucleus can
CHprCH\
NH
CH
,/N
CHo
I \
CHg-CMe
(17)
(71)
CO
144
LUPINANE GROUP
C0
2
CHg.CH
(711)
CH-CH V
C H 3 . CHC '
NH <
CH2 Nv
CHg
(Till)
CH
yCH
CO
CH
2 , \
CH C
CH
II
NH N
CH
X
Me.CH (2T
C0
(II)
CYTISINE
145
octahydro-base. Glutaric acid is also produced when cytisine is hydrogenated to tetrahydrocytisine and the latter is oxidised by permanganate.
From (VIII) Spath and Galinowsky 10 derived five formulas for cytisine
depending upon the way in which the imino-group is fitted into the tetrahydrohemicytisylene formula, and of these three are eliminated by Ing's
observation l x that when methylcytisine is oxidised with barium
permanganate it is converted into a mixture of two isomeric lactams,
C12H1402N2, iV-methyl-a-cytisamide (m.p. 214-5) and 2V-methyl-0cytisamide (m.p. 179-80), each of which can be hydrolysed to the
corresponding cytisamic acid, C 12 H I6 0 3 N 2 .
In these lactams a
CH2NMe group in methylcytisine has been converted into
a CONMe group. Formula (IX) for cytisine would lead to two
lactams, which would be geometrical isomerides, and (X) would give rise
to two structural isomerides, (XI) and (XII), derived from methylcytisine.
CH
CH
Cx
CH
NH (A)
,CH
CH
| ( C ) ||
CH_(B) N
CH ^ .
CH
||
NMe CH, N
l\ /
I I l\ /
I XC0
CHg
CH
V
CHg
CH
CH-CHC
NMe CH N
| |\/
I
(XI)
CH
I XC0
CH 2 -CHCH
CH
and I
COCHdig
C0
(XII)
CH
\2
CH-CH-C
AC.N
(X)
,CH
COCHC
CH
CH N
CHp-CH.CJI,-,
CH,,-=*AC.N
CH
4
I I
CHP
CHp-CHMe
CHg-CHCHg
(XIII)
(XIV)
X
CH=C.C=H11
CH'= C C 0 C H
N
CH
II
II
JQHCite
N
CH
li
CHCMe
>
(XV)
(XVI)
146
LUPINANE GROUP
235,
374.
(5) F R E U N D , Ber.,
1901,
34, 6 0 5 ;
1904,
37, 1 6 ; 1906, 39, 8 1 4 ; Arch. Pharm., 1918, 256, 33. (6) J. Chem. Soc, 1913, 103,
97 ; see also CHAKRAVARTI et al., Brit. Chem. Abstr., 1934, A, 195 ; 1936, A, 742. (7)
Monats., 1919, 40, 15, 93. (8) J. Chem. Soc, 1931, 2195. (9) Ber., 1891, 24, 6 3 5 ;
Arch. Pharm., 1892, 230, 448 ; 1894, 232, 161. (10) Ber., 1932, 65, 1526 ; which also
quotes a Dissertation by B R E U S C H , Vienna, 1927. (11) J. Chem. Soc, 1932, 2778.
(12) Ber., 1933, 66, 1 3 3 8 ; 1936, 69, 761 ; 1938, 71, 721 ; 1943, 76, 947. (12a)
147
MATRINE
POLONOVSKI and LECOQ, Compt. rend., 1942, 214, 1912 ; Bull. Soc. chim., 1945, [v],
12, 83 ; LECOQ, ibid., 1943, [v], 10, 153, cf. SPATH 12 (1943). (13) Arch. Pharm., 1892,
230, 448 ; cf. BUCHKA and
MAGELHAES, Ber.,
(14)
J.
Chem. Soc,
103, 194. (14a) W H I T E , N. Z. Journ. Set. Tech., 1944, 25, B , 152. (15) Idem.,
1946, 27, B , 339.
1913,
ibid.,
'
>
CH3.N(0]4%4N)CO.OCH3
148
LUPINANE
GROUP
f
>l
Bromocs anide B
Bromocyanlde A
C
12H21N(00-OH3)N-Br-CN
(Hydrogenation, Pd)
(Hydrogenation, Pd)
norCyapamlde
Cl2H22H(C0.OH3)N.CH
1 (Hydrolysis, HOI)
|
12
ZZ
(Hydrolysis, HOI)
\
Z
(Hydrolysis, HC1)
lZ
ZZ
\
C
"H) 2
0 1 2 H2 4 0N 2
(Dehydrogenation, Pd)
(Dehydrogenation, Pd)
"IAA
12 H2 2 (NH) 2
(Dehydroa-matrinidlnej
(Oxidation,
KJ&1O4}
linolinl acid
(pyridine- 2:3-4l0(irboxylic acid)
Matrine is isomeric with lupanine (p. 128), and sophocarpine (p. 150);
and in common with anagyrine (p. 140), sophocarpine and aphylline
(p. 54), may be supposed to contain a lactam ring, though it differs from
them in the ease with which the lactam group undergoes alkaline hydrolysis
with the formation, e.g., of potassium matrinate, and in the fact that it
cannot be reduced to C 15 H 26 N 2 (sparteine or an isomeride) except by zinc
dust distillation. Lupanine and sparteine can be dehydrogenated to the
MATRINE
149
f-N-CO-CHlte
C
2
(A)
10H1
CH,
-CE-CH 2 -CHg
(B)
CH75CH5
CH -CH-
CO
I
-CH
I
CH,
CH0
CH,
CHs
| 2
CHo
-N
-CH
CH
C H - - N CH,
CH,
2
CH,
CHp
(I)
CH.
CH,
CH
I
I
CHoN"
en)
-CH,
-N
I
I
CH,
IC
CH- -CH
CHo2
<s
CH5CH-
CHo
, 2
CO
CH,
CHN-
HID
CH,
150
LUP1NANE
GROUP
PHARMACOLOGICAL
ACTION
151
oxygen atom is still " indifferent," though the second nitrogen atom has
become basic, e.g., in the dihydriodide, B . 2 H I . 3MeOH, m.p. 296-8 {dec).
The picrate has m.p. 143-4, the platinichloride, m.p. 241-2 (dec.), and
the methiodide, m.p. 261-2. Thermopsine is not hydrolysed by acids
or alkalis, is unsaturated to permanganate and attempts a t degradation
by the Emde, Hofmann or von Braun procedures proved unsuccessful.11
homoThermopsine, C17H24ON2. M.p. 224-5, [a] D + 86-9 (CHC13).
Crystallises in small needles (Orekhov et al., 1934). ll
Rhombifoline, C15H20O2N2. Amorphous. Salts: Perchlorate, m.p.
242 ; picrate, m.p. 207 (Manske).11
Rhombinine, C 16 H 22 0 2 N 2 (see also item 18(a), list, p. 118). Amorphous.
Salts : Perchlorate, m.p. 313 ; picrate, m.p. 253 (Manske).11 Octahydrorhombinine, C16H30O2N2, has b.p. 140/0-2 mm. and yields a perchlorate,
B, HC104, m.p. 213, [<x]D 40-9 (H 2 0).
REFERENCES
(1) J. Pharm. Soc. Japan, 1899, No. 8 4 ; cf. PLUGGE, Arch. Pharm., 1895, 233,
441. For more recent records of occurrence and characteristics see refs. (9) and (10).
(2) Ibid., 1928, 266, 1. This gives references t o t h e papers published in Japanese
journals. (3) W I N T E R F E L D and K N E U E R , Ber., 1931, 64, 152. (4) K O N D O , OCHIAI,
T S U D A and YOSHIDA, Ber., 1935, 68, 570. (5) K O N D O (with T S U D A ) , ibid., 1935, 68,
644 ; (with OCHIAI and TSUDA), ibid., 1899 ; Arch. Pharm., 1937, 275, 493 ; TSUDA,
Ber., 1936, 69, 4 2 9 ; TSUDA and MURAKAMI, J. Pharm. Soc. Japan, 1937, 57, 6 8 ;
OCHIAI (with I T O ) , Ber., 1938, 71, 938 ; (with NODA), J. Pharm. Soc. Jap., 1938, 58,
174; (with ITO and MARUYAMA), ibid., 1939, 59, 270. (6) Arch. Pharm., 1934, 272,
673; Ber., 1935, 68, 431. (7) Ibid., 1934, 67, 77, 1850 ; 1935,68,429. (8) OREKHOV,
et al., ibid., 1933, 66, 948. (9) Idem., ibid., 1933, 66, 948 ; 1934, 67, 77, 1850; 1935,
68, 429. (10) BRIGGS (with RICKETTS), J. Chem. Soc, 1937, 1795 ; (with TAYLOR),
ibid., 1938, 1206 ; (with RUSSELL), ibid., 1942, 507, 555. (11) OREKHOV, et al., Ber.,
1933, 66, 625 ; 1934, 67, 1394 ; 1935, 68, 820 ; cf. MANSKE and MARION, Can. J.
Res.,
PHARMACOLOGICAL
ACTION
OF
THE LUPINANE
ALKALOIDS. None of these alkaloids is of much importance in medicine,
though sparteine sulphate is so used, and in Russia the use of galenical
preparations of Thermopsis lanceolata (No. 37; list, p. 118) as respiratory
and circulatory stimulants has been proposed.1 Several of the plants
concerned are known as the cause of fatal poisoning cases notably laburnum
(Cytisus Laburnum) and Freise 2 has called attention to " cocobolo " wood,
derived from Apuleia molaris Benth., as the origin of a chronic poisoning
case due to the presence in the wood of a small proportion of cytisine. In
this connection special interest attaches to the microchemical detection of
cytisine of which a bibliography has been published by Wagenaar. 3
Reference has been made already to the " de-bittering " of lupin seeds
for use as a feeding-stuff for cattle and for this purpose Makaro and
Kondratyeva 4 have devised a scheme for the preparation of an alkaloidfree lupin flour, the recovered alkaloids being used as an insecticide. This
group of alkaloids is attracting some attention in Russia for this purpose
and sophocarpine, obtained from Ammothamnus lehmanni, has been tried
for the destruction of the web mite. 6
152
LUPJNANE
GROUP
PHARMACOLOGICAL
ACTION
153
piperidyl residue ; and Merrier and Mercier 20 have found that large doses
of diethylaminoethanol produce sparteine-like effects in dogs.
Cytisine. This base belongs to the same pharmacological group as
nicotine. 21 It is a powerful poison causing nausea, convulsions and death
by failure of respiration. The nicotine-like action is shared by iV-methylcytisine but the latter, according to Scott and Chen,22 who have made a
detailed study of its action, is weaker and has about one-fortieth the toxicity
of nicotine.
REFERENCES
(1) VARLAKOV, Khim.
Farm.
Prom.,
KUZNETSOV,
Farm. i. Farmakol., 1937, No. 7, 1 ; MASHKOVSKII, ibid., 1941, 4, 105; KHALETSKI and
FEDOROVA, Farmatsiya, 1946, 9, No. 5, 3 2 ; MAEVSKIL, Farmikol, i. Toksikol, 1945, 8,
49. (2) Samml. Vergiftungsfalien, 1936, 7, Abt. C, 1-8 (Chem. Abstr., 1938, 32, 4222).
(3) Pharm. Weekbl., 1930, 67, 205 ; cf. K L E I N and FARKASS, (Esterr. Bot. Zeit., 1930, 79,
107. (4) Trudy. Beloruss. SeVskokhoz. Inst., 1939,10, 47 ; cf. ISAEV, ibid., 1939, 8, 119.
(5) Social Sci. Tech. Tashkent, 1939, 7, 197. (6) J. Physiol., U.R.S.S., 1938, 25, 179.
(7) Brit. Med. J., 1943, ii, 322. (8) C. R. Soc. Biol, 1942, 136, 667, 732. (9) Tribuna
farm. (Brazil), 1944, 12, 1. (10) J. Chem. Soc, 1944, 274. (11) MERKULOV, Bull.
Biol. Med. exptl., U.R.S.S., 1938, 6, 64 ; NIKITIN, C. R. Acad. Sci., U.R.S.S., 1941, 32,
596; PANASCHENKO, Farmikol, i. Toksikol., 1946, 9, 26. (12) C. R. Soc. Biol., 1939,
131, 895. (13) Giorn. Batteriol., 1939, 22, 307. (14) Arch. exp. Path. Pharm., 1941,
197, 252. (15) J. Pharm. exp. Ther., 1941, 72, 23. (16) Ibid., 73, 151; LEVY-SOLAL
el al., Presse m,ed., 1946, 24, 349. (17) Arch. exp. Path. Pharm., 1943, 200, 536, 551.
(18) Ibid., p. 528. (19) Compt. rend., 1945, 220, 749 ; 221, 60 ; cf. GRAUBNER and
KRAUS, Arch. exp. Path. Pharm., 1937, 184, 235. (20) Boll. sci. facolta. Chim. ind.
Bologna, 1940,
159;
MERCIER, C. R.
140, 191.
(21)
DALE
and
LAIDLAW, J. Pharm. exp. Ther., 1912, 3, 205 ; J. Physiol, 1911, 43, 196 ; 1912, 44,
x i i ; ZACHOWSKI, Arch. exp. Path. Pharm., 1938, 189, 326 ; (with Z I P F ) , ibid., 1938,
190, 217. (22) J. Pharm. exp. Tfier., 1943, 79, 334.
isoQUINOLINE GROUP
ALKALOIDS OF THE CACTACEJE. Heffter* has recorded the
presence of alkaloids in a number of cacti, but only those of Anhalonium
spp. have been fully investigated. Heyl * obtained an amorphous base,
pilocereine, from Pilocereus sargentianus Ore, and Ducloux 1 extracted
from Gymnocalycium gibbosum. Haw., basic material which he regarded as a
mixture of the anhalonium bases, anhalonine, lophophorine and mezcaline.
Anhalonium spp. A number of plants known by the name " pellote "
and belonging to this genus are used in Mexico to produce intoxication
in the course of religious ceremonies. The best-known product of this
kind is the flowering heads of A. Lewinii Hennings, which have been
imported into Europe for use in medicine under the name " mescal or
mezcal buttons." The following Anhalonium alkaloids are known :
Hordenine (Anhaline), C10H15ON, in A. fissuratum Engelm.
Anhalamine, C u H 1 5 0 3 N, in A. Lezvinii.
Anhalidine (iV-methylanhalamine), C 12 H 17 0 3 N, in A. Lewinii.2^
Anhalinine(O-methylanhalamine), C 12 H 17 0 3 N, in A. Lewinii.21
Mezcaline, C n H 1 7 0 3 N, iV-methylmezcaline, C12H1903N,2(i;), and
N-acetylmezcaline, C13H1904N2(c), in A. Lewinii.
Anhalonidine, C 12 H 17 0 3 N, and O-methyl-d-anhalonidine, in A.
Lewinii.
Anhalonine, C 12 H 15 0 3 N, in A. Lewinii and A. Jourdanianum Lem.
Lophophorine, C 13 H 17 0 3 N, in A. Lewinii.
Pellotine, C 13 H 19 0 3 N, in A. Lewinii and A. Williamsii Lem.
Processes for the extraction and separation of the alkaloids are given
by Kauder 2(a) and Spath and Becke.2(6)
Anhaline, C10H15ON, was isolated by Heffter 1 from A. fissuratum, and
later identified by Spath as hordenine 3 (p. 638).
Anhalamine, C n H 1 5 0 3 N, occurs in microscopic needles, m.p. 187-8.
The hydrochloride, B . HC1. 2H 2 0, forms lustrous leaflets, m.p. 256-8
and the sulphate, B 2 . H 2 S0 4 , colourless prisms ; the picrate has m.p.
234-6. The base contains two methoxyl groups and one hydroxyl group.
A dibenzoyl derivative, m.p. 128-9, and a monobenzoyl derivative,
m.p. 167-5, are formed, the latter but not the former being soluble in
alkalis. The methyl ether of anhalamine is identical with anhalinine,
b.p. 130-4070-01 mm., m.p. 61-3, and the JV-methyl derivative is
anhalidine, m.p. 131-3.
Mezcaline (Mescaline), C u H 1 7 0 3 N, is a colourless alkaline oil, b.p.
180-180-5/12 mm., which absorbs carbon dioxide from the air, forming a
crystalline carbonate. The sulphate, B 2 . H 2 S0 4 . 2H 2 0, m.p. 183-6,
forms brilliant prisms ; the hydrochloride, m.p. 181, colourless crystals ;
picrate, m.p. 216-8 ; and the platinichloride (B . HC1)2 . PtCl 4 , m.p.
154
CACTUS
ALKALOIDS
155
156
isoQUINOLINE
GROUP
Mezcaline. Heffter proved tha mezcaline was not identical with the
base having the formula shown above, which he synthesised for this
purpose,5 and it was not until Spath began work on these alkaloids that
their relationships were cleared up. In his first paper 3 this author showed
that anhaline was identical with hordenine (/J-jp-hydroxyphenylethyldimethylamine, HO . C 6 H 4 . CH 2 . CH 2 . NMe2, p. 633), and described the
synthesis of mezcaline by the following series of reactions. Galloyl chloride
( 3 : 4 : 5-trimethoxybenzoyl chloride) was reduced by Rosenmund's
method 6 to 3 : 4 : 5-trimethoxybenzaldehyde, which was condensed with
nitromethane to a>-nitro-3 : 4 : 5-trimethoxystyrene,
C 6 H 2 . (OMe) 3 . CH : CH . N0 2 .
This, on reduction with zinc dust and acetic acid, yielded the corresponding
oxime, which was further reduced by sodium amalgam to /J-3 : 4 : 5trimethoxyphenylethylamine, C6H2(OMe)3 . CH 2 . CH 2 . NH 2 , and this
proved to be identical with mezcaline (I). Like the latter, it behaves on
analysis as if it contained the grouping NHMe but this had already been
disproved by Heffter.5 Interest in the remarkable physiological properties
attributed to mezcaline has led to many syntheses of this alkaloid and of
its isomerides and analogues.7
Anhalamine. When mezcaline is condensed with formaldehyde it
yields 6 : 7 : 8-trimethoxy-l : 2 : 3 : 4-tetrahydrowoquinoline and the
quaternary iodide obtained from this is identical with dimethylanhalamine
methiodide. 8 It follows that O-methylanhalamine must be 6 : 7 : 8 trimethoxy-1 : 2 : 3 : 4-tetrahydroisoquinoline. The free hydroxyl group
was shown to be at C8 by Spath and Becke,9 who found that the product
( I I : R = Et), formed by O-ethylation of anhalamine, gave 4 : 5 dimethoxy-8-ethoxyphthalic acid anhydride, m.p. 106-7, on oxidation
with potassium permanganate. Anhalamine is therefore 8-hydroxy-6 : 7dimethoxy-1: 2 : 8 : 4-tetrahydroioquinoline ( I I : R = H). Anhalidine
is Ar-methylanhalamine and anhalinine the O-methyl ether ( I I : R = Me)
CACTUS
ALKALOIDS
157
of anhalamine. **' The structure of anhalamine had already been established by the synthesis of the alkaloid from 5-hydroxy-3 :4-dimethoxybenzaldehyde, which was converted into j8-5-hydroxy-3 :4-dimethoxyphenylethylamine, and the latter condensed with formaldehyde, the
hydroxyl group being protected by ethylcarbonation or benzylation up to
the last stage. 10
Pellotine and Anhalonidine. The 2V-acetyl derivative of mezcaline
(I: NH2* NHAc), on treatment with phosphoric oxide, yields 6 : 7 : 8 trimethoxy-l-methyl-3 :4-dihydroisoquinoline (picrate, m.p. 181-2),
which, on successive catalytic hydrogenation and treatment with methyl
sulphate, yields 6 : 7 : 8-trimethoxy-l : 2-dimethyl-l : 2 : 3 : 4-tetrahydroisoquinoline identical with O-methylpellotine (picrate, m.p. 167-8),
whence it appears that pellotine must be a dimethyl ether of 6 : 7 : 8 trihydroxy-1 : 2-dimethyl-l : 2 : 3 : 4-tetrahydrowoquinoline.
Pellotine
and anhalonidine on complete methylation yield the same product, and as
anahalonidine is a secondary base and differs from pellotine by containing
CH2 less, it must be a dimethyl ether of 6 : 7 : 8-trihydroxy-l-methyl1 : 2 : 3 : 4-tetrahydrowoquinoline, 11 and pellotine should be A'-methylanahalonidine.
The position of the free hydroxyl group in these two alkaloids is either
C6 or C8, since Spath has shown that the OiV-diacetyl derivative of /3-5hydroxy-3:4-dimethoxyphenylethylamine, when heated in toluene
solution with phosphoric oxide, yields a product which must be either
6-acetoxy-7 : 8-dimethoxy-, or 8-acetoxy-6 : 7-dimethoxy-l-methyl-3 : 4dihydrowoquinoline. On reduction with tin and hydrochloric acid it is
converted into anhalonidine, which must therefore be 6-hydroxy-7:
8-dimethoxy(or
8-hydroxy-6 : 7-dimethoxy-)-l-methyl-l : 2 : 3 : 4tetrahydroisoquinoline. Similarly the methiodide of the acetoxy-compound on reduction yields, by loss of acetic acid and addition of two
hydrogen atoms, pellotine, proving the latter to be N-methylanhalonidine. 12
The position of the free hydroxyl group was finally shown by Spath 13 to
CH2
5HP
MeoL
IKH
MeO
(I) Mezcaline
"
i Y r"
Meol !l ) m
OR
CH
2
(II) Anhalamine
(R = H )
MeOi^
A/"
Meol
\m
CHMe
(III) Anhalonidine
MeO FP \\
MeO
pH2-CH (OEt)
pH
Meol
1 JN
h-0
CHgPh-0
CHe
(V)
158
isoQUINOLINE
GROUP
\\/\/
H2C0
(VIII) Anhalonine
CH2
/<?2
ol
H
INHAO
C-/
(VII)
CH2
JleoL J l JMH
CHMe
(XI) S a l s o l i n e
(XII) Hydrohydrastinlne
CACTUS
ALKALOIDS
159
160
JSOQUTNOLINE
GROUP
The ett-form of this substance, 6 : 7-dimethoxy-l-methyl-l : 2 : 3 : 4tetrahydroisoquinoline, which had already been synthesised by Sch6pf
and Bayerle, 23 in the course of their biogenetic work on isoquinoline
alkaloids, was prepared by Spath and Dengel 23 and resolved into the dand J-forms. They recorded for the dl-form, m.p. 53-53-5, and for the
Z-form, m.p. 47-5-48-5, and [<x]J,6 59-7 (EtOH), which differ somewhat
from the figures first recorded for natural Z-salsolidine. Proskurnina and
Orekhov 23 (1939) explained these differences by showing that d- and
^-salsolidine each occurs in two forms, m.p. 41-5 and 71-3 (dry) produced
respectively by distillation in vacuo and crystallisation from water.
The third alkaloid, salsamine, has m.p. 155-7 (dec.) ; the hydrochloride,
m.p. 255-260 (dec.); picrate, m.p. 213-4 ; and picrolonate, m.p. 220-1.
Corypalline, C u H 1 5 0 2 N (Corydalis spp. Nos. 9, 22 ; list, p. 170). This
phenolic base, m.p. 168, picrate, m.p. 178, contains one methoxyl group
and on methylation yields 2-methyl-6 : 7-dimethoxytetrahydrot'soquinoline,
C 12 H 17 0 2 N, m.p. 82, and on ethylation, 2-methyl-6-methoxy-7-ethoxytetrahydroz'soquinoline, m.p. 65, whence the free hydroxyl appears to be
at C7 and this has been confirmed by the synthesis of corypalline by a
method analogous with that used by Spath, Orekhov and Kuffner.24
Corypalline is therefore hydrohydrastinine (XII) with the methylenedioxy
group replaced by MeO at C6 and . OH at C7 (Manske).23((t)
Other simple naturally occurring methyltetrahydnmoquinolines are
hydrohydrastinine (XII), (p. 164) found, like corypalline, in Corydalis spp.,
and hydrocotarnine found in opium (p. 201).
Pharmacology. Interest in the anhalonium alkaloids dates from the
investigations of Lewin 1 and Heffter.1 The general pharmacological
actions of mezcaline, anhalonine, anhalonidine and lophophorine show
certain qualitative similarities. 25 In the frog mezcaline depresses the
central nervous system. This effect is also observed in mammals ; death
is due to respiratory paralysis. The effect on the blood pressure varies
with the dose and the animal. In the chloralosed dog 26 it is mainly
depressant; in the decapitated cat 27 it has a pressor effect. 3 : 5Dimethoxy-4-ethoxyphenylethylamine
and 3 :4-diethoxy-5-methoxyphenylethylamine have a similar action to mezcaline, but are more toxic. 27
A series of methoxyphenylethylamines has been examined by Epstein,
Gunn and Virden. 28
Anhalonine produces increased reflex excitability in the frog after a
phase of paresis (Heffter,1 1898). The symptoms in the rabbit are
analogous, but the transitory paresis is less marked. The lethal dose of
the hydrochloride for rabbits is 0-16-0-2 gm. per kilo, body weight.
Anhalonidine is not so active and resembles pellotine in action. In
frogs it produces a type of narcosis or paresis, followed by a phase of
increased excitability. Larger doses have a curare action. On mammals
the action is slight.
Lophophorine is the most toxic of the group. No preliminary paresis is
observed in either the frog or rabbit; 15-20 mg. per kilo, body weight is
fatal in rabbits.
CACTUS
ALKALOIDS
161
l<mafa., 1919, 40, 129 ; 1921, 42, 263. (3a) Ber., 1942, 75, 1558. (36) Ibid., 1938,
71, 2141. (4) ROSENTOALEB, Pharm. Zeit., 1931, 76, 658; DUCLOUX, Bev. Farm.
TLAWl ALU.
isoQUINOLINE
162
OBOUP
Buenos Aires, 1931, 74, 87. (5) Ber., 1901, 34, 8 0 0 4 ; (with CAPEXLHANN), 1905, 38,
3634. (6) Ibid., 1918, 5 1 , 585. (7) SLOTTA (with H E I X E R ) , Ber., 1930, 63, 3029 ;
(with SZYSZKA), J. pr. Chem., 1933 [ii], 137, 339 ; Ber., 1934, 67, 1106 ; J A N S E N , Rec.
trao. Chitn., 1931, 50, 291, 617 ; KINDUER (with PESCHKE), Arch. Pharm.,
1932, 270,
410 ; (with BKANDT), ibid., 1935, 273, 478 ; H A H N (with WASSMUTH), Ber., 1934, 67,
696, 1210; (with R U M P F ) (36); IWAMOTO a n d HARTUNG, J. Org. Chem., 1944, 9,
(11) SPATH,
ibid., 1921, 42, 97. (12) SPATH, ibid., 1923, 43, 477. (13) Ber., 1932, 65, 1778. (14)
Monats.,1933, 63, 141. (15) Ber., 1934,67,266. (16) Ibid., 1936,69, 755. (17) Monats.,
1923,44,103;
F R E U N D , Ber., 1903,46,4258.
1663. (19) Arch. Pharm., 1928, 266, 668. (20) Ber., 1929, 62, 1021. (21) Ibid., 1929,
62,2242. (22) Arch. Pharm., 1901, 239, 451. (23) Ber., 1933, 66, 841 ; 1934,67,878;
Bull. Soc. chitn., 1937, [v], 4, 1265 ; 1939, [v], 6, 44.; cf. SPATH and DENGEL, Ber., 1938,
71, 113, and SCHOPF and B A Y E R L E , Annalen,
J.
Res., 1937, B , 15, 159. (24) Ber., 1934, 67, 1214. (25) DIXON, J. Physiol., 1899, 25,12.
(26) RAYMOND-HAMET, Arch. exp. Path. Pharm., 1933,169, 97. (27) GRACE, J. Pharm.
Exp. Ther., 1934, 50, 359. (28) C. R. Soc. biol., 1935, 119, 828. (29) SLOTTA and
MtiLLER, Zeit. physiol. Chem., 1936, 238, 14 ; cf. BERNHEIM a n d BERNHEIM, J. Biol.
Chem., 1938, 123, 3 1 7 ; BLASCHKO, J. Physiol., 1944, 103, 13P. (30) MOGILEWA,
Arch. exp. Path. Pharm., 1903, 49, 137. (31) " Gifte und Vergiftungen," Berlin, 1929.
p . 724. (32) " Der Meskalinrausch," Berlin, 1927 ; see aslo BUCHANAN, Med. Ann.,
1931, 12. (33) CRITCHLEY, Brit. J. Inebr., 1931, 28, 99. (34) GUTTMANN, J. ment.
Sci.,
Compt.
rend. Soc. Biol., 1935, 118, 591. (36) ROCA, An. Inst. biol. Univ. Mix., 1931, 2, 137.
(37) LUDUENA, Compt. rend. Soc. Biol., 1936, 121, 368. (38) Idem., ibid., 1933, 114,
809, 950, 951, 953 (with LEWIS), p . 814 ; R E T I , ibid.,ip. 811. (39) J. Physiol,
V.R.S.S.,
1938, 24, 1174. (40) WASTL, Hahnemannian Month., 1946, 81, 243.
ALKALOIDS OF HYDRASTIS
CANADENSIS
L. The rhizomes
of this North American plant (Ranunculacese) contain three alkaloids, of
which one, hydrastine, is, for convenience, dealt with here though the
sub-group, phthalidewoquinolines, to which it belongs is typically developed in the botanical order Rhceadales (pp. 169 and 200); the other two,
berberine and canadine, are described under Berberis alkaloids (p. 328).
The drug is no longer official in the British or United States Pharmacopoeia.
The British Pharmaceutical Codex states that it contains hydrastine about
2 per cent, and berberine about 2-5 per cent., though lower and higher
figures are frequently quoted. 1 A phytochemical investigation of
alkaloidal production and distribution in the plant has' been made by
Gillis and Langenhan. 2 Processes for the isolation of the total alkaloids
and for the separation and purification of hydrastine have been published
by Power,3 Schmidt and Wilhelm, 4 Freund and Will B and Schmidt.6 As
hydrastine is a potent alkaloid, much attention has been given to its
estimation in hydrastis and its galenical preparations. Processes of this
kind were published in the British Pharmacopoeia of 1914, and the United
States Pharmacopoeia, 10th Revision, 1926. Assay methods for the liquid
and solid extracts are included in the British Pharmaceutical Codex, 1934,
and for the crude drug, extracts and tincture, in the United States National
Formulary VIII. 7 A process for the estimation of berberine in Hydrastis
tincture has been described by Awe.7
Hydrastine, C gl H u O e N. This alkaloid was isolated by Perrins,8 and
HTDBASTINE
163
164
isoQUINOLINE
GROUP
CH : NMeCl
. /
C H 0
7 4 2
CBO
7 4 2
"CHg.CHg.NHUe
CH .CH
2
2
Hydrastinine
Hydrastinine c h l o r i d e
C00H
CH.OH
r,HX
/
CHO
7 4 2
and ( I I )
7 4 2.
N3H.CHg.NHMe
\ , CH
.CH .NMe
C
7H42
.CH .NHMe
2
CO . NMe
C H
7 42
I
CH.CH
CH.CH
2
2
Hydrohydrastinine
Oxyhydrastinine
The intermediate products (I) and (II) lose water, forming hydrohydrastinine and oxyhydrastinine respectively. 1 6 Alkaline permanganate
converts oxyhydrastinine into hydrastinic acid ( I I I ) , C n H 9 0 6 N , needles,
m.p. 164 ; this in t u r n is oxidised b y dilute nitric acid t o hydrastic acid
methylimide (IV), C 1 0 H 7 O 4 N, m . p . 227-8, which, when warmed with
potassium hydroxide solution, furnishes methylamine and hydrastic
acid (V).
/CO.NHMe
CHO
7 4 2\cO.C00H
( H I ) Hydrastinic
acid
-CO,
"C0-
Nile
/CHO
C1 H . O8 . ^
* ^CH 2 .CH 2 .HMe 3 I
(TT) Methylhydrastlnlne
methlodlde
-5"
-C00H
7H42\
/ CHO
^
^CH:CH 2
|Vn) HTdra'stal
HYDRASTINE
165
Hydrastic acid
methyllmlde
Hydrastic sold
Hydrastlnlc acid
CH2.NlIe
CH2.CH2
Hydrohydrastinine
CH_
^> B HrT
Oxyhydrastinine
CHO
CH
*\r
CH-S \
-CH : NMeCl
0
^ V 2 \ CH .CH
2
2
Hydrastinine chloride
166
isoQUINOLINE
GROUP
CH2
'
4 2
^-CH 2 . CH2
HYDRASTINE
167
168
GROUP
TSOQUINOLINE
the eye in 10 per cent, solutions it causes dilatation of the pupil. In the
dog some of the drug is excreted in bile as well as in the urine (Bemardbeig
and Caujolle).32
REFERENCES
(1) F o r other figures see WASICKY a n d JOACHIMOWITZ, Arch. Pharm.,
1917, 255,
4 9 7 ; CLARK and W I N T E R , Trans. Boy. Soc. Canada, 1926, [iii], 20, I I I , 307 ; MARKWELL,
Chem. and Drug., 1937, 126, 9 0 ; JERMSTAD, Norsk, farm. Tids., 1936, 44, 325, 3 3 9 ;
POLACCI and GALOTTI, Boll, Soc. ital. biol. sper., 1942, 17, 652. (2) J. Amer.
Pharm. Assoc, 1931, 20, 210, 3 2 9 ; cf. HIROSE and LANGHENHAN, ibid., 1930,
19, 349. (3) Pharm. J., 1884-5, [iii], 15, 297 ; 1885-6, [iii], 16, 1092. (4) Arch.
Pharm., 1888, 226, 329. (5) Ber., 1886,19, 2797. (6) Amer. J. Pharm., 1919, 91, 270.
(7) F o r other methods a n d comments see BECKURTS, Apoth. Zeit., 1896, 1 1 , 552 ;
GORDIN a n d PRESCOTT, Arch. Pharm., 1899, 237, 439 ; PUCKER, Pharm. Rev., 1908,
26, 132 ; VAN D E B HAAR, Pharm. Weekbl., 1911, 48, 1302 ; DAVID, Pharm. Post., 1915,
48, 1 ; DE WAAL, Pharm. Weekbl., 1915, 52, 1423 ; SCHMIDT, Amer. J. Pharm., 1919,
91, 270 ; DIETERLE, Arch. Pharm., 1923, 261, 85 ; RATJRICH, Anal. Fis. Quim., 1926,
24, 647, 665, 668 ; ALBANESE and PEDRONI, Ann. Chim. Applic, 1928, 18, 429 ;
NEUGEBAUER a n d BRUNNER, Pharm. Zeit., 1933, 78, 1077; 1937, 82, 1212 (microchemical) ; GREEN, Bull. Nat. Form. Comm., 1942, 10, 288 ; 1944, 12, 169 ; COPLEY,
Ibid., 1946, 14, 149; BROCHMANN-HANSEN, Med. fra. Norsk, farm, selsk., 1944, 6,
149; 1946, 8, 2 ; HAMMOND, Pharm. Arch., 1944, 15, 56 (a review); A W E , Apoth.
Zeit., 1937, 52, 1359. (8) Pharm. J., 1862, p i ] , 3, 546. (9) Silliman's J., 1863, 36,
57. (10) Ber., 1887, 20, 88. (11) Bee, trail. Chim., 1886, 5, 291. (12) J. Chem. Soc,
1910,
J.
Amer.
Pharm. Assoc, 1948, 37, 4 1 . (13) GAEBEL, Arch. Pharm., 1910, 248, 207. (14) Ber.,
1887, 20, 88. (15) See also REICHARD, Pharm. Zenlr., 1911, 52, 1253 ; STEENBERG,
Svensk. Farm. Tidskr., 1940, 44, 309 ; KIRKPATRICK, Quart. J. Pharm.,1946,19,8.
(16)
F R E U N D and W I L L , Ber., 1887, 20, 88, 2400 ; see also F R E U N D , 1889, 22, 456, 1156 ;
cf. MCGEOGH and STEVENS, J. Chem. Soc, 1934, 1465. (17) Annalen, 1888, 249, 172;
cf. F R E U N D , Ber., 1889, 22, 2329; Annalen, 1892, 271, 3 2 0 ; (with LACHMAN), Ber.,
1889, 22, 2322. (18) Cf. ROSSIN, Monats., 1892, 12, 486. (19) Syntheses of hydrastic
acid have been effected b y P E R K I N and ROBINSON, J. Chem. Soc, 1907, 1086 ; and
STEVENS and ROBERTSON, ibid., 1927, 2790. (20) Annalen, 1895, 286, 18. (21)
F R E U N D , Ber., 1887, 20, 2403. (22) German Patent 267,272 (Chem. Soc. Abstr., 1914,
[i], 79). (23) J. Chem. Soc, 1904, 85, 1006 ; cf. STEINER, Bull. Soc. chim. biol., 1924,
6, 231 ; a n d H O P E and ROBINSON, J. Chem. Soc, 1911, 99, 2118. (24) Ibid., 1912,
101, 1595 ; cf. TOPTSCHIEV, J. Appl. Chim. Buss., 1933, 6, 529. (25) F R E U N D , German
Patents, 241,136, 242,217, 242,573, 259,873 (Merck) (Chem. Soc. Abstr., 1912, [i], 383,
487 ; 1913, [i], 1095); and Annalen, 1913, 397, 30. (26) DECKER and collaborators,
German Patents, 234,850, 245,523, 267,699 (Chem. Soc. Abstr., 1911, p ] , 906 ; 1914,
[i], 198). F o r other similar syntheses of hydrastinine and its homologues or related
substances see DECKER and collaborators, Ber., 1909, 42, 2075 ; Annalen, 1913, 395,
299, 321, 328, 342 ; P I C T E T a n d K A Y , Ber., 1909, 42, 1973 ; F R E U N D , ibid., 1911, 44,
2356 ; KAUFMANN and collaborators, ibid., 1913, 46, 2929 ; 1916, 49, 675 ; 1917, 50,
1630 ; E . MERCK, German Patents 279,194, 280,152 (Chem. Soc Abstr., 1915, [i], 709
710); ROSENMUND, Ber. Deut. Pharm. Ges., 1919, 29, 200 ; German Patents 320,840,
336,153 (Chem. Soc Abstr., 1920, [i], 680 ; 1921, [i], 587) ; VON BRAUN, Ber., 1923, 56,
690 ; Soc. Chem. Ind. Basle ; British Patent 191,233 (Chem. Soc Abstr., 1923, [i], 371 ;
H A W O R T H , P E R K I N and P I N K , J. Chem. Soc,
Arch.
Pharm., 1927, 265, 389 ; 1932, 270, 353 ; KITASATO, Acta Phytochim (Jap.), 1927, 3,
325 ; GRYSZKIEWICZ-TROCHIMOWSKI, Arch. Chem. Farm., 1935, 2 , 148 ; TOMITA a n d
SATOMI, J. Pharm. Soc Jap., 1938, 58, 165 ; D E Y a n d GOVINDACHARI, Current Sci.
(India), 1944,13, 203. (27) Ber., 1889,22, 2337. (28) ROSER, Annalen, 1889,254,357 ,
F R E U N D a n d R O S E N B E R G , Ber.,
1890, 2 3 , 4 0 4 ;
F R E U N D , Annalen,
1910, 377;
(31) Ibid.,
BH(EADALE8
ALKALOIDS
169
1934 1315. (32) For pharmacological work on hydrastine and hydrastinine see
JOACHIMOGLXI and K E E S E B , Heffter's Handbuch der Pharmakol., 1924, 2, 2, 1120 ;
BAYLE and FABRE, Compt. rend., 1925,180, 605 ; BERNARDBEIG and CAUJOLLE, Compt.
rend. Soc. Biol., 1935, 119, 1299; WELCH and HENDERSON, J. Pharm. Exp. Ther.,
1934, 51, 482.
170
JSOQUINOLINE
GROUP
RHGSADALMS ALKALOIDS
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
supposed. Osada * isolated bulbocapnine, protopine d-tetrahydropalmatine, and two bases, (a) phenolic, m.p. 205, and
(b) non-phenolic, m.p. 228-230. A further phenolic base, m.p. 175,
was recorded by Asahina, which Manske suggests may be bicuculline.18
C. lutea (L).DC. t'soCorydine (luteanine), Z-wocorypalmine, ochrobirine, protopine, Z-stylopine, Z-tetrahydropalmatine. 21
C. micrantha (Engelm.) Gray. Capauridine, capaurine, protopine,
scoulerine, Z-tetrahydropalmatine : bases, F 41, m.p. 177 ; F 42,
m.p. 239 ; F 43, C 17 H u ON(OMe) 3 , m.p. 230 {dec), all phenolic.17
C. montana (Engelm.) Britton. Capauridine, capaurimine, capaurine,
corydaline, protopine, scoulerine, cZZ-tetrahydropalmatine : bases,
F 56, C19H1502N(OMe)4, m.p. 207; F 57, reduction product
of a quaternary, amorphous base; C16H12N(OMe)3, m.p. 129
(Manske22).
C. nobilis Pers. Bicuculline, corlumine, cZ-wocorypalmine, corytuberine, cryptopine, protopine, stylopine (tetrahydrocoptisine),
d- and dZ-tetrahydropalmatine ; bases, F 53, C 17 H 17 0 4 N, m.p. 183 ;
F 54, C17H1703N(OMe)2, m.p. 143, phenolic ; F 55, m.p. 209,
phenolic.23
C. ochotensis Turcz. Aurotensine (d- and dZ-scoulerine), cryptocavine,
ochotensimine, ochotensine, protopine : base F 49, C18H20O3N(OMe),
m.p. 228 (dec), phenolic. Acetylornithine is also present. 24
C. ochroleuca Koch. Bicuculline, Z-corypalmine, Z-isocorypalmine,
ochrobirine, protopine, Z-tetrahydropalmatine : base, F 45,
C20H19O8N, m.p. 268 (dec), phenolic, no methoxyl groups ; F 46,
C u H 9 0 2 N, 1/2 H 2 0, m.p. 227, not phenolic, contains a dioxymethylene but no methoxyl group. 25
C. ophiocarpa Hook. Z-Adlumine, berberine, Z-canadine, Z-corypalmine,
cryptocavine, a-aZZocryptopine, ophiocarpine, protopine: base,
F 40, m.p. 196.26
C. pallida Pers. Capauridine, capaurimine, capaurine, corypalline, protopine, d- and dZ-tetrahydropalmatine : base, F 51,
C17H13N(OH)(OMe)3, m.p. 171; methylates to <ZZ-tetrahydropalmatine. 27
C. platycarpa Makino. Aurotensine (d- and eZZ-scoulerine), bicuculline,
corybulbine, ?'socorydine, corydaline, Z-wocorypalmine, protopine,
dZ-stylopine (tetrahydrocoptisine), Z-tetrahydropalmatine, also a
netural nitrogenous substance, C6H9ON, m.p. 172.28
C. scouleri HK. Z-Adlumine, bicuculline, capnoidine, cheilanthifoline,
corlumidine, corlumine, cryptopine, a-aZZocryptopine, protopine,
scoulerine.29
C. sempervirens (L) Pers. Z-Adlumine, bicuculline, capnoidine,
cryptopine,80 protopine; base, F 20, C 18 H 23 0 5 N, m.p. 221, no
methoxyl.
C. sibiriea Pers. Bicuculline, cheilanthifoline, corlumine, cryptopine,
ochotensine, ochrobirine, protopine, scoulerine. Bases:
F15,
172
(27)
(28)
(29)
(31)
(32)
(33)
(34)
(35)
(36)
(37)
(38)
(39)
TSOQUINOLINE
GROUP
RH(EADALEI3
ALKALOIDS
173
174
JSOQUINOLINE
QBOUP
REFERENCES
(1) MANSKE, Can. J. Res., 1933, 8, 210. (2) SCHLOTTEBBECK, Amer. Chem. J.,
1900, 24, 2 4 9 ; (with WATKINS), Pharm. Archiv., 1903, 6, 17. (8) FOOTE, J. Amer.
Pharm. Assoc, 1932, 12, 246. (3a) SOINE and GISVOUJ, ibid., 1944, 33, 185. (4)
SCHLOTTEBBECK, J. Amer. Chem. Soc., 1902, 24, 2 3 8 ; SANTOS a n d ADKILLEN, ibid.,
1932, 54, 2923 ; de ALMEIDA, Brit. Chem. Abstr., 1936, A. 652. (5) MANSKE, Can.
J. Res., 1943, B , 21, 140. (5a) EIJKMANN, Rec. trav. Chim., 1884, 3, 12 ; HOPFGABTNEB,
Monats., 1898, 19, 1 7 9 ; SCHLOTTEBBECK (with MURRDLL), Ber., 1900, 33, 2 8 0 2 ;
(with BLOME), Pharm. Rev., 1905, 23, 310 ; SCHMIDT, Arch. Pharm., 1901, 239, 401 ;
MOMOYA, J. Pharm. Soc. Jap., 1919, No. 444. (56) BATTANDIEB, Compl. rend., 1891,
114, 1122; 1895, 120, 1276; J. Pharm. Chim., 1891, 24, 3 5 0 ; MILLER, J. Amer.
Pharm. Assoc, 1929, 18, 12. (5c) MACCIO, Arch, pharm. y bioquim. Tueuman Arg.,
1946, 3, 27. (6) GODEFROY' J. Pharm., 1824, 10, 6 3 5 ; PBOBST, Annalen, 1839, 29,
123 ; W I L L , ibid., 1840, 35, 113 ; EIJKMANN, Rec. trav. Chim., 1884, 3, 182 ; SCHMIDT
and SELLE, Arch.Pharm.,
ibid., p . 395 ; SCHLOTTEEBECK, Amer. J. Pharm., 1902, 74, 584. (7) GADAMEB, Apolh.
Zeit., 1924, 39, 1569.
(9) GADAMEB
and WINTERFELD, Arch. Pharm., 1924, 262, 589. For estimations of alkaloids see
NEUGEBAUER and BBUNNE, Apoth. Zeit., 1937, 52, 1038 ; A W E and NEHRLiCH,iSid-aeirf.
Apoih. Zeit., 1939, 79, 429. (10) Arch. Pharm., 1908, 246, 381. (11) Chin. J. Physiol.,
1928,2,203; 1 9 2 9 , 3 , 6 9 , 3 0 1 ; 1 9 3 3 , 7 , 3 5 ; 1934, 8,155 ; 1936,10, 537. (12) HUANGMINLON, Ber., 1936, 69, 1727 ; cf. H E Y L , Apoth. Zeit., 1910, 25, 137. (13) Can. J. Res.,
1933, 9, 436 ; 1937,15, 159 ; 1938,16, 81 ; cf. EPPSON, J. Amer. Pharm. Assoc, 1935, 24,
113 (see also Ref. 27).
1 7 , 9 4 ; 1940,18,288. (15) ibid.,* 1942, B , 20, 57. (16) Ibid., 1940, B , 18, 97. (16a)
i&i'd., 1946,B, 24, 66. (17) Ibid., 1939, B , 17, 57. (18) J. Pharm. Soc Japan, 1920, No.
463,766; cf. Can. J. Res., 1933,8, 142. (19) Arch.Pharm., 1908,246,401; cf. SCHMIDT,
ibid., p . 575. (20) J. Pharm. Soc Japan, 1927, No. 547, 99, 100, 102, 104. (21) Can.
J. Res., 1939, B , 17, 89 ; 1943, 21, 13. (22) Ibid., 1942, B , 20, 49. (23) Ibid., 1940,
B , 18, 288, cf. BIRSMANN, Inaug. Diss. Dorpat, 1892 (Chem. Soc. Abstr., 1893, i, 446).
(24) Can. J. Res., 1940, B , 18, 75. (25) Ibid., 1939, B , 17, 95. (26) Ibid., 1939, B , 17,
51. (27) Ibid., 1940, B , 18, 80 and ref. (13). (28) Ibid., 1943, B , 21, 13. (29) Ibid.,
1936, B , 14, 347 ; 1940, B , 18,100. (30) Ibid., 1933, 8, 407 ; 1938, B , 16, 89. (31) Ibid.,
1936, B , 14, 354 ; 1938, B , 16, 89 ; 1940, B , 18, 100. (32) HAABS, Arch. Pharm.,
1905, 243, 1 5 4 ; H E Y L , Apoth. Zeit., 1910, 25, 36. (33) Go, J. Pharm. Soc. Japan,
1929, 49, 125 ; 1930, 50, 122. (33a) MANSKE, Can. J. Res., 1943, B , 2 1 , 111. (34)
F B E D N D and J O S E P H I , Ber., 1892, 25, 2411 ; Annalen, 1893, 277, 1. (35) GADAMER
and KNORCK, Apoth. Zeit., 1926, 41, 928. (36) GADAMER and ZDZGENBEIN, Arch.
Pharm., 1902, 240, 19. (37) Ibid., p p . 23, 83. (38) GADAMEB, ibid., 1911, 249, 30.
(39) MERCK,
ibid.,
GADAMER
and
ZDSGENBEIN,
1902, 240,
94.
(40) WACKENRODER, Berz. Jahrb., 1826, 7, 220. (41) SCHMIDT, Arch. Pharm., 1908,
246, 575. (42) SPATH, MOSETTIG and TROTHANDL, Ber., 1923, 56, 877, cf. ref. (35).
(43) D O B B I E and L A U D E R , J. Chem. Soc, 1893, 63, 485. (44) GADAMEB, SPATH and
1927, 265, 675, cf. ref. (35). (45) GADAMEB, ibid., 1911,
(47) H A A R S , Arch.
Pharm.,
1905, 243, 154. (48) GADAMEB, Festsch. A. Tschirch, 1926, 36 (Chem. Zentr., 1927, {,
2558). (49) Can. J. Res., 1943, B , 2 1 , 117. (50) Ibid., 1932, 7, 258 ; 1938, 16, 8 1 .
(51) Ibid., 1937, B , 15, 274. (52) Ibid., MANSKE, 1932, 7, 265 ; 1938,16, 81, cf. FISCHER
a n d SOELL, Pharm. Archiv., 1902, 5, 1 2 1 ; BLACK, EGGLESTON, K E L L Y a n d T U R N E R ,
J. Agr. Res., 1923, 23, 55. (53) MANSKE, Can. J. Res., 1933, 8, 592 ; 1934, 10, 521 ;
1938,16, 81 ; EGGLESTON, BLACK and K E L L Y , J. Agr. Res., 1929, 39, 477. (54) Can. J.
Res., 1934, 10, 5 2 1 ; cf. H E Y L , Arch. Pharm., 1903, 241, 3 1 3 ; ASAHINA, ibid., 1909, 247,
201.
J.
Pharm. Soc. Japan, 1928, 48, 85. (57) GADAMEB, Apoth. Zeit., 1901, 16, 621 ;
DANCKWOBTT, Arch. Pharm., 1912, 250, 6 1 3 ; 1922, 260, 94. (58) Can. J. Res.,
* I n this and later references t o Can, J. Res, t h e author is R . H . F . Manske.
OPIUM
ALKALOIDS
175
1942, B , 20, 5 3 . (59) FISCHER, Arch. Pharm., 1901, 239, 421 (with T W E E D E N )
Pharm. Archie., 1902, 5, 117. (60) BRINDEJONC, Bull. Soc. Chim., 1911, [iv], 9,
97. (61) Can. J. Res., 1938, B , 16, 4 3 8 ; 1940, B , 18,100 ; cf. SCHMIDT, Arch. Pharm.,
1901,
(61a) E F R O S , Farmatsiya,
1946, 9, N o . 5 , 22.
(63) KONOVALOVA,
JUNOSOV and OREKHOV, J. Gen. Chem. Russ., 1939, 9, 1939 (Brit. Chem, Phys.
1940, A i i i , 550).
BATTANDIER, J. Pharm.
FISCHER,
59
Abstr.,
Chim.,
cf.
1839, 3 1 , 250 ;
(66) With MARION and LEDINGHAM, J. Amer. Chem. Soc., 1942, 64,1659. (67) JUNUSOV,
KONOVALOVA and OREKHOV, Ber., 1935, 68, 2158 ; J. Gen. Chem. Russ., 1940, 10, 641.
(68) PAVESI, Chem. Soc. Abstr., 1905, i, 3 6 8 ; 1907, i, 870. (69) KONOVALOVA, JUNUSOV
and OREKHOV, Ber., 1935, 68, 2277. (70) PAVESI, Chem. Soc. Abstr., 1906, i i , 4 8 3 ;
cf. HESSE, Annalen, 1866, 140, 146, and A W E , Forst Forschritte, 1939, 15, 117. (71)
GADAMER and K L E E , Arch. Pharm., 1911, 249, 39. (72) K I . E E , ibid., 1914, 252, 211 ;
GADAMER, ibid., p . 274. (73) KONOVALOVA, JUNUSOV and OREKHOV, Bull. Soc. Chim.,
1939, [v], 6, 811 ; see also Brit. Chem. Physiol. Abstr., 1939, Aii, 565 ; 1940, Aii, 111,
197.
Pharm.,
ibid.,
ALKALOIDS OF OPIUM
Opium is the sun-dried latex of the unripe capsules of the opium
poppy Papaver somniferum, L. I t is produced in many tropical and subtropical countries, but only on a large scale in India, China, Iran, Yugoslavia, Bulgaria, Soviet Russia and Turkey. That used in medicine is
mostly the Turkish and European varieties, but Indian and Iranian
opiums are imported for extraction of the alkaloids. For various reasons,
but mainly as the result of international efforts, centred in the League of
Nations, to limit the production of opium and its alkaloids to the quantities
required for legitimate use in medicine, 1 much interest has been shown
in recent years in the details of the cultivation and utilisation of the
opium poppy, apparently in the hope of securing more efficient control
of this trade. As examples of this kind of activity reference may be made
to the account given by Vrgoc of the production of opium in Macedonia,1'"*
Machiguchi's description of opium preparation in Japan, 2 and information
on the modern form of " druggists' " opium produced in the Turkish
Government Factory. 3 Experiments in the cultivation of the opium poppy
and the production of opium have often been made in Northern and
Central Europe of which an account has been published by Thorns.4
A description of experiments in England about 1821-2 has also appeared.4'"'
Recent examples have been described in Denmark, Italy and Rumania, 5
the results of which show there is no difficulty in producing opium of
satisfactory morphine content in the temperate zone, though opium
production in the traditional fashion is not likely to be economically
possible in such areas.
A good deal of local information has also been published regarding
the quality, as measured by morphine and codeine content, of the opium
available in some of the producing countries, e.g., India, Iran and Man-
176
isoQUINOLINE
GROUP
OPIUM
ALKALOIDS
177
178
isoQUINOLINE
GROUP
OPIUM ALKALOIDS
179
180
isoQUINOLINE GBOUP
1936, 136, 6 2 4 ; cf. LAFINE, 15th Congress Indust. Chem., Brussels, 1936, 111.
(4) Arbeiten. Pharm. Inst. Universitat, Berlin, 1907, 4, 2 0 4 ; 1909, 6, 198 ; Ber. deut.
pharm. Ges., 1923, 33, 25. (4a) Pharm. J., 1948, 160, 151. (5) (Denmark),
BAGGESGAARD-RASMUSSEN and SALOMONSEN. Dansk. Tids. Farm., 1936, 10, 1 ;
JESPEHSEN, ibid., p . 16. (Italy), ZANDA, Arch. Farm. Sperim., 1939, 67, 2 9 ;
CORAZZA, ibid., p p . 18, 82. (Rumania), BOTH, Apoth in OH., 1942, 1, 137
(Chem. Abstr., 1944, 38, 308b). (6) (India), DUNNICLDJFE, Nature, 1937, 140,
92 ; RAKSHIT, lnd. J. Pharm., 1942, 4, 53 ; Sci. and Cult., 1942, 8, 16. (Iran),
NEZAMIE, Bull.
Sci. Pharmacol.,
Hep. Inst. Sci. Res. Manchoukuo, 1938, 2, 221 ; (with Yoso), 1940, 4, 375. (7) CHAKRAVARTI and MEHBSTRA, J. Ind. Chem. Soc, Indust. News Edit., 1943,6,52 ; RASMIDATTA,
Thai. Sci. Bull., 1940, 2, Nos. 3-4, p . 129 (Chem. Abstr., 1941, 35, 5254). (8) Bull. Sci.
Pharmacol., 1938, 45, 265 ; 1939, 46, 376. (9) Pharm. Monats., 1930, 11, 73 (Chem.
Abstr., 1930,24, 3322; 1931,25,2518). Ber. ung. pharm. Ges., 1936,12, 387; Hungarian
Pat. 109,788 (Chem. Abstr., 1934, 28, 5182); British Pat. 406,107; German Pat. 524,964 ;
U.S. Pat. 2,009,181. For technical comments on t h e process see W U E S T and F R E Y ,
Festschrift Barell, 1936, 556. F o r comments on t h e possible results of this extension of
the source of supply of morphine see Lancet, 1934, 227, 662, and Munch. Med. Woch.,
J a n . 6, 1939, p . 39. F o r work in other countries see (for France) HAZARD et al., Ann.
Pharm. franc, 1943, 1, 135. COMAR, ibid., 1943, 1, 89 and (for Sweden) TELENIUS,
Chem. Abstr., 1946, 40, 5883. (10) KUSSNER, Merck's Jahresb., 1940, 54, 29 (Chem.
Abstr., 1941, 35, 8203); see also (for France) GUILLAUME and F A U R E , Ann. pharm.
franc, 1946, 4, 160 : (for Holland) VAN ITALLIE, ibid., p . 156. (11) Repts. Council Sci.
Indust. Res., Australia, 1941-2,1942-3, p p . 11 ; B E R E N S , Chem. andDrugg., 1943,139,
198; BARNARD and FINNEMORE, J. Council Sci. Ind. Res. Aust., 1945,18, 2 7 7 ; LOFTUS
H I L L S , ibid., p . 286. (12) J. Pharm. Chim., 1828, 14, 436. (13) DIETERICH, Helfenberger Annalen, 1888, 76 ; 1890, 63 ; DEBOURDEAUX, Bull. Sci. Pharmacol, 1910, 17,
3 8 2 ; J. Pharm. Chim., 1911, [viii] 4, 13, 65, 105. (14) GRIFFITHS a n d WHALLEY,
Chem. and Ind., 1940, 59, 765. An account of the work of t h e Commission of Experts
is given in t h e Quarterly Bulletin, Health Organisation, League of Nations, 1935, 4, 809 ;
1938, 7, 429. (14a) JERMSTAD, Ber. Deut. Pharm. Ges., 1920, 30, 398 ; Norges Apotek.
Tids., 1940, 48, 215 ; HOLLMAN, Pharm. XVeekbl., 1925, 62, 52 ; 1926, 63, 1337 ; E D E R ,
Festsch. A. Tschirch, 1926, p . 392 ; (with MAERKI), Pharm. Acta Helv., 1927, 2, 21 ;
(with STUCKI), ibid., 1932, 7, 259 ; (with WAECKERLIN), Compt. rend. XII' Cong. Int.
Pharm., 1935, 99 ; Quart. J. Pharm., 1937,10, 680 ; Pharm. Acta. Helv., 1940, 15, 227 ;
BOEHM, Apoth. Zeit., 1929, 44, 88 ; STUBER and KLJATSCHKINA, Arch. Pharm., 1930,
268, 2 0 9 ; 1933, 271, 217; cf. ANGELETTI, Ann. Chim. Farm., 1938, 3 7 ; NOPILI, Boll.
Chim. Farm., 1940, 79, 2 1 8 ; STICH, Pharm. Zeit., 1930, 75, 1233; REIMERS, Arch.
Pharm., 1931, 269, 506 ; Dansk. Tids. Farm. 1930, 4, 237 ; VAN ARKEL and VAN DEB
W I E L E N , Pharm. Weekbl., 1931, 68, 3 0 9 ; RAKSHIT, Analyst, 1931, 56, 7 1 1 ; Ann.
Chim. Anal., 1935, [iii], 17, 315 ; BAGGESGAARD-RASMUSSEN (with KEIMERS), Dansk.
Tids. Farm., 1931, 5, 21, 145 ; 1935, 9, 229 ; 1937, 11, 278 ; Pharm. Acta Helv., 1932,
7, 249 ; Arch. Pharm., 1935, 273, 129 ; (with JACKEROTT and JESPERSEN), Dansk.
Tids. Farm., 1934, 8, 185 ; Pharm. Ada Helv., 1936, 11, 307 ; (with SCHOU), Arch.
Pharm., 1930, 268, 673 ; BLISS et at., Amer. J. Pharm., 1933,105, 458 ; 1935,107, 193 ;
VAN ITALLIE, Pharm. Weekbl., 1934, 71, 4 ; LAURENCE and LABARRE, J. Pharm. Chim.,
1934, [viii], 20, 353 ; MANNICH (with HANDKE and BAUMGARTEN), Arch. Pharm.,
1935, 273, 97, 199 ; (with SCHWEDES), Apoth. Zeit., 1913, 28, 82 ; 1942, 280, 3 8 6 ;
cf. NICHOLLS, Analyst, 1937, 62, 4 4 0 ; LINDHOLM, Farm. Notisbl., 1946, 55, 1 5 0 ;
WALLINGFORD and HOMEYER, J. Amer. Pharm. Assoc, 1936, 25, 4 0 2 ; WINTERFELD,
DoRLBand RAUCH, Arch. Pharm., 1937, 275, 445 ; cf. MANNICH, ibid., 1941, 279, 388 ;
(146) KOLTHOFF, Pharm. Weekbl., 1925, 62, 1 0 6 ; cf. HOLLMAN, ibid., 1925, 62, 5 2 ;
CAINES, Pharm. J., 1927, 118, 751 ; BAGGESGAARD-RASMUSSEN and K E I M E R S ,
Dansk.
Tids. Farm., 1931,5, 21 ; Pharm. Acta Helv., 1932, 7, 249 ; R O N G E , Apoth. Zeit, 1943,
58,142. (14c) GoRis, 8 WuESTandFREY, , KiJATSCHKrNA,X*tTO.-Pan.Prom.,1934 ) No.
4 , 2 9 ; GINSBERG and KRASCHEVSKI, Prom. Org. Chem., 1 9 3 6 , 2 , 1 0 4 ; D E B U C and L E L D J U ,
Compt. rend. Cong. 18, Chim. Indust., 1938, p . 95 ; RASMUSSEN and ILVER, Dansk.
Tids.
OPIUM ALKALOIDS
181
Pharm., 1945,19, 71 ; TKAUTNER, Aust. Chem. Inst. J., 1946,13,2 55. (lid) NICHOLLS,
Analyst, 1922, 47, 5 0 6 ; 1937, 62, 4 4 0 ; BAGGESGAARD-RASMUSSEN and SCHOU, Arch.
Pharm., 1930, 268, 6 7 3 ; LAURENCE, J. Pharm. Chim., 1930, [viii], 11, 3 3 6 ; DAVID,
Pharm. Zeit., 1931, 76, 706, 7 4 8 ; KLJATSCHKINA and STUBER, Arch. Pharm., 1933,
271, 2 1 7 ; ROZENFELD, Farm. Zhur., 1932, 8-9, 2 4 6 ; VJNOGRADOVA, J . Appl. Chim.
Bass., 1933, 6, 150; VAN ARKEL, Pharm. Weekbl., 1935, 72, 3 6 6 ; 1937, 74, 1934;
GARRETT, Quart. J. Pharm. Pharmacol., 1937, 10, 466 ; POETHKE, Arch. Pharm., 1940,
279,109 ; MATCHELT and LEVINE, Ind. Eng. Chem. Anal. Edit., 1941,13, 264 ; ADAMSON
^ n d HANDISYDE, Quart. J. Pharmacol., 1946, 19, 3 5 0 ; Analyst, 1945, 70, 305.
(14e) BALLS, J. Biol. Chem., 1927, 71, 537, 543 ; (with W O L F F ) , 1928, 80, 379 ; K E E S E R
and KEESER, Arch. exp. Path. Pharm., 1928, 127, 230 ; FLEISCHMANN, Biochem. Zeit.,
1929, 208, 392 ; MAIER, Arch. exp. Path. Pharm., 1931, 161, 163 ; RISING and L Y N N ,
J. Amer. Pharm. Assoc, 1932, 21, 334 ; ELLINGER and SEEGER, Arch. exp. Path. Pharm.,
1933, 174, 168 ; K E I L and K L U G E , ibid., 1934, 174, 493 ; EMERSON, Proc. Soc.
Exp.
Biol. Med., 1934, 31, 1004; (with MOODEY), Univ. Calif. Pharmacol. Publ., 1939, 1,
No. 18, p. 2 3 5 ; DECKERT, Arch. exp. Path. Pharm., 1936, 180, 6 5 6 ; Zeit.
Anal. Chem., 1938, 112, 241 ; WACHSMUTH, Bull. Soc. chim. biol., 1938, 20,
1419; CAHEN and F E U E R , Compt. rend., 1939, 208, 1907; FIGHTENBERG, Compt.
rend. soc. biol., 1939, 130, 3 1 6 ; SCHIRM, Apoth. Zeit., 1940, 55, 1 0 6 ; T O F T ,
Arch. Int. Pharmacodyn, 1945,70,370 (15) Pharm. Rev., 1904, 22, 348. (16) Analyst,
1911, 36, 489. (17) (with SINGH), ibid., 1918, 43, 2 0 5 ; (with S E N ) , ibid., 1920, 45,
321 ; (with SANGHI), ibid., 1923, 48, 16. (18) DEMBECK, Bull. Nat. Formulary
Cttec,
1941, 9,119 ; BROWNLEE, Pharm. J., 1943,151,152; CHANDLER, Analyst, 1946, 71, 140.
(19) Magyar Gy6g Tdrsas Ert., 1931, 7, 429 (Chem. Zentr., 1931, ii, 3644). (20) J.
Chem. Ind. Moscow, 1931, 8, 161. (21) (a) Pharm. Weekbl., 1903, 40, 189 ; Bull. Sci.
Pharmacol., 1910,17, 59 ; (b) Analyst, 1923, 48, 53 ; VAISBERG et al., Farmatsiya, 1947,
10, No. 1, 26 ; (c) PLUGGE, Arch. Pharm.,
1887, 225, 3 4 3 ; KLJATSCHKINA,
ibid., 1933, 271, 558 ; ANNELER, Barell Festschrift, 1936, 344. (d) BAGGESGAARDRASMUSSEN and REIMERS, Dansk. Tijds. Farm., 1931, 5, 21. (e) ANNELER,
Arch. Pharm., 1920, 258, 130; KLJATSCHKINA and SOROCHINSKAYA,
Farmatsiya,
1939,
No.
5,
8 ;
ADAMSON,
HANDISYDE
and
HODGSON,
Pharm.
J.,
1947,
159,
207. (22) Anales farm, bioquim. (Buenos Ayres), 1940, 11, 6. (23) Zeit. anal.
Chem., 1943, 124, 35. (24) Ibid., 1942, 124, 344. (25) Rev. exp. bioquim. Argentina,
1942, 8, 17. (25a) Quart. J. Pharm. Pharmacol., 1945, 18, 338 ; RASMUSSEN et al.,
Dansk. Tids. Pharm., 1945,19, 41. (26) GREGORY, Annalen, 1833, 7, 261 ; ROBERTSON,
J. Pharm., [ii], 19, 158 ; ANDERSON, Annalen, 1853, 86, 180 ; cf. MERCK, ibid., 18361839, 18, 79 ; 21, 202 ; 24, 46. For an account of this process, as used a t the Government Opium Factory, Ghazipore, India, see Pharmacographia Indica, 1890, i, 82.
(27) " D i e Fabrikation der Alkaloide," 1927; see also CHEMNITIUS, Pharm.
Zent.,
1929, 70, 101 and Pharm. J., 1945, [iv], 101, 220. (27a) Ann. pharm.
franc.,
1947, 5, 121. (28) J. pr. Chem., 1924, [ii], 108, 247. (29) Pharm.
Zent.,
1927, 68, 307. (30) Khim. Farm. Prom., 1933, 127. (31) Allen's " Commercial
Organic Analysis," 5th Edit., London, Vol. VII., p. 671. (32) See, for
example, PATZUKOW, RUSS.
Pat.
127;
CHITRIN), 18,747 ;
BENZYL/SOQUINOLINE SUB-GROUP
Papaverine, C20H21O4N. This alkaloid, first obtained by Merck,1
occurs in the mixture precipitated by ammonia from the mother liquors
of opium extract from which morphine and codeine have been separated
in Gregory's process, and methods for its isolation from this mixture have
been published by Hesse and others. 2 The alkaloid may be purified by
conversion into the acid oxalate, B . H 2 C 2 0 4 , m.p. 196 3 or 201-5-202,*
which is nearly insoluble in alcohol.
Papaverine crystallises in rhombic prisms or needles, m.p. 147,
[a]D 0, is insoluble in water, soluble in hot alcohol or chloroform,
and slightly so in cold alcohol or ether. It is a weak base for which, according to Wales, there is no satisfactory indicator, though bromophenol-blue
has its colour change at the right point for this alkaloid.5 The hydrochloride, B . HC1, forms monoclinic plates, m.p. 225-6, sparingly soluble
in water (1 in 37 at 18). The picrate forms quadratic plates, m.p. 186.*
Some of the colour reactions formerly ascribed to papaverine were
due to cryptopine present as an impurity, 3 but the following test is said
to be given even by synthetic papaverine. With pure cold sulphuric acid
it dissolves to a colourless solution, which becomes rose-red at 110,
darkening to violet at 200, the colour being discharged on adding water.
According to Foster, 3 if as little as 0-2 per cent, of cryptopine is present
a colour is produced on solution in cold sulphuric acid. Warren 6 states
that Marquis's reagent (sulphuric acid and formaldehyde) gives with
papaverine ferricyanide a blue colour, changing to violet, green and brown.
Constitution. Knowledge of the structure of papaverine is principally
due to the work of Goldschmiedt and collaborators. 7 It behaves as a
tertiary amine, and gives a methiodide, B . CH 3 I . 4H 2 0, m.p. 60-5 or
195 (dry). On treatment with hydriodic acid and red phosphorus the
alkaloid furnishes four molecular proportions of methyl iodide, and yields
papaverolirie, C16H9(OH)4N . 2H 2 0, m.p. 260 (dec.) (see Kitasato and
Robinson'). When oxidised with potassium permanganate under varying
conditions 7<"> it yields papaveraldine and papaverinic acid, and as
simpler products of these two substances, 6 : 7-dimethoxytsoquinolinecarboxylic acid, and m-hemipinic, veratric and pyridine-2 : 3 :4-tricarboxylic acids.
Papaveraldine (Xanthaline), C20H19O5N. This substance forms colourless
scales, m.p. 210, yields well-crystallised yellow salts, which are dissociated
in water, and reacts as a tertiary base, forming a methiodide, m.p. 133-5.
It gives an oxime existing in two stereoisomeric forms, and contains four
methoxyl groups.
The demethylated product, papaveraldoline,
C 16 H 7 ON(OH) 4 , has been prepared by Oberlin.8 Miss Dobson and W. H.
Perkin have shown that the alkaloid, XANTHALINE, isolated from opium
by T. and H. Smith, is identical with papaveraldine.9 On reduction with
182
183
PAPAVERINE
(MeO)d -CJJ-CT
b ^.QO
">N-Alk
CH
/ \
C-COOH
II
CH
C-COOH
,CH
/ \/\
CH
C
C-OCtt,
CH
C-0CH-
CH
COOH-C
^ _ ^
X3-0CH,
II
COOH-C
^CH
Cinchomeronic acid
/ x
C-OCH,
CH
>
CH
Dimethoxyisoquinoline
taHemipinic acid
/\-:~/\ r
f
0 C H
3\
\4H3
HOOC-C
VOCE,
'
VCOOH
CH
c-OCH,
CH
IcoOH
NC/V
Papaveraldine
\ /
Pyridine2 : 3 : 4
tricarboxylic acid
184
SUB-GROUP
BENZTLTSOQUINOLINE
yc\
EOOC-C
c o
HOOC-C
CH
>c\
CH
CH
-CH
MeO-C
/cv
CH
-J>\
CH
CH
CH
C-OMe MeO-C
C
CH
^CH
^ciOMo
^CH N CH
Papaverinic acid
Papaverine
II
CH
C-OMe
^C-OMe
(II)
(V)
CO
CH
OMe
(HI)
OMe
(IV)
Olie
die
(vi)
Olio
(VII)
cue
PAPAVERINE
185
Mannich and Walther * found that the methyl ethers of such alcohols,
RCH(OMe)CH2NHCOR',. as prepared by Rosenmund's
method, 21 undergo a similar change when boiled in xylene with phosphorus
oxychloride ; and both they and Rosenmund 2 2 used this method for the
synthesis of papaverine and allied substances.
When Pictet and Finkelstein l 9 condensed ^omoveratrylamine with
/iomoveratroyl chloride and effected ring closure in the product, they
obtained 3 : 4-dihydropapaverine (VII) but were unable to oxidise this to
papaverine. This final step was achieved by Spath and Burger 23 by the
use of platinised asbestos at 200 in presence of air, and these authors
found that tetrahydropapaverine (X) can be dehydrogenated to papaverine
under similar conditions.
In an attempted synthesis of papaverine based on Rugheimer's 24
preparation of 6 : 7-dimethoxywoquinoline from veratrylaminoacetal
(MeO)2C6H3NHCH2(OEt)2, Allen and Buck 2 5 reduced deoxyveratroin oxime, (MeO)2CeH3C(NOH)CH2C6H3(OMe)2, to a^-di(3 : 4-dimethoxy)-phenylethylamine,
(MeO)2C6H3CH(NH2)CH2C6H3(OMe)
but the condensation product between this amine and bromoacetal
decomposed in attempts to convert it into papaverine.
In an effort to prepare 1 : 2-dihydropapaverine, Buck 26 dehydrated
oj-/jomoveratroylaminoacetoveratrone (III) with phosphoryl chloride, and
subjected the product (V) to catalytic reduction, followed by the action
of phosphorus pentachloride in the cold. The final product was assumed
to be 1 : 2-dihydropapaverine ; but Young and Robinson 27 interpret this
synthesis differently, and their formulas (V) and (VI) are given above,
the final product being 3 : 4-dihydropapaverine (VII), which Buck thus
prepared for the first time in a crystalline condition, m.p. 97-8 ; picrate,
m.p. 151 ; perchlorate, m.p. 238 (dec).
CHr
OMe
(Villa)
OMe
(IX)
OMe
OMe
(X)
OMe
186
BENZTLisoQUINOLINE
SUB-GROUP
187
LAVDAN08INE
OMe
Tetrahydro
papaverine
die
3:4Dihydropapaverine
CMe
Pavine
188
BENZYLisoQUINOLINE
SUBGROUP
MeO
OUe
3'U OMe
(III)
(IV)
>
MeOr
^^
v-x
IteOl
CHg.mtsg
CHOH
ycm * OHC-/^
\oife
LAUDANOSINE
189
46
190
BENZYLisoQUINOLINE
SUB-GROUP
to each other as the two acetyl derivatives, the first having lost a methyl
group and the second a methyl group and two atoms of hydrogen. In each
case the simple demethylated product gives a weak indole reaction with
Ehrlich's reagent, whereas the demethylated and dehydrogenated substance
gives an intense indole reaction with this reagent. Further, the tetracetyl
derivative, m.p. 148, on hydrolysis followed by methylation, yields the
methiodide, m.p. 242-3, described above.
To dehydrolaudanosoline chloride Robinson and Sugasawa,50 and
independently Schopf and Thierfelder 49 ascribe formula (VI), which makes
it 2 : 3 : 11 : 12-tetrahydroxy-8-methyldibenzotetrahydropyrrocolinium
chloride. The primary tetracetyl-derivative, m.p. 148, is represented by
(VII: R = acetyl) and the second acetyl derivative, m.p. 215, by
(VII: R = acetyl) with an ethylenic linkage between carbon atoms 15
and 16. Similarly, the initial tetramethoxy-derivative is to be represented
by (VI) with the four hydroxyl groups replaced by methoxyl groups ; the
primary product formed on heating, by loss of methyl chloride, will be
represented by ( V I I : R = OMe), and the second product, m.p. 201-3,
of the reaction will be represented by ( V I I : R = OMe), with an ethylenic
linkage between C15 and C16.
Proof of formula (VI) for dehydrolaudanosoline salts was provided by
a study of its exhaustive methylation, the products at the first and second
stages of the application of this process being 5 : 6-dimethoxy-2-(3' : 4'dimethoxy-6'-vinylphenyl)-l-methyldihydroindole (VIII) and 6-dimethylamino-3 : 4 : 3' : 4'-tetramethoxy-6'-vinylstilbene (IX) respectively.
LAUDANINE
191
tion by sodium amalgam, gives trimethylamine and 3 : 4 : 3 ' : 4'-tetraniethoxy-6'-ethyl-a/?-diphenylethane (XI). This substance was prepared
independently by subjecting laudanosine to a two-stage Hofmann
degradation, when it furnished tetramethoxyvinylstilbene (laudanosene:
XII), which crystallises from warm alcohol in large needles, m.p. 94-5,
and had already been prepared by Decker and Galatty. 62 On hydrogenation in presence of Adams's platinic catalyst it gave (XI).
The foregoing account is based mainly on Robinson and Sugasawa's 50
paper, but substantially the same ground is covered by Schopf and
Thierfelder,49 who give additional details, some of which are referred to
above. Among other points dealt with by these authors is the ozonisation
of (IX), which gave rise to m-opianic acid, m-hemipinic acid, 6-dimethylaminoveratraklehyde and 6-dimethylamino-6'-aldehydo-3 : 4 : 3' : 4'-tetramethoxystilbene,
(MeO)2C6H2(NMe)2CH : CHC6H2(CHO)(OMe)2,
m.p. 144-6.
In extension of this work, Sugasawa and Yoshikawa 53 have shown
that dWzomolaudanosoline (XIII), on oxidation by chloranil in presence of
acetic acid, also gives rise to a dehydro-product, which on methylation
furnishes 2 : 3 : 1 1 : 12-tetramethoxy-8-methyl-6 : 7 : 15 : 16-tetrahydro5 : 18 : 9 : 14-dibenzopyridocolinium salts (XIV).
192
BENZTLJSOQVINOLINE
SUB-GROUP
LAUDANIDINE
193
MeO-C'
MeO-C
MeO-C.
CrOMe
C-OH
i-OMe
1Laudanoslne
C-OMe
1Laudanine
(laudanidine]
H NH,2
194
BENZYLJSOQUINOLINE
SUB-GROUP
:MIe
C-OMe
C-OMe
IVIII)
C^OMe
N-MethylnorpapavqrlnliuB
betaine
-\l- -Laudanine
R = H: R' - Ke
Codamine
R = Me: VT= H
protoPapaverlne
R = H
CODA MINE
195
.Troup was determined by Spath and Epstein, 69 who found that codamine
ethyl ether on oxidation with potassium permanganate yielded veratric
acid so that the free hydroxyl group must be in the tsoquinoline nucleus,
and therefore in position 6 or 7. When the same oxidising agent is applied
under carefully controlled conditions in faintly alkaline solution, the
ethyl ether yields 6-methoxy-7-ethoxy-l-keto-2-methyl-l : 2 : 3 :4-tetrahydroz'soquinoline, m.p. 120-1, which was identified by comparison with
the synthetic product, thus establishing formula (IX : R = M e ; R'=C 2 H 6 )
for ethylcodamine, and with the ethoxyl replaced by a hydroxyl group,
for codamine (IX : R = Me ; R ' = H), so that codamine is ^-laudanine
with the positions of the hydroxyl and methoxyl groups in the woquinoline
nucleus interchanged. As a primary material for the synthesis of codamine,
Spath and Epstein 69 used protopapaverine, C17H1302N(OMe)2, prepared
and so named by Hesse, 6 and by Pictet and Kramers, 67 who called it
trimethylpapaveroline. It is formed along with other products when
papaverine hydrochloride is heated to 235, a molecule of methyl chloride
being evolved. I t separates from alcohol in colourless tablets, decomposing at 240 (P. and K.), in yellowish leaflets, decomposing at 260 (H.),
or in yellowish crystals, m.p. 279-80 (dec), according to Spath and
Epstein. The hydrochloride, B . HC1 . 5H 2 0, has m.p. 66-7 or 200 (dry);
the acid oxalate, B . H 2 C 2 0 4 . 5H 2 0, forms octahedral yellow crystals,
m.p. 138 (dry); the picrate melts at 206-5. Sodium and potassium
derivatives have been prepared. Spath and Epstein 69 showed that protopapaverine is not a partially demethylated papaverine, since it is not
reconverted to papaverine by diazomethane and it contains only two
methoxyl groups, the third methyl group of papaverine being now attached
to nitrogen. On reduction with tin and hydrochloric acid and treatment
of the reduced product with diazomethane, (iMaudanosine is formed. On
oxidation with permanganate it furnishes veratric acid, so that the
veratryl group of papaverine is still intact, and the free hydroxyl
group, must be in the woquinoline nucleus. This view is confirmed by
the fact that on treatment with diazomethane it yields iV-methylno?-papaverinium phenolbetaine (VIII), which is one of the by-products in
the formation of protopapaverine from papaverine hydrochloride. On
the basis of this experimental evidence, Spath and Epstein assigned
formula (X : R = H) to protopapaverine. On treatment with methyl
iodide it is converted into 7-hydroxy-6-methoxy-3' : 4'-dimethoxybenzylwoquinoline methiodide, m.p. 63-4, which was transformed to the methochloride, m.p. 70-1, and this, on reduction with tin and hydrochloric
acid, yielded dZ-codamine (IX : R = Me ; R' = H), identified as the
Picrate, m.p. 187-8, by its methylation to dZ-Iaudanosine and by the
oxidation of its ethyl ether to 6-methoxy-7-ethoxy-l-keto-2-methyl1 : 2 : 3 : 4-tetrahydroisoquinoline. Like dZ-laudanine, dZ-codamine has not
been deracemised.
Armepavine, C16H13(NMe)(OH)(OMe)2, H 2 0 . (Items 51, 5 3 ; list,
P- 173.) M.p. 100 (upprox.) or 148-9 (dry), [a] D - 118-7 (CHC13), gives
a hydrochloride, m.p. 151-2, oxalate, m.p. 211-12, and methiodide,
72
196
BENZYLvsoQUINOLINE
SUB-QROUP
C6H/
It has been stated already (atropine, p. 112) that there are two types
of spasmolytic drug, the neurotropic, typified by atropine, and the musculotropic or myotropic to which papaverine belongs. In laboratory work the
two types are usually tested against spasm induced by acetylcholine and
PHARMACOLOGICAL
197
88
"
*0
o
o
o
o"
o
01
T"7
5
8 s.
28
8
8 8
I !
go
Hi
l-H 01
r-< 00
CO
CO
If
88.
88
^T
- l Oo
*=> io*i
1-1
!-H
T-l
CO
n*l
W CO
1 1 1 1 I 1
=ico
CO
CO
H3
CO
CO
00
CO ^
00,0
0,00
ACTION
33
01 01
W3 CO
II ii ii
<s o
-0.
.8
198
BENZYLTSOQUINOLINE
SUB-GBOUP
F O S T E R , Analyst,
1946,
71, 139. (4) SFATH and POLGAR, ibid., 1926, 59, 2787. (5) J. Ind. Eng. Chem., 1926,
18, 390.
P Y M A N a n d R E Y N O L D S , 1910,
97, 1323 (footnote); WARREN, J. Amer. Chem. Soc, 1915, 37, 2402. For other colour
reactions or comments upon them see WAGENAAR, Pharm. Weekbl., 1927, 64, 1085 ;
EKKERT, Pharm. Zent., 1933, 74, 2 4 ; K U B L I , Pharm. Acta Helv., 1935, 10, 1 5 6 ;
ROZEBOOM, Pharm. Weekbl., 1935, 72, 4 9 8 ; A W E , Pharm. Zent., 1936, 77, 157.
(7) Monats., 1883, 4, 704 ; 1885, 6, 372, 667, 956 ; 1886, 7, 488 ; 1887, 8, 510 ; 1888,
9, 42, 327, 349, 679, 762, 778 ; 1889, 10, 673, 692 ; 1898, 19, 324. Papaveroline and
derivatives, see KITASATO and ROBINSON, J. Chem. Soc, 1932, 785.
Proc. Ind. Acad. Sci., 1944, 19A, 21, for oxidation by selenium dioxide. (8) Arch.
Pharm., 1927, 265, 256. (9) Pharm. J., 1893, [iii], 52, 7 9 3 ; DOBSON and P E R K I N ,
J. Chem. Soc, 1911, 99, 1 3 5 ; a n d MASON and P E R K I N , ibid., 1914, 105, 2013.
(10) STUCHLIK, Monats.,
Soc,
1925, 127, 1466 ; cf. GADAMER, Arch. Pharm., 1915, 253, 274. (11) GOLDSCHMIEDT,
Monats., 1885, 6, 954 ; 1886, 7, 485 ; 1887, 8, 510. (12) CLAUS, Ber., 1883, 16, 1284.
(13) GOLDSCHMIEDT, Monats.,
1888, 9, 327.
OSTERSETZER,
ibid., 1888, 9, 7 6 2 ; ROSSIN, ibid., 1891, 12, 486. (15) Cf. GOLDSCHMIEDT and
HONIGSCHMID, Monats., 1903, 24, 681. (16) GOLDSCHMIEDT, ibid., 1888, 9, 7 7 8 ; cf.
KONIGS, Ber., 1899, 32, 3612. (17) Annalen, 1903, 329, 37. (18) Compt. rend., 1909,
149, 210. (19) Cf. PICTET and FINKELSTEIN, Ber., 1909, 42, 1979; Compt. rend.,
1909, 148, 925. (20) Arch. Pharm., 1927, 265, 1 ; MANNICH and FALSER, ibid., 1929,
267, 601. (21) Ber., 1913, 46, 1034. (22) (with NOTHNAGEL a n d RIES'ENFELDT), ibid.,
1927, 60, 392. (23) Ibid., 1927, 60, 704. (24) (with SCH6N), ibid., 1908, 41, 17 ; 1909,
42, 2374. (25) J. Amer. Chem. Soc, 1930, 52, 310. (26) Ibid., 1930, 52, 3610. (27) J.
Chem. Soc, 1933, 274. (28) Ber., 1930, 63, 2098. (29) Ibid., 1935, 68, 24, 1310;
1936, 69, 622 ; see, however, SPATH (with K U F F N E R ) , ibid., 1935, 68, 496, 1744 ; (with
K U F F N E R and KESTZLER), 1936,69, 378. (30) J. Chem. Soc, 1924,125, 2176. (31) Angew.
Chem., 1933, 46, 766. (32) (with PESCHKE), Arch. Pharm., 1934, 272, 60, 236 ; (with
GEHLHAAR), ibid., 1936, 274, 377. (33) J. Pharm. Soc Japan, 1933, 53, 223 (German
text). (34) Ibid., 1935, 55, 58 ; (with TSUDA), 194 ; (with KAKEMI), 244 (English
text). (35) J. Soc. Chem. Ind., 1945, 64, 84. (36) J. Chem. Soc, 1946, 701. (37) J .
pr. Chem., 1940, [ii], 154, 157. (37a) J. Org. Chem., 1939, 4, 71. (38) Monats., 1880,
7, 485 ; 1898, 19, 324 ; (39) Ber., 1904, 37, 3321. (40) J. Chem. Soc, 1909, 95, 1610 ;
1915, 107, 176 ; cf. PYMAN and REYNOLDS, ibid., 1910, 97, 1320. (41) J. pr. Chem.
1903, [ii], 68, 190. (42) Ber., 1926, 59, 2787. (43) D E C K E R a n d GALATTY, ibid., 1909,
42, 1179. (44) PYMAN, J. Chem. Soc, 1909, 95, 1 2 6 7 ; (with BHAGWAT a n d MOORE),
ibid., 1931, 4 4 3 ; cf. GADAMER, Arch. Pharm., 1915, 253, 274. (45) Ber., 1900, 33,
2346; cf. PYMAN and REYNOLDS, J. Chem. Soc, 1910, 97, 1323. (46) J. Chem. Soc,
1936, 731 ; K I N G and L'ECUYER, ibid., 1937, 4 2 7 ; GADAMER, Arch. Pharm., 1911,
249, 680. (47) Ibid., 1927, 265, 256. (48) J. Chem. Soc, 1932, 785. (49) Annalen,
1932, 497, 2 2 ; 1939, 537, 148 (cf. THIEBFELDEB, Inaug. Diss. Munich, 1931). (50) J.
PHARMACOLOGICAL ACTION
199
Chem. Soc, 1932, 789. (51) E M D E , Arch. Pharm., 1912, 391, 88. (52) Ber., 1909,
42 1179- ( 3 3 ) J- Chem. Soc, 1933, 1583 ; for further syntheses see J. Pharm. Soc
Japan, 1937, 57, 2 9 6 ; Ber., 1938, 71, 1860; Proc Imp. Acad. Tokio, 1941, 17, 102.
(54) Annalen, 1932, 497, 47, 59. (55) J. Chem. Soc, 1933, 280. (56) Annalen, 1870,
153 4 7 ; Ber., 1871, 4, 693.
(58) GOLDSCHMIEDT,
Mo'nats'., 1892, 13, 691. (59) J. pr. Chem., 1902, [ii], 65, 42. (60) Monats., 1920, 4 1 ,
297 cf- D E C K E R a n d E I C H L E R , Annalen,
Ber.,
1920, 53, 119- ( 6 1 ) Monats., 1921, 42, 273. (62) Ibid., 1926, 47, 733. (63) Ber.,
1925^ 58,200. (64) ^rc/j.P/jarro., 1890, 228, 419. (65) Ber., 1925,58,1272. (66) Ibid.,
1 9 3 0 ' 63, 1498, 2343 ; 1931, 64, 2827 ; 1934, 67, 1261. For the principles involved
see FREUDENBERG, ibid., 1914, 47, 2 0 2 7 ; W O H L and FBEUDENBERG, ibid., 1923, 56,
309 ; CLOUGH, J. Chem. Soc, 1918, 113, 526. (67) Arch. Sci. phys. not., 1903, [iv],
15 121. (68) Annalen, 1913, 395, 377 ; cf. DECKER and DUNANT, ibid., 1908, 358,
288.
(69) SPATH and E P S T E I N , Ber., 1926, 59, 2791 ; 1928, 6 1 , 3 3 4 ; cf. SCHOPF. 4 9
(70) KONOVALOVA, J U N U S O V and OREKHOV, Ber., 1935, 68, 2158 ; J. Gen. Chem.
Ituss., 1940, 10, 641. (71) KATZ (with LINDNER), Amer. J. Physiol., 1941, 133, 155 ;
(with E L E K ) , J. Pharm. exp. Ther., 1942, 74, 335 ; J. Amer. Med. Assoc, 1942, 120,
434; 1943, 122, 1 9 6 ; WEGRIA a n d NICKERSON, J. Pharm. exp. Ther., 1942, 75, 5 0 ;
MCEACHERN, SMITH and MANNING, Amer. Heart J., 1941, 21, 25. (72) Zent. Physiol.,
1902,16, 68 ; Med. Klin., 1913, 9, [ii], 1796 ; POPPER and FRANKE, Deut. Med. Woch.,
1912, 38, 1318. (73) J. Pharm. exp. Ther., 1917, 9, 121, 1 9 7 ; 1918, 11, 389, 419.
(74) See, for example, KREITMAIR, Arch. exp. Path. Pharm., 1932, 164, 509 ; (with
WOLFES), Deut. med. Woch., 1930, 1 7 0 3 ; LANGECKER and STARKENSTEIN, Klin.
Woch, 1931, 10, 2257 ; VON ISSEKUTZ et al., Arch. exp. Path. Pharm., 1932, 164, 158,
173 ; 1936, 182, 390 ; E D I T . , Brit. Med. J., 1934, i, 812 ; SAMAAN, Quart J. Pharm.,
1936, 9, 23 ; BRUCKNER and FODOR, Ber.,
K U L Z a n d ROSENMUND,
ibid., 1939, 72, 19, 2161. (75) HEILBRON et al., J. Chem. Soc, 1943, 401, 404, 406, 413,
417,
138,
J. Amer. Chem. Soc, 1943, 65, 262, 1582 ; BLICKE (with GRIER), ibid., p . 1725 ; (with
TSAO), ibid., 1944, 66, 1645; LEIIMANN, J. Pharm. exp. Ther., 1945, 83, 8 6 ; (with
YOUNG), ibid.,-p. 9 0 ; (with KNOEFEL), ibid., 1944,80, 335 ; (with CHASE and YONKMAN),
ibid., 1944, 81, 174 ; cf. COLEMAN and BYWATERS, J. Amer. Chem. Soc, 1944, 66, 1821,
and R O W E , J. Amer. Pharm. Assoc,
J. Pharm. exp. Ther., 1945, 84, 387 ; STERN, Arch. exp. Path. Pharm., 1942, 199, 251 ;
cf. GENUIT and K U B E L , ibid., 1943, 202, 110. (76) J. Pharm. exp. Ther., 1946, 86,
230 ; for another laboratory comparison see RICHARDS et al. (77) J. Amer. Pharm.
Assoc, 1943, 32, 249. (78) Ann. Rev. Biochem., 1944, 13, 549. (79) " T h e Pharmacology of t h e Opium Alkaloids," Part 2, p . 1007, Iaudanosine, p . 1042, laudanine,
p. 1044. Supplement 165, U.S. Public Health Reports, Washington, 1943. (80) " Elements de Pharmacodynamic speciale," Paris, Masson & Co., 1932, Tome I, p . 178.
(81) BABEL, quoted by PICTET and ATHANASESCU," also Rev. Mid. Suisse Roman,
1899, 19, 657. (82) STARKENSTEIN, Ileffter's Handbuch der Pharmakol., 1924, 2, 2, 1007.
(83) C. R. Soc. Biol., 1935, 119, 107.
PHTHALIDEWOQUINOLINE SUB-GROUP
Narcotine, C 22 H 23 0 7 N. This alkaloid, probably found by Derosne in
1803, was first definitely isolated by Robiquet, 1 who gave it the formula,
C 23 H 25 0 7 N, which was changed by Matthiessen and Foster 2 to that now
in use. In the extraction of morphine and codeine narcotine remains
in the water-insoluble residue, from which it may be extracted by dilute
hydrochloric acid, re-precipitated by sodium bicarbonate and recrystallised
from boiling alcohol. It crystallises from alcohol in needles, m.p. 176,
[a]j - 207-35 (EtOH), [a] D 198-0 (CHC13), + 50 (1 per cent, hydrochloric acid) 3 ; it is nearly insoluble in water, sparingly so in cold 85 per
cent, alcohol or ether, readily in benzene, acetone or ethyl acetate;
insoluble in cold alkalis or ammonia, but soluble in hot alkalis or " milk
of lime." With acids it forms unstable salts that are dissociated by water,
and the alkaloid can often be extracted by indifferent solvents from its
solutions in dilute acids. The salts are dextrorotatory. The hydrochloride,
B . HC1, crystallises with 0-5 to 4-0 H 2 0, is very soluble in water, decomposing into basic salts on standing in solution ; platinichloride; amorphous ; oxalate, B . H 2 C 2 0 4 , m.p. 174, [a]| + 39-5 ( H 2 0 ) ; phthalate,
B . C 8 H 6 0 4 , m.p. 160, [<x]f + 115 (CHC13) 5(o>; sesquisulphate,4
B 4 . 3H 2 S0 4 . 6H 2 0 ; picrate, m.p. 175.5
The alkaloid dissolves in sulphuric acid with a greenish colour, changing
to red and reddish-violet on warming or long standing. With sulphuric
acid containing a trace of nitric acid a deep red colour is produced.
According to Labat, 6 a solution of narcotine in sulphuric acid- gives, on
warming with gallic acid, a deep blue coloration, due to the liberation of
opianic acid. This reaction is also given by hydrastine. Duqu6nois and
Ellert 6(o) have described several complex salts of narcotine of which they
recommend the silicotungstate for the estimation of the alkaloid.
Constitution. Narcotine is a weak, monoacidic, tertiary base. It contains a methylimino-group and three methoxyl groups, and, when heated in
closed tubes with dilute hydrochloric acid, furnishes a series of demethylated
derivatives 2 : dimethylwornarcotine, C 19 H 14 0 4 N . OH(OCH3)2, methyltiornarcotine, C 19 H 14 0 4 N(OH) 2 . OCH3, nomarcotine, C 19 H 14 0 4 N(OH) 3 .
When the alkaloid is heated with water at 150, or boiled with dilute
acids, it is hydrolysed into hydrocotarnine, and opianic acid. Similar
decompositions are induced by acid oxidation or acid reduction, thus :
(1) dilute nitric acid furnishes opianic acid, C10H10O5, and cotarnine,
C 1 2 H 1 5 0 4 N; (2) zinc and hydrochloric acid produce meconin, C10H10O4,
and hydrocotarnine, C 12 H 15 0 3 N.
Meconin, C10H10O4, was isolated from opium in 1832 by Dublanc,
and also occurs in Hydrastis canadensis. It crystallises from water in
prisms, m.p. 102, and dissolves in alkaline solutions, forming unstable
salts of meconinic acid, C 10 H lg O s , of which it is the lactone. It was200
NARCOTINE
201
C.CO0H
X.CH0
<-
CH
C.COOH
p.OCHg
V.OCH.5
CH
C.0CH3
^C'OCEj
Hemlplnlc a c i d
Opianic a o l d
X.CH2.0
CH
< L
CCO
CH
^C.OC^
^C.0Cn3
Mecoaln
202
SUB-GROUP
PHTHALIDETSOQVINOLINE
with excess of methyl iodide and subsequent warming with dilute hydrochloric acid, is converted into worcotarnine methine methiodide (IV) and
this, on treatment with alkali, decomposes into ?iorcotarnone (V) and
trimethylamine. This loss of methyl from a methoxyl group also occurs
with the anil of o-methoxybenzaldehyde, which on similar treatment
yielded o-hydroxybenzaldehyde, whence it was argued that in cotarnine
the methoxyl group and the aldehyde group, the presence of the latter in
cotarnine being indicated by the formation of cotarnine-oxime, m.p. 165-8,
were in the o-position to each other.
Cotarnic acid may therefore be represented by (VI), and this was
confirmed by Perkin, Robinson and Thomas, 18 who synthesised cotarnic
acid, starting from 5 : 6-methylenedioxy-l-hydrindone (VII) which was
nitrated in position 7, the nitro-group converted in the usual way to a
OMo
0H:HHPh
H 2 c:
site 31
OCi
H2C
ICHg
a\
H2<
.Of
0l
oLN-.
J1C00H
JJCOOH
/
CH2
(IV)
(VI)
OMe
|HM63l
01
-
0L
(IX)
H 2 0:
}W{
0H2
(VII)
H2o:
(VIII)
C o t a r n i c a c i d I VI)
W- OH3OH
(XI)
hydroxyl group, the latter methylated, and the condensation product (VIII)
with piperonal, oxidised yielding cotarnic acid (VI).
Cotarnine with methyl iodide furnishes cotarnine hydriodide and
cotarnine methine methiodide, C u H u 0 4 NMe 3 I (IX), which is decomposed
by alkalis into trimethylamine and cotarnone (X), C11H10O4, rhombic
plates, m.p. 78. The latter yields an oxime, m.p. 130-2, and is oxidised
by potassium permanganate to a mixture of cotarnic acid (VI) and
cotarnlactone, C u H 1 0 O 6 (XI), brilliant leaflets, m.p. 154, which is
convertible into the corresponding acid, cotarnonelactone acid, leaflets,
m.p. 90-100 (dec). The lactone on further oxidation yields cotarnic acid.16
NARCOTINE
203
Cotarnine
Cotarnine chloride
Hydrocotarnine
/O.C
H
2C\
C.CHOH.N.CH,
I I
- C *
P-WZ~
? C
^o
\ /
Cotarnine (Decker)
/O.C
H C
C.CH=N( CH,).OH
I
0-C,
C.CH-.CH,
\ /
Cotarnine In d i s s o c i a t i n g
solvents
204
PBTBALIDEisoQUINOLINE
SUB-GROUP
CHMe
CH2
CH2
CH2
MeO
Narcotine
Cue
KeO
IsoNarcotlne
The synthesis of meconin has been referred to already (p. 201). Cotarnine has been synthesised by Salway 31 from myristicin (I) as a startingpoint. This was transformed into |3-3-methoxy-4:5-methylenedioxyphenylpropionic acid (II), the amide of which was converted by Hofmann's
reaction into /3-3-methoxy-4 : 5-methylenedioxyphenylethylamine, and the
phenylacetyl derivative (III) of this condensed, by heating it in xylene
solution with phosphoric oxide, giving rise to the two possible dihydroisoquinoline derivatives. The first of these substances, 8-methoxy-6 : 7methylenedipxy-l-benzyl-3:4-dihydroisoquinoline (IV), on conversion
into the methochloride and reduction with tin and hydrochloric acid, gave
206
NARCOTINE
die
206
SUB-GROUP
PHTHALIDEJSOQVINOLINE
(3) A N N E T T , Analyst,
1923, 48, 5 3 ;
Trans. Chem. Soc, 1923, 123, 3 7 8 ; cf. PARISEIXE, Compt. rend., 1934, 198, 928.
(4) D O T T , Pharm. J., 1928, 120, 292, 301. (5) MAPLETHORPE and E V E B S , ibid., 1925,
115, 137. (5a) VOLMAR et al, Compt. rend., 1939, 208, 2000. (6) Bull. Soc chim.,
1909, [iv], 5, 742, 743. (6a) Bull. Soc chim., 1939, [v], 6,1582. For other colour reactions
see REICHARD, Pharm. Zent., 1907, 48, 44. (7) Annalen, 1898, 301, 351. (8) J. Chem.
Soc, 1925, 127, 195. (9) H E S S E , Annalen, Suppl., 1872, 8, 326. (10) PYMAN and
R E M F R E Y , J. Chem. Soc, 1912, 101, 1595 ; cf. KONDO and NAKAZATO, J. Pharm.
Soc. Japan, 1924, N o . 507, 326 ; TANAKA, MIDZUNO a n d OKAMI, ibid., 1930, 89 ; a n d
TOPTSCHIEV, J. Appl.
Chim. Russ.,
(12) ANDERSON, ibid., 1853, 86, 1 8 7 ; cf. R O S E R , ibid., 1888, 249, 156.
(13) D O T T ,
Pharm. J., 1907, [iv], 24, 78. (14) Ibid., 1924,113, 688 ; 1931,127,520. (14a) Svensk.
Farm. Tidskr., 1940, 44, 309. (15) ROSER, Annalen, 1888, 249, 156 ; cf. FREUND and
W U L P F , Ber., 1902, 35, 1737 ; and GAEBEL, Arch. Pharm., 1910, 248, 207. (16) R O S E R ,
Annalen,
(17) Ber.,
and
STERNBERG, ibid., 1934, 67, 2095. (18) J. Chem. Soc, 1909, 95, 1977; for a
later synthesis see SrAmet al." (19) Annalen, 1888, 245, 3 1 1 ; 247, 1 6 7 ; 1888,
249, 156, 168 ; 1889, 254, 334, 359 ; cf. F R E U N D and B A C K E R . 1 7
(20) J. pr.
Chem.,
1893, [ii,] 47, 222. (21) Ber., 1899,32,3109 ; 1 9 0 0 , 3 3 , 2 2 0 1 ; cf. FBJECND and BAMBERG,
ibid., 1902. 35, 1739. (22) J. Chem. Soc, 1903, 83, 598 ; 1 9 0 4 , 8 5 , 1 2 1 . (23) VONGE-
NARCEINE
BICHTEN, Ber., 1880, 13, 1635; Annalen,
1886, 234, 116.
207
(25) F R E U N D a n d P R E U S S ,
Ber.,1900, 33, 380 ; DECKER, ibid., p . 2273 ; HANTZSCH, ibid., 1899, 32, 3109 ; 1900,
33, 2201. (26) LIEBERMANN (with K R O P F ) , ibid., 1904, 37, 211 ; (with GLAWE), p . 2738 ;
KROPF, ibid., p . 2744.
(28) Ber., 1903, 36, 4257 ; 1904, 37, 3334 ; (with R E I T Z ) , 1906, 39, 2219 ; (with B O D E ) ,
1909, 42, 1746; (with LEDERER), 1911, 44, 2353. (29) J. Chem. Soc., 1911, 99, 775
(30) Ber., 1896, 29, 183, 2040 ; cf. K E R S T E N , 1898, 31, 2098 ; and J O N E S , P E R K I N and
ROBINSON, J. Chem. Soc., 1912, 101, 258. (31) J. Chem. Soc, 1910, 97, 1208; cf.
DECKER and BECKER, Annalen, 1913, 395, 328. For a more recent synthesis see
KINDLER and PESCHKE, Arch. Pharm., 1932, 270, 353. (32) Pharm. J., 1878, [iii,]
9 , 8 2 ; 1893, [iii,] 23, 794. (33) Ber., 1907, 40, 3280 ; Annalen, 1910, 377, 223. (34) J.
Chem. Soc., 1914, 105, 2085 ; see also ibid., 1911, 99, 1153, 2114 ; 1913, 103, 361 ;
1914, 105, 1 4 5 6 ; GREENWOOD a n d ROBINSON, 1932, 1370.
(36) JORGENSEN, Ber., 1869, 2, 460 ; W R I G H T , J. Chem. Soc,
RICHTEN, Annalen, 1881, 210, 7 9 ; 1882, 212, 1 6 5 ; ROSER, ibid., 18S8, 245, 311 ;
1889, 254, 359. FREUND and LEDERER, Ber., 1911, 44, 2353. (37) Arch. esp. Path.
Pharm., 1937, 184, 331.
208
PHTHALIDETSOQUINOLINE
SUB-GBOUP
(VI)
Olie
(IV)
CUe
KEIXER, Amer. Chem. J., 1899, 22, 61 ; FRERICHS, Arch. Pharm., 1903,241, 259;
HOPE and ROBINSON, J. Chem. Soc, 1914, 105, 2100 ; RODIONOV, Bull. Soc. chim.,
209
BICUCULLINE
Annalen,
210
SUBGROUP
PHTHALIDETSOQUINOLINE
l III)
CHg
CH5-O
NMa
/
CH.OH
PHARMACOLOGICAL
ACTION
211
212
PHTBALIDETsoQmNGLlNE
SV&-QROUP
have little action when pure, probably owing to the instability of its salts
and the sparing solubility of the free base.
Bicuculline, bicucine and adlumine have been compared pharmacologically with hydrastine by Welch and Henderson. 15 Bicuculline resembles
hydrastine in action, but is about 100 times as active as a convulsant.
Bicucine induces convulsions in rabbits in about the same dose as hydrastine. Adlumine is a weaker convulsant than any of the other three but
acts more powerfully on the uterus than either bicuculline or hydrastine.
According to Rice, 16 corlumine lies between bicuculline and adlumine as a
convulsant and its action on isolated rabbit intestine and guinea-pig uterus
is similar to that of other members of the group. An extensive series of
Manske's alkaloids of the Fumariaceae has been examined by Anderson
and Chen,17 including adlumidine and capnoidine ; all the bases are stated
to stimulate isolated guinea-pig or rabbit uterus and capnoidine inhibited
isolated rabbit intestine. Capnoidine was also exceptional in resembling
J-wocorypalmine (p. 291) in inducing catalepsy in young monkeys. Though
cularine (p. 313) has not been suggested as a member of either the benzylor phthalidewoquinoline group it has been compared pharmacologically by
Reynolds 18 with papaverine and hydrastine. As a convulsant, cularine
was about one-tenth as potent as hydrastine. Like papaverine, and more
definitely than hydrastine, a 1 per cent, solution produced anesthesia of
the rabbit cornea. Intravenous injection in the rabbit induced a temporary
fall in blood pressure. Unlike hydrastine, it diminished the contractility
and tonus of isolated rabbit intestine, but like hydrastine it augmented
contraction and tone of isolated guinea-pig or rabbit uterus. In the
perfused frog heart cularine produced an increase in contractility and tone,
while hydrastine decreased contraction but augmented tone.
REFERENCES
(1) MANSKK, Can. J. Bes., 1933, 8, 142. (2) P E R K I N a n d T B I K O J U S , J. Chem.
1926, 2925 ; SPATH and H O L T E K , Ber., 1927, 60, 1891. (3) M A N S K E , Can. J.
Soc,
Res.,
1933, 9, 436. (4) Amer. Chem. J., 1900, 24, 249 ; (with WATKINS) Pharm.
Archiv.,
1903, 6, 27. (5.) Can. J. Bes., 1933, 8, 210, 404 ; 1938, B , 16, 89. (6) J. Chem. Soc,
1909,95,1266. (7) Ibid., 1936, 199. (8) Ibid., 1911, 99, 1153 ; 1931,236. (9) Can. J.
Res., 1936, B , 14,325, 3 4 7 , 3 5 4 ; 1937, B , 15,159. (10) Ibid., 1938, B , 16, 81. (11) Ibid.
1933,
J.
Med. Res., 1930, 18, 35 ; (with KNOWLES), ibid., p . 5 ; DIKSHIT, ibid., 1932, 19, 7 6 5 ;
H A Y A S H I , Jap. J. Med. Sci., [iv], Pharmacol.,
1930, 5, 9 0 ;
HATCHER, J. Pharm. exp, Ther., 1934, 15, 411. (13) ZIMMERMANN, Arch. exp. Path.
Pharm., 1937, 184, 336. (14) Ber., 1935, 68, 656. (15) J. Pharm. exp. Ther., 1934,
51, 482, 492. (16) Ibid., 1938, 63, 329. (17) Fed. Proc, 1946, 5, 163. (18) J. Pharm.
exp. Ther., 1940, 69, 11.
MORPHINE SUB-GROUP
Morphine, C 17 H 19 0 3 N. In 1803 D:rosne, x an apothecary practising in
Paris, observed the separation of a crystalline substance, when a syrupy
aqueous extract of opium was diluted with water. This crystalline
material was probably narcotine, or a mixture of that alkaloid with
morphine. Seguin, in 1804, read to the Institute of France a paper in
which he described the isolation of morphine, although he did not recognise
its basic character. This paper was not published till 1814, and, in the
meantime, Serturner had obtained both morphine and meconic acid from
opium, and pointed out that the former was the first member of a new
class of substances, " the vegetable alkalis." 2 The composition of the
alkaloid was first determined by Liebig in 1831, who represented it by the
formula, C 34 H 36 0 6 N 2 , which was reduced by Laurent 3 in 1847 to the
simple formula now in use.
Morphine crystallises from dilute alcohol in colourless, trimetric
prisms containing 1H 2 0, becomes anhydrous at 100, and then melts at
254 (dec). It is bitter to the taste and sparingly soluble in most solvents.
The solubilities given by different observers vary somewhat (e.g., boiling
alcohol 1 in 80 to 1 in 36, in cold alcohol 1 in 210 to 1 in 300).4 Miiller 4
gives the following figures : water (1 in 3,533), ether (1 in 7,632), benzene
(1 in 1,599), chloroform (1 in 1,525), ethyl acetate (1 in 537). According
to Florio, the solubility in amyl alcohol is about 1 in 50 at 78. Miiller's
figure for solubility in benzene is unusually high, and though Prescott 5
states that freshly precipitated morphine dissolves in 1,997 parts of
benzene, whilst the crystallised alkaloid dissolves in 8,930 parts, the
alkaloid is generally stated to be " insoluble " in benzene. Morphine is
soluble in limewater (1 in 100 at 25), or in alkali hydroxide solutions, but
less so in ammonia solution (1 in 117, sp. gr. 0-97, Duflos). The base is
laevorotatory, [x]f - 130-9 (MeOH), - 70 in excess of alkali. It is a
monoacidic base, and its salts, which are usually well-crystallised, are
neutral to litmus and methyl orange. The average pH of morphine salts
is 4-68, and methyl red has been suggested as a suitable indicator for
titration of the base. 6 The salts chiefly used in medicine are the sulphate,
hydrochloride and acetate, though the tartrate, bimeconate and others
have also been employed. The sulphate, B 2 . H 2 S0 4 . 5H 2 0, forms small
silky crystals or cubical masses from water, is soluble in water (1 in 15-5 at
25, or 1 in 0-7 at 80), or alcohol (1 in 565 at 25, or 1 in 240 at 60). It
chars at 250, but does not melt. It is laevorotatory, [a]J,5 - 100-47 + 0-96c
(HjjO). The hydrochloride, B . HC1. 3H 2 0, forms colourless silky needles
from water, [a]*,5" - 100-67 + l-14c in water (Hesse), or - 111-5 at 25
in dry alcohol (Schryver and Lees), is soluble in water (1 in 17-2 at 25,
or 1 in 0-5 at 80), or alcohol (1 in 42 at 25, or 1 in 35-5 at 60). The
21S
214
MORPHINE
SUB-GROUP
215
PSEUDOMORPHINE
.,,
'/,
216
MORPHINE
SUBGROUP
24
MORPHINE
ISOMERIDES
217
Sub stance
Formula
H.p.
[a]D
a-Chloromorphide
17H182HC1
193
-375-20
(MeOH)
B.HCl,[a]D-315.3;
B.Mel, m.p.207
P-Chloromorphide
17 H 18 0 8 H C 1
188
-5
B.Mel,
m.p.210(deo)
Bromomorphide
17H 18 0 2 BBr
169-170"
+65-90
(MeOH)
B.Mel,
m.p.200
a-Chlorocodide
ieH202HC1
152-3
-381-2
(MeOH)
B.Mel, in.p.168;
[d]D-215
^
P-Chlorocodide
18H202HC1
196-7
-10
(BtOH)
Bromooodide
tf^HgoOgBBr
168
+56-5
(EtOH)
Salts
(He OH)
218
MORPHINE
SUBGROUP
Methylation product
M.p.
[a]D
Oxidation product .
M.p.
[a]
Exhaustive methylation product.
Morphine,
a-tsomorphine.
254
247
130-9
167
Codeine.
woCodeine.
155
172
135
- 155
Codeinone.
187
- 205
3 : 4 : 6-trimethoxyphenanthrene.
Methylation of the
isomeric
codeines
gives the primary
methylmorphimethines,
Codeine,
iso-Codeine, aHo-^-Codeine,
^t-Codeine,
a-isomer.
y-isomer.
^-isomer.
e-isomer.
m.p. . 119 m.p. . 166
oil
m.p. . 130
[o]D . - 214 [o]D
+ 65 [a]
- 178 [a] D - 120
(both stable to alkali)
M.p.
which by action
of
alcoholic
potash yield the
s e c o n d a r y methylmorphimethines.
'
/3-isomorphine. y-tsomorphine.
182
278
- 216
94
alio- 0-Codeine ^-Codeine.
116-117
181
- 235-4
- 94
0-Codeinone.
174
25
3 : 4 : 8-trimethoxyphenanthrene.
-'
/5-isomer,
S-isomer,
m.p. . 134 m.p. . 113"
[a]
+ 438 [a]D
+ 284
THBBA1NE
219
220
MORPHINE
SUB-GROUP
soluble in 15-8 parts of water at 10. The salicylate is sparingly soluble in,
water, and may be used for the separation of thebaine from other opium
alkaloids.39 The picrate has m.p. 217. Thebaine gives a blood-red
coloration with sulphuric acid, which turns orange-yellow, and eventually
olive-green on warming,40 and with nitric acid it is at first colourless but
becomes yellow in a few minutes.
Porphyroxine, C 19 H 23 0 4 N. In 1837 Merck 41 isolated from opium a
product to which he gave this name, and which Hesse iZ subsequently
found to be a mixture of alkaloids, including rhoeadine and meconidine.
A similar substance was obtained by Dey in 1882, both these preparations,
having the property of forming purple-coloured solutions with dilute acids.
Rakshit *3 has examined the material dissolved by ether from an extract
obtained by triturating a mixture of Indian opium and lime with water,
and has isolated from it a substance to which he assigns the above name
and formula. It is described as crystallising from light petroleum in pale
yellow or colourless, transparent prisms, m.p. 134-5, [a]ff 139-9
(CHC13), soluble in water, dilute acids, acetone, chloroform and moderately
so in alcohol, benzene, sparingly in ether or light petroleum and almost
insoluble in lime water or alkalis. Solutions in dilute acids become red on
exposure to air. The alkaloid gives a red colour with sulphuric acid.
The salts are mostly crystalline, B . HC1, m.p. 155, [x]f 118-8 (H 2 0),
prismatic needles; nitrate, B . H N 0 3 , m.p. 122, feathery tablets,
MiT 115-4 ( H 2 0 ) ; the platinichloride, m.p. 204 (dec), and picrate,
B . C 6 H 3 0 7 N 3 , m.p. 198, (dec.) are crystalline powders.
In a later paper Rakshit 44 showed that porphyroxine behaves as a
tertiary base, yielding a methiodide, m.p. 150-2, and a methosulphate,
m.p. 205 (dec.). The presence of a hydroxyl group was indicated by the
formation of a monoacetyl derivative, m.p. 125, [a] D 187-2 (EtOH),
and this group must be non-phenolic as the base is insoluble in alkali.
Porphyroxine also forms a crystalline oxime, m.p. 198 (dec), and a
semicarbazone, m.p. 244 (dec). It contains one methoxyl group, and the
methylmethosulphate, on treatment with potassium hydroxide in methyl
alcohol, yields methylporphyroxine, C20H25O4N. The methylmethosulphate, on reduction with sodium amalgam in dilute sulphuric acid,furnishes methyltetrahydroporphyroxine, C20H29O4N, colourless plates,
m.p. 150, but the parent base could not be hydrogenated. On distillation
with zinc dust porphyroxine furnishes phenanthrene, ammonia and
trimethylamine, and when heated with potassium hydroxide solution
(2 per cent.) and hydrogen peroxide, codeine and formic acid are produced;
thus :
C 18 H 23 0 3 N : CO + KHO + H 2 0 2 = C 18 H 21 0 3 N + H . CO . OK + 2 H 4 o |
On the basis of these results, Rakshit represents porphyroxine as codeintf
with a CO group as a bridge in the aromatic ring in Pschorx's codeiMJ
formula (see p. 234). Machiguchi 45 isolated from Japanese opium M
product identical in melting-point and other characteristics with porphyf
roxine, which on examination proved to be a mixture of codamine, laudr
221
POBPHYROXINE
nine and meconidine, and Rajagopalan 45(o) was unable to find porphyroxine
in Indian opium and suggested that Rakshit's alkaloid was impure
codeine. Bamford found that the porphyroxine test is not distinctive
for Indian opium, and that a substance giving this test also occurs in
Turkish opium.46
REFERENCES
(1) Ann. Chim., 1803, 45, 257. (2) Gilbert's Annalen, 1817, 55, 56 ; 57, 192 ; 1818,
59 50. For an account of Sertiirner's discovery, see HANZLIK, J. Amer. Pharm.
Assoc.,1929,18, 375. (3) Ann. Chim. Phys., 1847, [iii], 19, 359. (4) Apoth. Zeit., 1903,
18 257 ; cf., however, 1 in 6,700 for water found by BAGGESGAABD-RASMUSSEN and
REIMEBS, Arch. Pharm., 1935, 273, 129. (5) Pharm. J., 1875, [iii], 6, 404. (6)
KOLTHOFF, Biochem.
Zeit., 1925, 162, 2 8 9 ; Pharm. J., 1927, 118, 1 2 6 ; cf.
MORTON, ibid., 1926, 116, 567. (7) For other tests for the detection of morphine
see OLIVER, Chem. Soc. Abstr., 1915, [ii], 7 5 ; E K K E R T Pharm. Zent., 1926, 67,
498 ; 1928, 69, 1, 19, 198 ; 1929, 70, 1 6 5 ; 1930, 71, 5 5 0 ; SANCHEZ, J. Pharm.
Chim., 1937, [viii], 25, 3 4 6 ; WAGENAAR, Pharm.
Weekl., 1927, 64, 1119
(microchemical); REIMERS and GOTTLIEB, Dansk. Tids. Farm., 1947, 21, 14.
The following relate t o biological material : HERRMANN, Biochem. Zeit., 1912, 39, 216 ;
DOVEY, Analyst, 1927, 52, 26 ; BAMFORD, ibid., 1931, 56, 586 ; PANSE, Fort. Therap.,
1932, 8, 629 ; MUNCH, J. Amer. Pharm. Assoc, 1934, 23, 766, 1185 ; 1935, 24, 557.
(8) MATTHIESSEN and WRIGHT, Annalen,
MAYER, Ber.,
1871, 4, 121 ; (with WRIGHT), ibid., 1872, 5, 1 1 0 9 ; FULTON, J. Lab. Clinical Med.,
1928, 13, 750 ; OPARINA, KARASINA and SMIRNOV, Khim. Farm. Prom., 1934, No. 5,
18 and Russ. Pat. 40,981. (9) J. Org. Chem., 1940, 5, 334. (10) GBIMBERT and
LECLERE, J. Pharm. Chim., 1915, [vii], 11, 23. F o r other tests see VAN MIKO, Pharm.
Zent., 1927, 68, 193; COLE, J. Roy. Soc. N.S.W.
1947, 81, 80. (11) KNORR
(with ROTH), Ber., 1907, 40, 3356; (with R A B E ) , ibid., 1908, 41, 3050;
PSCHORR, JACKEL and FECHT, ibid., 1902, 35, 4 3 7 7 ; FOLKERS, J. Amer. Chem.
Soc., 1936, 58, 1814. (12) J. Pharm., 1835, [ii], 21, 5 5 5 ; Annalen, 1835, 16,
27. (13) Ibid., 1867, 141, 8 7 ; 1 8 8 4 , 2 2 2 , 2 3 4 ; 1 8 8 6 , 2 3 4 , 2 5 3 . (14) Compt. rend.,
1858, 46, 598. (15) Ber., 1880, 13, 86 ; 1886, 19, 1760. (16) BALLS, J. Biol.
Chem., 1927, 71, 537, 543 ; (with WOLFF), ibid., 1928, 80, 403. (17) FULTON, Amer. J.
Pharm., 1933, 105, 503. (18) LEULIER and DREVON, Bull. Soc. Chim. biol., 1932, 14,
521 ; J. Pharm. Chim., 1935, [viii], 22, 97. (19) Arch. Pharm., 1928, 266, 641 ; cf.,
however, STICK, Pharm. Zeit., 1928, 73, 1513. (20) J. Amer. Chem. Soc, 1934, 56,
1930. (21) Annalen, 1833, 5, 106. (22) For another process see BYLINKIN, Russ. P a t .
3,381, Brit. Chem. Abstr., 1929, B , 538. (23) GRIMAUX, Compt. rend., 1881, 92, 1140,
1228; 1881, 93, 67, 217, 591. (24) E.g., German Patents 39,887, 92,789, 95,644,
96,145, 102,364, 107,225, 108,075, 131,980, 189,843, 214,783, 224,388, 247,380, 418,391 ;
Russ. P a t . 20,083 (Chem. Zent., 1931, ii, 3664) ; 50,438 (ibid., 1938, ii, 953) ; 191,609
(ibid., 1939, ii, 4 2 0 ) ; RODIONOV, Bull Soc. chim., 1926, [iv], 39, 3 0 5 ; other ethers
of morphine and its isomerides, see FARIS and SMALL, J. Org. Chem., 1936, 1, 194.
(25) For constants of codeine crystals, see K L E Y , Rec. trav. Chim., 1903, 22, 3 6 7 ;
HEYDRICH, Zeit. Kryst. Min., 1910, 48, 243 ; WRIGHT, J. Amer. Chem. Soc, 1916, 38,
1647 ; W H E R R Y and YANOVSKY, J. Wash. Acad. Sci., 1919, 9, 505. (26) BAGGESGAARD-
RASMUSSEN and SCHOU, Pharm. Zent., 1924, 65, 729. (26a) CAUSSE, Compt.
rend.,
1899, 128, 1 8 1 ; KNOLL and Co., D . R . P . 175,068; K N O R R el al., Ber., 1909, 42, 3 5 1 1 ;
SMALL and MALLONEE, J. Org. Chem., 1940, 5, 286 ; 1947, 12, 55. (27) Other reactions
useful for the detection of codeine are described by WAGENAAR, Pharm. Weekbl., 1927,
64, 671 (microchemical) ; HEIDUSCHKA and MEISNER, Arch. Pharm., 1927, 265, 455
(microchemical);
D E HAAS, Pharm. Weekbl., 1930, 67, 508. (28) Ibid., 1932, 69, 990.
(29) Pharm. J., 1891, [iii], 21, 878, 916, 955, 9 9 6 ; cf. MATTHIESSEN and B U R N S I D E ,
Annalen, 1871, 158, 131 ; MERCK, Arch. Pharm., 1891, 229, 161 ; G8HLICH, ibid., 1893,
<wl, 235 ; KNORR and R O T H , Ber., 1907,40, 3356 ; J . WIERNTIR & Co., Ger. P a t . 489,185
(Chem. Zent., 1930, i, 1863). (30) SCH3PF and HIBSCH, Annalen, 1931. 489, 235 ; SMAIX,
222
MORPHINE
SUB-GROUP
Ber.,
(35) Annalen, 1835,16, 38. (36) Ibid., 1836,19, 9. (37) Ibid., 1853, 86, 184. (38) Ibid.,
1870, 153, 4 7 ;
cf. K A N E W S K A J A , J. pr.
Chem.,
(39)
PLUGGE,
Itec trav. Chim., 1887, 6, 157. (40) F o r other methods of detection see REICHARD,
Pharm. Zent., 1906, 47, 623 ; and WAGENAAR, Pharm. Weekbh, 1927, 64, 472.
(41) Annalen, 1837, 21, 201. (42) Ibid., 1870, 153, 47. (43) J. Chem. Soc, 1919, 115,
455. (44) Ber., 1926, 59, 2473. (45) J. Pharm. Soc. Japan, 1926, N o . 529, p . 19.
(45a) RAJAGOPALAN, J. Org. Chem., 1945, 10, 175. (46) Analyst, 1930, 55, 445.
CH30\
> ^ C 16 H 16 0 N
CHOH^ 1 6 i 6
Codeine
CH30\
> ^clRHifi0H
C 0 ^1 6 1 6
Codeinone
CH~0v.
<
C la Hi K 0N
CHgO.C^ l 6 1 5
Thebaine
223
CONSTITUTION
HO-C^
Morphine
r*wo-C\
HO-HO^
apoLIorphlne
CH,0-Ck
Codeine
CH.,0-0.
Codeinone
CH30-8
Morphothebaine
Thebenine
GI 3 0-'dv.
01411120 1
' "
0113 2
'
~*
^13H7,OH
CH 8 0H-CH 2 -H(GH 3 ) 2 .
MORPHINE 8VB-QS0UP
224
Type I .
Type I I .
Alkaloid
Morphine!
3-Methoxy-4-hydroxyphenanthrene, or
3-methoxy-(4:5)-oxyphenanthrene.
Codeine_)
Thebaine
3:6-Dimetb.oxy-4-hydroxyphenanthrene.
-apoMorphlne
3:4-Dimethoxy-8-vinylphensnthrene .*
Morphothebaine
3:4:6-Trimeth6xy-8-vinylphenanthrene . f l
y-ieoMorphlne"
Type I I I . f -Codeine
3-Methoxy-4:8-dihydroxyphenanthrene."
y&--Codeinone__
Type IV.
Thebenine
a^^-Trimethoiy-S-vinylphenantarene.' 4
The basic product in these reactions varies with the nature of the
initial substance and the character of the degradation process, as the
following selected instances show :
CONSTITUTION
Substance
a- or e-lfethylmorphimethine
225
Degradation products
(a) Basic (o) Heutral-.
Degrading
Agent
Aeetio anhydride
(a) Ethanoldimethylamine,
~
H0*CH2'CH2*N(CH3)2'
(b) 3-Methoxy-4-aoetoxy
phenanthrene."
p-Methylmorphlmethine
Sodium ethoxide
a-Methylmorphimethine
methiodide
Hofmann prooess
(a) Trimethylamine.
(b) 3-Methozy-( 4:5)""
oxyphenanthrene.'1'
Codeinone
Acetic anhydride
(a) Ethanolmethylamine,
H0-CH2-CH2'HHCH3.
(b) 3-Methoxy-4:6-diacetoxy""
phenanthrene. ,0s
Codeinone methiodide
Alcohol at 160
it
Thebaine
Benzoyl chloride
(a) Ethanolmethylamine,
~
H0-CH2- 0H 2 -1SHMe '
(b) 3:6-Dimethoxy-4-
""
henzoxyphenanthrene.10
The nature of the basic product formed in these reactions was important
in connection with the earliest attempts to devise a constitutional formula
for morphine, when it was assumed that the oxygenated basic products, resulted from the hydrolysis of an oxazine ring containing the
" indifferent " third oxygen atom of morphine. Knorr, the author of
various " oxazine " formulas for morphine, disposed of it by providing
two other explanations. He showed that by the action of hydrogen chloride
on oc-methylmorphimethane, a mixture of ethanoldimethylamine and
tetramethylethylenediamine is obtained, produced, he suggested, from the
initial extrusion product, chloroethyldimethylamine by the action of the
alkali used in working up the reaction mixture. Similarly, by the action
of sodium ethoxide in alcohol on a-methylmorphimethine or on codeinone
methiodide, dimethylaminoethyl ether, accompanied by some dimethylamine in the case of codeinone, is formed, as it is also in the action of
alcohol at 160 on the methiodide of either thebaine or codeinone. In
these cases Knorr assumed that the initial product is vinyldimethylamine;
which reacts with (1) alcohol, to give dimethylaminoethyl ether; (2) with
PLANT ALK.
MORPHINE
226
SUBGROUP
acetic acid (in the case of acetic anhydride degradations) to give the
hydramine acetate; and (3) with dimethylamine to give tetramethylethylenediamine,20 as shown in the following equations :
U)
ICH3)2!KB=CH2
CgHg-OH =
(2) (CH3)2K-CE=CH2
CHg-COOH =
(3)
+ SH(CHg)8=
(CH3)2S-CHM3H2
(CHg) gN-CH^-C-CgH,.
(CHg) gN-CHg-CH^-CO-CHj
(CHglgN-CHg-CHg-NlCHg^
HC:
HC"
A /-
HCro
HC
II
HC,
y*
II
H09
\ ,
5 CH
HOl
CH
CH
Morphol
' \
HC
A
v
HC.
CH
\ /
Morphenol
.C-OH
HC
/v
C-OCH,
3
II
C-OH
HC,
CH
H'
II
HC
HC'
:-OCH 3
C-OH
C-OH
3-Mettio]cy-4:6-dlhydroiyplienantarene
from codeinone.
II
HC^/^CH3
Thebaol
CONSTITUTION
227
for the three primary bases, morphine, codeine and thebaine, it will be
convenient to deal with those now generally accepted for opomorphine,
morphothebaine and thebenine, since in these derivatives the protean
changes characteristic of the parent alkaloids are no longer possible. To
these may be added isothebaine, which is of special interest since it is found
in Papaver orientate (p. 173).
apoMorphine, C 17 H 17 0 2 N. This alkaloid has been described already
(p. 214) but the constitutional formula to be assigned to it remains to be
dealt with. Though apomorphine differs in empirical composition from
morphine only by 1 mol. of water, it results from a much more profound
change in the morphine nucleus than is implied by that difference. The
following particulars are taken mainly from papers by Pschorr et al.ia
apoMorphine contains one methylimino-group, and the presence of two
hydroxyl groups is indicated by the formation of a dibenzoyl derivative,
colourless prisms, m.p. 156-8, [<x]i>7 + 43-4 (CHC13), a monomethyl ether
(i/>-opocodeine, p. 215), and a dimethyl ether, oil, [a]1,5" 148 (EtOH). 11
The latter forms a crystalline hydriodide, m.p. 220, [a]},6 49 (EtOH),
and a methiodide, m.p. 195, [a]}f 46 (EtOH), 11 which, on treatment
with alkali, furnishes dimethylopomorphimethine, of which the methiodide,
m.p. 242-4, on boiling foi twenty minutes with dilute potassium hydroxide
solution, decomposes into trimethylamine and a dimethoxyvinylphenanthrene, C 14 H 7 (OMe) 2 CH=CH 2 , rhombic tablets, m.p. 80 (picrate,
violet needles, m.p. 128). This, on oxidation with permanganate, gives a
3 :4-dimethoxyphenanthrenecarboxylic acid, m.p. 196, which was
NlteBa
228
MORPHINE
SUB-GROUP
CONSTITUTION
229
230
MORPHINE
SUB-GBOUP
(IX) for this alkaloid. Definite proof of this location was first provided by
Gulland and Virden,36 who suggest formula (VIII) for thebenol in view
of the ease of formation and stability of six-membered oxide rings. These
authors showed that the neutral product formed by the exhaustive
methylationofthebeninemustbe3 : 4 : 8-trimethoxy-5-vinylphenanthrene,
since it furnished on catalytic reduction 3:4:8-trimethoxy-5-ethylphenanthrene (XII), m.p. 165-6, identical with this material synthesised
for comparison. The synthesis was effected by condensing 2-nitro
veratraldehyde and sodium 6-methoxy-3-ethylphenylacetate to transa-(6'-methoxy-3'-ethylphenyl)-2-nitro-3 : 4-dimethoxycinnamic acid (X),
reducing this to the corresponding amine (XI), which by the diazo-reaction
in presence of copper powder, cyclised to 3 : 4 : 8-trimethoxy-5-ethylphenanthrene-9-carboxylic acid, which, by elimination of carbon dioxide, gave
the required substance (XII).
CH O-C^
3 !l
)CH
Cook and Thomson 36(a) have prepared 1-azapyrene, C15H9N, m.p. 157-9,
which they suggest is identical with thebenidine, C15H9N, m.p. 144-8,
obtained by Vongerichten 36(a) along with pyrene by distilling thebenine
with zinc dust.
Morphothebaine, C 18 H 19 0 3 N. This tertiary base results from the
action of hydrochloric acid on thebaine at 80-90 in closed vessels,37 or in
a similar manner from codeinone.29 It forms colourless crystals, which
become tinted green or blue when kept, m.p. 197 (dec), [a]^5" 130
(EtOH). The base furnishes a characteristic acid hydrochloride, B 2 . 3HC1,
colourless needles, m.p. 254-5, which is converted by water or alcohol to
the normal hydrochloride, B . HC1, minute needles, m.p. 256-60. The
CONSTITUTION
231
methiodide, B . Mel, crystallises from acetic acid and has m.p. 221-2.
With diazomethane it yields a dimethyl ether, which has not been
crystallised, [cc]D - 184-8 (Klee 87) or - 172-7 (Gulland and Haworth ss\
but gives a crystalline d-acid tartrate, needles, m.p. 208-9 (dec), [<x]D 75
(H 2 0). Morphothebaine is not coloured by sulphuric acid, but with nitric
acid it gives a red colour changing to reddish brown. Erdmann's reagent
(sulphuric and nitric acids) produces a green colour changing to dirty
bluish-violet, and Frohde's reagent (sulphomolybdic acid) bluish-green
changing to dull violet.38 A relationship of morphothebaine to i/j-epistephs.nine (p. 361) has been suggested.
The alkaloid behaves like afiomorphine when boiled with benzoyl
chloride, forming a tribenzoyl derivative, m.p. 184, in which two benzoyl
radicles enter hydroxyl groups, and a third induces scission of a saturated
heterocyclic ring.39 The product, on oxidation with chromic acid in acetic
acid, yields tribenzoylmorphothebainequinone, isolated as a phenylhydrazone, C 45 H 36 0 7 N3, crystallising in red needles, m.p. 227, and forming
with o-phenylenediamine an azine, C 45 H 38 0 6 N 3 , m.p. 201. On hydrolysis
with alkali, the two O-benzoyl-groups of the tribenzoyl-derivative are
removed and JV-benzoylmorphothebainequinone, C 25 H 21 0 6 N, brown
prisms, m.p. 267, is obtained, which yields a phenylhydrazone, reddishbrown needles, m.p. 271, and an azine, C 31 H 25 0 4 N 3 , brownish prisms,
m.p. 274-5 0 . 40 Knorr and Pschorr 89 had already shown that the alkaloid
on treatment with sodium methoxide and methyl iodide in methyl alcohol
at 100 is converted into a methinemethiodide, C 22 H 28 0 3 NI, m.p. 266-8,
which on treatment with alkali decomposes into a trimethoxyvinylphenanthrene, m.p. 60-1, yielding on oxidation a trimethoxyphenanthrenecarboxylic acid, m.p. 201. This acid was shown by Pschorr and Rettberg 41
to yield via the Curtius procedure a tetramethoxyphenanthrene, m.p.
108-9, which in the following year Pschorr and Knoffler 42 synthesised
and showed to be 3 : 4 : 6 : 8-tetramethoxyphenanthrene (XIV), thus
confirming formula (XIII) suggested by Pschorr and Halle 40 in 1907 for
morphothebaine, and from which tribenzoylmorphothebaine may be
written as (XV). Pschorr and Halle's formula has been confirmed by
Gulland and Haworth's synthesis of morphothebaine dimethyl ether, 38
effected by the conversion of 2'-nitro-3' : 4'-dimethoxyphenylaceto-jS-3methoxyphenylethylamide (XVI) by the action of phosphorus pentachloride in chloroform at atmospheric temperature into 2'-nitro-6 : 3' : 4'trimethoxy-l-benzyl-3 : 4-dihydrowoquinoline (XVII), which crystallised
from methyl alcohol in faintly yellow prisms, m.p. 121-3, and yielded a
methiodide, yellow needles, m.p. 220 (dec). The latter on reduction with
zinc dust and hydrochloric acid was converted into 2'-amino-6 : 3' : 4'trimethoxy-l-benzyl-2-methyltetrahydroMoquinoline (XVIII) which was
transformed into dZ-morphothebaine methyl ether (XIII: 2 -OH replaced
by 2 -OMe) by diazotisation and heating. The dl-base is an oil yielding a
crystalline hydriodide, colourless needles, m.p. 227 (dec). It was deracemised by crystallisation of the acid d-tartrate, the Z-base hydrogen d-tartrate
separating first in stellate groups of colourless needles, m.p. 208-9 (dec),
232
MORPHINE
SUB-GROUP
[1D 74-8 from which the oily Z-base, [a] D 173-5 (CHC13) was
recovered. The methiodide crystallised from alcohol in colourless needles,
m.p. 195, [a] D - 87-1 (H 2 0). The corresponding figures found for the
dimethyl ether of Z-morphothebaine prepared from thebaine were hydrogen
d-tartrate, m.p. 208-9 (dec), [a] D 75 (Klee 37 gives 74-3); base
(a)D 172-7 (Klee gives 184-8); methiodide, m.p. 195, [a]D 88-2.
The following results were found for the d-isomeride isolated from
the mother liquors of the Z-base hydrogen d-tartrate and purified by conversion into and crystallisation as the hydrogen Z-tartrate. Base, oil,
[a]D + 174-2 (CHC13); hydrogen Z-tartrate, m.p. 208-9 (dec), []D
+ 75-5 (H 2 0).
CH0-Cs
8,C-0CH
BzO-C
C-CH -CH_-M4eBz
(XVIII)
CONSTITUTION
238
MORPHINE
234
SUB-GROUP
CHo
I 2
CH
^CH V " NMe
I I I I I IT |
HO.CH
CH CH
\ VCH
/ \ NCH/
(XXII) Knorr (1903]
(XXIII) Psohorr
(1902)
H0.HC6
N
CH2 \CH2
(XXIV) Knorr (1907)
In the following year Ach and Knorr 46 found that in the oxidation of
codeine by chromic acid there is produced a hydroxycodeine, C 18 H 21 0 4 N,
m.p. 207-8, which contains two hydroxyl groups (diacetyl derivative,
m.p. 160-1) and degrades by Hofmann's method, followed by treatment
of the resulting hydroxymethylmorphimethine, C 19 Hg 3 0 4 N, with acetic
anhydride, to ethanoldimethylamine and a diacetyl derivative (m.p. 201)
of a methoxydihydroxyphenanthrene, 47 indicating that a hydroxyl group
CONSTITUTION
$$d
has been inserted, the position of which must be at 9 dr" Id in the pherianthrene nucleus, since on oxidation by chromic acid the diacetyl deriva-*
tive, C 19 H 16 0 6 , loses an acetoxy-group and is converted into methylacetylmorpholquinone, C 17 H 12 0 5 , m.p. 206-9 0 , 48 which had already been
synthesised by Pschorr and Vogtherr 49 and shown to be 3-methoxy-4acetoxy-phenanthrene-9 :10-quinone. The conclusion was drawn from
these results that, as the new hydroxyl group in hydroxycodeine is alcoholic,
not phenolic, in character, the two possible positions for it, viz., C9 and C10,
must be hydrogenated in codeine. The presumed " hydroxymethylmorphimethine," which is amorphous, but forms crystals, C 19 H 23 0 4 N . (C2HB)20,
m.p. 50-60, with 1 jmol. of ether, and yields a series of crystalline salts,
proved on further investigation to be a ketone 50 (oxime hydrochloride,
m.p. 279 ; semicarbazone, m.p. 106-7 ; monoacetyl derivative, m.p. 81),
and it was therefore re-named ketodihydromethylmorphimethine. These
changes were explained by Pschorr and Einbeck 50 as due to the formation
of a double linkage between C9 and C10 as a result of the opening of the
reduced pyridine ring, hence the nitrogen of the ethanamine chain must
be attached at C9 (or C10) in codeine. This sequence of changes may be
illustrated by the following partial formulae derived from (XXIII) :
236
MOBPHINE SUBGROUP
'K>
ISCH
VJ
C-R
CH
/ H 2
CH-OH
2 /x
/*z
'C-OH 0
CH-OH
(XXVI) Knorr^Iorlein (1907)
(XXV)
CH
*A //h
C^OH 0
C^OH
(XXVII) M o r p h i n e . von E r a u n 1914
A
CH
(XX7III)
CH,
CONSTITUTION
237
8
-OH
C-OH \ )
(XXX) M o r p h i n e
CH-0H
(Freund,
1905)
C&0Me\/
14
CH-NKo
C30Me
(XXIX) T h e b a i n e
(Freund, 1905)
14
238
MORPHINE
SVS-&SOUP
239
CONSTITUTION
CH
KMs
C-OMe
(XXXIII) Thebaine
CH.
(M)H \ s
( F a l t i s , 1917)
CH
NMe
CH-0H
(XXXIV) Morphine
240
MORPHINE
SUB-GROUP
CH
C
NMe
CH
XH
,6CH
HC
I
MeO-C
CH
'CH
\ . /
CH
C
NMe
CH
.C
P4C
HC
\ N. /
CHOH
.CH,
7CH
CH0H
(b) Codeine (Gulland and
~ Robinson, 1923).
l a ) C o d e i n e ( G u l l a n d and R o b i n s o n , 1933)
The principal reason adduced for the essential new feature in this
formula is that the linkage to carbon atom 13 explains why in morphine
and its allies the formation of phenanthrene derivatives and an aminoethanol derivative always takes place simultaneously. Such a change
cannot occur except under conditions which will add a hydrogen atom
or a hydroxyl group at position 13. Thus the conversion of oc-methylmorphimethine into acetylmethyJmorphol and acetoxyethyldimethylamine
is regarded as taking place in the following way :
CH
.CH
./' \ /
T >
:*?C-C3
Co
HC
\
CH ^CH-CH -NMe.,
TCH
AcO-HCs
\./
\ HBOH
0
q-Meth-[Tlmorphlmethla
7CH.
2
AcO-^CH
Intermediate product
+
AoO-CH2-CHa-NUe2
Ac e t y l a a t h y l m^fhni
241
CONSTITUTION
I!
HC2
CH9 \
CH
-HMe
I
,CH
'is 2
1\'CH'|
C
sCH
7 CH
Z
. \
/ \ 6 /
N
i-OMexO
CH-OH
>C-OMeN0
CH-OH
(XXXVI) Codeine
and
C-OMe
IXXXVII) T h e b a i n e ( G . and R
(G. and R.
19251
1925)
w
C-OMe V
(XXXVIII)
/
CO
Hydroxycodeinone
242
MORPHINE
SUBGROUP
^
C=CHCH2CO.
243
CONSTITUTION
in alcohol in presence of platinic oxide t o dihydrothebainone-J-5 : 6 methyl enolate, from which it differs only in having an additional ethylenic
linkage (C 7 C 8 ).
The formulae a n d chief characteristics of these reduction products are
as follows :
MeO
\ . Q ^
OMe
Dihyarothe'baine
MeO
M e O ^ ^ 0-^^"
Tetrahydrothebalne
Thebaine
MeO
Dihydrothebainone- A5:6-methyl enoltfte
Dihydrothebainone
^ Me
OMa
Dihydrothebainol-6methyl ether"
20
u~i
Dihydrothebaine,
LaJi>
^ 1 9 ^ 2 3*-* 3 ^ prismatic plates, m . p . 162-3
266-8 (C 6 H 6 ) ; picrate, m . p . 235 ; methiodide, m.p. 257. To be
distinguished from phenolic dihydrothebaine, m . p . 154 3 1 prepared by
reduction of thebaine with sodium in alcohol.
Tetrahydrothebaine,
C 1 9 H 2 5 0 3 N (dihydromorphine dimethyl ether),
m . p . 83, [a]},8 - 152-7 ( E t O H ) ; B . H C 1 . 3 H 2 0 , m.p. 115-6 ; picrate,
m . p . 220 ; B . Mel, m.p. 115-6, re-melts 212. 7 1
Dihydrothebainone (see p . 250).
Dihydrothebainol
(Skita). 8 2 C 1 8 H 2 5 0 3 N, m.p. 1 6 5 ; [a]f - 36-5
( E t O H ) ; methiodide, m . p . 273. To b e distinguished from t h e betterknown dihydrothebainol, m . p . 138-142, [m]^ 46-2, prepared b y
reducing dihydrothebainone with sodium amalgam (Speyer and Siebert 5 2 ).
Dihydrothebainone-A-5
: 6-methyl enolate, C 1 9 H 2 6 0 3 N, m . p . 164-165-5,
[a]2,5" 115-7 ( E t O H ) . Cold N/HC1 converts it into dihydrothebainone
hydrochloride. 7 2 T h e isomeric dihydrothebainone-J-6 : 7-methyl enolate
is formed on catalytic hydrogenation of phenolic dihydrothebaine. I t has
m . p . 127-8, [a]2,7" 8 ( E t O H ) a n d yields dihydrothebainone on acid
hydrolysis. 7 2
Thebainone methyl enolate. C 1 8 H 2 3 0 3 N. This possible intermediate in
the hydrogenation of thebaine t o dihydrothebainone-id-5 : 6-methyl enolate
(see above) has m.p. 154-6, [oc]jf + 9-6 (EtOH). 7 2
Dihydrothebainol-6-methyl
ether. C 1 9 H 2 7 0 3 N, m.p. 140-5-142, [a]2,1"
23-4 ( E t O H ) ; fumarate, m . p . 198-201 (dec.).
The 4-methyl ether is a liquid, but all attempts to prepare dimethyl
ethers of the two known dihydrothebainols failed; the relationship
244
MORPHINE
SUBGROUP
between the latter and this new dihydrothebainol-6-methyl ether has not
yet been determined.
Schopf and Winterhalder suggested that in the hydrogenation of
thebaine a molecule of hydrogen is first added at C8C14 producing
dihydrothebaine, which under energetic hydrogenation suffers disruption
of the oxygen bridge, forming dihydrothebainone. In dihydrothebaine,
the chain . O . CH . C(OMe) : CH . resembles in certain respects a system
of conjugated double linkages and it seems likely that in the formation of
dihydrothebainone, addition of hydrogen occurs at the ends of this chain
forming the intermediate, which Small and Browning have now isolated,
viz., dihydrothebainone-A-5 : 6-methyl enolate.
Most of the dihydrothebainone produced from thebaine is formed
under mild conditions of hydrogenation and probably not via dihydrothebaine, but by way of thebainone methyl enolate and dihydrothebainoneA-5 : 6-methyl enolate as described above.
When addition of hydrogen takes place simultaneously at C8C14 and
6
C C7 tetrahydrothebaine is formed and it is argued that formation of the
tetrahydro-base supports Gulland and Robinson's formula, since Wieland
and Kotake's C15C6 bridge (XL) would not be reduced under the mild
conditions used.
Schopf 71 has also obtained direct evidence for the location of the
carbon end of the ethanamine chain by submitting dihydrocodeinoneoxime
to a Beckmann rearrangement. This process, the steps in which are
illustrated by partial formulae for ring III, should provide an aldehyde
(XLVc) if the oxime is correctly represented by the Gulland and Robinson
formula (XLVb) and a ketone (XLVIc) if it has the structure (XLVIb)
required by the Wieland and Kotake formula.
When cold thionyl chloride is allowed to act on dihydrocodeinoneoxime,
there is formed a substance (m.p. 196-8, picrate, m.p. 207-8 ; acetyl
derivative, m.p. 225; oxime, m.p. 218-9), from which the required
\ 5 / | \
CH
co *.
\ CH /
\/K/
HC
I
N0H=C
I CH
CH-(
2,CH,
2
NC
(ILV.a)
V.
Cy
A/
OHC
(b)
NC
NC
CH
I CH
CH4_ 2
8
CE
oc
N0H=C
ex
(o)
CH
|NHO
A/
CH,
I "CH
CH
2CH 0
NC.
Cay*)
KETONES
245
246
MORPHINE
8UB-QR0UP
[<x]^ - 242 (EtOH). (Cf. deoxycodeine-C, formula II, p. 253.) 6-Methyldihydrocodeine could not be demethylated to the corresponding 6-methyldihydromorphine (see below) but it was degraded via 6-methyldihydromethylmorphimethine, isolated as the hydrochloride, C20H28O3NCl,
m.p. 241-3, [a]| 6-7 (EtOH), to the nitrogen-free product, 6-methyl6-hydroxy-13-vinylhexahydromorphenol, C18H20O3, which sublimes a t
100/0-l mm. and has [a]| + 24-4 (EtOH).
Dihydromorphinone, C 17 H 19 0 3 N, and derivatives. Dihydromorphinone
( L I I I ; MeO >- HO) is formed when morphine in solution is treated with
relatively large quantities of platinum or palladium catalyst under various
conditions.75(b) It melts at 262-3 and yields an oxime, m.p. > 234.
The hydrochloride is the drug known as " dilaudid." On O-methylation dihydromorphinone yields dihydrocodeinone (see above), and when
dissolved in ether and treated with methyllithium the corresponding
tertiary alcohol, 6-methyldihydromorphine, C 18 H 23 0 3 N, m.p. 209-211,
[a]^ 147 (EtOH), is formed. This on methylation with diazomethane gives 6-methyldihydrocodeine as described above (Small and
Rapoport 75<a)).
Methyldihydromorphinone, C 18 H 21 0 3 N, was prepared by Small, Fitch and
Smith 56 by the action of magnesium methyl iodide on dihydrothebame,
the resulting phenolic methyldihydrothebainone (LI with Me at C5
or C7, p. 248), m.p. 192-3, [a]f 20-5 (EtOH) being converted
by the Schopf process 81 to methyldihydrocodeinone (LIII with Me
at C5 or C7), m.p. 144-144-5, [oc]|3 - 146-9 (EtOH), which is demethylated by boiling with hydrobromic acid to methyldihydromorphinone,
m.p. 243-5 (vac.), [a]|4 140-7 (EtOH) yielding a hydrochloride,
m.p. 315-8 (vac. dec), [<x]?,4 104-8 (H 2 0). The essential intermediate
in this process, methyldihydrothebainone, can also be obtained by the
action of the Grignard reagent on dihydrocodeinone enol acetate, m.p. 152153-5, itself produced by catalytic rearrangement 76(a) of codeine (XXXVI,
p. 241) to dihydrocodeinone (LIII), and treatment of the latter with acetic
anhydride and sodium acetate. The location, C5 or C7, of the entering
methyl group in these compounds is discussed by Small et al.i6 in the
1938-39 papers.
U-Hydroxycodeinone, C 18 H 19 0 4 N, may be prepared by the action of
hydrogen peroxide on thebaine in glacial acetic acid, or by the oxidation
of either codeine or thebaine with sodium dichromate. 68 Certain of its
reactions bearing on the constitution of codeine have been mentioned
(ZLVII) Oodelpono
(XLVIII) -Jr-Coaelnone
(LIII) PlhydrogodalnoM
KETONES
247
m.p. 272-4 (vac.), [a]|4 89 (H 2 0), hydriodide B . H I . H 2 0, m.p. 25560 (vac.), oxime decomposing at 279-80 and acetyl derivative,
m.p. 185, [a]|5 + 21 (dil. acetic acid). On catalytic hydrogenation
it is converted into dihydrohydroxycodeinone (LIII, with . OH at C14),
m.p. 218, [a]f,5 97 (dil. acetic acid), of which the hydrochloride,
B . HC1, 2-5 H 2 0, has m.p. 270-2 (dec.) and [ a ] f - 123 (H 2 0). The
further reduction products of 14-hydroxycodeinone have been investigated
by Lutz and Small.66
i[>-Codeinone (iso-Codeinone). This isomeride of codeinone is produced
by the oxidation of i/i-codeine or the stereoisomeric aZZo-</<-codeine (p. 218).76
It crystallises from alcohol, has m.p. 174-5, [a]"" 25 (EtOH), gives
a crystalline methiodide, m.p. 220 [a]p5 12 (H 2 0), and a crystalline
semicarbazone, m.p. 180. In contrast with codeinone, it condenses with
benzaldehyde 67 to form benzylidene-^-codeinone (oil), of which the
methiodide has m.p. 250. It also forms an amorphous wonitroso-i/icodeinone, which decomposes at 200. Reference has been made already
to the principal reactions of i/i-codeinone on the results of which formula
(XLVIII) is assigned to it, for which Lutz and Small 68 have produced
confirmatory evidence in the course of their reduction experiments with
this substance.
Thebainone and met&Thebainone, C 18 H 21 0 3 N. When thebaine is
treated with stannous chloride in strong hydrochloric acid, it yields as
principal product a substance, which was named thebainone by Pschorr,
Pfaff and Herrschmann. 77 It is produced by hydrolysis of the COCH3
group at position 6 in thebaine, followed by reductive rupture of the C 4 -C 5
oxygen bridge, and is also obtainable by a similar method from codeinone
(Knorr " ) . As the oxygen bridge has been broken, thebainone is a
misleading name, but the more appropriate name, dihydrothebainone, had
already been applied to an isomeric substance obtained by the catalytic
hydrogenation of thebaine. 78 Further, Schopf has produced evidence for
the view that in Pschorr's thebainone the carbon end of the ethanamine
chain is not at C13 as in thebaine, but at G14, and on that ground has
suggested that the name should be changed to wietathebainone, the old
name thebainone being reserved for an isomeride (see below) with the
carbon end of the ethanamine chain at C13, which, in conjunction with
Hirsch, he has also isolated from the complex mixture of products formed
by the action of stannous chloride in hydrochloric acid on thebaine, but
which was first prepared by Pschorr 79 during a study of j8-ethylthiocodide
under the name " S-free ketone," and has been re-obtained by that method
by Morris and Small 80 in the course of work on ethylthiocodides.
A further anomaly in nomenclature is thebainol, the name applied to
the substance formed by the alkaline reduction of metathebainone, and
which was at first believed to be formed by reduction of the carbonyl
group, but which Gulland and Robinson 8 1 proved to be a ketone. It is
isomeric with dihydrothebainone referred to above, and has been re-named
dihydrometathebainone (Schopf). The interrelationships of these substances are shown by the following formulae :
248
MORPHINE
MeO-0
00
( I I I ) metaThaDalaone (Schopf)
MeO-C
00
( I ) Dlhydrometathebalnone ( Sohopf)
UeO-0
SUB-GROUP
C-OMe
Thebaine (0 and R)
KeO-C
Thebalzone (W and S)
lie 0-ft
00
(XlIX) Ihebalnone
MeO.O
(Schopf)
CO
( I I ) Dlhydrothebalnonel Sohopf)
Thebainol (Paohorr)
KETONES
249
attachment of the carbon end of the ethanamine chain at C13, and of the
possible new points C14 is regarded as the most probable. On this basis
metathebainone is represented by (LII). This representation is in harmony
with the fact that Gulland ' 5 obtained only a monobenzylidene (m.p. 233)
and a monopiperonylidene (m.p. 176) derivative from metathebainone.
Further, Schopf and Perrey, 81 in applying the method of constructing
CHg
CH
Nile
\/~H v/*2
metaTheUalnone
CHg
CH
NUe
xAA/"2
Dlhydrometacodelnone
250
MORPHINE
SUB-GROUP
METHINE
BASES
251
OH NT
CH-OH
p- & Y ~ l a < a i o r p l i l p e
aIaoMorphlne
;CH
\
-We.
CH.OH
Z]
VNM82
H-OH
a - & V-Mathyliiinrphlmethinea
- & ^f -Methylmorphlmettilnes
CH 2
CH-
^CHP4
CH-HMe.
2
to ^OHg
C-OMe 0'
CH-OH
B-Methylmorphlmethine
Neoplne
5 -Methylmorphlmethlne
(g-Codelne)
at C8C14. It has m.p. 86-S8-50 and gives a methiodide, m.p. 253-8 (dec).
On demethylation by boiling in acetic acid containing hydrogen bromide
6-acetyldihydromorphimethine, m.p. 200-202-5 [a]?4 + 118-4 (CHC13),
is produced, which is readily hydrolysed to a dihydromorphimethine,
m.p. 174-6, [a]*6" + 92-8 (CHC13). The latter on methylation yields a
new dihydromethylmorphimethine: oil, B . HC1, m.p. 227-30 (vac),
[a]*4' + 47-0 (H 2 0) (Mosettig 84<a>). The location of the ethylenic linkage
BMe2
(II)
has not been ascertained for this substance but it, like ^-dihydromethylmorphimethine, can be hydrogenated catalytically to tetrahydro-amethylmorphimethine (II) isolated as the hydrochloride, B . HC1, m.p. 22931 (vac.); [a]f 32-8 (H 2 0), in which unsaturation in rings II and III,
the source of structural isomerism in the initial products, has disappeared.
252
MORPHINE
SUB-GROUP
253
DEOXYCODEINES
V. Tetrahydrodeoxycodeine
III. Dlhydrodeoxyoodeine-D
Type
B.p.
[]
Deoxyoodeine-A
122
+118-1
J>eoxyoodeine-C
II
106
-197-4
Deoxycodeine-D
liquid
Dihydrodeoxyoodelne-B
IV
128-131
-106-9
Dihydrodeoxycodelne-C
IV
109-111
+5.6
Dlhydrodeoxyoodeine-D
III
107
-82-5
Dihydrodeoxycodeine-E
IV
139
Tetrahydrodeoxyoodelne
' V 145-7
-32-4
Salts
B.HC1, m . p . 2 3 4 - 5 0 , [ a ] | 8 - 1 2 - l ;
B.H 2 0 2 0 4 , m.p.220-1
m.p.l990;salloylat,m.p.l98
1. There are two hemlhydrates, m.p. 124-6 and 151-2; the anhydrous base has
m.p.159-161.
2. After sublimation has m.p. 173.
3. There are
two
254
MORPHINE
SUB-GROUP
in
,Ms
/BIS
oi
(in)
(ID
CHI) - c ^ o <s>
H0
(v)
OH
~ ^
01
H0
0H
(Vi)
H^
in)
->
255
CONSTITUTION
CH
NMe
,CH 2
CH
NMe
92
A /\>~z
&-0H
(T
CH-OH
Dlthebalnone
The points of junction are taken as 2 : 2'- by analogy with the 2 : 2'junction in |3-dinaphthol. Small and Faris 87 have recorded a number of
observations on i/i-morphine, for which this formula does not account. In
favour of the formula is the fact that 2-bromomorphine cannot be oxidised
to a similar bimolecular product. On the other hand, ^t-morphine forms
only a monomethyl ether, which is devoid of phenolic character, indicating
the presence of only one phenolic hydroxyl group. Further, though the
formula is symmetrical, the two nitrogen atoms show different characters ;
thus, on methylation, a monomethyl ether methiodide is produced, and a
dimethiodide can only be obtained by gentle oxidation of morphine
methiodide to the so-called basic ^t-morphine methiodide methohydroxide,
convertible to the dimethiodide by dilute hydriodic acid. The same authors
have prepared y-^r-morphine by similar oxidation of y-isomorphine, and
this product closely resembles ^-morphine in properties being bimolecular
in structure, as indicated by molecular weight determinations, and forming
a tetracetyl derivative and a monomethyl ether methiodide. Hydro-
MORPHINE
256
SUB-GROUP
1922, 430, 1 ; H I L L ,
Inaug. Diss. Frankfurt, 1925 ; SCHOPF and HIRSCH, Annalen, 1931,489, 224. (2) KNORR,
Ber., 1889, 22, 185, 1113 ; 1894, 27, 1144 ; 1904, 37, 3494. (3) Ibid., 1900, 33, 1824.
For t h e gradual elucidation of t h e chemistry of morphol and allied substances see
VONGERICHTEN et al., ibid., 1882, 15, 1484 ; 1886, 19, 792 ; 1896, 29, 65 ; 1897, 30,
2439 ; 1898, 31, 5 1 , 2924, 3198 ; 1899, 32, 1521 ; 1900, 33, 352. (4) Ibid., 1900, 33,
1810. For later syntheses see SMITH, J. Chem. Soc, 1916, 109, 568 ; BARGER, ibid.,
1918, 113, 2 1 8 ; FIESER, J. Amer. Chem. Soc., 1929, 51, 9 4 0 ; Ber., 1931, 64, 701.
(5) VONGERICHTEN, ibid., 1896, 29, 67 ; 1898, 31, 51 ; 1900, 33, 352. For an improved
method of preparation see MOSETTIG and MEITZNER, J. Amer. Chem. Soc, 1934, 56,
2738.
(6) VONGERICHTEN a n d DITTMER, Ber., 1906, 39, 1718. (7) Annalen, 1912,
391, 40.
32, 1521. (10) (a) KNORR, ibid., 1903, 36, 3074; (b) ibid., 1902, 35, 4 4 0 0 ; (c) F o r
similar reactions with thebaine see F R E U N D , ibid., 1895, 28, 941 ; 1897, 30, 1357;
PSCHORR a n d H A A S , ibid., 1906, 39, 16.
ibid., 1902, 35, 4377 ; (with KARO), ibid., 1906, 39, 3124. (12) KNORR and PSCHOBR,
ibid., 1905, 38, 3 1 5 3 ; PSCHORR (with H A L L E ) , 1907, 40, 2 0 0 4 ; (with RETTBERG),
Annalen, 1910, 373, 5 1 ; (with KNOFFLEB), ibid., 1911, 382, 50. (13) PSCHORR,
CONSTITUTION
257
(14) F R E U N D
1928, 921.
3494. (17) VONGEBICHTEN, ibid., 1896, 29, 65 ; 1900, 33, 352. (17a) J. Biol. Chem.,
1928, 80, 403. (18) KNORR, Ber., 1904, 37, 3499. (19) KNORR, ibid., 1907, 40, 2032 ;
(with HORLEIN), p. 3341. (20) KNORR, ibid., 1904, 37, 3494, 3499, 3507. (21) KNORR,
ibid., 1905, 38, 3145 (footnote). (22) (With JAECKEL and FECIIT), ibid., 1902, 35, 4377 ;
(with K A R O ) ,
(with E I N B E C K
and SPANGENBERG),
1984, 1995, 1998 ; (with BUSCH), 1907, 40, 2001. (23) Decomposition of opomorphine
by Emde's method, see FALTIS and KRAUS, Monats., 1921, 42, 377. (24) Ber., 1929,
62, 321 ; cf. GULLAND a n d V I R D E N , J. Chem. Soc., 1929, 1794. (25) Ber., 1929, 62, 325.
(26) ./. Chem. Soc., 1913, 103, 947. (27) Ibid., 1929, 1666. (28) FREUND, MICHAELS
and GOBEL, Ber., 1897, 30, 1357. (29) K N O R R , ibid., 1903, 36, 3074. (30) KNORR
and H O R L E I N , ibid., 1907, 40, 2032. (31) F R E U N D and HOLTHOF, ibid.. 1899, 32, 168.
(32) Ibid.,
1910, 373, 5 1 .
1897,
30, 1357; 1910, 43, 631. (36) J. Chem. Soc., 1928, 921. (30a) J. Chem. Soc., 1945,
395;
FREUND
and HOLTHOF, ibid., 1899, 32, 168. For preparation see also K L E E , Arch. Pharm., 1914,
252, 211 ; SCHOPF and BORKOWSKY, Annalen, 1927, 458, 148, (38) J. Chem. Soc, 1928,
2083.
(38a) Ibid., 1929, 1444. (39) KNORB and PSCHORR, Ber., 1905, 38, 3153.
(40) PSCHORR and H A L L E , ibid., 1907, 40, 2004. (41) PSCHORR and RETTBERG, Annalen,
1910, 373, 51. (42) Ibid., 1911, 382, 50. (43) (a) F R E U N D and SPEYEH, Ber., 1910, 49,
1287; (6) GULLAND a n d ROBINSON, J. Chem. Soc, 1923, 123, 8 0 ; (e) SCHOPF a n d
BORKOWSKY, Annalen, 1927, 458,148 ; cf. GULLAND and V I R D E N . " (44) (a) GULLAND a n d
ROBINSON, Mem. Proc. Manchester Lit. Phil. Soc, 1924-25, 69, 79 ; (b) WIELAND and
K O T A K E , Annalen,
1925, 444, 69. (45) K N O R R , Ber., 1889, 22, 1113 ; 1899, 32, 742 ; 1903,
36, 3080. (46) Ibid., 1903, 36, 3008. (47) KNORR and SCHNEIDER, ibid., 1906, 39,
1414. (48) KNORR and HORLEIN, ibid., 1906. 39, 3252; cf. Ref. (4). (49) Ibid.,
1902, 35, 4412. (49a). (With L E E ) , J. Amer. Chem. Soc, 1947, 69, 1996; (with L E E
and MOORADIAN), ibid., p . 1998; (with MANN), ibid., p . 2000. (50) PSCHORR and
EINBECK, Ber., 1907, 40, 1 9 8 0 ; KNORR and H O R L E I N , ibid., p . 2042.
1907, 40, 3341.
(51) Ibid.,
1900, 77, 1 0 2 4 ;
KNORR
(with HORLEIN), Ber., 1807, 40, 376, 3341, 4 8 8 3 ; (with WAENTIG), idem, p . 38C0 ;
FREUND,
MELBER
and SCHI.ESINGER,
SIF.BERT, Ber., 1921, 54, 1519 ; KONDO and OCIIIAI, ibid., ] 930, 63, 646.
and
For an excellent
resume of the literature up to 1932 see " Chemistry of the Opium Alkaloids " by SMALL
and LUTZ, Supplement No. 103, Public Health Reports, U.S. Govt. Printing Office,
Washington, U.S.A., and for later developments t h e following papers by SMALL and
collaborators : Deoxymorphines : SMALL (with MORRIS), J. Amer. Chem. Soc, 1933,
55, 2874 ; (with Y U E N and EILERS, idem, p . 3863. Dcoxycodeines : (with Cohen),
ibid., 1931, 53, 2214, 2227 ; 1932, 54, 802 ; (with MOSETTIG and COHEN), idem, p . 793 ;
(with LUTZ), ibid., 1934, 56, 1738, 1741 ; (with LUTZ and W I L D E R ) , idem, p . 2066 ;
(with Y U E N ) , ibid., 1936, 58, 192 ; (with FAKIS and MALLONEE), J. Org. Chem., 1940,
5,334 ; (with MALLONEE), idem, p . 350. The three stereoisomeric forms of deoxyecdeineC are described by GOTO a n d A R A I , Annalen,
CAHN. 6 5 (55) Ibid., 1926, 451, 55. (56) Ber., 1905, 38, 3234 ; SMALL et al., J. Amer.
Chem. Soc, 1935, 57, 2651 ; 1936, 58, 192, 1457 ; J. Org. Chem., 1938-39, 3, 204, 509 ;
1947, 12, 839 ; Brit. P a t . 492,702 ; 495, 251 ; U.S. P a t . 2,178,010. For an explanation of these results, see ROBINSON, Nature, 1947,160, 815. (57) WIELAND and SMALL,
Annalen, 1928, 467, 17. (58) Ber., 1916, 49, 1287. For applications of the formulae
see J. pr. Chem., 1916, [ii], 94, 135 ; 1920, [ii], 101, 1 ; also Ber., 1920, 53, 2250 ;
1921, 54, 1519, 2647, 2976 ; 1922, 55, 1329 ; Annalen, 1922, 430, 1, in which F R E U N D
or SPEYER and collaborators deal mainly with reactions designed t o test this and
PLANT ALK.
258
MORPHINE
SUB-GROUP
KNORR'S formula. (59) Arch. Pharm., 1917, 255, 85 ; with HECZKO), Monats.,
1922, 43, 255 ; (with SUPPAN), Pharm. Monats., 1923, 4, 189. (60) J. pr. Chem., 1893,
[ii],47, 584. (61) Ber., 1900,33, 352. (62) J.pr. Chem.,1907, [ii],76,428. (S3) Annalen
1911, 382, 306. (64) J. Chem. Soc., 1923, 123, 985, 998. The former paper contains
a useful selected bibliography of literature on morphine, codeine and thebaine. (65) Mem.
Manchr. Lit. Phil. Soc, 1924-25, 69, 79 ; cf. SCHOPF and BORKOWSKY, Annalen, 1927,
452, 249 ; LUTZ a n d SMALL, J. Org. Chem., 1939, 4, 220.
(66) F R E U N D a n d S P E Y E R ,
J. pr. Chem., 1916, [ii], 94, 135 ; Ger. P a t . 286,431 ; E . MERCK, Ger. Pat. 411,530.
(67) J. Chem. Soc, 1923,123, 1001 ; cf. VON BRAUN and CAHN, Annalen, 1926, 451, 57 ;
SCHOPF, ibid., 1927, 452, 212 ; (with BORKOWSKY), ibid., 1927, 458, 148 ; LUTZ a n d
SMALL, J. Amer. Chem. Soc, 1935, 57, 2651. (68) OLDENBURG, Ger. P a t . 260,233 ;
SKITA and FRANCH, Ber., 1911, 44, 2862 ; F R E U N D , M E L B E R and SCHLESINGER, J.
pr.
SPEYER and
S A R R E 7 4 ; KNOLL and Co. 75fal ; MERCK and Co., D . R . P . 415,097. (70) CAHN and
ROBINSON, J. Chem. Soc, 1926, 9 0 8 ; cf. W I E L A N D (with KOTAKE), Annalen, 1925,
444, 69 ; Ber., 1925, 58, 2009 ; (with GARBSCH), ibid., 1926, 59, 2490. (71) Annalen,
1927, 452, 211 ; (with W I N T E R H A L D E R ) , p . 232 ; SANDERMANN, Ber.,
cf. MANNICH, Arch. Pharm., 1916, 254, 349. (72) SMALL and BROWNING, J. Org. Chem.,
1938-9, 3, 618. (73) A C H and KNORR, Ber., 1903, 36, 3 0 6 7 ; KNORR, ibid., 1900,
39, 1 4 0 9 ; (with H O R L E I N ) , ibid., 1907, 40, 4 8 8 9 ; F R E U N D , 1905, 39, 8 4 4 ; MERCK,
Ger. P a t . 408,870, 421,217.
1920, 53,
2250. For other derivatives of codeinone and their reactions see SPEYER and SARRE,
ibid., 1924, 57, 1404, 1409, 1422, 1 4 2 7 ;
(75) GULLAND, J. Chem. Soc, 1928, 703. (75a) J. Org. Chem., 1947, 12, 284. (75b)
KNOLL, A.G. Fabr., Ger. P a t . 365,683; 380,919; 607,931; 617,238; 623,821.
(70) KNORR and HORLEIN, Ber., 1907, 40, 2032, 3341. (77) Ibid., 1905, 38, 3 1 6 3 ;
KNORR, ibid., p. 3171. For descriptions see GULLAND and ROBINSON, J. Chem. Soc,
1923,
1 0 0 3 ; CAHN, ibid.,
458, 148.
Annalen,
1927,
ibid., 1921, 54, 1560. (79) Annalen, 1910, 373, 1, 15. (80) J. Amer. Chem. Soc, 1934,
56, 2159. (81) The following papers deal with t h e constitution of " thebainone " :
PSCHORR, P F A F F a n d HERRSCHMANN, Ber., 1905, 38, 3160 ; GULLAND a n d ROBINSON,
./. Chem. Soc, 1923, 9 9 8 ; CAHN, ibid., 1933, 1 0 3 8 ; KONDO and OCIIIAI, Annalen,
1929, 470, 2 2 4 ; SCHOPF (with WINTERHALDER), ibid., 1927, 452, 2 3 2 ; (with
BORKOWSKY),
(with P F E I F E R ) ,
(with
PERREY),
1930, 483, 169 ; (with HIRSCH), 1931, 489, 224. For a study of the reduction products
of mefathebainone see SMALL and MEITZNER, J. Amer. Chem. Soc, 1933, 55, 4602.
(82) For papers on dihydrothebainone see F R E U N D , S P E Y E R and GUTTMANN,
Ber.,
1920, 53, 2250 ; SKITA et al., ibid., 1921, 54, 1560 ; GULLAND and ROBINSON, J. Chem.
Soc, 1923, 9 9 8 ; SCHOPF (with WINTERHALDER), Annalen, 1927, 452, 2 3 2 ; SMALL,
FITCH and SMITH, J. Amer. Chem. Soc, 1936, 58, 1457. (83) For another method of
oxygen bridge formation in alkaloids of t h e thebainone type see KONDO and IKAWA,
Ber.,
1907, 40, 3 6 5 2 ;
FALTIS,
Monats., 1922, 43, 382 ; WIELAND and SMALL. 5 7 For other papers on t h e ozonisation
of alkaloids of this group see SPEYER, Ber., 1929, 62, 209 ; (with P O P P ) , ibid., 1926, 59,
390; (withRoELL), 1930, 63, 539 ; (with KOULEN), 1931, 65, 2815. (84) For the results
of a study of the reduction products of a-, J3-, and y-isomorphines and of ^-codeine
and allo-\j/-codeine see SMALL (with LUTZ), J. Amer. Chem. Soc, 1928, 50, 2466 ; 1932,
54,4715; 1934,56,1741; 1935,57,361,2651; (with FARIS), 1935, 57, 363. (84O)VONGERICHTEN, Ber., 1899, 32, 3278 ; cf. MOSF.TTIG, J. Org. Chem., 1940, 5, 401, and VON
BRAUN a n d CAHN, Annalen, 1926, 451, 55. (b) F R E U N D et al., J. pr. Chem., 1920,
101, 1 ; W I E L A N D (with KORALEK), Annalen, 1923, 433, 267 ; (with KOTAKE), 1925,
444, 69 ; S P E Y E R a n d K O U L E N (ibid., 1924, 438, 34).
PHARMACOLOGICAL
1886, 19, 1760;
Chim. Phys.,
Soc. chim.,
1909, [iv], 5, 9 3 4 ;
Ann.
1909, [viiij, 17, 501 ; Compt. rend., 1909, 148, 1681. (87) SMALL ami
F A R I S , J. Amer.
1928.
BERTRAND a n d M E Y E R , Bull.
259
ACTION
type see ibid., 1935, 515, 297 ; Bull. Chem. Soc. Japan, 1929, 4, 107 ; 1935, 10, 252.
Opium Alkaloids
of Unknown
Constitution
ACTIOX
OF THE MORPHINE
GROUP
260
MORPHINE
SUB-GROUP
PHARMACOLOGICAL
ACTION
261
This second report deals with 125 morphine derivatives and a large
n u m b e r of synthetic substances. The latter have nuclei akin to that of
morphine, viz., phenanthrene, phenanthrylene oxide, dibenzofuran,
phenanthridine or carbazole, a n d are provided with side-chains, whose
n a t u r e and location were suggested b y the results of observation of the
effects of such groups in morphine. The conclusions arrived a t in this
notable research cannot be summarised with the brevity necessary for
the present purpose, b u t t h e mode of work adopted m a y be illustrated
b y t h e following table of pharmacological results recorded for a few of
the morphine derivatives investigated. The figures given are doses
(milligrammes per kilogramme) necessary to produce the effect named a t
t h e head of the column in which they occur. These numerical estimates
have t h e following significance :
Toxicity.
L.D/50, subcutaneously in mice.
Convulsant action. The minimal dose causing convulsions during
determination of L.D/50.
General depression. The minimal dose preventing immediate righting
of at least 15 out of '20 rats, t h i r t y minutes after intraperitoneal injection.
Analgesia.
Intramuscular dose necessary in 4 out of 5 cats, to require
an increase of pressure on the tip of the tail to evoke a response.
Exciting effect. The minimal dose inducing signs of exciting action in
a t least 2 out of 5 cats.
Same of drug
Convulsant
Toxicity Action
General
Depression
Analgesia
Exciting
Effect
Emetic
Action
Respiratory
Effect
Morphine
531
531
6.75
0.75
0.57
Diaoetylroorphine
262
196
1.10
0.43
0.40
Codeine
241
161
36.1
8.04
8.04
35
35
in)
7.87
7.87
8.74
(*)
Dihydromorphine
133
(c)
17.7
0.26
1.77
0.17
0.11
Dihydrocodeine
225
168
14.1
7.20
6.45
3.22+
0.9
84
67
0.88
0.17
0.17
0.08
0.011
86
47
4.2
1.28
0.86
2.56+
0.08
1.34
0.69+
0.10
Benzylmorphine
Dihydromorphinone
Dihydroeodeinone
0-. 22 0.15
(0.3 to' 0.015
(2.nil
1.3
16.0+
Hydroxydihydrocodeinone
426
426
1.34
0.89
Dihydrodeoxymorphine-D
104
104
0.32
0.08
0.16
(d)
0.012
Dlhydroxydeoxycodeine-D
131
65
2.12
1.96
1.96
0.65+
0.08
31
31
4.36
0.87+
94
161
124
4.36
71
Thebaine
Thebainone
Dihydrothebainone
(a) With 20-mgm. dose, three rats had convulsions and two died. Smaller doses
did not depress the righting reflex.
(b) Doses up to 20 mgm. had no significant effect on respiratory rate or minule
volume.
(r) Convulsions infrequent with fatal doses.
(d) No emetic effect up t o 1-0 mgm.
262
MORPHINE
SUB-GROUP
Emetic action. The minimal dose causing a cat to vomit or show signs
of nausea.
Respiratory effect. The minimal, effective, depressant dose as measured
b y Wright and Barbour's method. 7
The objective of the Committee is t o find an analgesic as effective as
morphine b u t without the disadvantageous, secondary effects of the latter
and particularly the danger of addiction, which its use involves. I n 1941
the Committee issued a report 8 on the results of their work during 1929-41,
fn which they call attention to two morphine derivatives in which particular features of the action of morphine have been notably modified,
dihydrodeox.ymorphine-D 8(a) (p. 254) and methyldihydromorphinone 8(0)
(p. 246). I n the latter, analgesic action is stated t o have been increased
more t h a n narcotic and euphoric effects, emetic action is suppressed and
there is a significant decrease in addiction liability and the rate of developm e n t of tolerance. I t seems therefore t h a t it is possible to v a r y selectively
the individual components of the total pharmacological effect, by chemical
modification of the structure of the morphine molecule.
N-&\lylnormorphine is a n example of a large pharmacological change due to a
relatively small structural modification; it is stated 9 to retain the
analgesic potency of morphine, b u t to be antagonistic to morphine in most
other respects, such as effect on respiration a n d on intestinal movement.
These general results have entailed much detailed chemical and
pharmacological work on the influence of structural changes on particular
items in t h e pharmacological action of morphine, e.g., its effect on
respiration. 1 0
According to Wright, 1 1 an enzyme occurs in rat, rabbit and man,
which hydrolyses diacetylmorphine, the two acetoxy groups being dealt
with a t different rates. Some evidence was also obtained t h a t the enzyme,
which hydrolyses atropine, also catalyses hydrolysis a t t h e 6-acetoxy
group in the mono- and di-acetylmorphines. Oberst 12 states t h a t in m a n
diacetylmorphine is completely hydrolysed to morphine, which is excreted
mainly in the conjugated form. The action of the enzyme is said to be
inhibited b y physostigmine xl a n d several other observations have been
made connecting the action of morphine with those (p. 549) of physostigmine, prostigmine, acetylcholine and choline-esterase. I t has been found
t h a t the analgesic action of morphine is potentiated b y prostigmine,
especially in addicts. 1 3 According t o Dastugue, 1 4 t h e action of acetylcholine,
b u t not t h a t of barium salts or of nicotine, on leech muscle is sensitised by
hydroxydihydrocodeinone, which in this respect is as potent as physostigmine, though it is less potent t h a n the latter in inhibiting the activity
of choline-esterase. The sensitising action is n o t shown towards the
action of acetylcholine on frog abdominal muscle or isolated rabbit
intestine. I t has also been stated t h a t the activity of choline-esterase is
inhibited by morphine, 1 5 and b y dihydromorphinone, b u t most strongly
b y dihydrodeoxymorphine-D. The degree of inactivation b y codeine
varies with the source of the enzyme. 1 6
i
Apart from the study of drug addiction in its clinical aspects, 1 7 much
PHARMACOLOGICAL
ACTION
263
264
MORPHINE
SUBGROUP
PHARMACOLOGICAL
ACTION
265
clinical trial and found that a dose of 100 mgm., orally or intramuscularly,
eight times a day in 118 patients, whose pain would have justified the use
of opiates, gave complete relief in 64 per cent., partial relief in 24 per cent,
and no relief in 12 per cent, of cases. The analgesic action was greater
than that from 1 grain (65 mgm.) of codeine but less than that from \ to
\ grain (15 to 20 mgm.) of morphine. Other evaluations of pethidine in
terms of morphine have been made by Hardy, Wolff and Goodell,32 by
Batterman and Himmelsbach and others. 33 Numerous clinical trials with
pethidine for the relief of pain due to post-operative, pathological and
other conditions have also been conducted in recent years. 34 The possibility of addiction arising from the use of this drug has been investigated
and seems to be less than with morphine. 35 The increasing use of the drug
has naturally led to the introduction of methods for its detection,36 and
its estimation, 37 especially in urine. 38 It has also stimulated interest in
the synthesis of substances of this type, or developed from it, and to a
smaller extent of other types sometimes based on isolated features of the
Robinson morphine formula.39 A further outcome of this activity is the
renewed attention given to methods for the determination of the pain
threshold and the effect of analgesics in raising it, as a means of evaluation
for these drugs. 40
A useful review of information on pethidine has been published by
Batterman and Himmelsbach, 33 and an admirable summary of information on synthetic analgesics has been provided by Morrison and
Rinderknecht. 40(a)
Codeine (morphine methyl ether) resembles morphine in its general
effect, but is less toxic and its depressant action less marked and less
prolonged, whilst its stimulating action involves not only the spinal cord,
but also the lower parts of the brain. In small doses in man it induces
sleep, which is not so deep as that caused by morphine, and in large doses
it causes restlessness and increased reflex excitability rather than sleep.
The respiration is slowed less than by morphine (cf. table, p. 261). Cases
of addiction for codeine can occur but according to Wolff they are rare. 41
The best known ethers of morphine are ethylmorphine and benzylmorphine (cf., table, p. 261), both used to replace morphine or codeine for
special purposes.
According to Eddy, as quoted by Small, the analgesic action of neopine,
ncomorphine, 6-acetylneomorphine or 3 : 6-diacetylneomorphine (p. 218)
is definitely less than that of morphine and its corresponding analogues.
The first two are about half as toxic as codeine and morphine respectively;
and the second pair are more toxic than their morphine analogues. None
of the four shows the Straub reaction and the convulsant action is less
marked.
eupoMorphine. This decomposition product of morphine shows some
of the morphine effects, but the accent is much more on the excitant than
on the depressant action. The medullary excitant action is the most
prominent, and in susceptible animals is exercised mainly on the vomiting
centre, causing emesis with its concomitant symptoms of nausea, sweating,
266
MORPHINE
SUB-GROUP
etc. In animals where it does not cause vomiting there are other signs of
central irritation. Large doses produce convulsions. I n addition t o its
use as a n emetic, it has also been found useful in subemetic doses as a
sedative in delirium tremens.
Thebaine stands at the other end of the series from morphine and is a
convulsant poison rather t h a n a narcotic (see table, p . 261). Hildebrandt 42
states t h a t it excites the reflexes of cold-blooded animals b u t in
dogs it exerts a narcotic and anti-emetic effect resembling t h a t of
morphine rather t h a n t h a t of chloromorphide. The alkaloid is scarcely
used in medicine as such, b u t is a primary material for the preparation of
certain of the modern morphine derivatives, such as hydroxydihydrocodeinone and methyldihydromorphinone.
Comprehensive summaries of the pharmacological information available
regarding codeine, o/pomorphine and thebaine are given in the report
already referred t o . 5
Thebenine and Morphothebaine.
Little pharmacological work seems
to have been done on these two degradation products of thebaine, b u t
Hildebrant 42 records t h a t as compared with thebaine, thebenine is a
much less potent excitant, and t h a t in spite of its resemblance to apomorphine, morphothebaine is much weaker as an emetic. Morphothebaine
dimethyl ether ( 3 : 4 : 6-trimethoxyaporphine), which is related t o bulbocapnine and to corydine (pp. 306, 308), has been examined b y Gunn. 4 3
Large doses in mice produce clonic convulsions, followed b y central motor
paralysis and death from respiratory failure. The symptoms indicate
supra-spinal stimulation of the central nervous system. Small doses
stimulate respiration in mammals. The alkaloid has a sympathicolytic
action resembling t h a t of ergotoxine in many ways b u t differs (a) in having
no primary stimulant action on smooth muscle, (b) in paralysing more
readily the peripheral, cardio-accelerator mechanism in the heart, (c) in
causing adrenaline-reversal of blood pressure and of action on the uterus
of the rabbit b u t not of the cat, and (d) having a very transient action in
the intact animal. The L.D.50 for mice b y intraperitoneal injection is
0-11 gm./kilo.
isoThebaine.
According to Konson a n d Saksonov, 44 this alkaloid
stimulates, and later depresses, the central nervous system. Subcutaneous
injection induces emesis in dogs and cats. Intravenous injections cause
transitory vaso-dilation with inhibited or halted respiration. I t raises the
tonus and lowers the amplitude of contraction of mouse intestine a t a
concentration of not less t h a n 40 parts per million.
REFERENCES
(1) Arch. exp. Path. Pharm., 1902, 47, 368. (2) Zeit. physiol. Chem., 1903, 38, 16.
(3) Verh. Ges. Deut.Nat. Arzte, 1912, [ii],2, 481. (4) Ber., 1916, 49, 2655. (5) Supplement No. 165 to Public Health Reports, 1943, Washington, U.S.A. (6) Supplement
No. 138 to Public Health Reports, 1938, Washington, U.S.A. (7) J. Pharm. exp. Ther.,
1937, 61, 422. (8) National Research Council, U.S.A. Report of Committee on Drug
Addiction, 1929-41 and Collected Reprints. (8a) J. Amer. Med. Assoc, 1947, 134,
2 9 1 ; E D D Y , J. Amer. Pharm. Ansoc, Pract. Pharm, Edit., 1947, 8, 430. For
267
PHARMACOLOGICAL ACTION
J. Amer. Chem. Soc., 1941, 63, 3 1 4 ; WEIJLARD and ERICKSOX, ibid., 1942, 64, 869.
(10) SUMWALT et al., J. Pharm. exp. Ther, 1941, 73, 229, 246, 258, 2 7 4 ; see also
OEUKERS, Arch. exp. Path. Pharm., 1940, 194, 296. (11) Science, 1940, 92, 244 ; J.
Pharm. exp. Ther., 1942, 75, 328 ; 1946, 87, 109 ; MASSART and DUFAIT, Naturwissenschaften, 1941, 29, 572. (12) OBERST, J. Pharm. exp. Ther., 1943, 79, 266 ; also ibid.,
1941,
1944, 8 1 , 3 7 4 ;
1945, 83, 85. (13) SLAUGHTER (with PARSONS a n d MUXAL), J. Amer. Med.
Assoc,
1940, 115, 2058 ; (with TREADWELL and GALES), J. Lab. Clin. Med., 1943, 28, 1199;
AXDREWS, J. Amer. Med. Assoc, 1942, 120, 525 ; cf. CHIU and CHOU, Proc Chin.
Physiol. Soc, 1943, 1, 125 ; HIMMELSBACH et al., J. Pharm. exp. Ther., 1942, 76, 50.
(14) C. R. Soc. Biol., 1940, 133, 646 ; (with DODEL and BRESSON), ibid., p. 429 ; (with
GAXDOUR), ibid., p . 595. (15) E A D I E , J. Biol. Chem., 1941, 138, 597. (16) WRIGHT,
J. Pharm. exp. Titer., 1941, 72, 45. (17) See, for example, WILLIAMS, OBERST a n d
BROWX, U.S. Public Health Reports, 1946, 61, 1, 37. (18) See, for example, WILLIAMS,
J. Pharm. exp. Ther., 1939, 67, 2 9 0 ; HIMMELSBACH, ibid., 1941, 73, 91 ; AXDREWS
and HIMMELSBACH, ibid., 1944, 81, 288 ; AXDREWS, Psychosom. Med., 1942, 16, 451.
(19) HIMMELSBACH, J. Pharm. exp. Ther., 1939, 67, 239 ; 1941, 71, 42. (20) OBERST,
REICIIARD, L E E , CLARK and HIMMELSBACH, Fed. Proc,
sec also E D D Y , Amer. J. Med. Sci., 1939, 197, 464 ; and for papers on other special
aspects of addiction, HIMMELSBACH, J. Pharm. exp. Ther., 1940, 70, 293 ; (with
AXDREWS), ibid., 1943, 77, 17 ; 1944, 81, 288 ; ANDREWS, J. Clin. Invest., 1943, 22,
511, 517. (21) E D D Y 2 0 ; Edit., J. Amer. Med. Assoc, 1941, 117, 4 5 3 ; DODDS,
(1946) 2 2 ; REGXIER, Chimiotherapie, p . 59, Masson e t cie., Paris, 1942 ; TIFFEXEAU,
Paris Medical, 1935, p . 59 ; FOURXEAU, Chim. et Ind., 1938, 39, 1043. (22) Nature,
1943,151, 614 ; 1944, 154, 514 ; Proc. Roy. Soc, 1944, B, 132, 119 ; DODDS, Brit. Med.
Bull, 1946, 4, 88 ; DOWXMAN, Brit. J. Pharmacol., 1947, 2, 207. (23) Nature, 1946,
158, 202. (24) R E A D and STEELE, J. Chem. Soc, 1927, 910. (25) J. Amer. Chem. Soc,
1946, 68, 624. (26) U.S.A. Dept. of Commerce Report, P.B. 981, p . 96-A ; B.I O.S.
Final Rept., No. 116, Item 24, pp. 51, 52, 65. (a) J. Pharm. Exp. Ther., 1940, 87, 63 ;
(with ROBBINS), Science, 1940, 104, 587. (b) J. Amer. Chem. Soc, 1947, 69, 188,
2454; see also BRODE a n d H I L L , ibid., 1947, 69, 724; J. Org. Chem., 1948, 13,
191 ; a n d EASTON, GARDNER and STEVENS, ibid.,
p . 976, 2941 ;
(with E V A N I C K ) ,
1948, 70, 76. (c) Nature, 1947, 159, 6 7 9 ; 160, 095. (27) Deut. Med. Woch.,
1939, 65, 9 6 7 ; SCHAUMANN, Arch. exp. Path. Pharm., 1940, 196, 1 0 4 ; E I S L E B , Ber.,
3941, 74, 1433. (28) DIETRICH, Deut. Med. Woch., 1939, 65, 9 0 9 ; K L E I N , Munch.
Med. Woch., 1939, 86, 1074. (29) ROSEXTHAL, ibid., p . 1079. (30) SCHAFER, Deut.
Med. Woch., 1939, 65, 970. (31) Quart. J. Pharm., 1940, 13, 318 ; (a) J. Pharm. exp.
Ther., 1941, 73, 319 ; (b) Ann. int. Med., 1944, 21, 7, 17 ; (c) J. Amer. Pharm. Assoc,
1940, 35, 1 1 3 ; see also BATTERMAN, Arch. int. Med., 1943, 71, 345, a n d CLARK. 2 0
(32) J. Clin. Invest., 1940, 19, 649, 659. (33) J. Amer. Med. Assoc, 1943, 122, 222 ;
WOOLFE and MACDONALD, J. Pharm. exp. Ther., 1944, 80, 3 0 0 ; CHRISTIE, Lancet,
1943, 244, 294. (34) For example, pain arising from pathological conditions : BRANWOOD, Edin.Med.
Post-operative pain : BATTERMAN, Arch. int. Med., 1943, 71, 345 ; (with MULHOLLAND),
Arch. Surg. Chicago, 1943, 46, 404. Obstetric pains : GALLEN and PRESCOTT, Brit.
Med. J., 1944, i, 176 ; SPITZER, ibid., p. 179 ; H O R I , Can. Med. Assoc. J., 1944, 51, 509 ;
BARNES, Brit. Med. J., 1947, i, 437. War injuries : CHRISTIE. 3 3 Neurological cases :
FITZGERALD a n d MCARDLE, Lancet, 1943, 244, 296. (35) HIMMELSBACH, J.
Pharm.
exp. Ther., 1942, 75, 64 ; 1943, 79, 5 ; ANDREWS, ibid., 1942, 75, 338 ; 1942, 76, 89 ;
POLONIO, Lancet, 1946, 252, 292. (36) KEENAN, J. Amer. Pharm. Assoc, 1946, 35, 338.
(37) MILOS, Amer. J. Pharm., 1945, 117, 3 4 3 ; MUNDELL, J. Assoc Off. Agr. Chem.,
MORPHINE SUB-GROUP
268
1045, 28, 7 1 . (38) LEHMAN a n d A I T K E N , J. Lab. Clin. Med., 1943, 28, 787 ; O B E R S T ,
J. Pharmacol,
exp. Ther.,
LINDQUIST, Dansk. Tids. Farm., 1943, 17, 173 ; (6) B E R G E L , MORRISON and R I N D E R KNECHT, J. Chem. Soc, 1944, 265, 267 ; (with H A WORTH), p . 261 ; (with H I N D L E Y ) ,
WALKEB, Chem. and Ind., 1948, 155 ; (e) BARLTROP, J. Chem. Soc, 1946, 958 ;
HORNING, et al., J. Amer. Chem. Soc., 1947, 69, 2929: ( / ) KOELSCH, J. Amer.
Chem. Soc, 1943, 65, 2093, 2458-2465. (40) W O L F F et al.32 ; (with SCHUMACHER),
Science, 1940, 92, 110 ; ANDREWS, J. Clin. Invest., 1943, 22, 517 ; (with WORKMAN),
J.
Pharm.
et al."(b)
exp. Ther.,
; D O D D S , LAWSON,
SIMPSON
a n d WILLIAMS,
J.
Physiol.,
GLAZEBROOK
1945, 104, 4 7 ;
ERCOLI and LEWIS, J. Pharm. exp. Ther., 1945, 84, 301 ; THORP, Brit. J.
Pharmacol.,
Pharmacol.,
1946, 2, 149. (40a) Jubilee Vol. Dr. E. C. Barell, 1946, p . 252 (Hoffmann La Roche,
Basle); see also, L E E , BERGER, ZIERING and HEINEMANN, ibid., p . 264, a n d J. Org.
Chem. 1947, 12, 885, 894, 9 0 4 ; FOSTER and CARMAN, J. Pharm. exp. Ther., 1947,
91, 195. (41) Bull. Health Organisation League of Nations, 1938, V I I , 546. (42) Arch,
exp. Path. Pharm., 1911, 65, 54 ; (with HARNACK), ibid., 1909, 61, 343. (43) J. Physiol.,
1941, 100, 64. (44) Farmakol. i. Toksikol., 1946, 9, 14.
ALKALOIDS OF Sinomenium acutum Rehd. and Wils. Although this
Japanese plant belongs to the Menispermacerc, it is convenient to deal
with it here because its principal alkaloids, sinomenine and disinomenine,
belong to the morphine sub-group. Of the other four alkaloids present,
tuduranine is related to morphothebaine and wothebaine and comes into
this section in which are also included the two alkaloids of unknown
constitution, acutumine and diversine. The sixth alkaloid, sinactine, is
Z-tetrahydroepi'berberine, and is described along with its chemical relatives
(p. 338). Sinomenium acutum thus contains alkaloids belonging to three
different groups, and is typical of the botanical family Menispermacese,
which includes the alkaloid-bearing genera Anamirta (p. 349), Archangelisia
(p. 329), Chondrodendron (p. 363), Cissampelos (p. 363), Cocculus (p. 350),
Coscinium (p. 329), Jatrorrhiza (p. 329), Menispermum (p. 350), Stephania
(p. 361), Tiliacora (p. 350) and Tinospora (p. 329).
Sinomenine, C 19 H 23 0 4 N. This alkaloid, first isolated by Ishiwari, X has
been investigated by Kondo 2 and by Goto. 3 I t crystallises in stellate
groups of needles and has two melting-points, 161 and 182. The specific
rotation [a]??" is - 70-76 (EtOH). The hydrochloride, B . HC1. 2H 2 0,
decomposes a t 231 and has [a]j' 82-4 (dry salt: H 2 0 ) ; the aurichloride is amorphous. The alkaloid contains two methoxyl groups and
one methylimino-group ; it is soluble in alkalis, gives a greenish-blue
colour with ferric chloride and forms a monobenzoyl derivative (prisms,
m.p. 225) and a monomethyl ether (needles, m.p. 175), so that the third
oxygen atom is present as a phenolic hydroxyl group. The fourth oxygen
is in a carbonyl group (oxime, m.p. 254 (dec.); semicarbazone, m.p. 264
[dec.) ). On catalytic hydrogenation the base is converted into dihydrosinomenine, ClfrH2604N (needles, m.p. 199 ; [x] + 170-5). On distillation with zinc dust, phenanthrene and trimethylamine are produced, and,,,
269
SINOMENINE
HC.OMe
{I) Sinomenine (Goto,
1926)
(III) Sinomenine
(Kondo 1929 )
MeO.C
H0.C
80
06'
N
,C
HpC
2
CH
I OH
I CHgiT
00
co
MMe
0H~-CH 2
N
C.0Me
i
(VI) I
(IV) Sinomenine
(Goto 1929)
The ease with which one methoxyl group is lost in this reduction was at
first explained by assuming carbon atom 5 as its point of attachment,
but in the following year the same authors ' prepared by Pschorr's method
3:4:6:7-tetramethoxyphenanthrene, colourless prisms, m.p. 124-5,
which proved to be identical with Goto's dimethylsinomenol, and on this
270
MORPHINE
SUB-GROUP
basis the labile methoxyl group was placed a t C , the rest of the structure
of ring I I I being left open pending determination of the character of this
ring in thebainone, sinomenine being regarded as the J-form of a hypothetical d-7-methoxythebainone. I n a later paper 2 the same authors
still leave open t h e question of the a t t a c h m e n t of t h e carbon end of the
ethanamine chain a t C 5 (Knorr) or C 1 3 (Gulland and Robinson), b u t suggest
C 8 -C 1 4 as the position of the ethylenic linkage (formula I I I ) (instead of the
bridge, C 1 6 -C 8 , adopted originally) on the ground t h a t sinomenine has none
of the properties of an enolic methyl ether. The similarity of the colour
reactions of sinomenine and thebainone, viz., blue with ammoniacal silver
solution in acetone and purple (soluble in chloroform) with alkaline solution
of potassium ferricyanide, led Goto 8 to accept this representation of
sinomenine in principle, b u t he preferred t o place the ethylenic linkage a t
C 7 -C 8 , and accepted linkage of C 15 ~C 13 for the ethanamine chain (formula
IV), which brings the representation of sinomenine into harmony with
the current view 9 of the constitution of thebainone (p. 248).
Since t h e n numerous papers have been published 10 dealing with the
reactions of sinomenine and its derivatives, especially by Goto and his
collaborators, 1 0 and the results have disclosed no necessity for the modification of formula (IV). Goto and Sudzuki x l found t h a t , on reduction with
sodium amalgam, dihydrosinomenine yields the rf-form (m.p. 138,
[ a ] n + 59-17 ; semicarbazone, m . p . 235) of dihydrothebainone 12
(formula V). I n this reaction the methoxyl group at 7 is again eliminated,
and if the reduction of dihydrosinomenine is effected by the Clemmensen
method, the carbonyl group is also removed with the formation of tetrahydrodeoxycodeine (II). Goto, Takubo and Mitsui 10 (1931) showed t h a t
by the Schopf and Pfeifer 10 process, d-dihydrothebainone, in parallel with
the behaviour of its tero-isomeride (p. 250), could be converted into
d-1-bromodihydrocodeinone, m.p. 206, [a]jf + 161 (CHC13). The latter
on catalytic hydrogenation gave (Z-dihydrocodeinone, m.p. 1C3, [a.]'jf
+ 207-4 (CHC1 3 ), which Goto and Arai 10 (1941) showed could be hydrogenated, in pyridine solution in presence of platinic oxide, to (-)-) dihvdrocodeine, C 1 8 H 2 3 0 3 N, 2 H 2 0 , m.p. 87-8 or 110 (dry), [a]?,0" + 146-4
( E t O H ) and this in t u r n demethylated t o ( + ) dihydromorphine, m.p. 1 5 8 9= [*]D + 151-5 (EtOH) giving a hydriodide, "m.p. 285, [a] D + 87-9
(H20).
When sinomenine is heated with hydrochloric acid and the product
treated with ammonia solution, fo's-demethylsinomenylidene, ( C l g H 2 1 0 3 N ) 2 ,
is formed, 1 1 which crystallises from chloroform, has m.p. > 312,
[a]},7 + 3 3 5 - 5 , contains two methoxyl groups and two carbonyl groups
(dioxime, m . p . > 3 1 5 ) and is represented by partial formula (VI), in which
it is assumed t h a t t h e enolic methyl ether group a t 7 has been hydrolysed
to a carbonyl group, and junction between two residual molecules, effected
by two ethylenic linkages formed in each case between the carbonyl group
a t C 6 of one residual molecule and the methylene group a t C 8 of t h e other.
I n this reaction an intermediate product sinomenine h y d r a t e , 1 3 C 1 9 H 2 6 0 5 N
(prisms, m . p . 139 or 160, [<x]D + 40-8), is formed and can be isolated if
271
DISINOMENINE
.
.
.
.
222
245
Plates
>290
263
265 (dec.)
>290
+ 149-8
Pink
(//-Disinomenine.
227
243
Slender needles
>290
268
>290
>290
- 12703
Yellow
272
MORPHINE
SUBGROUP
C-OMe
(VII)
19
QAainomenlne
C-OMe
XH
(VIII)
base.
Formula (VII) was, therefore, assigned to disinomenine, and it
was suggested t h a t in i/i-disinomenine there is probably a different mode of
linkage of the ethanamine chain. 1 7 Mention has been made already of a
bimol ocular alkaloid of a different type, viz.,
fo's-demethylsinomenylidene
(p. 270) (partial formula VI), obtainable from sinomenme. A third t y p e
is produced by the action of sodium amalgam on sinomenine in dilute
sodium hydroxide solution. The substance obtained has the formula
(C 1 8 H i 2 0aN) 2 , m.p. 304, [a] D 24-4!), crystallises from alcohol in stout
prisms, contains only two methoxyl groups, yields a disemicarbazone,
gives a diazo-reaction as intense as t h a t with sinomenine, and resembles
sinomenme in its colour reactions with ferric chloride, alkaline potassium
ferricyanide and formaldehyde-sulphuric acid. These properties seem to
preclude junction in the 1 : 1'-position, and it is assumed t h a t junction
takes place a t the 8 : 8'-position, and the substance is represented as bis8 : 8'-demethoxydihydrosinomenine (VIII). 2 0 Similar studies have been
made of other bimolecular alkaloids of this series, e.g., ^-morphine (p. 255),
dithebainone 21 (p. 256), I- and d-bis-1 : l'-thebenone, 1 : l'-dithebaol, 2 2
I- and d-bis-1 : l'-/5-tetrahydrodeoxycodeine. 2 3 Another type of bimolecular
alkaloid of this series, is t h e 7 : 7'-methylenefcisdihydrocodeinone obtained
by Rapoport and Small b y the action of formaldehyde a n d dimethylamine on dihydrocodeinone. 2 3 f a ;
Sinactine, C2oH 21 0 4 N. See i-Tetrahydroepiberberine, p . 338.
Acutumine, Cj^j^HgjOgN. This base, isolated b y Goto a n d Sudzuki,
TUDURANINE
273
274
MORPHINE
SUB-GROUP
doses stimulate, larger doses stimulate and then paralyse the plain muscle
of the intestine and uterus. According to Takaori, diversine has a similar
action to sinomenine, but is more toxic. The effects of sinomenine and
parasinomenine (diversine) on various aspects of metabolism have been
compared with those of quinine, another protoplasmic poison and found,
as a rule, to be less active. 29
REFERENCES
(1) Chem. Soc. Abslr., 1921, i, 354. (2) KONDO and OCHIAI, Annalen, 1929, 470,
224. (This summarises and extends six papers in J. Pharm. Soc. Japan, 1923, No. 497,
511 ; 1924, No. 503, 8 ; 1926, No. 538, 1008 ; 1927, No. 539, 17 ; 1928, No. 549, 914,
923 ; cf. TAKAORI, Deut. med. Woch., 1936, 62, 1635.) (3) Proc. Imp. Acad. Tokyo,
1926, 2, 7, 167, 414 ; cf. OCHIAI, J. Pharm. Soc. Japan, 1924, No. 503, 8 ; for similar
degradations by acetic anhydride see GOTO, SHISHIDO and TAKUBO, Annalen, 1932,
497, 289 ; GOTO, IIDA and SHISHIDO, Bull. Chem. Soc. Japan, 1933, 8, 366. (4) J.
Pharm. Soc. Japan, 1926, No. 538, 1008 ; 1929, 49, 556 ; Ber., 1930, 63, 646 ; cf. GOTO
and MITSUI, Bull. Chem. Soc. Japan, 1931, 6, 33. (5) Ber., 1921, 54, 1519. (6) SMALL
and COHEN, J. Amcr. Chem. Soc, 1931, 53, 2227. (7) J. Pharm. Soc. Japan, 1927,
No. 539,17 ; No. 549, 913,923. The synthesis was confirmed by GOTO and SUDZUKI, Bull.
Chem. Soc. Japan, 1929,4,163; see also GOTO and SHISHIDO, ibid., 1941,16,170. (S)Ibid.,
1929, 4, 103 ; (with SUDZUKI), ibid., p . 244. (9) SCHOPF and HIKSCH, Annalen, 1931,
489, 224. (10) Bull. Chem. Soc. Japan, 1929, 4, 195 ; 1930, 5, 73, 93, 165, 223, 282,
311, 315 ; 1931, 6, 33, 79, 126, 197, 229 ; 1932, 7, 223 ; 1933, 8, 366 ; 1935, 10, 481,
597; 1 9 4 2 , 1 7 , 1 1 3 , 3 0 4 , 3 9 3 , 4 3 9 ; 1 9 4 3 , 1 8 , 1 1 6 , 1 4 3 , 2 1 8 ; 1 9 4 4 , 1 9 , 1 4 0 ; Ber., 1930,
63, 2096 ; Annalen, 1931, 485, 247 ; 489, 86 ; 1932, 494, 1 ; 495, 122 ; 497, 289 ; 499,
169 ; 1933, 501, 304 ; 503, 277 ; 507, 290 ; 1941, 547, 194 ; see also SCHOPF and
P F E I F E R , ibid., 1930, 483, 1 5 7 ; (with H I R S C H ) , 1932, 492, 2 1 3 ; and OCHIAI a n d
1929,
4, 244. The results of a sodium amalgam reduction of sinomenine are much more
complicated than is here implied, see KONDO and OCHIAI, J. Pharm. Soc. Japan, 1926,
No. 538, 1008 ; OCHIAI, ibid., 1929, 49, 556 ; (with HAKOZAKI), ibid., 1930, 50, 300 ;
GOTO and MITSUI, Bull. Chem. Soc. Japan, 1930, 5, 282 ; GOTO and SHISHIDO, ibid.,
1935, 10, 599. (12) F H E U N D , SPEYER and GUTTMANN, Ber., 1920, 53, 2250.
(13) GOTO
5, 168. (14) GOTO a n d NAMBO, ibid., 1930, 5, 73. (15) GOTO, NAMBO a n d INABA,
ibid., p . 223. (10) GOTO a n d SUDZUKI, ibid., 1929, 4, 1 0 7 ; cf. K O N D O a n d OCHIAI,
./. Pharm. Soc. Japan, 1927, No. 549, 124. (17) GOTO, Proc. Imp. Acad. Tokyo, 1926,
2, 414 ; see also GOTO and TAKUBO, Bull. Chem. Soc. Japan, 1931, 6, 126. (18) GOTO,
ibid., 1929, 4, 129. (19) GOTO and NAKAMURA, ibid., 1929, 4, 196. (20) GOTO and
SUDZUKI, ibid., 1929, 4, 244 ; cf. GOTO a n d INABA, ibid., 1930, 5, 93.
KITASATA, Annalen, 1930, 481, 81 ; GOTO (with OGAWA), ibid., 1934, 511, 202. (22) GOTO,
MICHINAKA and SHISHIDO, ibid., 1935, 515, 297 ; (with ARAI), Bull. Chem. Soc. Jap.,
1943, 18, 248. (23) GOTO a n d SHISHIDO, Bull. Chem. Soc. Japan, 1935, 10, 252.
(24) Ibid., 1929, 4, 220. (25) J. Pharm. Soc. Japan, 1923, No. 497, 511. (26) Annalen,
1935, 521, 175. (27) Ibid., 1937, 530, 142. (28) Ibid., 1939, 539, 2 6 2 ; Bull. Chem.
Soc. Jap., 1941, 16, 329.
Proc.
Imp. Acad. Tokyo, 1933, 9, 390 ; NAKANO, ibid., 1935, 20, 15 ; TAKAORI, Deut. med.
Woch., 1936, 62, 1634 ; R I N , Proc. Jap. Pharm. Soc, 1938, 12, 1 9 4 ; Fol. pharmacol.
Jap., 1938, 25, 1 4 0 ; I T O , ibid., 1940, 30, 197. A summary of results is given b y
KRUEGER et ah, Suppl. No. 165, Pub. Health Reports, U.S.A., p . 999.
RH(EADINE
275
276
ISOQUINOLINE
GROUP
277
CHELEBYTHSINE
S P I T H and ZAJIC, Ber., 1936, 69, 2448.
279 ; Forsch. Fortschritte, 1939, 15, 117. (6) Loc. cit. and B. C. 1st Lombardo, 1905,
[ii], 38, 117 ; Gazzetta, 1907, 37, [i], 629 ; 1914, 44, i, 398 (Chem. Soc. Abstr., 1905,
i, 368 ; 1907, i, 870; 1914, i, 457 "(pharmacological) and 719. (7) J. Pharm., 1813,
170. (8) Arch. Pharm., 1911, 249, 3 9 ; 1914, 252, 274. (9) Ibid., 1914, 252, 211.
(10) Ber., 1935, 68, 2158. (11) Ibid., 1935, 68, 2277.
O T H E R PAPAVERACEOUS
a-NAPHTHAPHENANTHRlDINE
ALKALOIDS
SUB-GROUP
isoQUINOLINE
278
GROUP
[111)
i
Chelarvtbrlne,
C Elr,0.N,H,0
c xi *% &
(I)
q-Horeoohelldonlne.
C H O N
21 23 5
C-Ox
,c~c /
0-C
\ /' \
JXale-OH
CH
//
(III) Chelldonlne. C
H,0 N
EO 19 5
^02H
C-COH
\ /
CO F.-C
C-Ox
I
CH
C-O' 2
CH 2 -0-C
(VIII)
3:4-Methy_lene;
dioxyphthallc
acid/
(VII)
Hydrastlc
acid.
(VI) T ^ t r a g a t h o i y - H - f f l e t h y l .d^Uydro'-qnayhthaphenanthricllne.
(V)
a -Naphthaphanaatbrldlna
CHELIDONINE
279
280
isoQUINOLINE
GROUP
SANOUINARINE
281
heated more rapidly. Crystallised from alcohol, it had m.p. 195-7, and
is then probably an alcoholate. It is soluble in organic solvents with a
bluish-violet fluorescence ; the salts are red. The </i-cyanide is colourless,
and has m p. 238.
In view of the importance of establishing the relationship of sanguinarine
to chelidonine the steps by which the latter alkaloid was converted into
^-chelerythrine by Gadamer and Winterfeld 9 may be mentioned. 0Acetylchelidonine (p. 279) was oxidised by mercuric acetate to didehydrochelidonine (i/r-cyanide, C 21 H ls 0 5 N 2 , m.p. 194-6), which behaves as a
tertiary base, and when boiled in aqueous alcoholic solution is converted
into an anhydro-base, dihydro-i/i-chelerythrine, C20H16O4N, which deposits
as the reaction proceeds, in crystals, m.p. 187-8, and is readily oxidised,
e.g., by mercuric acetate to i/i-chelerythrine, C20H13O4N, which crystallised
from ether, has m.p. 239-42 (dec). The identity of this substance with
sanguinarine was established by Gadamer and Stichel.17 The ^-cyanide
(cf. cotarnine i/r-cyanide, p. 204), C 21 H 14 0 4 N 2 , crystallises from chloroform
on addition of alcohol, has m.p. 237-5-238, and is colourless. The hydrochloride, C20H13O4N . HC1 . 3H 2 0, forms long, thin copper-red, or blood-red
needles.
The nature of the nucleus in chelidonine and sanguinarine was established by Spath and Kuffner,13 who showed that both alkaloids on distillation with zinc dust yielded a-naphthaphenanthridine (V), first prepared
by Graebe,15 and on that basis formula (IV) was suggested for sanguinarine.
The relationship between chelerythrine (II) and sanguinarine (IV)
was also established by Spath and Kuffner,8 who showed that dihydrochelerythrine (p. 278) and dihydrosanguinarine, C20H15O4N, m.p, 188-9,
prepared from the natural alkaloid, and obviously identical with the
dihydro- i/i-chelerythrine of Gadamer and Winterfeld (see above), on replacement of the methylenedioxy-groups by methoxyl groups yielded the same
substance, viz., tetramethoxv-iV-methyldihydro-a-naphthaphenanthridine
(VI).
282
JSOQUINOLINE
GROUP
SYNTHETICAL E X P E R I M E N T S .
Richardson, Robinson and Seijo 1 8
have described the synthesis of a substance which is believed to be tetramethoxytetrahydrobenzphenanthridine ( X I ) . I t was obtained by condensing veratraldehyde a n d acetoveratrone to 3 : 4 : 3 ' : 4'-tetramethoxychalkone, which b v addition of hydrogen cyanide yielded y-keto-a-cyano-aydiveratrylpropane, C 6 H 3 (OMe) 2 . CH(CN) . C H 2 . CO . C 6 H 3 (OMe) 2 . This
was hydrolysed successively to the corresponding amide and keto-acid,
and the latter reduced b y Clemmensen's method t o ay-diveratrylbutyric
acid, C 6 H 3 (OMe) 2 . CH(C0 2 H) . C H 2 . C H 2 . C 6 H 3 (OMe) 2 in which ring
closure was effected b y t r e a t m e n t with phosphoryl chloride, yielding
l-keto-6 : 7-dimethoxy-2-veratryl-l : 2 : 3 : 4-tetrahydronaphthalene (IX).
The latter, either b y direct interaction with formamide or via the oxime
and amine and t r e a t m e n t with formic acid, was converted into 1-formamido6 : 7-dimethoxy-2-veratryl-l : 2 : 3 : 4-tetrahydronaphthalene (X), and in
this the second ring closure was made in toluene solution by phosphoryl
chloride t o (XI) with (XII) as a less likely alternative.
A series of " open " analogues of chelidonine has been prepared by
Noller and Kneeland 18(a) in the form of tertiary amino-alcohols of the type,
CH 2 Ar-NMe . (CH 2 ) 2 . C H O H . CH 2 Ar' where Ar and x\r' m a y be ( i f P h
or (2) C e H 3 : C H 2 0 2 or (3) C 6 H 3 (OMe) 2 . They were made for pharmacological test b u t none of them showed the spasmolytic action, which led
to the suggestion of chelidonine as a substitute for papaverine.
Oxychelidonine, C 2 0 H 1 7 O 6 N. (Item 7 ; list, p . 169.) This alkaloid was
obtained b y Gadamer and Theissen 9 from residues from the technical
extraction of chelidonine, and is one of the products formed when the
latter is oxidised with mercuric acetate. I t crystallises from a mixture of
chloroform and alcohol in slender needles, m.p. > 285, [a] D + 102-5,
yields no salts, contains one methylimino-group and two methylenedioxy
groups. I t is assumed t h a t a cyclic methylene group near the alcoholic
hydroxyl group a t C 1 0 ( I I I , p . 278) has been converted into a carbonyl
group which inhibits acylation, b u t no positive evidence for the presence
of a carbonyl group could be obtained. Wintgen's oxychelidonine, 1 9
C 2 0 H 1 9 O 6 N . H 2 0 , appears to be an amine oxide.
Methoxychelidonine, C 2 1 H 2 1 0 6 N. (Item 7 ; list, p . 169.) In a systematic
investigation of chelidonine extraction residues, Gadamer and Winterfeld, 9
isolated this alkaloid. I t crystallises from alcohol in prisms, m.p. 221,
M D + H 5 - 8 and gives a crystalline hydrochloride and aurichloride,
B . HAuCl 4 , m . p . 237-8. I t contains one methoxyl group, two methylenedioxy groups, one hydroxyl group (O-acetyl derivative, amorphous,
m.p. 147, [<x]D + 55-5), and a methylimino-group.
Accepting Gadamer and Winterfeld's view t h a t this base is a methoxychelidonine, von Bruchhausen a n d Bersch 1 0 suggested t h a t the methoxyl
group was probably a t C^ (III, p . 278).
Oxysanguinarine, C 20 H 13 O 6 N, was isolated b y Spath, Schlemmer,
Schenck a n d Gempp 20 b y chromatographic analysis of blood root alkaloids,
and was also prepared b y oxidation of sanguinarine nitrate b y potassium
ferricyanide in alkaline solution. I t was purified b y crystallisation from
PHARMACOLOGICAL
ACTION
283
chloroform and sublimation in a high vacuum, and had m.p. 360-1 (corr.,
vac.), [a] D 0, and is represented by formula (IV) with the change
-NMe . OH : CH- into -NMe . CO- in ring (II).
Of the papaveraceous plants providing these a-naphthaphenanthridine
alkaloids, the most interesting is the celandine, Chelidonium majus, which,
though obsolete in British and American medical and pharmaceutical
practice, still attracts attention elsewhere. Its pharmacognosy has been
investigated by Cappenberg and Harms.21<a) A microchemical test for
identification of the crude drug has been devised by Ramsted 21(6) and both
in Germany and Russia processes for estimation of the alkaloidal content
of the drug have been published.21(c)
Pharmacological Action. From the foregoing account of the chemistry
of these alkaloids, it will be realised that the material available for pharmacological examination may have been of doubtful purity, and it is probable
that a careful pharmacological comparison of pure specimens of the four
principal alkaloids of the sub-group would yield interesting results.
Chelidonine is said to be only slightly toxic. Chelidonine and a-homochelidonine produce some depression of the central nervous system and
slight narcosis. They resemble papaverine in their action on muscle and
the heart, and produce insensibility of the skin on local application by
paralysing the ends of the sensory nerves. Respiration is retarded and
deepened. In view of the papaverine-like action on muscle, Hanzlik has
suggested the use of chelidonine in asthma and colic.22 According to
Greathouse, the immunity of Sanguinaria canadensis to root-rot is due
to the alkaloids it contains. 23
REFERENCES
(1) Arch. Phurm., 1890, 228, 441 ; cf. SCHMIDT, ibid., 1901, 239, 405, 397. (2) Ibid.,
1919, 257, 298. (3) Ibid., 1920, 258, 1G0. (4) tier., 1931, 64, 1123. (5) Annalen,
1839, 29, 120 ; cf. WINTGEN, Arch. Pharm., 1901, 239, 448. (0) Ibid., 1893, 231, 145,
101 ; cf. B A U E R and
H E D I N O E R , ibid., 1920,
258,
167 ; and
GADAMER and
STICHEL,
(7) Ibid.,
1917,
50, 212 ; 1921, 54, 2021 ; Ilelv. chim. Acta., 1923, 6, 232. (8) Ber., 1931, 64, 2034.
(9) Arch. Pharm., 1919, 257, 2 9 8 ; 1920, 258, 1 4 8 ; ibid., 1924, 262, 2 4 9 ; (with
D I E T E R L E ) , p. 257 ; (with W I N T E R F E L D ) , pp. 452, 589 ; (with STICHEL), p. 488 ; (with
THEISSEN), p. 578. (10) Ber., 1930, 63, 2520 ; 1931, 64, 947. (11) Inaug. Diss.
Marburg, 1927. (12) Ibid., 1928. (13) Ber., 1931, 64, 370. (14) Ibid., 1927, 60,
1897. (15) Annalen, 1904, 335, 127. (16) Mag. Pharm., 1829, 23, 125. (17) SCHMIDT,
KOENIG and TIETZ, Arch. Pharm.,
1901, 239, 409 (bibliography of early literature) ; BAUER and HEDINGER, ibid., 1920,
258, 167 ; GADAMER and STICHEL, ibid., 1924, 262, 498 ; KOZNIEWSKI, Bull. Acad. Sci.
Cracow, 1910, p. 235. (18) J. Chem. Soc, 1937, 835 ; cf. NOLLER, D E N Y E S , GATES and
WASLEY, J. Amcr. Chem. Soc., 1937, 59, 2079 ; (18a) NOLLER and KNEELAND, ibid.,
1946, 68, 201 ; cf. NOLLER and CASTRO, ibid., p. 203. (19) Arch. Pharm., 1901, 239,
438.
(20) Ber.,
1938,
276,
500. (21a) Deut. Apoth. Zeit., 1939, 54, 4 0 ; (6) Pharm. Acta Ilelv., 1941, 16, 1 5 ;
(c) NEUGEBAUER and BRUNNER, Pharm. Zent., 1937, 78, 1 7 ; Apoth. Zeit., 1937, 52,
1038;
SCHENK
and
GRAF, Arch.
Pharm.,
1937,
275,
113,
166;
RODIONOV
and
284
isoQUINOLINE
GROUP
Merck's Jahresb., 1936, 50, 104 ; DANIEL and SCHMALTZ, Pharm. Zentr., 1938, 79, 99 ;
SEEL, STIEDA and PEPLAU, Hippokrates, 1939, 10, 1281. (23) Plant Physiol., 1939,
14, 377.
ALKALOIDS OF CORYDALIS AND ALLIED GENERA
The remaining woquinoline alkaloids cannot be pigeon-holed neatly
into either botanical or chemical groups. A strictly chemical arrangement
separates t h e considerable number of alkaloids not y e t allocated t o chemical
groups from t h e alkaloids of known constitution with which they are
associated in t h e plant. A botanical arrangement on t h e other hand
separates closely related alkaloids, thus t h e protoberbermes are typically
developed in t h e Ranunculaceae, Berberidaceas, Menispermaceae, Anonacese
and Rutacese, while their tetrahydro-derivatives occur in t h e Rhccadales,
especially in Corydalis species. I n view of t h e interest now being shown
in t h e biogenesis of alkaloids and other constituents of plants, it seems
desirable t o adopt a botanical arrangement and t o discuss t h e alkaloids
of Corydalis a n d allied genera separately from those of Berberis a n d its
associates (p. 328).
I t is convenient to group together under t h e above heading t h e alkaloids
obtained from t h e remaining species of t h e Rhceadales, viz., Corydalis,
Dicentra, Adlumia and Glaucium, since a number of alkaloids occur in
more t h a n one of these genera a n d apart from t h e simple isoquinoline
derivative, corypalline, they are divisible into four chemical types of which
one, t h e bicuculiine sub-group, h a s been dealt with already (p. 209) along
with its relatives, t h e phthalideisoquinolines. The other three types are
represented by (a) the tetrahydroprotoberberines (corydaline
sub-group),
(b) t h e cryptopine sub-group, and (c) t h e aporphines (bidbocapnine sub-group).
The Corydalis and Dicentra species are distinguished b y t h e number
and variety of t h e alkaloids they contain, and separation a n d isolation of
the latter is a difficult problem. General methods have been devised b y
Gadamer, Ziegenbein and Wagner, : ( a ) Gadamer, Spath and Mosettig 1 ( 6 ) and
Manske, 1(c) b u t most of t h e workers on these alkaloids have made contributions t o this subject.
TETRAHYDROpro/OBEEBEMNE SuB-GROUP
Corydaline, C 2 2 H 2 7 0 4 N. (Items 8, 9, 3 1 ; list, p p . 170-2.) After t h e
discovery of this alkaloid b y Wackenroder, 2 Wicke 2 analysed well-crystal- i
lised salts and adopted t h e formula C 1 8 H 1 9 0 4 N. Birsmann 3 changed this
t o C 2 2 H 2 3 0 4 N, which Dobbie a n d Lauder 4 altered t o C 2 2 H 2 8 0 4 N, this in
t u r n being modified by Freund and Josephi 5 t o C 2 2 H 2 7 0 4 N.
Corydaline crystallises from alcohol in short, six-sided prisms, m.p. 135,
[a]| -f- 300 (CHC13), is sparingly soluble in cold alcohol, b u t dissolves
readily on warming," is easily soluble in ether or chloroform, insoluble in
water or alkalis. Exposed to air, it gradually oxidises t o t h e yellow
dehydrocorydaline. It forms well-crystallised s a l t s ; t h e hydriodide,
B . H I , forms pale yellow prisms of indefinite melting-point; the nitrate,
B . H N 0 8 , tablets, m.p. 1 9 8 ; and the hydrochloride, B . H C l . 2H 2 O f
CORYDALINE
285
Oxidation by permanganate
C ^ H ^ H
I
Oxidation by dilute nitric acid
Dehydrociorydallne
Corydaldine,
fi fl
U 133B
m-Hemiplnlc
acid
Hemlplnio
Corydie acid,
C H 0 N
acid
Methylpyrldlnetricarboxylic acid.
W6N
m-fiemlplnlo
acid
irf
f
Corydilic
acid.
'U 1 7"H 1 5 0 8 N
a-Hemlpinlc acid
m-^emlplnlo
acid
Methylpyridlnetricarboxylic aold
Pyridinetetraoarboxyllo
acid. CjH.O-N
286
isoQUINOLINE
GROUP
/ \
OH
/ \
MeO.O
^C.CH-
/ \
O.COJi
(V) Corydaldine
DEHYDROCORYDALINE
287
288
GROUP
JSOQUINOLINE
formula was approved by Spath and Mosettig 18 after a critical investigation of the degradation of corydaline by the methods of Hofmann and
Emde, and confirmed by von Bruchhausen's preparation 19 of dZ-corydaline,
m.p. 135-6 from palmatine-acetone by the action of methyl iodide and
reduction of the methylated product. Under these conditions it is the
hydrogen atom attached to C 13 which is reactive, and is replaced by
methyl. 20 Further evidence in this direction was provided by von
UeO
a / \
/
(XI)
OMe
(III)
OMe
ra2
I IV
vvy
CMe
\0lie
<
H0,0
. i
II ii
CMa
(XIII)
H I 0H
I
a
/
(XIV) Me2S.0H2.0H2
\H3
'
Me 2 N.CH 2
BMOU
JJIOO-H HH
(IVT) 0U
OH,
*
s*
MeOli,
(xni) ou
HH
co.j
CH2
"oL
'X
1X71II) 0U
H
CO
en
CH
CORYDALINE
289
(XXI)
10
290
JSOQVINOLINE
2
GROUP
COBYPALMINE
291
26; list, pp. 170-1). The Z-form has m.p. 204, yields a hydrochloride,
m.p. 268-9 and a diethyl ether, m.p. 155. Gadamer et al.30 showed that
Knorck's d-scoulerine contained two methoxyl groups and on methylation
yielded d-tetrahydropalmatine. The diethyl ether on gentle oxidation gave
6-methoxy-7-ethoxy-l-keto-l : 2 : 3 : 4-tetrahydrowoquinoline and on
drastic oxidation produced a mixture of 5-methoxy-4-ethoxy- and 4methoxy-3-ethoxy-phthalie acids, both isolated and identified as the
ethylimides. These facts are in harmony with the representation of
scoulerine by formula (XXV), R' = R 3 = OH ; R 2 = R 4 = OMe).
Manske has isolated from several papaveraceous plants an alkaloid
aurotensine (items 9, 19, 23, 44, 47, 48; list, pp. 170-3) which occurs in
rhombic plates, m.p. 128 [<X]D 69-9 and appears to be an addition
compound of Z- and dZ-scoulerine (Manske 29 ). Its dimethyl ether [caseanine
item 10 : list, p. 170), m.p. 115-6 (hydrated) or 142 (ex benzene) must
be tetrahydropalmatine (p. 292) and casealutine, found with caseanine,
was shown later by Manske to be Z-Mocorypalmine.
cZ-Tetrahydrocolumbamine (isoCorypalmine;
2-hydroxy-3 : 9 : 10trimethoxytetrahydroprotoberberine), C20H23O4N. (Items 10, 15, 18, 20, 23,
31; list, pp. 170-1.) Aminute quantity of this alkaloid isolated by Knorck 29
was investigated by Gadamer, Spath and Mosettig.30 It crystallises from
methyl alcohol, has m.p. 239-41 (this and the following m.ps. are
determined in vacuo), is dextrorotatory and contains three methoxyl groups.
Its identity was established by its preparation from rf-canadine (XXVI).
The latter was demethylenated 81 to the 2 :3-dihydroxy-base,
C17H13(OH)2(OMe)2N, m.p. 252-3, and this methylated by means of
diazomethane, producing a mixture of the fully methylated base dtetrahydropalmatine (XXVII) with the two partially methylated bases,
corypalmine (XXV : R 2 = -OH (see below) ) and the required substance,
m.p. 239-41, alone or 240-1 mixed with the natural alkaloid, which
must therefore be represented by formula (XXV: R 1 = OH ;
R 2 = R 3 = R 4 = OMe). Z-Tetrahydrocolumbamine was similarly prepared from Z-canadine ; it had m.p. 241-2 and the tZZ-form had m.p. 221-2
and mixed m.p. 222-3, with dZ-tetrahydrocolumbamine. The Z- and dlforms of isocorypalmine also occur naturally (see items quoted above).
It may also be noted that Manske's base F 51 (item 22 ; list, p. 171)
is isomeric with the two corypalmines and like them methylates to tetrahydropalmatine.
^-Corypalmine (d-tetrahydrojatrorrhizine ; S-hydroxy-2 : 9 : 10-trimethoxytetrahydroprotoberberine), C20H23O4N. (Items 10, 11, 20, 21, 29, 31, 39 ;
list, pp. 170-2.) This alkaloid isolated by Spath, Mosettig and Trothandl 32
forms minute colourless crystals, m.p. 235-6, [a]*,6" + 280 (CHC13), and
on methylation with diazomethane yields d-tetrahydropalmatine. The
position of the hydroxyl group was established by Spath and Mosettig,33
who treated corypalmine with diazoethane and oxidised the resulting
corypalmine ethyl ether with permanganate to 7-methoxy-6-ethoxy-lketo-1 : 2 : 3 : 4-tetrahydrot'soquinoline. As mentioned under tetrahydrocolumbamine (see above) in the preparation of the latter alkaloid from
10a
292
isoQUINOLINE
GROUP
(XXlf)
(XZVI) Canadian
(ZXVII)
TatrahTiroTOlmatlne
TETRAHYDROCOPTISINE
293
isoQVINOLINE
294
OBOUP
in mice : corydaline 135-5 12-8 ; Wsocorypalmine, 132-6 5 ; d-, dland Z-tetrahydropalmatine, 126-0 4-96 ; 121-5 6-65 ; 110-9 7-88
respectively. All the alkaloids stimulated isolated guinea-pig or rabbit
uterus. Corydaline arid i-isocorypalmine stimulated intestines in weak but
inhibited them in strong solution. Fall of blood pressure was induced by
all the alkaloids on intravenous injections in etherised cats. There was
little difference in the action of the three stereoisomeric forms of tetrahydropalmatine.
REFERENCES
(1) (a) Arch. Pharm., 1902, 240, 19 ; (6) ibid., 1927, 265, 675 ; (c) Canad. J. Res.,
various papers, 1933-36. (2) WACKENRODER, Berz. Jahrb.-, 1826, 7, 220 ; W I C K E ,
Annalen, 1866, 137, 274. (3) Inaug. Diss. Dorpat, 1888. (4) J. Chem. Soc, 1892, 61,
244. (5) Annalen, 1893, 277, 1. Cf. ZIEGENBEIN, Arch. Pharm., 1896, 234, 492 ;
MARTINDALE, ibid., 1898, 236, 214. (6) D O B B I E and LAUDER, J. Chem. Soc.,
1902,
81, 145 ; 1903, 83, 605. Cf. H A A R S , Arch. Pharm., 1905, 243, 165. (7) D O B B I E and
MARSDEN, J. Chem. Soc, 1897, 71, 665. (8) Ibid., 1924, 125, 632. (9) Arch.
1905,
243,
165.
(10)
D O B B I E and
L A U D E R , J.
Chem. Soc,
1899,
75, 670;
Pharm.,
cf.
PERKIN,
ibid., 1890, 57, 1027. (11) Ber., 1925, 58, 1274. (12) J. Chem. Soc, 1934, 1263.
(13) SCHMIDT, Arch. Pharm., 1896, 234, 4 8 9 ; HAARS, ibid., 1905, 243, 165. Cf.
D O B B I E and
MARSDEN, J.
Chem. Soc,
1897,
71,
659.
(14)
GADAMER and
WAGNER,
KLEE,
(16) Ber., 1921, 54, 3074 ; cf. GADAMER, Arch. Pharm., 1915,
253,
295.
274;
1916,
254,
(17)
Ibid.,
1921,
259,
246;
cf.
KOEPFLI
and
PERKIN,
J. Chem. Soc, 1928, 2989. (18) Annalen, 1923, 433, 138. (19) Arch. Pharm., 1923,
261, 31 ; (with STIPPLER), ibid., 1927, 265, 152. (20) FREUND et at, Annalen, 1913,
397, 1 ; 1915, 409, 188 ; 1916, 411, 1. (21) Ber., 1929, 62, 1024. (22) Annalen, 1893,
277, 1. (23) BUUNS, Arch. Pharm., 1901, 239, 39 ; 1903, 241, 634. (24) J. Chem.
Soc, 1901, 79, 87. (25) Arch. Pharm., 1902, 240, 19. (26) (With SAWAI), ibid., 1925,
263, 602 ; (with STIPPLER), ibid., 1927, 265, 152. (27) (With SAWAI), ibid., 1926, 264,
401.
(28) Ber.,
1926,
59, 2800.
J.
Res.,
1936,
B , 14,
347,
354 ; 1938, B , 16, 81, 153 ; 1939, B , 17, 89 ; 1940, B , 18, 414 ; 1943, B , 21, 111.
(29) KNORCK, Inaug. Diss. Marburg, 1926. (30) Arch. Pharm., 1927, 265, 675.
(31) SPATH and MOSETTIG, Ber., 1927, 60, 383.
162;
1910,
248,
220;
1903,
241,
318.
(35)
Ber.,
(33)
Ibid.,
1905,
1926,
59,
1496.
(36)
SPATH
(with LEITHE), ibid., 1930, 63, 3007 ; (with KRUTA), Monats., 1928, 50, 341. (37) J.
Chem. Soc, 1927, 2261. (38) Ber., 1931, 64, 1131. (39) KITASATO, Proc Imp. Acad.
Tokyo, 1926, 2, 124. (40) J. Chem. Soc, 1926, 1780; ibid., 1927, 548 (footnote).
(41) Ber., 1929, 62, 1029.
and
W A T K I N S , Ber.,
1902,
Pharm.,
Res.,
1939,
(43) SCHLOTTERBECK
B , 17, 89 ; 1942,
B,
Pharm.,
(45) ANDERSON
and
Cryptopine Sub-Group
This series of ten alkaloids may appropriately be called the cryptopine
sub-group, since the characteristic nuclear structure of the type was
first made clear by Perkin's investigation of cryptopine. They are closely
related to the proioberberines, with which they are interconvertible by two
characteristic reactions, which have been of great value in their investigation. The two alkaloids formerly known as fi- and y-homochelidonines
have now been renamed a- and j8-aKocryptopines respectively to distin-
CRYPT OPINE
295
296
TSOQUINOLINE
GROUP
The formation of (A) and (C) indicates that cryptopine must have in
its structure the grouping I, whilst the production of (B) and (D) shows
that the alkaloid must also contain the piperonyl ring in the form of
grouping II, and from these the structure of anhydrotetrahydromethylcryptopine is represented by formula I I I :
cx;
HeO (/
MeO
(I)
PH,
(ID
mV
KeoX\.CH:CH_-/^
A;o
Meol
j|.CH:CHg \ = /
|
wS/
Me
CBTPTOPINE
O-CO-OH,
j
2
1II
C-CHg-CHg-HMe-CHg-C
JJeO/^
I
*"\I
JO
MeoL
297
"C-CHOH-CH*z
"
8 ""3 '
C-OHg-CHg-lOle-CHg-0,
0 CHa
0CH,
Cryptopine
Plhydrocryptoptne
./s
)IeO ^
W
MeOl
OH CH5
2
0'
p-CHj-OHg-:
C-CHg-CHg-raieCl-CHjrC
0
Cug
IsoDlhydrocryptoplne chlorides
Anbydrodlhydrocryptopine
OMe
A <
N-Methyllsotetrahydroperterlnes
>B
(p. 337) have been added, to illustrate the parallelism between the two
series.
This parallelism between the derivatives of berberine and cryptopine
was fully investigated by Perkin in two particularly interesting directions.
The formulae assigned to the two parent alkaloids and to the chlorides of
isocryptopine and berberinium, represent cryptopine as related to an
alkaloid isomeric with berberinium hydroxide, which Perkin named
epiBERBERiNE, and which he prepared by de-iV-methylating isocryptopine
chloride, producing dihydroanhydroe^nberberine, which closely resembles
dihydroanhydroberberme, and from which eptberberine can be obtained by
the action of mild oxidising agents such as iodine or mercuric acetate 9 .
The reverse change, viz., the conversion of berberine derivatives by
AT-methylation into substances constituted similarly to corresponding
derivatives of cryptopine, was achieved by the methylation of dihydroanhydroberberine, to the methochloride, which corresponds to isocryptopine chloride and resembles it closely in character and reactions. 10
From this a number of new substances closely resembling the corresponding cryptopine derivatives have been prepared.
298
isoQUINOLINE
GROUP
Berberlnlum chloride
lsoCryptoplne chloride
eplBerherlnlum hydroxide
ITni)
(a)
PROTOPINE
299
300
isoQUINOLINE
GROUP
H2CV
0
(n)
^-ca^-rcg-ii-co-c
N
^
0
CH-CHg-0
a |
(III)
\
(IV)
C-
ITI)
o I
^C-CHg-CHg-MlatOhCHg-O
(V)
I c
-OHCHo
C
2
CI
II C
O-CHg-CHg-MMeOl-OHg-O
I
-OHCH-
^C-CHjj-CHa-N-CHjr^
- CHCB0
IC-CHg-CHg-NKe-CHg-C
CH,
PROTOPINE
301
the partial formulae (I) to (VI) used in the following brief description of
Haworth and Perkin's synthesis of protopine. 18
The process used is analogous .with that adopted for the synthesis of
cryptopine (p. 298). The methyl ester of iV-/?-piperonylethyl-3 : 4-methylenedioxyAowiophthalamic acid (I), was treated with phosphoryl chloride
and so converted into 2:3:9:10-&smethylenedioxyoxyprofoberberine
(II), which was reduced electrolytically to 2 : 3 : 9 : lO-fo'smethylenedioxytetrahydroprofoberberine (III), of which the methochloride (IV) is
identical with wodihydroprotopine chloride, which can be prepared from
protopine as already stated above.
This substance under the action of alkali passed into anhydrodihydroprotopine A, C20H19O4N, m.p. 120 (V), the amine oxide (VI) of which
rearranges into protopine by the action of acids.
Ochrobirine, C20H18O6N(OH), CH3OH. (Items 15,20, 26 ; list, p. 171.)
The base has m.p. 138-9 or 198 (dry), [a]2,1" + 35-9 (CHC13), and yields
a monoacetyl derivative, m.p. 177. On treatment with zinc-amalgam in
dilute acid it changes into an isomeric base, m.p. 238. As ochrobirine
gives colour reactions similar to those of protopine, Manske suggests that
it may be 13-hydroxyprotopine, i.e., a hydroxyl in the methylene group
contiguous to the carbonyl group.18'"'
a- and /5-aZZoCryptopines (/?- and y-Homochelidonines). These alkaloids,
now known to be stereoisomerides, have been recorded from a number of
plant genera (a-form : items 1, 4, 5, 6, 7, 9, 10, 11, 21, 24, 28, 32, 35, 39,
43, 46, 49, 60 ; ,8-form : items 6, 7, 43, 60 ; list, p. 169). An exceptional
occurrence of /2-aZZocryptopine is that in Zanihoxylum brachyacanthum
F. Mull (Rutacese).19 The two alkaloids were first separated by Schmidt,
Koenig and Tietz 20 ; their results were confirmed by Schmidt and Fischer 21
and by Schmidt and Wintgen,22 who showed that the two were interconvertible physical isomerides.
oc-aZZo-Cryptopine, C 21 H 23 0 5 N, crystallises from acetic ether in monoclinic prisms, m.p. 159-60, and is readily soluble in chloroform or acetic
ether, less so in alcohol. The hydrochloride, B . HC1. 1JH 2 0, forms
colourless needles, and is readily soluble in water; the nitrate, hydrobromide and hydriodide are also crystalline; the platinichloride,
B 2 . H 2 PtCl 6 . 2|H 2 0, is amorphous, but the aurichloride, B . HAuCl4,
m.p. 187, forms blood-red crystals. The alkaloid dissolves in sulphuric
acid, forming a yellow solution changing to violet- and carmine-red. It
is a tertiary base, yields two methiodides, m.p. 185 and m.p. 211, and
contains two methoxyl groups.
/?-aZZo-Cryptopine, C 21 H 23 0 5 N. This form crystallises with mol. of
alcohol in colourless needles, m.p. 170-1 (dry), [a] D 0. The hydrochloride, B . HC1. 1|H 2 0, forms small colourless needles, m.p. 175" (dec),
and the aurichloride, B . HAuCl4, blood-red, warty crystals, m.p. 192
(dec.); the latter is said to be identical with the aurichloride of the a-form.21
The methiodide, B . CH 3 1. 2 JH 2 0, forms yellow prisms ; the alkaloid is
a tertiary base and contains two methoxyl groups, a methylenedioxy
group and a methylimino group. 19
902
TSOQVINOLINE
GROUP
CORYCAVINE
303
used by Perkin for cryptopine (p. 295) eventually yields 4-methoxy-8ethoxy-o-toluic acid, m.p. 175, whence it is concluded that hunnemannine
is a-aMocryptopine with the methoxyl group at position C9 replaced by
hydroxyl.23'0'
Corycavine, C21H2105N. (Item 31, list; p. 172.) This alkaloid was
isolated by Freund and Josephi, 24 and was subsequently examined by
Gadamer, Ziegenbein and Wagner,25 Gaebel,26 Legerlotz 27 and Gadamer
and von Bruchhausen. 28 It crystallises from hot dry alcohol in rhombic
tablets, m.p. 217-8 or 221-2 (in a vacuous tube), [a] D 0, and is
insoluble in water, cold alcohol or alkalis. The hydrochloride, B . HC1,
forms needles, m.p. 219 ; the hydriodide, B . H I . H 2 0, small yellowish
needles, m.p. 236; the platinichloride, (B . HC1)2. PtCl 4 , yellowish
crystals, m.p. 214 (dec.); the aurichloride, B . HAuCl4, has m.p. 178-9
(dec). Corycavine forms a methiodide, rhombic tablets, m.p. 218 ; and
behaves as a tertiary base containing a methylimino-group. It contains
two melhylenedioxy groups, 26 but no hydroxyl or methoxyl. The alkaloid
dissolves in sulphuric acid, giving a dirty green solution changing to reddish
violet, and in nitric acid, producing a greenish-yellow colour passing into
orange-red.
Corycavamine, C21H2105N, was first obtained by Gadamer, Ziegenbein
and Wagner 25 and can be purified by recrystallisation of the nitrate from
boiling water. The free base forms rhombic columns, m.p. 149, [a]2,0"
+166-6 (CHC13).
The hydrochloride and hydriodide crystallise in
needles, but the platinichloride is amorphous. The alkaloid contains
two methylenedioxy groups, but no methoxyl. When corycavamine is
melted it is converted into corycavine. Both alkaloids give the same
colour reactions, yield the same methine base, m.p. 153, and are believed
to be stereoisomeric.
Corycavidine, C22H2505N, was isolated by Gadamer.29 It crystallises
from hot chloroform with one molecule of the solvent, melts at 212-3, has
[ a ] f + 203-1 (CHCI3), and yields a crystalline hydrochloride and nitrate,
and an amorphous red aurichloride, m.p. 170 (dec.). It contains two
methoxyl groups, one methylenedioxy-group and a methylimino-group and
behaves as a tertiary base on exhaustive methylation. When heated at
209, it is converted into an inactive modification, m.p. 193-5. Corycavidine gives with sulphuric acid a yellow colour, becoming grey and
finally greenish on warming.
Constitution of Corycavine, Corycavamine and Corycavidine. The
constitution of corycavine was first investigated by Gadamer and von
Bruchhausen, 30 who altered the formulas, C 23 H 23 0 5 N and C 23 H 23 0 6 N,
previously suggested for the alkaloid, to C 21 H 21 0 5 N as now accepted, and
thereby made clear its isomerism with corycavamine, and accounted for its
formation from the latter by simple fusion. They also showed that on
treatment with phosphoryl chloride, corycavine yielded isocorycavine
chloride, C^H^C^NG . 3H 2 0, thick, reddish-yellow needles. On reduction
the alkaloid furnished dihydrocorycavine, C a H 2 3 0 6 N, m.p. 205-6, which
like the unreduced base is converted by phosphoryl chloride into a
304
isoQUINOLINE
GROUP
PHABMACOLOOICAL
ACTION
305
by the methods due to Freund and Fleischer 33 for the production of 4methyldihydroberberine, and to Gadamer for the reduction of the latter
and subsequent conversion to the anhydro-base (cf. p. 337). von Bruchhausen 3 1 also found that corycavidine methosulphate is reduced by
sodium amalgam in dilute sulphuric acid to tetrahydromethylcorycavidine,
C23H3105N (oil: [a.]f + 39-9 (CHC13); B . HC1, m.p. 190), which on
evaporation in dilute hydrochloric acid yielded the corresponding anhydrobase, C 23 H 29 0 4 N (III) with O . CH2 . O replaced by 20Me in ring c), oil;
B . HC1, m.p. 233-5. The latter on oxidation by potassium permanganate
in acetone furnished 2-methyl-3 : 4-dimethoxyacetophenone (as I with
20Me in place of . O . CH 2 . O) and iV-methylhydrastinine (II). On the
basis of these two main reactions and with the support of a number of minor
observations von Bruchhausen assigned formula (VII) to corycavidine.
Pharmacology. Though these alkaloids have not been compared
pharmacologically as members of the same group, considerable resemblance
in action is traceable in the results recorded for those that have been
examined. Cryptopine depresses the higher centres, and finally causes
spinal paralysis in frogs ; the heart is also slowed or stopped in diastole.
In mammals the drug causes convulsions without increased reflex excitability. Respiration is first stimulated then diminished.34 Beginning
with Heathcote, 34 more attention seems to have been given to the general
pharmacology of cryptopine and especially to its action on smooth muscle,
in which respect, according to Heathcote, it resembles papaverine but is
much weaker. Mereier, Delphaut and Blache 34 have compared the action
of cryptopine with those of papaverine and berberine and find that all
three alkaloids in sub-lethal doses, show similar effects on arterial blood
pressure, respiration and heart; on the intestine, isolated or in situ, and
on the vegetative nervous system, berberine and cryptopine behave alike,
but papaverine shows differences. On the whole cryptopine stands between
papaverine and berberine but is in general closer to the latter in action.
Protopine in small doses has a narcotic action in frogs, while large doses
abolish reflex activity and show a curare-like action. At times there is
evidence of medullary stimulation. According to Bolm 35 large doses
(18 to 200 mgm. per kilo) given parenterally to experimental animals
induce excitement or convulsions. Small doses slow the heart, lower
blood pressure and have a quieting effect. Protopine has an inhibiting
action on isolated frog heart, muscle or nerve and a stimulating action on
guinea-pig intestine. According to Anderson and Chen,35 the L.D.50
(mgm./kilo) for protopine hydrochloride by intravenous injection in mice
is 35-9 1-90. For cryptopine Delphaut and Blache 34 record the m.l.d.
of the hydrochloride as 190 mgm./kilo, for subcutaneous injection in
guinea pigs.
Peters's results for corycavine and corycavamine indicate that these
two alkaloids produce narcosis in frogs followed by paralysis of the spinal
cord, and in mammals increased secretion of tears and saliva and epileptiform convulsions without increase of reflex irritability ; they also adversely
affect the heart. 8 *
306
isoQUINOLINE
GROUP
KOLLMAR, Arch. Pharm., 1923, 261, 153 ; OSADA, J. Pharm. Soc. Japan, 1927, 547, 100.
(18) HAWORTH and P E R K I N , J. Chem. Soc, 1926, 1769 ; for related synthetical experiments, see STEVENS, ibid., 1927, 178 ; 1935, 663. (18a) Can. J. Res., 1936, B , 14, 354 ;
1939, B , 17, 89. (19) JOWETT and PYMAN, J. Chem. Soc, 1913, 103, 291. (20) Arch.
Pharm., 1893, 231, 1 3 6 ; cf. SCHMIDT and SELLE, ibid., 1890, 228, 441. (21) Ibid.,
1901, 239, 409, 421. (22) Ibid., 438. (23) Ibid., 1919, 257, 2 9 8 ; 1920, 258, 148.
(23a) MANSKE, MARION and LEDINGHAM, J.
Amer.
Chem.
Soc,
(24) Annalen, 1893,277, 1. (25) Arch. Pharm., 1896,234, 528 ; 1902,240,19. (26) Ibid.,
1910, 248, 207. (27) Ibid., 1918, 256, 161. (28) Ibid., 1921, 259, 247 ; 1922, 260, 97.
(29) Ibid., 1911, 249, 30. (30) Ibid., 1922, 260, 97. (31) VON BRUCHHAUSEN, ibid.,
1925,263,584. (32) Ber., 1927,60,1891. (33) Annalen, 1915,409,188. (34) SCHRODER,
Arch. exp. Path. Pharm., 1883, 17, 1 4 0 ; ZUTZ, ibid., 1897, 38, 4 0 8 ; MUNK, Diss.
Berlin, 1873 ; and SIPPEL, Diss. Marburg, 1874, quoted by STARKENSTEIN, Heffter's
Handb., 1924, 2, 2,1012 ; HEATHCOTE, J. Pharm. Exp. Ther., 1925, 25, 35 ; MERCIER,
et at, Compt. rend. Soc. biol., 1938, 127, 554, 1018, 1022 ; LUDUENA, Rev. Soc. Argent,
biol, 1938, 14, 339. (35) VON E N G E L , ^4rcft. exp. Path. Pharm., 1890, 27, 49 ; MEYER,
ibid., 1891, 29, 420, 4 3 8 ; B O L M , ibid., 1940, 195, 3 0 4 ; ANDERSON a n d CHEN, Fed.
Proc, 1946, 5, 163. (36) Arch. exp. Path. Pharm., 1904, 51, 130. (37) Ibid., 1892,
29, 397. (38) VON ENGEL, quoted by SCHMIDT, Arch. Pharm., 1893, 231,143. (39) For
other information on cryptopine and protopine, see H A L E , Amer. J. Physiol., 1909, 23,
389,408 ; MEISSNER, Biochem. Zeit., 1916,73, 236; L A BARRE, Arch. int. Pharmacodyn.,
1924, 28, 429.
Aporphine Sub-Group
Bulbocapnine, C 19 H 19 0 4 N. (Items 14,27,31,33; list, pp. 170-2.) This
alkaloid, first isolated by Freund and Josephi, 1 crystallises from dry
alcohol in rhombic needles, m.p. 199, [a] D + 237-1 (CHC13), is soluble in
alkalis (developing a green coloration), and is re-precipitated by carbon
dioxide. The hydrochloride forms needles, m.p. 270 {dec.); the platinichloride is crystalline, m.p. 200 and 230 (dec). The methiodide forms
brilliant needles, m.p. 257. The phosphate is the salt used injpaedicine.
The base dissolves in sulphuric acid with an orange-red colour changing
slowly to violet, and gives a reddish-brown colour with nitric acid. After
BULBOCAPNINE
307
CH2
NMe
C0,H
C02H
MeO
H,C 0
H,C 0
reduction with zinc dust in strongly acid solution gave 2'-amino-3': 4'dimethoxy-6 : 7-methylenedioxy-l-benzyl-2-methyltetrahydrowoquinoline
(dihydrochloride, glistening prisms, m.p. 231 (dec.)) represented by formula
(IX), and in this the phenanthrene ring closure was effected by diazotisa-
308
isoQUINOLINE
GBOUP
CORYTUBERINE
309
and in the other at C5. To determine which was which Spath and Berger
demethylenated bulbocapnine methyl ether (IV, p. 307, HO replaced by
MeO) producing the phenolic base (XII), C 1 8 H 1 9 0 4 N. MeOH, m.p. 118120. This, on partial methylation, yielded corydine and since (1) methylalation must have taken place in ring (D), and (2) corytuberine (XI) on
methylation yields corydine, the latter must be represented by formula
( X I I I ) ; and since the monomethylation of corytuberine also gives rise to
isocorydine, this in turn must be represented by formula (XIV).
(X)
OUs
(XI)
OMe
(XV)
OMe
(XIII)
OMe
(XII)
OH
(XIV)
OMe
310
isoQUINOLINE OBOUP
needles, m.p. 243 (dec), [a]D + 196. These figures are in good agreement
with those recorded by Gadamer.12 The d-hydrogen tartrate of the /-form
also melted at 219-21 (dec), and had [<x]D 148-2. A similar synthesis
was effected by Spath and Hromatka 18 in the same year.
Eximidine, C17H14ON(OMe)s. (Item 36; list, p. 172.) A phenolic base,
m.p. 133, yielding a methiodide, m.p. 218 (dec). It is isomeric with
corydine and possibly belongs to the aporphine group (Manske).19
REFERENCES
(1) Annalen, 1893, 277, 10. (2) Arch. Pharm., 1902, 240, 81. (3) J. Chem. Soc,
1903, 83, 612. (4) Arch. Pharm., 1911, 249, 503, 598. (5) Ber., 1928, 61, 322. (6) J .
Chem. Soc, 1928, 1132. (7) Ber., 1928, 61, 1334. (8) Arch. Pharm., 1893, 231, 131.
(9) Ibid., 1902, 240, 9 4 ; 1911, 249, 503, 641, 669. (10) GADAMER, ibid., 1911, 249,
669. (11) J. Chem. Soc, 1893, 63, 485. (12) GADAMER, Arch. Pharm., 1911, 249, 641.
(13) Ber., 1931, 64, 2038. (14) J. Chem. Soc, 1911, 99, 2114. (15) (With OBERLIN
and SCHOLLER), Arch. Pharm., 1925, 263, 81. (10) J. Chem. Soc, 1926, 1987 ; cf. 1914,
105, 1456. (17) Ibid., 1928, 1834. (18) Ber., 1928, 61, 1692. (19) Can. J. Res., 1933,
8, 592.
Dicentrine, C20H21O4N. (Items 36, 37, 39, 40 ; list, pp. 172-3.) This
alkaloid crystallises, from ether, alcohol, or ethyl acetate in prisms,
m.p. 168-9 [<x]D +62-1 (CHC13), and yields well-crystallised salts. It
contains two methoxyl groups and yields a monoacetyl derivative, colourless leaflets, m.p. 202, which is not hydrolysed even by boiling alcoholic
potash. 1 The methiodide, B . CH 3 I. H 2 0, has m.p. 224, and according
to Manske,2 yields a methine base, m.p. 158-9, the methiodide of which
with potassium hydroxide solution decomposes into trimethylamine and
a crystalline substance, presumably a substituted phenanthrenyl-ethylene,
which polymerises on recrystallisation.
Dicentrine was synthesised by Haworth, Perkin and Rankin from
6'-nitroveratrylhydrohydrastinine 3 (I) buff-coloured needles, m.p. 118,
which was reduced to 6'-aminoveratrylhydrohydrastinine (II) (oil:
dihydrochloride, prisms, m.p. 250 (dec.) ) , and the latter diazotised in
presence of copper powder (Pschorr reaction) to dZ-dicentrine (III). The
synthetic alkaloid forms colourless prisms, m.p. 178-9; and yields
crystalline salts, hydrochloride, m.p. 263-5 (dec); methiodide, m.p. 2289 ; picrate orange prisms, m.p. 188-9. Like the natural alkaloid it
dissolves in sulphuric acid to a colourless solution which soon becomes
reddish-violet, and gives green to blue colours with Erdmann's, Frohde's,
and Mandelin's reagents. This synthesis confirms the formula suggested
by Gadamer 4 for dicentrine, from data recorded by Asahina 1 and the
similarity of dicentrine to glaucine. The synthetic dZ-base was subseC
.o/V ' %/T
GLAUCINE
311
Glaucine, C21H2504N. (Items 28, 31, 36, 37, 39, 47, 48 ; list, pp. 172-3.)
This substance was isolated by Probst, 1 but was first prepared in a pure
state by R. Fischer.2 It crystallises in yellow, rhombic prisms, m.p. 119120, [a] D + 113-3 (EtOH), is readily soluble in alcohol or chloroform and
sparingly so in benzene or hot water. The hydrochloride, B . HC1 . 3H 2 0,
forms colourless crystals, and the hydrobromide, B . HBr, pale pink
crystals, m.p. 235. The alkaloid itself is tasteless, but the salts are
bitter. Glaucine dissolves in sulphuric acid, forming a colourless liquid
which becomes bright blue on standing or violet when warmed. Nitric
acid gives a transient green tint; Frohde's reagent (sulphomolybdic acid
in sulphuric acid) yields a green passing into blue. Glaucine behaves as a
tertiary base and contains four methoxyl groups. It was synthesised by
Gadamer 3 by treating a diazotised solution of aminolaudanosine (I)
with copper powder, when ' phenanthreno-N-methyltetrahydropapaverine,'
which proved to be dZ-glaucine (II), was formed, thus :
/ \ A /\H3
OH3O.C \
\H2
/ \ A A0*3
OH O./ Y
>
zV
3
CH.0.C
\z rv > \ / v v
CH 3 0.(5
C.NH 0
OHjO.O
ID OHjoVo
OH
CH
OH3O.O
OH
i i
OH
( n ) CHgoV*^
312
isoQUINOLINE
GROUP
249,
REFERENCES
(2) Arch. Pharm.,
1904,
37, 1926.
(4)
(3) GADAMER,
WAHNAT, Ber.,
1925,
58,
2768 ; BARGER et al., J. Chem. Soc.,1928, 2919 ; Ber., 1933, 66, 450. (5) GADAMER,
Arch. Pharm., 1914, 252, 211. (6) MANSKE, Can. J. Res., 1933, 8, 5 9 2 ; 1938,
B, 16, 81.
PHARMACOLOGICAL
ACTION
313
administration of amphetamine, but when the two drugs are given in the
reverse order the antagonistic effect is slight.8 In monkeys the condition
was prolonged by convulsions induced by leptazole, but hypoglycemic
shock produced by injection of insulin had no effect on the catalepsy. 9 The
results of earlier investigations of the catalepsy induced by bulbocapnine
have led to the use of the alkaloid in medicine,10 especially in the treatment
of diseases in which involuntary movement is a symptom as in Paralysis
agitans and St. Vitus' dance.
Glaucine causes slight narcosis in animals, interrupted by epileptiform
convulsions. I t is also a depressant of the heart and blood vessels and
damages striated muscle. According to Iwakawa,1X small doses of dicentrine
have a narcotic action in frogs and mammals. Larger doses cause convulsions of medullary origin in frogs. The convulsions in mammals arise
from centres above the cord. The heart and vasomotor centre are also
damaged in mammals, while the respiratory centre is stimulated transitorily before being paralysed.
REFERENCES
(1) Arch. exp. Path. Pharm., 1904, 51, 130; GADAMER, Arch. Pharm., 1905, 243,
150. (2) J. Pharm. exp. Ther., 1936, 56, 85 ; 1938, 62, 16. (3) Ibid., 1934, 50, 100 ;
1935, 55, 40. (4) YAMAO and OKUSHIMA, Jap. J. med. Sci., 1941, [ivj, 14, 4 3 ; O P P E N HEIMEK, G L Y E R a n d HAMILTON, Proc. Soc. exp. Biol. Med., 1942, 5 1 , 7 9 ; MOLITOR. 2
(5) AOYAMA, Mitt. med. Ges. Okayama, 1939, 51, 576, 1278 ; 1938, 50, 2085 ; see also
FRIEDERICI, Arch, ges. Physiol., 1944, 248, 51. (6) Mitt. med. Ges. Okayama, 1939,
51, 804, 814, 1019 ; Arb. med. Fak. Okayama, 1939, 6, 279. (7) Arch, nierland.
Physiol., 1938, 23, 254 ; see also VEHARA, Jap. J. med. Sci., 1940, [iv], 12, Proc, 8 6 ;
DERYATIN, J. Physiol.
U.R.S.S.,
exp.
Ther., 1941, 73, 375 ; K O K , VAN HARREVELD and WATERMAN, Acta brev. neerland.
Physiol., 1938, 8, 90. (8) SPIEGEL, J. Pharm. exp. Ther., 1938, 63, 438. (9) K E N N E D Y ,
J. Neurol. Psychiat., 1939, 2, 115 ; 1940, 3, 27 ; OTTAVIANO and PAPPALARDO, Boll.
Soc. Hal. biol. sper., 1946, 22, 1082. (10) See, for example, SCHALTENBKAND, et al.,
Pflager's Archiv., 1925, 209, 623, 643, 653, 6 6 4 ; Klin. Woch., 1924, 45, 2 0 4 5 ;
FLEISCHHACKER, Deut. med. Woch., 1926, 52, 352 ; AMADON and CRAIG, J.
Pharm.
exp. Ther., 1935, 54, 3 3 4 ; BRtrcKE, Arch. exp. Path. Pharm., 1935, 179, 504; 1936,
182, 3 2 4 ; RAYMOND-HAMET, Compt. rend., 1936, 202, 357. (11) Arch. exp. Path.
Pharm., 1911, 64, 3 6 9 ; cf. W A U D , J. Pharm. exp. Ther., 1936, 58, 332.
MINOR CORYDALIS ALKALOIDS. The following four alkaloids have been
isolated by Manske from various Corydalis species but have not yet been
assigned to chemical groups. Cularine has been compared pharmacologically with papaverine and hydrastine, and may prove to be related
to one of these alkaloids.
Chrycentrine, C lg H 15 0 6 N (item 3 4 ; list, p . 172), m.p. 216, nonphenolic, contains a dioxymethylene, but no methoxyl groups. 1
Cularine, C17H14ON(OMe)3 (items 12, 35, 36, 37, 39; list, pp. 170-2),
m.p. 115, [a]|5 + 285 (MeOH), yields a sparingly soluble acid oxalate,
m.p. 245 (dec), and a hydrochloride, m.p. 207. In Dicentra eximinia
it is accompanied by a non-phenolic base, F 30, C18H12ON(OMe)8, m.p. 102,
which is probably -W-demethylcularine. In Corydalis claviculata it is
associated with one or'more O-demethylcularines (F52) of which one,
eularidine, j7H14ON(OH)(OMe)a (item 3 5 ; list,^). 172), m.p. 157, has
314
JBOQUINOLINE
GROUP
RCEMEBINE
315
1940, [v], 7, 70 ; c/. BARGER and WEITNAUER, Helv. Chim. Acta, 1939, 22, 1041 ;
MARION and GRASSIE, J. Amer. Chem. Soc, 1944, 66, 1290.
316
JSOQUINOLINE
GROUP
ANOLOBINE
1939, 51, 1447. (6) J. Pharm. Soe. Jap.,
ef. SHDSTA, ibid., 1927, N o . 544, 79.
317
(IV) Roenerlna
(V) Anolobine
(VI) Artabotrine
318
JBOQUINOLINE
GROUP
SUAVEOLINE
319
320
VioQUINOLINE
GROUP
LAUROTETANINE
321
/?-3': 4'-dimethoxyphenylethylamide (IV), m.p. 160, to 6 : 7-dimethoxyl-6'-nitro-4'-methoxy-3'-ethoxybenzyl-3 : 4-dihydrowoquinoIine, m . p . 1 7 4 5, of which the ethiodide, m.p. 207 {dec), was reduced to the corresponding aminotetrahydroisoquinoline (V), and (b) ring closure in the
latter by successive t r e a t m e n t with sodium nitrite, 2iV-sulphuric acid and
zinc dust and hydrochloric acid, into 3 : 5 : 6-trimethoxy-2-ethoxy-iVethylrtoraporphine (III) isolated as the hydriodide, m.p. 205-10 (dec),
which is identical with OA r -diethyllaurotetanine hydriodide. The Hofmann
degradation of both products leads to 3 : 5 : 6-trimethoxy-2-ethoxy-8vinylphenanthrene, m . p . 142. Spath and Tharrer, 9 by exhaustive
methylation of laurotetanine ethyl ether, obtained a trimethoxyethoxyvinylphenanthrene, m . p . 136-8 (cf. Barger et al., loc. cit.), which was
oxidised to the corresponding acid, m . p . 222-3, and this on decarboxylation furnished a trimethoxyethoxyphenanthrene, m.p. 114-6, identical
with 3 : 5 : 6-trimethoxy-2-ethoxyphenanthrene (VI) synthesised for
comparison. The hydroxy group in laurotetanine, which is ethylated in
this group of substances, m u s t therefore be in position 2.
./V-Methyllaurotetanine, C 20 H 23 O 4 N. This alkaloid was obtained by
Spath and Suominen 10 from Litsea citrata. I t distils a t 205-15 (air-bath
temperature) under a pressure of 0-01 m m . and is dextro-rotatory. Diazom e t h a n e converts it into glaucine and Hofmann degradation of t h e ethyl
ether yields 3 : 5 : 6-trimethoxy-2-ethoxy-8-vinylphenanthrene, m . p . 140-1,
identical with t h a t obtained from laurotetanine (see above). The alkaloid
is therefore represented by formula I I (NMe replacing N H ) .
REFERENCES
(1) Ber., 1890, 23, 3537. (2) Arch. Pharm., 1898, 236, 601. (3) Bull. Jard. bot.
Buitenzorg, 1921, [iii], 3, 180 (Chem. Soc. Abstr., 1921, [i], 587). (4) BARGEK and
SIL^BERSCHMIDT, J. Chem. Soc, 1928, 2919 ; SILBERSCHMIDT, THESIS, Edinburgh, 1926.
(5) SPATH and STRAUHAL, Ber., 1928, 61, 2395. (6) J. Chem. Soc, 1929, 658. (7) Ibid.,
1981,2893. (8) Ber., 1933, 66, 450. (9) Ibid., 1933, 66, 583. (10) Ibid., 1933, 66,
1344.
PLANT ALE.
322
isoQUINOLINE
GROUP
LAURELINE
323
MeO
(I) Dlcentrlne
(IV) Laurepuklae
(II) Actinodaphnine
(V) Pukateine
I III) Laurotetanine
(VI) Laureline
324
isoQUINOLINE
OROUP
BOLDINE
325
326
isoQUINOLINE
GROUP
6 - nitro - 4 - methoxy - 3 - ethoxyphenylacet - /5 - 4' - methoxy - 3' - ethoxyphenylethylamide, m.p. 157-5 ( I ; R = OEt) in which ring closure to
(III)
(II)
(I)
7-methoxy-6-ethoxy-l : 6'-nitro-4'-methoxy-3'-ethoxybenzyl-3 : 4-dihydrowoquinoline, m.p. 163-5, was effected, and the methiodide, m.p. 188
{dec), of the latter reduced to 7-methoxy-6-ethoxy-l : 6'-amino-4'-methoxy-3'-ethoxybenzyl-2-methyltetrahydroisoquinoline ( I I ; R = OEt), which
was converted by the Pschorr reaction (diazotisation in presence of copper
powder) to 3 : 5-dimethoxy-2 : 6-diethoxyaporphine (III; R = OEt). This
synthetic dl-iovm being unsuitable for comparison with the diethyl ether
of natural boldine, both were treated with ethyl chlorocarbonate 6 and
sodium hydroxide to produce the substance (IV ; R = OEt) in which the
centre of asymmetry of boldine no longer exists. The two products had
m.p. 114-5 alone or mixed. In view of the close relationship of boldine
and laurotetanine (p. 320) it is interesting to note that Barger and Silberschmidt 7 state that a substance resembling boldine accompanies laurotetanine in Litsea citrata.
REFERENCES
(1) J. Pharm. Chim., 1872, 16, 191. (2) Merck's Jahresb., 1922, 36, 110. (3) Ber.
1925, 58, 2 7 6 8 ; 1926, 59, 85. (4) Ibid., 1933, 66, 904. (5) Ibid., 1933, 66, 988.
(6) Cf. GADAMER and KNOCH, Arch. Pharm.,
501.
PHARMACOLOGICAL
ACTION
327
328
isoQUINOLINE
GROUP
BERBERIS
ALKALOIDS
329
isoQUINOLINE
330
GROUP
ibid., 1927, N o . 542, 4 8 ; Proc. Imp. Acad. Tokyo, 1926, 2, 124. (2) MOLLET and
CHRISTIANSEN, J. Amer. Pharm. Assoc, 1934, 23, 3 1 0 ; H O W E , ibid., 1939, 28, 422.
(3) PERRINS, J. Chem. Soc, 1862, 15, 341 ; GROSS, Amer. J. Pharm., 1873, 14, 193 ;
HOOPER, Pharm. J., 1912, [iv], 34, 482. (4) SCHULTZ, J. Pharm., 1884, [iii], 14, 273 ;
GORDIN, Arch. Pharm., 1902, 240, 146. (4a) VASHISTHA and SIDDIQUI, J. Jnd. Chem.
Soc, 1941, 18, 641. (5) MAHLA, Silliman's Amer. J., 1862, [2], 33, 43 ; P E R R I N S , J.
Chem. Soc, 1862, 15, 340. (6) PERRINS, Pharm. J., 1862, 3, 567. (6a) J. Amer.
Pharm. Assoc, 1943, 32, 1 ; 1944, 33, 205, 210 ; Science and Culture, 1942, 7, 619,
(7) A. G. P E R K I N , J. Chem. Soc, 1897, 71, 1194. (8) ARATA, Rep. Pharm.,
1892, 45.
(9) CROMWELL, Biochem. J., 1933, 27, 860. (10) SCHILBACH, Inaug. Diss. Marburg,
1886 (quoted b y WEIIMER). (11) NEPPACH, Amer. J. Pharm., 1878, 373. (11a) J.
Pharm. Exp. Ther., 1940, 69, 64. (12) OREKHOV, Arch. Pharm., 1933, 271, 323.
(12a) J. Amer. Pharm. Assoc, 1941, 30, 247. (13) GURGUEL, COSTA, DA SILVA, Bull.
Assoc. Brasil. Pharm., 1934, 15, 11 ; JANOT a n d GOUTAREL, Bull. Sci. Pharmacol.,
1941,48,215. (14) KoNDOandToMiTA, ^ircft. PAarTO., 1930, 268, 549. (15) BUCHNER,
Annalen, 1835, 24, 228 ; POLEX, Arch. Pharm., 1836, [ii], 6, 2 6 5 ; WACKER, Vjschr.
prakt. Pharm., 1861, 10, 545 ; H E S S E , Ber., 1886, 19, 3190 ; SCHULZ, J. Amer. Pharm.
Assoc,
1926, 15, 33 ; SPATH (with K O L B E ) , Ber., 1925, 58, 2280 ; (with POI.GAR)
Monats., 1929, 52, 1 1 7 ; VON BRUCHHAUSEN and SCHULZE, Arch. Pharm., 1929, 267,
617. (16) PARSONS, Pharm. J., 1882-83, [iii], 13, 46 ; R U D E L , Arch. Pharm., 1891,
229, 631 ; POMMEREHNE, ibid., 1895, 233, 127 ; GORDIN, ibid., 1902, 240, 146 ; N E U G E -
BAUER and BRUNNER, Pharm. Zeht. 1939, 80, 113, 241 ; Deut. Apolh. Zeit., 1939, 54,
326. (17) CASTRO, SANTOS and VALENZUELA, Univ. Philipp. Nat. appl. Sci. Bull.,
1932, 2, 401. (17a) GREATHOUSE (with WATKINS), Amer. J. Bot., 1938, 25, 743 ; (with
RIGLER) Plant Physiol, 1940, 15, 563. (18) E I J K M A N , Bee trav. Chim., 1884, 3, 197 ;
KITASATO, J. Pharm. Soc. Japan, 1925, No. 5 2 2 , 1 ; N o . 535, 71 ; TAKASE and OHASHI,
ibid., 1926, No. 535, 70 ; MANUWA, SAKAI and K A N , ibid., 1926, No. 536, 80 ; KITASATO
Pharmacol,
TOMITA and T A N I , J. Pharm. Soc. Jap., 1941, 61, 83. (21) P E R R I N S , Pharm. J., 1852,
12, 188 ; STENHOUSE, J. Chem. Soc, 1867, 20, 187 ; VARIER a n d P I L L A I , Curr. Sci.,
1943, 12, 228 ; CHILD and NATHANIEL, ibid., p . 255 (Brit. Chem. Physiol Abstr., 1944,
A . i i i , 1 5 6 ; A.ii, 8 7 ) ; (21a) TasMixetal., Arch. Pharm., 1930,268, 314. (22) GADAMER,
ibid., 1902, 240, 450 ; GORDIN, 1902, 240, 146 ; GUNZEL, 1906, 244, 257 ; F E I S T , 1907,
245, 586 ; SPATH and POLGAR, Monats., 1929, 52, 117 ; SPATH a n d B U R G E R , Ber.,
Soc,
1895,67, 418. (25) MUBAYAMA (with SHINOZAKI), J. Pharm. SQC, Japan, 1926, No. 530,
BERBERINE
331
32 ; (with TAKATA), ibid., 1927, No. 550, 146. (26) DEY and PILLAY, Arch. Pharm.
1933, 271, 477 ; (with DAVID and RAJAMANIKAM), Ind. J. Med. Res., 1935, 22, 765 ;
LOBSTEIN and HESSE, Bull. Sci. Pharmacol., 1931, 38, 157. (27) JOWETT and PYMAN.
J. Chem. Soc, 1913, 103, 291, 825. (28) CHEVALIER and PELLETAN, J. Chim. Med.,
1826, 2, 314; PERRINS, J. Chem. Soc, 1862, 15, 342 ; LA FORGE and BARTHSX, J .
Org. Chem., 1944, 9, 250. (29) LE PRINCE, Bull. Sci. Pharmacol, 1911, 18, 343.
(30) GIACOSA (with MONARI), Gazzetta, 1887, 17, 362 ; (with SOAVE), ibid., 1889, 19,
303 ; cf. PRIESS, Ber. Deut. Pharm. Ges., 1911, 21, 227 ; THOMS, Chem. Zeit., 1910,
34, 1279 ; cf. THOMS, ibid., 1922, 46, 856 ; (with THCTMEN), Ber., 1911, 34, 3717.
332
JSOQUINOLINE
GROUP
HpC.
2<
BERBERINE
339
,c.oCH
A\i
HC,
I
i " SB
^
Js
CH
i k j 4CH
J ( ( 7 SCH2
9 /\8/|\6/
^CH | ^0Hg
HC
II
I
/^/\/\y
CHjO.C^IO
/ \ I
3C.6
CHjOrO
CHjO.O
3
X.O
II
CH
HOHNH
i C_CHg
i CH
C
y\/v/\/
\
/
0H30>C
x\
\
/
0HO C&s
isoQUINOLINE
334
GBOUP
H = C (CHi 2 OB )X: 6 H 2
(ltoO)
9-C.HX "" i
V
2
"
'
T '
6 2^CH=^0H)-CH,-CH,
( V I I ) Ammonium form
(Berberlnlum hydroxide)
. C B = C - ( CH0
LC-H,
2 2
6 2
,/'
(MeO)
?^66Hg^
2
2
CHOH-N-CH.,
(YIII)
CH.,
C a r b i n o l form
IBerberine)
CH=C-(CH20^-C6H2
CH=C-(CH 2 0 2 ).C 6uH 2
|
and ( M e O ) 2 - C 6 H ^
|
CO-N
CH CH 2
E
2
(X)
O
x
v
b
e
r
b
e
r
l
n
e
Dlhydroberberlne
(MeO) -<; 6 H 2
( DC)
/<^<j-<CH22^6H2
-S;H=NCH CH 2
(XII)
neoOxyberterlne
I XH=C-(CH.0).C H
(MeO).-C.H/
|
2 2 |6 2
(XI)
IsoOxyberberlne
MeO
MeO
MeO
CH -CO-CH,
2
o
1X7)
(XIV)
CH -C0-CH 3
(XIII) Berberineacetone
partial formula (XIV) and (XV), and (XII) represents it as a phenolbetaine, a view in harmony with its conversion into methoxyberberinium
iodide by methyl iodide.
Syntheses
of Berberine
BERBERINE
335
336
isoQUINOLINE
GROUP
have been described. Perkin, Ray and Robinson 3S found that the
j3-piperonylethylamide of meconincarboxylic acid (XXI), when heated
at 100 for several hours with phosphoryl chloride yielded a product,
which on reduction with zinc dust in boiling acetic acid formed oxyberberine
(XXII), and since the latter can be reduced to tetrahydroberberine 36
(XVIII), and this in turn oxidised to berberine, the synthesis of oxyberberine is also a synthesis of berberine.
As one outcome of an investigation into methods for the synthesis
of the berberine type of alkaloid by Perkin and his collaborators,37 in the
course of which an extensive series of bases related to, or associated with
berberine, including the interesting " linear" berberine (paraberine),
were prepared, Haworth, Perkin and Pink 38 devised a general method
for such syntheses, of which examples are given under protopine (p. 299)
and cryptopine (p. 295), and which was applied by Haworth, Koepfli
and Perkin 39 to oxyberberine and palmatine (p. 342). For these two
alkaloids it involved the preparation of 3 :4-dimethoxyAo??iophthalic
anhydride, 40 which was condensed with /?-piperonylethylamine and the
resulting phthalamic acid (XXIII), as the methyl ester, boiled with
phosphorus oxychloride, which converted it into oxyberberine (XXII).
The nomenclature and numbering of formulae for berberine and its
derivatives is based on the system adopted by Buck, Perkin and Stevens 41
for the parent substance of the series, >rofoberberine (XXIV). Awe 41
has suggested that tetrahydro^rofoberberine should be called " berbine "
and used as the basis of a system of names for these alkaloids.
Canadine ([-Tetrahydroberberine), C20H21O4N. (Items 3, 28 ; list, p. 328,
and 11, 21, 28, 31 ; list, p. 170.) In 1873, Hale 42 obtained indications of
a third alkaloid in Hydrastis canadensis, which was isolated and named
" c a n a d i n e " by Schmidt and Wilhelm. 43 It forms silky needles, m.p.
133-4, [a] D - 299 (CHC13), or - 432 (CS2), insoluble in water, but
readily soluble in ether. The hydrochloride, B . HC1, and nitrate,
B . HN0 3 , a r e crystalline, lasvorotatory, and slightly soluble in water.
The alkyl halide addition products of canadine exist in two forms, and
as shown later, have received much attention from investigators. The
a-methiodide, C 21 H 24 0 4 NI, crystallises from hot water in prisms, melts
at 220, and re-melts at 250 (dec), the second m.p. being due to conversion
at 230 into the /?-methiodide. The latter forms small prisms, m.p. 264
(dec), from water. Z-a-Canadine methochloride, C 21 H 24 0 4 NC1. H 2 0,
isolated by Jowett and Pyman from Zanthoxylum brachyacanthum F .
Muell. crystallises from dry alcohol in colourless, prismatic needles,
m.p. 262 (con., dec), [a] D 137-0 (H 2 0). The Z-j8-canadine methochloride, C 21 H 24 0 4 NC1. 6H 2 0, crystallises from water in large, colourless,
oblong prisms, m.p. below 100 (air-dry) or 262 (dried at 100), and has
[]D 153-8 (monohydrate, H 2 0). Canadine gives an olive-green colour
changing to brownish-black with sulphovanadic acid, and a similar colour
changing to brownish-red with Frohde's reagent.
Gadamer 44 by fractional crystallisation of dZ-tetrahydroberberine
bromocamphorsulphonate, isolated a laevorotatory alkaloid identical
337
CANADINE
CH
2
O'
)CH0H-C=-C
NH
CHs-CHp
'\^
(A) (^-carbinol ba3e
\ /\
,CH~C=^-
' 1 * 1 -
C
HK-CH5-CH0
2
/ \ 3 / \
^
(B) Tetrahydroberberine
.y Prober
lkoxlae'
\ / ^
C
II
NR
I
C
CH~C=C
I
HR-i
(E) cJanaydro-baae
CH.
N
0
II
c
I
CEUOH-CH,
Z
S
/ \ /
(C) C g -carbinol base
I
\ / \
I
I
CHC-C
I
cuc=c
I
I
\n0
(F) C 2 -enhydro-base
338
isoQUlNOLINE
GROUP
Me OH
1Canadlne
methohydroxlde
Base(a)
dlTetrahydroberberine
methohydroxlde
YVV
A
Basefcl
NMe
""2
BasefM
CH
339
SINACTINE
CH2
Ophlooarplne
CE2
Slnaotine
CKZ
Ohellsnthif ollne
Cheilanthifoline, C17H13N(OH)(OMe)(02H2C).
(Items 11, 24 26;
list, p. 170.) M.p. 184, [a]l - 311 (MeOH). The O-methyl ether has
m.p. 177 and is identical with sinactine. The O-ethyl ether has m.p. 144
and on oxidation with permanganate furnishes 6-methoxy-7-ethoxy-lketo-1 : 2 : 3 : 4-tetrahydrowoquinoline, m.p. 195, indicating that the
hydroxyl group of the alkaloid is at position 2 in the tetrahydroproZoberberine nucleus,5* i.e., cheilanthifoline is 2-O-demethyltetrahydroepiberberine.
Capauridine (cZZ-capaurine), C17H12N(OH)(OMe)4. (Items 9, 16, 17, 22 ;
list, p. 170.) M.p. 208, [a] D 0. On methylation with diazomethane it
yields (ZZ-capaurine O-methyl ether, m.p. 142 (see below).
Capaurimine, C17H12N(OH)2(OMe)3. (Items 17, 22; list, p. 171.)
M.p. 212, [a]|4 287 (CHC13). Diazomethane converts it to capaurine
O-methyl ether, m.p. 152 (see below). It has been shown recently,
(1947),64fal that the two hydroxyl groups are at C 1 and C9.
Capaurine, C17H12N(OH)(OMe)4. (Items 9, 16, 17, 22 ; list, p. 170.)
M.p. 164. Yields an O-methyl ether, m.p. 152, which on oxidation by
iodine to the quaternary iodide, followed by reduction to the tetrahydrobase forms capauridine methyl ether, m.p. 142; capauridine must therefore be dZ-capaurine. Capaurine ethyl ether, C23H29OsN, m.p. 134, on
oxidation furnishes 3-ethoxy-4 : 5-dimethoxyphthalic acid. The methyl
ether on oxidation by potassium permanganate gives hemipinic acid
340
isoQUINOLINE GROUP
-;o/X OMe
HO
OMe
MeO
y\
2
OMe
(I)
CH2
MeoL
CH2
COOH
IcHO
Hfll
OMe
(III
.(IV)
OMe
JcE2
0B2
(III)
BEBBERIS
341
ALKALOIDS
(8) GORDIN a n d
PRESCOTT, ibid., 1899, 237, 439 ; GORDIN, ibid., 1901, 239, 638. Detection of berberine
in plants, ibid., 1902, 240, 146 ; cf. F E I S T , ibid., 1918, 256, 1. (9) Ibid., 1900, 238, 6.
(10) Ibid., 1914, 252, 192. (11) Pharm. Post., 1915, 48, 1. (12) Arch. Pharm., 1917,
255, 497. (13) Pharm. Zeit., 1936, 81, 1416 ; Pharm. Zentr., 1937, 78, 17 ; 1939, 80,
113, 241 ; Apoth. Zeit., 1937, 52, 1038 ; cf. A W E , ibid., p . 1359 ; Sud-deutsch Apoth.
Zeit., 1939, 79, 429 ; see also BROCHMANN-HANSSEN, Pharm. Acta. Helv., 1946, 21, 23.
(14) (Esterr.Bot. Zeit., 1928, 7 7 , 1 . (15) Pharm. Weekbl., 1930, 6 7 , 7 7 ; MARTINI, Chem.
/lfcsZr.,1940,34,8182; 1942,36,6307. (16) Pharm. Weekbl, W6d,73,764. (17) GADAMER,
Arch. Pharm., 1905, 243, 33. (.18) SHEDDEN, Pharm. J., 1900, [iv], 11, 89. (19) For
other reactions, see HIRSCHHAUSEN, Zeit. Anal. Chem., 1885, 24, 157. (20) J. Chem.
Soc, 1889, 55, 63 ; 1890, 57, 992 ; 1910, 97, 305. For earlier work, see W E I D E L , Ber.,
1879, 12, 410 ; SCHMIDT, ibid., 1883, 16, 2589 ; Arch. Pharm., 1892, 230, 287 ; LINK,
ibid., 291. (21) J. Chem. Soc, 1910, 97, 321 ; cf. P E R K I N , ibid., 1890, 57, 1002. (22)
Arch. Pharm., 1901, 239, 648 ; Chem. Zeit., 1902, 26, 291 ; Arch. Pharm., 1905, 243, 31.
Voss a n d GADAMER, ibid., 1910, 248, 43 ; cf. ROSER, Chem. Zeit., 1902, 26, 385;
(23) Monats., 1910, 31, 557. (24) DECKER, Ber., 1903, 36, 2568. (25) J. Chem. Soc,
1911,99,1340. (26) Ber., 1904, 37, 4677. (27) J. Chem. Soc, 1918,113, 503. (28) Ibid.,
1912, 101, 262. (29) Ibid., 1911, 99, 1692. (30) GADAMER, Arch. Pharm., 1905, 243,
42. (31) Compt. rend., 1911, 152, 1102; 153, 3 8 6 ; Ber., 1911, 44, 2480. (32) J.
Chem. Soc, 1917, 111, 905 ; cf. SPATH and KRUTA, Monats., 1928, 50, 341. (33) J.
Chem. Soc, 1924, 125, 1675 ; cf. BUCK, P E R K I N and STEVENS, ibid., 1925, 127, 1462
(34) Ibid., 1924, 125, 1686 ; cf. BUCK and DAVIS, J. Amer. Chem. Soc, 1930, 52, 660.
(35) J. Chem. Soc, 1925, 127, 740 ; cf. FREUNDLER, Bull. Soc chim., 1914, [iv], 15,
465. (36) PERKIN, J. Chem. Soc, 1918, 113, 764. (37) Ibid., 1925, 127, 1434, 1444,
1448,1453; 1 9 2 6 , 3 2 ; 1927,2265,2275; 1929,196; see also (a) CHAKRAVARTI et al.,
Brit. Chem. Abstr., 1933, A, 169 ; 1934, A, 669 ; 1935, A, 94, 767 ; J. Chem. Soc, 1938,
172 ; (b) STEVENS, J. Chem. Soc, 1935, 663. (38) Ibid., 1925, 127, 1709 ; cf. SPATH,
B E R G E R a n d KUNTARA, Ber., 1930, 6 3 , 134 ; L E I T H E , ibid., p . 2343 ; SUGASAWA et al.,
Ber., 1940, 73, 782. (39) J. Chem. Soc, 1927, 548 ; cf. SPATH a n d QUIETENSKY,
Ber.,
1764. (41) Ibid., 1925, 127, 1462 ; cf. A W E , Arch. Pharm., 1932, 270, 156. (42) Amer.
J. Pharm., 1873, 45, 247 ; cf. LERCHEN, Jahresb., 1878, 144 ; and BURT, Pharm. J.,
1875-76, [iii], 6, 467. (43) Arch. Pharm., 1888, 226, 329. (44) Ibid., 1901, 239, 648 ;
Voss a n d GADAMER, ibid., 1910, 248, 43 ; cf. L E I T H E , Ber., 1930, 63, 2343 ; BERSCH
and SEUFERT, Ber., 1937, 70, 1121. (45) Arch. Pharm., 1890, 228, 596, 604. (46) Ibid.,
1892, 230, 287, 291. (47) J. Chem. Soc, 1912, 101, 1220. (48) Ibid., 1913, 103, 817 ;
cf. F R E U N D a n d FLEISCHER, Annalen,
Res.,
1939, 17, 51 ; 1942, 20, B , 57. (50) Bull. Chem. Soc. Jap., 1929, 4, 220. (51) GOTO
and KITASATO, J. Chem. Soc, 1930, 1234. (52) Ber., 1931, 64, 2048. (53) Idem.,
p . 2827.
(54) MANSKE, Can. J. Res., 1936, 14, B , 347, 354 ; 1938, 16, B , 438 ; 1940,
18, B , 100. (54a) J. Amer. Chem. Soc, 1945, 67, 95 ; 1947, 69, 1800. (55) J. Pharm.
Soc
Jap.,
1941, 6 1 , 83.
1941, 18,
041. <57) Ibid., 1940, 17, 289 ; 1942, 19, 238 ; 885 ; J. Amer. Pharm. Assoc,
30, 247. (58) Ibid., 1944, 33, 210 ; Set. and Cult., 1942, 7, 618,
1943,
342
TSOQUINOLINE
GROUP
PALMATINE
343
(XCTTI)
344
isoQUINOLINE
GROUP
PHARMACOLOGICAL ACTION
345
tetrahydroworenine, which is therefore to be regarded as /?-methyltetrahydrocoptisine, i.e., worenine stands in the same relation to coptisine
(p. 344) as dehydrocorydaline (p. 286) does to palmatine (p. 342).
Pharmacological Action. Berberine is moderately toxic to the larger
animals. In the rabbit it causes dyspnoea, cardiac damage, lowered blood
pressure and paresis. Haemorrhages and congestion of the lungs are
found post mortem; renal damage has also been reported. It is said
that berberine is mostly destroyed in animals but in man considerable
amounts appear in the urine after oral administration. The alkaloid has
been recommended 19 for the treatment of oriental sore (cutaneous
leishmaniasis). The chief use in Western medicine has been on account of
its bitter taste, drugs containing berberine, such as barberry bark, being
used as bitter tonics and stomachics. Berberine has some bactericidal
action, 20 and its presence in Mahonia trifoliata and M. Swaseyi is said to
be a factor in the resistance of these plants to a root fungoid disease.21
According to Seery and Bieter,22 it has some trypanocidal action, and
Brahmachari 23 has used it as an adjunct to quinine in the treatment of
malaria.
Canadine is bitter and in small doses causes drowsiness and depression.
In large doses it gives rise to transient excitement succeeded by depression
and paralysis of the central nervous system. Its injection is followed by
violent peristalsis with diarrhoea. It is said to have no effect on the blood
pressure. The pharmacological action of canadine a- and fi-methochlorides
was examined by Laidlaw,24 who found both to have the curare-like action
common to ammonium bases, the /3-isomeride being the more active ;
the relative activities of the four optically active forms are given as
la. : da. : Ifi : d/3 = 1 : 9 : 12 : 28.
Reynolds and Waud 25 found that capaurine produced paralysis on
injection into the lymph sac of frogs, and convulsions when injected into
mice or rabbits in doses of 100-200 mgm./kilo. It depressed the activity
of the heart, intestine and uterus. The methyl ether caused convulsions
in frogs, but otherwise acted like capaurine.
Umbellatine was examined by Gupta and Kahali, 26 who found that it
killed Paramcecium at 1 in 500 and Leishmania tropica at 1 in 50,000,
but did not inhibit L. donovani or Entamoeba histolytica at 1 in 10,000. It
remembles berberine in the nature and range of its pharmacological
activity but is more active in producing cardiovascular response and is
possibly more potent in the treatment of oriental sore.
According to Biberfeld,27 palmatine, calumbamine and jatrorrhizine all
paralyse the central nervous system in frogs ; palmatine also produces
this effect in mammals and differs from the other two in stopping respiration, probably by paralysis of the respiratory centre. All three alkaloids
lower the blood pressure on intravenous injection, palmatine being the
most active.
REFERENCES
(1) Arch. Pharm., 1906, 244, 257. For earlier work see GADAMER, ibid., 1902,
240, 450 ; GOBDIN, idem, p. 146. (2) Ibid., 1907, 245, 586 ; (with SANDSTEDE), 1918,
isoQUINOLINE
346
GROUP
256, 1 ; (with DSCHU), 1925, 263, 294 ; (with A W E ) , 1931, 269, 660 ; (with A W E and
ETZBODT), 1934,
272,
817.
(3) Monats.,
1927,
BURGER,
Ber.,
1926, 59, 1486. (3a) Arch. Pharm., 1938, 276, 199. (4) SPATH (with BOHM), Ber.,
1922, 55, 2985 ; (with DUSCHINSKY), ibid., 1925, 58, 1939 ; (with MEINHARD), ibid.,
1942,
75, 400 ;
F E I S T and
DSCHU.2
(5)
SPATH and
B U R G E R , Ber.,
1926,
59,
1486.
(6) Ber., 1926, 59, 1496 ; SPATH and LANG, ibid., 1921, 54, 3064. (7) Ibid., 1925, 58,
2 2 6 7 ; SPATH and MOSETTIG, 1927, 60, 383.
1927, 548.
(9)
Cf.
R A Y , J. Ind. Chem. Soc, 1927, 4, 403. (10) Monats., 1928, 50, 341. (11) Bee. Trav.
chim., 1884, 3, 197. (12) Mitt. Med. Ges. Tokyo, 1910, 24, 15. (13) Acta Phytochimica,
1927, 3, 177 ; J. Pharm. Soc. Jap., 1925, No. 522, 1 ; No. 523, 7. (14) Arch. Pharm.,
1910, 248, 276 ; (with STOEPEL), ibid., 1913, 251, 321.
Ber.,
1930, 63, 3007. (16) KITASATO, Proc. Imp. Acad. Tokyo, 1926, 2, 124 ; Acta Phytochimica, 1927, 3, 175. (17) Ber., 1929, 62, 1029. (18) J. Pharm. Soc. Jap., 1927,
No. 542, 48 ; Acta Phytochimica, 1927, 3, 210. (18a) Ber., 1905, 38, 2653. (19)
KARANCHANDAMI, Ind.
Med.
Gaz.,
1927,
62,
558 ;
D A S GUPTA and
DIKSHIT,
ibid.,
1929, 64, 67. For general information on the pharmacology of berberine, see CHOPRA.
D I K S H I T and CHOWHAN, Ind.
J. Med.
Res.,
(20) D I C K , Arch.
Surg.
Chicago, 1940, 41, 287. (21) GREATHOUSE and WATKINS, Amer. J. Bot., 1938, 25, 743,
(22) J. Pharmacol, exp. Ther., 1940, 69, 64. (23) Ind. Med. Gaz., 1944, 79, 259. (24)
J. Pharmacol, exp. Ther., 1913, 4, 461. (25) Can. J. Res., 1944, 22, E , 64. (26) Ind.
J: Med. Res., 1944, 32, 53. (27) Zeit, exp. Path. Pharm., 1910, 7, 569 (quoted Arch
Pharm., 1918, 256, 31).
BISBENZYLwoQUINOLINE ALKALOIDS
There are now known a considerable number of alkaloids containing
two distinct woquinoline nuclei, such as emetine and its congeners (p. 394),
and in the morphine sub-group, ^-morphine, dithebainone (p. 255),
disinomenine and its pseudo-isomeride (p. 268). The most important
collection of such alkaloids is the bisbenzyKsoquinoline or biscoclaurine
section of which the following two alkaloids, berbamine and oxyacanthine,
are examples, but which is typically developed in the Menispermacese.
Berbamine, C37H40O6N2. This alkaloid, isolated from the root-bark of
Berberis vulgaris by Hesse, 1 was given the formula C 18 H 19 0 3 N by Rudel, 2
which was accepted until Santos 3 altered it to C 37 H 40 O 6 N 2 , making it
isomeric with oxyacanthine, for which Spath and Kolbe 4 had already
proposed this formula. Berbamine crystallises from alcohol with 4H 2 0
in leaflets, m.p. 156 or 172 (dry) or from light petroleum in warty masses,
m.p. 197-2100,2 [<x]D + 108-6 (CHC18). The sulphate and the nitrate are
crystalline. The alkaloid gives the same colour reactions as oxyacanthine
(see below), and being closely related to that alkaloid its constitution is
dealt with under oxyacanthine. Berbamine methyl ether, m.p. 182,
[a] D + 132, occurs in Stephania cepharantha as the alkaloid isotetrandrine.
Oxyacanthine, C37H40O6N2. This alkaloid was isolated by Hesse, 1
and assigned the formula, C 19 H 21 0 3 N, by Rudel, 2 which was altered by
Spath and Kolbe 4 to that given above. It crystallises from alcohol in
needles, m.p. 208-9 (216-7 in vac.), [a] D + 279 (CHC13) (G. and von B. 4 ).
The hydrochloride, B . 2HC1, m.p. 270-1 (vac.), [a]|9 + 188-5 (H 2 0), is
sparingly soluble in dilute hydrochloric acid ; the hydrobromide, B . 2HBr,
has m.p. 273-5 (dec, vac.); the nitrate forms needles, m.p. 195-200
(dec), and is sparingly soluble in water. Oxyacanthine dissolves in nitric
acid with a yellow colour, is not coloured by sulphuric acid, but on further
OXTACANTHINE
347
addition of nitric acid becomes red. Molybdic acid in sulphuric acid gives
a dirty violet tint changing to yellowish-green. It gives a blue colour
with a mixture of ferric chloride and potassium ferricyanide.
Oxyacanthine contains three methoxyl groups, and one phenolic
hydroxyl group is indicated by the preparation of an O-benzoyl derivative,
a potassium derivative and a methyl ether (identical with trilobamine
methyl ether, p. 357) yielding a hydrochloride, C 38 H 42 0 6 N 2 . 2HC1, m.p.
261. Oxyacanthine methyl ether dimethiodide, C 40 H 48 O 6 N 2 I 2 , m.p. 25560, can be degraded by Emde's method in two stages to a nitrogen-free
substance, C 36 H 40 O 6 , m.p. 124-5, and trimethylamine, suggesting the
monocyclic attachment of each nitrogen atom in the form of a methyliminogroup (Spath and Kolbe 4 ). These results were confirmed by Gadamer
and von Bruchhausen, 4 who added further observations, of which those
with acylating agents and with ethyl chloroformate indicated the presence
of methyltetrahydrowoquinoline nuclei. These authors suggested that
the remaining two oxygen atoms are present as ether linkages. In a further
study of the alkaloid, Spath and Pikl 5 showed that oxyacanthine methyl
ether dimethiodide yielded an ammonium base, which when boiled with
potassium hydroxide solution produced an optically inactive base,
C 40 H 46 O 6 N 2 , m.p. 152-3. This on oxidation by potassium permanganate
gave 2-methoxy-5 : 4'-dicarboxydiphenyl ether, m.p. 313-4 (XXXIV :
R = Me), the identity of which was established by its synthesis from
methyl p-bromobenzoate and potassium methyl wovanillate. The facility
of degradation by the Emde and Hofmann processes indicates that
oxycanthine probably contains two tetrahydroi'soquinoline nuclei. On
this basis Spath and Pikl proposed formula (XXXV : R = H) for oxyacanthine, the position assigned to the hydroxyl group being based on the
production of j)-hydroxybenzoic acid, when oxyacanthine is fused with
potassium hydroxide and the formation of 2-ethoxydiphenyl ether
5 : 4'-dicarboxylic acid, m.p. 288-5-289-5 (XXXIV: R = Et), when
oxyacanthine ethyl ether dimethiodide is treated like its methyl analogue
(see above). This structure explains the formation of an optically inactive
base in the first stage of the exhaustive methylation processes by the
disappearance of the centres of asymmetry marked *. The main features
of this formula were confirmed by von Bruchhausen and Schultze,6 who
modified slightly the orientation of the methoxyl groups in the two
isoquinoline nuclei, von Bruchhausen and Gericke ' showed that the
methine base, C40H46O6N2, m.p. 152 (see above) formed in the first stage
of the Hofmann degradation process with oxyacanthine, is ozonised to the
dialdehyde, m.p. 72 corresponding to (XXXIV) and a nitrogen-containing
dialdehyde, C 25 H 34 0 6 N 2 , needles, m.p. 76, which is represented by
(XXXVI) since its dimethiodide, C 27 H 40 O 6 N 2 I 2 , m.p. 259 (dec), on
treatment with alkali, breaks up into trimethylamine and a nitrogen-free
substance, C21H20O6, m.p. 140, which must be the trimethoxydivinyldiphenyl ether dialdehyde, m.p. 140 (XXXVII), since on reduction by
the Clemmensen method it furnishes 2 : 3 : 2'-trimethoxy-6 : 5'-dimethyl5 :4'-diethyldiphenyl ether, m.p. 86-5 (XXXVIII), the constitution of
348
JSOQUINOLINE
GROUP
(XI)
MENISPEEMACEOUS
BASES
349
1932, 497, 9 0 ;
(9) Quoted in
Merck's Jahresb., 1916, 30, 174. (10) RAYMOND-HAMET, Compt. rend., 1933, 197,
1354 ; Compt. rend. Soc. biol., 1942, 136, 112.
ALKALOIDS OF THE MENISPERMACEJE
350
isoQUINOLINE
GROUP
MINISPEBMACEOUS
BASES
351
Annalen,
ments by Liebig, ibid., p. 203. (2) OHTA, Ber. ges. Physiol., 1925, 33, 352 ; for pharmacology see OHTA, Kitasato
Compt. rend. Soc. biol., 1937, 125, 509. (3) GRESHOFF, "Verslag van het onderzoek
naar de Plantenstoffen van der Ned.-Ind.," Batavia, 1890 ; PLUGGE, Arch. exp. Path,
Pharm., 1893, 32, 266 ; KONDO and K O N D O , J. Pharm. Soc. Japan, 1925, No. 524, 876.
(4) K O N D O a n d TOMITA, J. Pharm. Soc. Jap., 1927, 47, 39 ; 1928, 48, 83 ; 1930, 50, 9 1 .
(5) K O N D O a n d TOMITA, Ibid., 1931, 5 1 , 4 5 1 . (6) K O N D O a n d NAKASATO, Ibid., 1924,
44, 691 ; 1926, 46, 41 ; 1935, 55, 170 ; Arth. Pharm., 1931, 269, 433. (7) KONDO,
NARITA a n d MURAKAMI, J. Pharm. Soc. Jap., 1941, 6 1 , 117 ; MANSKE, Can. J. Res.,
1943, 2 1 , B i 17. (8) K O N D O a n d NARITA, J. Pharm. Soc. Jap., 1927, N o . 542, 40 ;
352
GROUP
TSOQUINOLINTS
1929, 49,103 ; (with MURAKAMI), 1941, 61, 117. (9) SANTOS, Rev. Filip. Med. Farm.,
1931, 22, No. 9 ; SULIT, Thesis Univ. Philipp., 1934; for pharmacology see GARCIA,
Phil. J. Sci., 1940, 71, 361. (10) KONDO et al., J. Pharm. Soc. Jap., 1938, 58, 2 7 6 ;
U.S. P a t . 2,206,407. (11) KONDO and TOMITA, J. Pharm. Soc. Jap., 1939, 59, 207 ;
U.S. P a t . 2,248,241. (12) KONDO a n d YANO, J. Pharm. Soc. Jap., 1928, 48, 15.
(13) CHOU, Chin. J. Physiol, 1935, 9, 2 6 7 ; 1938, 13, 167. (14) CHU, ibid., 1939,
14, 315. (15) VAN ITAIXIE and STEINHAUER, Pharm. Weekhl., 1922, 59, 1381. (16)
J. Biol. Chem., 1935, 109, 681 ; cf. KUBOTA, Folia Pharmacol. Jap., 1931, 12, No. 2,
328, 338 ; 1934, 18, Nos. 2 - 3 , 143, and OHTA. 2 (17) J. Chin. Chem. Soc, 1935, 3 ,
260, 365 ; 1937, 5, 14 ; 1940, 7, 123. (18) Pharm. Chem. Res. Rep. (China), 1935, 1,
13, 29, 37. (19) Ber., 1939, 72, 519. (20) "Chinese Medicinal Plants of the Pen
Ts'ao Kang Mu," A.D. 1596, Peiping, 1936. (21) Chin. J. Physiol., 1937, 11, 25 ; cf.
H s u , J. Chin. Pharm. Ass., 1940, 2, 327. (22) Bull. Nat. Acad. Peiping, 1935, 6, 13.
(23) J. Chin. Pharm. Assoc, 1936, 1, 327.
In the following descriptions of coclaurine and the chief bisbenzyl/soquinoline alkaloids, the numbers in brackets after the names of the
alkaloids refer to the numbered items in the foregoing list.
Faltis x has made a number of suggestions regarding possible modes
of origin of these alkaloids in plants, and useful summaries of information
dealing with biological and chemical relationships in the group have been
published by King 2 and by Kondo and Tomita. 3
Coclaurine, C 17 H 19 0 3 N. (Item 3 ; list, p. 350.) This alkaloid was
first fully investigated by Kondo. 4 I t crystallises in plates, m.p. 221,
[a]f(9 17-01, forms a crystalline hydrochloride, m.p. 264, and a
methiodide, m.p. 155. The hydrochloride gives a violet colour with
ferric chloride changing to green on warming. The alkaloid contains one
methoxyl, but no methylimino group,.'-'Its solubility in alkali indicates
the presence of phenolic hydroxyl groups and the formation of a non-basic,
NMeH
B t 0
CH
(n:n>)\/
CH
J.
NUe.Et
xcyi
CO H
(IV) 0U
DAURICINE
353
12
354
isoQUINOLINE
GROUP
X M , - / *
via azlactone^ H O ^ C . C H , /
(EC)
(VIII)
(VII)
6-methoxy-3 : 4'-di(carboxymethyl)-diphenyl ether (X). This with homoveratrylamine gave 6-methoxydiphenyl ether 3 : 4'-diacetdifeomoveratrylamide (XI), which by treatment with phosphorus pentachloride was
converted into the bisbenzylisoquinoline derivative (XII) and this, on
reduction followed by methylation gave a-methyldauricinemethine (VIII)
identical with that prepared from dauricine (VII).
Magnoline, C32H25O(0H)3(0Me)2(NMe)2. The leaves of the Caucasian
tree, Magnolia fuscata (Magnoliacese), yield 1-5 to 2 per cent, of total
alkaloids, of which the fraction, about one-tenth, insoluble in hot benzene,
on solution in hot alcohol deposits the phenolic alkaloid magnoline,
m.p. 178-9, [<X]D 9-6 (pyridine), which yields vitreous salts with the
halogen acids but gives a crystalline picrate, m.p. 160-2 {dec.) and
picrolonate, m.p. 190 (dec). The base is converted by diazomethane into
a trimethyl derivative, m.p. 109-110, which is oxidised by permanganate
in acetone to (a) 2-methoxy-5 : 4'-dicarboxydiphenyl ether, identical with
Spath's acid 7 from oxyacanthine methyl ether (p. 347) and (b), the lactam,
l-keto-6 : 7-dimethoxy-2-methyltetrahydroisoquinoline.7(0).
When the
TETRANDRINE
355
0H2 HMe
-0-<T
HO
MeH
CH2
356
isoQUINOLINE
GROUP
TRILOBAMINE
357
When heated at 150 for three hours menisine is converted into tetrandrine (Chou 14 ).
Trilobamine, C 36 H 38 0 6 N 2 . (Item 5 ; list, p. 350.) This phenolic base
has m.p. 195, [a]J>5 +356-6 (dilute acetic acid), forms a dihydriodide,
m.p. 264 (dec), and an amorphous dimethyl ether, m.p. 169, which was
eventually shown to be identical with the monomethyl ether of oxyacanthine (p. 347).
When the methine base derived from trilobamine diethyl ether ethiodide
is oxidised by permanganate it furnishes 2-ethoxydiphenyl ether 5 : 4'dicarboxylic acid, identical with that (XXXIV ; p. 348, R = Et) similarly
formed from oxyacanthine (p. 347) or dauricine (p. 353) and in the present
case derived from the diphenyl ether residue represented by rings (1) and
(2) in formula (A) or (B). This fixes the position of one hydroxyl group at
OR 3 in (A) or (B); the position of the second is still undetermined but it
may well be OR 1 in ring (3) of (A) or ring (4) of (B). 15
358
isoQVINOLINE
CHg
GBOUP
CH2
H2C
H2C
NMa
Ss\y
CH
CH 2
CH
/
(E)
OMe
CH2
Meo/v/N,CH2
Etj/XoMe
I*L JoH
(H)
OHC
CHO
OMe
to
M.p.
t] D
Notes
1720
+108.6
182
+146
2170
+263.1
Stereoisomeride of berbamine
methyl ether.
210
-878
+855.1
Methylates to tetrandrlne.
237-8
1880
+290
208-9
Jrllobamlm, CggH^OglOHlgtOMelgdMelg
198
+279
+366.6
Uethylates to ozyaoanthine
methyl ether.
Trilobine, CatUM0^ft.
(Items 4, 5 ; list, p. 350.) This alkaloid
crystallises in prisms, m.p. 285, [^9 + 296-8 .(CHC1S). The hydro-
TRILOBINE
359
Me,N
Ct-
(xm)
ICH0
inn)
potassium permanganate to a tetracarboxylic acid, C 17 H 10 O u , m.p. 192-7
(methyl ester, C12H302(OMe) (C02Me)4, m.p. 85), which on fusion with
potassium hydroxide furnishes protocatechuic acid, and is therefore
provisionally represented by (XVI). On the basis of these results Kondo
and Tomita 17 suggested (XVII: R or R' = OMe) as representing trilobine,
and its structural isomeride wotrilobine (see below), since both alkaloids
yield the same degradation products, and the only difference between them
must lie in the position of the methoxyl group R or R' in (XVII).
On stereochemical grounds Faltis 9 proposed formulae conforming with
the general type (XVIII) in which the CH 2 . R and CH 2 R' groups
may each be alternatively
CH2
OMe
v 4-o-
or
CH 2
V / ->0
isoQUINOLINE
360
GROUP
(XIV to XVI, p. 359) require revised formulae and (XVI), for example,
becomes (XVI, Faltis, 1941).
MeO
C02H O
(XVI) ( P a l t i s , 1941)
(XIX)
STEPHANIA
ALKALOIDS
361
isoQUINOLINE GROUP
362
SCHWARZ), ibid., 1941, 74, 79 ; Annalen, 1932, 497, 69 ; 499, 301. (2) Ann. Repts.
Chem. Soc, 1933, 30, 242. (3) Arch. Pharm., 1936, 274, 65. (4) (With KONDO), J.
Pharm. Soc. Jap., 1925, 45, 876 ; 1926, 46, 104 ; 1928, 48, 56, 166 ; 1930, 50, 63.
(5) J. prakt. Chem., 1930, [ii], 126, 24. (6) J. Pharm. Soc. Jap., 1927, 47, 40 ; 1929,
49, 103 ; 1930, 50, 589 ; Ber., 1930, 63, 2420. (7) Ibid., 1929, 62, 2251. (7a) PYMAN,
J. Chem . Soc, 1909, 95, 1272. (76) Bull. Soc. Chim., 1938, [v], 5,1257 ; J. Gen. Chem.,
V.R.S.S., 1940, 10, 707. (7c) Ibid., 1946, 16, 129. (7d) Farmakol i Toksikol, 1945,
8, 17. (8) KONDO, NARITA and UYEO, ibid., 1935, 68, 519. (9) J. Pharm. Soc. Jap.,
1929, 49, 51 ; 1930, 50, 26 ; Annalen, 1932, 497, 90 ; cf. FALTIS, ibid., 1932, 499, 301.
(10) VON BRUCHHAUSEN (with GERICKE), Arch. Pharm., 1931,269,115; (withOBEREMBT
and FELDHAUS), Annalen, 1933, 507, 144. (11) KONDO and KEIMATSU, J. Pharm. Soc.
Jap., 1935, 55, 63 ; with TOMITA. 3 (12) Ber., 1932, 65, 472 ; cf. FALTIS, Annalen,
1932, 497, 69.
(14) Chin. J.
KEIMATSU, J. Pharm. Soc. Jap., 1934, 54, 108 ; KONDO and KEIMATSU, ibid,, 1935,
55, 2 5 ; Ber., 1938, 71, 2553. (17) KONDO (with NAKAZATO), J. Pharm. Soc.
Jap., 1924, 44, 691 ; 1926, 46, 41 ; (with TOMITA), ibid., 1927, 47, 39 ; 1928, 48, 83 ;
1930, 50, 127 ; Annalen, 1932, 497, 104 ; for pharmacological action, see TSURUTA,
Folia Pharmacol. Jap., 1926, 3, 280. (18) KONDO " and Arch. Pharm., 1986, 274,
173 ; cf. FALTIS, Annalen, 1982, 499, 301 ; Ber., 1941, 74, 79. (19) J. Pharm.
Soc. Jap., 1980, 50, 9 1 ; 1985, 55, 100; Arch. Pharm., 1986, 274, 78. (20) KONDO
CHONDRODENDRON BASES
363
and TOMITA, J. Pharm. Soc. Jap., 1931, 51, 461 ; 1935, 55, 170 ; Arch. Pharm., 1931,
269, 441 ; 1936, 274, 74. (21) J. Pharm. Soc. Jap., 1924, 44, 5 ; 1927, 47, 31, 126;
1928, 48, 163 ; 1931, 51, 55 ; (with WATANABE), 1938, 58, 46. (22) Mitt. med. Ges.
Tokyo, 1931, 740. (23) Chin. J. Physiol., 1937, 11, 13. (24) Ibid., 1937, 11, 29;
CHOU, LU and WANG, 1937, 12, 163. (25) Folia Pharmacol. Jap., 1926, 3, 280. (26)
OHTA, Kitasato Arch. exp. Med., 1925, 6, 259, 283 ; RAYMOND-HAMET, Compt. rend.
Soc. Biol., 1937, 125, 509. (27) Schweiz. Apoth. Zeit., 1945, 83, 198 ; see also JUNOO,
Med. et Hyg., 1946, 4, 1.
Alkaloids of Greenheart, Boxwood and " Pareira brava." In 1843,
Maclagan isolated from greenheart bark (bebeeru), (Nectandra Rodiosi,
Hook) the alkaloids bebeerine and sepeerine ; the latter, a yellowish resin
for which the names flavobuxine and pelluteine have also been used. 1
Later, Walz 2 stated that bebeerine was identical with buxine, which
Faure 3 had obtained from boxwood (Buxus sempervirens L.) in 1830.
Fliickiger * also regarded buxine and bebeerine as identical, and affirmed
the identity of the latter with pelosine, which Wiggers 5 isolated from
Cissampelos Pareira L., the roots of which have appeared in commerce
as " Pareira brava," and which Fliickiger had himself prepared from
Chondrodendron tomentosum, Ruiz and Pav, supposed to be the source of
true " Pareira brava," and now of special interest as a source of tube
curare (p. 373). Scholtz 6 confirmed the statement that pelosine and his
bebeerine, now known to be derived from pareira root bark, are identical,
but regarded buxine as distinct from either. Other alkaloids were isolated
from greenheart wood by Maclagan and Gamgee,7 and from boxwood by
Barbaglia,8 but do not appear to have been further investigated. In 1921,
Faltis and Neumann 9 stated that the true source of " Pareira brava " is
Chondrodendron platyphyllum (St. Hil.) Miers, containing alkaloids
different from those of greenheart, and that in consequence the name
" bebeerine " should be restricted to alkaloids from greenheart, and
that the alkaloids of " pareira brava " should be known as " chondodendrines." Since the same authors state that commercial bebeerine is
made from " pareira brava," this means that bebeerine should be re-named
chondodendrine. This suggestion has been adopted in the case of isobebeerine, which is now generally called wochondodendrine or zsochondrodendrine. These two names arise from the fact that Ruiz and Pavon
wrote the generic name Chondodendron in mistake for Chondrodendron
and purists have insisted upon the correction (King, 10 1935). The name
bebeerine persists though Faltis uses chondodendrine, and a new complication has arisen by the identification of Boehm's curine (p. 374) with
Z-bebeerine. Much of the work done in recent years on these alkaloids
has been carried out with commercial bebeerine, from which the following
alkaloids have from time to time been isolated by the independent work
of Scholtz 6 and Faltis 9 :
(1) Bebeerine (Pelosine, a-Bebeerine, Chondrodendrine, Curine).
(2) isoChondrodendrine (isoBebeerine).
(3) p-Bebeerine (j8-Chondrodendrine).
(4) Bebeerine-B.
(5) ChondrodilW;
JSOQUINOLINE
364
GROUP
The data available regarding the last three probably need revision as
suggested by Faltis, Kadiera and Doblhammer.9
Chondrodine, C 18 H 21 0 4 N, amorphous, m.p. 218-20, [a] D 75
(EtOH). The hydrochloride, B . HC1, m.p. 274-5, occurs in yellow leaflets;
the picrate, m.p. 193-4, is a crystalline powder, and the picrolonate,
m.p. 185-6, forms greenish-yellow needles. The alkaloid contains a
methoxyl and a methylimino-group, and yields a crystalline dibenzoyl
derivative, m.p. 295. The diethyl ether hydrochloride, m.p. 258, forms
yellow needles (Scholtz,6 1911).
j8-Bebeerine, C 21 H 23 0 4 N, is amorphous and yields amorphous
salts. It has m.p. 124-50, [a]?,1" + 28-6 (EtOH), or - 24-7 (pyridine),
and its reactions indicate that the formula may be extended to
C19H1602(NMe)(OMe)(OH).9 According to Scholtz 6 (1913) it has the
formula, C 18 H 21 0 3 N, and yields a crystalline methiodide, m.p. 80
(hydrated) or 258-9 {dry, dec). According to Faltis, Kadiera and
Doblhammer,9 this may be a diastereoisomeride of bebeerine.
Bebeerine-B, C22H2305N, a yellow powder, m.p. 220 (dec), [a] D + 56'7.
Its reactions indicate the presence of the following groups,
C20H15O2(NMe) (OH)a(OMe).
On fusion with potash protocatechuic acid is formed.9
Alkaloids of Chondrodendron platyphyllum
The confused state of knowledge referred to above has been clarified,
at least as regards the alkaloids of " pareira brava " and the botanical
source of this drug, by Dr. H. King, 10 (1940), who has confirmed the
statement of Krukoff and Moldenke 10 that genuine " pareira brava " is
the root of Chondrodendron platyphyllum (St. Hil.) Miers, though some
may also be obtained from C. microphyllum (Eichl.) Moldenke ; these two
plants are native to Brazil and authentic samples from both have been
examined by King as well as roots of C. candicans (Rich ex DC.) Sandwith,
from British Guiana and the " pareira brava " root commercially available
in England. The results are summarised in the following table, the
predominant alkaloid being named first.
Speoies
locality
Organ
Alkaloids
Ch.platyphyllum
' "
Rio
Bahia
Root
d-isoChondrodendrlna . ^-bebeerine .
Root
Stems
Leaves
1-Bebeerine, d-l6oohoadroder.drine.
T Bebeerine
T Chondrofoline, d-lsoohondrodendrlne
^-bebeerine.
Ch.microphyllum
Bahia
Root
d-isoChondrodendrlne, d_-bebeerine.
Ch.candioans
British
Stem
~ ~ ~ G u i a n a
Pareira brava
d-Bebeerine, d-isoohondrodendrlne.
1-isoooalaurlne.
CHONDEOFOLINE
365.
MeO
HO
2
BH W
OH
I
Jl
nu
IfedL
I
II
j 0 ^
JNH
0H 2H2
(I)
(II)
(Ill)
366
isoQUmOLINE
OBOUP
the formula C lg H 19 03N, which was doubled by Faltis, Wrann and Kuhas.11
The alkaloid has been fully characterised by King 10 (1940). It crystallises
from methyl alcohol in microscopic needles, m.p. 316 (dec.); like bebeerine,
it gives a typical Millon reaction. The most characteristic salt is the
sulphate B . H 2 S0 4 , 15H 2 0, or B . H 2 S0 4 , 7H 2 0, after prolonged exposure
to air, m.p. 291-2 (dry; dec.) [a]546j + 115-6 (dry salt; H 2 0) equivalent
to
MD+99-7.
The hydrochloride, B . 2HC1, crystallises in plates or
rarely in needles, m.p, 333 (dec.) (cf. Scholtz,6 and Faltis and Neumann 9 ).
The methiodide, B . 2MeI, 8H 2 0, separates from methyl alcohol in short
prisms, m.p. 287 (dec.) or from water in microscopic, double square
pyramids ; it has [a]|f6, + 64-3 (H 2 0). Figures somewhat different from
the foregoing have been given by Dutcher 10 for the constants of
the alkaloid and its salts ; he also records for the base [<x]f>2 + 120
(N/10, HC1) or + 50 (pyridine). More recently King 20 has recorded for
the anhydrous sulphate [a] + 158-9 (c = 0-7 ; H 2 0) equivalent to
[a]Jf + 137 and in good agreement with the value + 135 recorded by
Faltis and Neumann 9 for a sample of the anhydrous salt. According to
Scholtz,8 wochondrodendrine forms a benzoyl derivative, m.p. 215. On
demethylation by hydrochloric acid, the alkaloid is stated to yield
wobebeeridine, C 34 H 34 0 6 N 2 , microscopic yellow cubes, m.p. 240, which
gives a green colour with ferric chloride.12
O-dimethyKsochondrodendrine has m.p. 272-3, [a] D 36-8 (EtOH),
and yields a methiodide having m.p. 312 and [ a ] ^ + 1-5 (dry salt ;
H 2 0) according to King, 10 while Faltis and Neumann 9 give [a]}6" 7
(50 per cent. EtOH). By the Hofmann method the metho-salt yields two
methine bases, C40H46O6N2, of which the a-form is optically inactive, has
m.p. 206-7, yields a hydrochloride, m.p. 299, and is distinguished from
the dextrorotatory /3-form by giving with sulphuric acid a red colour
changing to blue on heating. The /3-form has m.p. 167-168-5 and
[<x]D + 359 (EtOH). 9 The methiodides of the mixed methine bases
when treated with sodium hydroxide in methyl alcohol lose trimethylamine
and produce a nitrogen-free product, C l 8 Hi 6 0 3 but later doubled to
C 36 H 32 0 6 , crystallising in monoclinic tablets, m.p. >312. This, on oxidation
with potassium permanganate, furnished an acid, C 12 H 5 0(OMe) 2 (C0 2 H) 3 ,
m.p. 177-5-178. Identification of this acid proved difficult, but it was
eventually synthesised by Faltis and Frauendorfer li and shown to be 2 :
3-dimethoxy-5 : 6 : 4'-tricarboxydiphenyl ether (I), and on this basis a
Hi)
(in)
367
BEBEERINE
MaO
(VIII)
OMe
OOgH
SieO
(VII)
Olfe
0H:CH2
Hi
(VI)
HCfeO
368
isoQUINOLINE
GROUP
These results justified the nuclear structures (I) and (II) assigned to
bebeerine methyl ether and its nitrogen-free degradation product respec-
BEBEERINE
369
tively, but as both these substances were fully methylated there remained
the problem of the orientation of the hydroxyl and methoxyl groups in
bebeerine itself. From a study of the Millon reaction King 10 (1937)
concluded that in bebeerine one hydroxyl group was at OR 3 (formula I)
and this was confirmed later by the preparation of the amorphous 0-
(VI)
370
isoQUINOLINE
GROUP
C d . OR3
//
C b O C C
OCH2OC"
\
^
CbOCC
/
\
/
\
i.e., the -OR 3 group of Cd is replaced by one end of an inserted chain
CH2O, which now joins Cd to Ca.
REFERENCES
(1) Annalen, 1843, 48, 106. (2) Jahresb., 1860, 548. (3) Jahresb. Berz., 1830,
11, 245. (4) Pharm. J., 1869-70, [ii], 11, 192. (5) Annalen, 1840, 33, 81 ; cf. Pharmacographia by FLUCKIGEB and H A N B U B Y , London, 1879, p . 29.
2054 ; Arch. Pharm., 1898, 236, 530 ; 1899, 237, 199 ; 1906, 244, 555 ; 1911, 249,
408 ; 1913, 251, 136 ; (with KOCH), 1914, 252, 513. (7) Pharm. J., 1869-70, p i ] , 11,
19. (8) Gazzetta, 1883, 13, 249 ; Ber., 1884, 17, 2655. (9) Monats., 1912, 33, 873 ;
(with NEUMANN), ibid., 1921, 42, 311 ; (with K A D I E B A and DOBLHAMMEB), Ber., 1936,
69, 1271).
1157 ;
1940, 737 ;
cf. K B U K O F F a n d
M O L D E N K E , Brittonia,
1938, 3, 15 ;
DUTCHEB,
J. Amer. Chem. Soc., 1946, 68, 419 ; BBAZIL et al., Chem. Abstr., 1945, 39, 8061. (11)
Annalen, 1982, 497, 69. (12) SCHOLTZ, Arch. Pharm., 1915, 253, 622. (13) SCHOLTZ
CURABE
ALKALOIDS
371
1929, 62, 1 0 3 4 ; (with FRAUENDORFER), ibid., 1930, 63, 806. (15) FALTIS (with
DIETRICH, ibid., 1934,67,231 ; (with HOLZINGER, ITA and SCHWARZ), ibid., 1941,74, 79.
(16) Ibid., 1928, 61', 1698. (17) Chem. Soc. Ann. Rep., 1933, 30, 249. (18) Ber.,
1934, 67, 55. (19) J. Pharm. Soc. Japan, 1927, N o . 548, 107 ; Arch. Pharm., 1936,
274, 76 ; (with Tomita and Uyeo) Ber., 1937, 70, 1890 ; J. Chem. Soc. Jap., 1943, 64,
64, 70, 77,142,147 (Chem. Abstr., 1947,41,3803). (20) J. Chem. Soc. 1948, in t h e press.
ALKALOIDS OF CURARE
Curare, also written urari, ourari, woorari or woorali, is a phonetic
rendering of an Amazonian Indian name given to a group of plant extracts
prepared for use as arrow-poisons by natives in remote regions of the
Orinoco and Amazon valleys. There is an extensive literature 1 recording
travellers' descriptions of the preparation of curare, and information
regarding the botanical origin of the components of the drug. I t is clear
that the plants used vary in different districts, and that the belief
commonly held until recently that the active components of the drug are
derived from various S. American Strychnos spp. is not generally true.
The chemical evidence indicates that the alkaloids of two varieties of
curare are of the type found in menispermaceous plants, and the critical
summary of botanical evidence provided by King 2 (1937) for pot curare
supported this view, though it did not exclude the possibility that Strychnos
spp. might be ingredients in some preparations.
Since 1937 much more evidence has been published regarding menispermaceous plants as sources of the active components of curare. I t
should be understood that some of the plants used in preparing the drug
are now known not to contain curarising components, and evidence by
travellers that a particular plant is used, needs to be supplemented by
chemical and pharmacological evidence that the plant in question does
contain active constituents. After a critical survey of the literature and
herbarium material available, Krukoff and Moldenke 1 conclude that there
is clear evidence that the following menispermaceous species are used in
the preparation of curare :
Abuta imene (Mart) Eichl. ; A. rufescens Aubl.
Chondrodendron candicans (L. C. Rich.) Sandw.; C. iquitanum Diels ;
C. limaciifolium (Diels) Mold.; C. polyanthum Diels ; C. tomentosum, Ruiz and Pavon.
Telitoxicum minutiflorum (Diels) Mold.; T. peruvianum Mold.
Of these authenticated species, Chondrodendron candicans and C. tomentosum have been examined by King (pp. 364, 376) and the results of work by
Wintersteiner and Dutcher and by King on curares described as made
from C. tomentosum are given below.
According to Folkers and Unna, 3(a) the Peruvian chazuta curare
(bamboo type) is made from C. tomentosum R. and P., Annona ambotay
Aubl., Aristolochia rumicifolia Mart, and Zucc. and an unidentified plant
which is neither a menisperm nor a Strychnos. Of these four the first was
372
isoQUINOLINE
GROUP
markedly active and the third active in large doses. Of four other plants
tested at the same time C. limaciifolium proved inactive, Telitoxicum
minutiflorum active in large doses, Elissarrhena grandiflora active and
Strychnos cogens Benth. inactive. King 2 (1948) has shown recently that
the stems of Anomospermum grandiflorum Eichl. (synonym Elissarrhena
grandiflora) contain non-quaternary alkaloids and also yield a quaternary
fraction exerting a true curare action. In a preliminary study of botanical
material collected by Krukoff and Smith 3(6) in Brazilian Amazonia,
Folkers (3c) found that out of ten plant species used by the Tecuna Indians
three contained curarising components, Strychnos Castelncei Wedd (S.
Castelneana Baill.); S. toxifera Schomb. and a third Strychnos sp., allied
to S. Peckii, while two, Chondrodendron limaciifolium and Telitoxicum
minutiflorum were doubtful. Of twelve other species used by the Javas,
nine gave negative results, the active species being Strychnos Jobertiana
Baill, a second Strychnos sp. allied to S. diaboli Sandw. and Capparis sola,
Macbride ; the last-named plant is a surprising addition to possible sources
of curare, belonging to the botanical family Capparidacese. In this
connection it is of interest to note that A. J. Henry 3(c) of the Sudan Medical
Service has recently isolated tetramethylammonium iodide from Courbonia
virgata A. Brogn., also of this botanical family.
According to*Vellard,3(ci) a Strychnos sp. similar to S. medeola is used by
the Nambikwaras. Brasil, Campos and Kuhlmann 3(e) have mentioned
three S. American species of Strychnos, viz., S. diplinerva, S. off. albiflora
Prog and S. brevifolia A.D.C., in which, using extracts of the roots in
comparison with Tecuna curare, they have found curarising activity by
pharmacological tests in rabbits.
There are also on record a number of other observations regarding
S. American plants believed to be associated with this drug, e.g., Freise 4
has given preliminary descriptions of alkaloids isolated from the following
species :
(a) Undetermined Strychnos sp. : old bark ; eucurarine, C2oH23ON2,
m.p. 135-144 ; 0-13 mgm. per kilo toxic to frogs. Young bark ;
a base, C 23 H 28 0 4 N 2 , resembling vellosine (p. 736).
(b) Macoubea guyanensis. Macoubeine, C 22 H 26 0 2 N 2 , 4H 2 0, needles,
sublimes > 195, [a] D 55-5 (EtOH) ; 0-05 to 0-1 mgm. per
kilo, toxic to various animal species.
(c) Trymatococcus amazonicus. Base, m.p. 204, [<X]D 55-6.
(d) Elissarrhena grandiflora. Base, C 22 H 28 0 4 N 2 , H 2 0 , sublimes at 185.
(e) Elceophora abutifolia. Base, resembling cytisine (p. 142).
By fractionation of an extract of the bark of Strychnos lethalis Barb.,
Carneiro 6 has obtained two products, strychnolethaline, C 22 H 27 0 4 N, and
curalethaline, Cg 5 H 31 0 7 N, which he has also isolated from samples of
curare.
In view of increasing interest in the medical applications of curare
attention is being given to the elimination of inert material and the
provision of a more uniform product. 6 Of primary importance in this
CURARE
ALKALOIDS
373
374
isoQVINOLINE
GROUP
TUBOCURARINE
375
different signs, are not enantiomorphous. Their relationship was established by King 8 in the following way. When d-bebeerine is completely
methylated it furnishes amorphous O-dimethylbebeerine methosalts, of
which the methochloride on degradation by Hofmann's method gave a
mixture of three methine bases separable as their crystalline methiodides :
(A) m.p. 234, [a] 0 ; (B) m.p. 230 [a] 0 ; (C) m.p. 190;
[*].i + 108 (MeOH).
In the second stage of the degradation the three O-dimethylbebeerinemethine methochlorides gave trimethylamine and a nitrogen-free substance,
^36^3206' m -P- 198-9, named O-dimethylbebeerilene.
CH
CH,
MeO.C"
fZ
MeO.O
,C
Nile
CH
Hf
,U
CH
H<r
CH
la
no
Me\/
V
CH
CH
*K / \.
( I ) NCH2
(II)
CHE
CH
Me0j/^\cH2.CH2.HKe2
UeoL
JcH=CH
C5H3(01te)
(KeO)(j5H3
Me2N.CH2.CH2H
(IV)
HeO/7
MeoL
BegN.CHg.CHg
IT)
\cH:CB2
J|CH=CH-
gHjlCMe)
376
TSOQUINOLINE
GROUP
CHONDOCURINE
377
dendrine dimethyl ether (p. 366), d-tubocurarine chloride (p. 374), Z-curine
and a new alkaloid, chondrocurine or chondocurine.
d-Chondocurine (d-chondrocurine), C 36 H 3g 0 6 N 2 , m.p. 232-4, [a]f,4
+ 200 (N/10 HC1) or + 1 0 5 (pyridine), yields a hydrochloride, m.p.
280-2, and a sulphate, B, H 2 S0 4 , 4H 2 0, m.p. 263-5 (dec), [a]|4 + 193
(dry salt; H 2 0), and in methyl alcohol gives a pink colour with ferric
chloride. The hydrochloride in aqueous solution shows a positive Millon
reaction after standing a few minutes. The dimethiodide (d-chondrocurarine
iodide), C 38 H 44 0 6 N 2 I 2 , m.p. 275 (dec), [a]f,4 + 184 (MeOH), is convertible
into an amorphous dimethochloride, [a]f,4 + 175, which is not identical
with d-tubocurarine chloride. On complete methylation by methyl iodide
in presence of potassium hydroxide in methyl alcohol, chondrocurine
yields d-O-dimethylchondrocurine dimethiodide, m.p. 266, [oc]4 + 160
(H 2 0), identical with d-O-dimethyltubocurarine iodide. Chondrocurine is
therefore not identical with the tertiary base corresponding to tubocurarine,
but like it belongs to the bebeerine series represented by the general
formula (I, p. 369). Its quaternary base d-chondrocurarine therefore has
the same structure and configuration as tubocurarine, and has one of its
two phenolic hydroxyls in the same position as tubocurarine, i.e., OR 3 in
the formula (p. 378). The other is either ORj or OR2, the alternative
position in either case being that of the phenolic hydroxyl in tubocurarine.
These results seemed to establish with certainty that the active
component of tube curare is derived from Chondrodendron tomentosum,
but the matter again became doubtful when King 18 reported that in the
stems of a carefully authenticated specimen of the plant, collected at
Tarapoto in Peru, he had found Z-curine and Z-tubocurarine chloride. This
is the first recorded natural occurrence of the latter and seems to indicate
either that the alkaloidal components of the plant are not constant in
character, or that the botanical description of Chondrodendron tomentosum
covers two species containing the dextro- and lasvo- quaternary alkaloids
respectively.
King 2 has pointed out (1948) that this position is like that obtaining
when "pareira brava " sometimes yielded d- and sometimes Z-bebeerine
for which an explanation was found in the collection of the drug from
two different species, Chondrodendron microphyllum and C. platyphyllum
respectively. The need for a similar botanical investigation of the
supposed C. tomentosum is emphasised by further results recorded by
King, who has examined (1) commercial curare made from the stems
of a bush-rope collected along the Madre de Dios river in the Cuzco
Province of Peru and (2) stems and leaves of a bush-rope collected
at Sisa in Tarapoto and said to be used by the natives to make arrow
poison. In both these materials the leaves of the plants used were
botanically examined and certified to be indistinguishable from the leaves
of C. tomentosum. The commercial curare (1) yielded the same alkaloids
as Dutcher found in his specimen of curare, and the other material
(2) gave d-tubocurarine chloride, Z-bebeerine (curine), d-chondrocurine, dwochondrodendrine and a minute quantity of a new alkaloid d-tomentocurine.
378
isoQUINOLINE
GROUP
z
'
Rl
"
(1) <i-Tubocurarine
chloride: R 4 = Me;
"
R3=H;R1andR2,
one is H and t h e
_ other Me.
2
(2) d-Chondrocurarine chloride: R 4 =
Me;R3=H;R1and
R a are H and Me in
reverse of (1).
CURARE
379
ALKALOIDS
H2C
CH-CK2-<
0
HgC-HJ,
RlO
0R2
MeH
CH2
380
JSOQUINOLINE
GROUP
These results indicate that this specimen of pot curare was of menispermaceous origin.
ALKALOIDS OF GOURD OK CALABASH CURARE. The toxic constituent
of this form, as prepared by Boehm, 16 was an amorphous curarine to
which the formula C19H26ON2 was assigned. Gourd curare has been
investigated in recent years by Wieland et al.19 and by Schmid and
Karrer.19'")
The process of isolation finally adopted by the former authors consists
in precipitating as reineckates the water-soluble bases contained in a
methyl alcoholic extract of the curare. The mixed reineckates are further
purified, by solution in acetone and precipitation with water as often as
may be necessary. The product so cleaned represents the bulk of the
biological activity of the crude drug; the mother liquors may contain
curine (p. 374), which indicates a menisperm as one of the components of
such curares. The mixed reineckates are then fractionated chromatographically over alumina and the components isolated as chlorides by the
use of silver sulphate and barium chloride in succession. This process has
been modified in detail by Schmid and Karrer, who have also found that
with their curare, the more soluble reineckate fraction includes less potent
quaternary alkaloids.
The material first used by Wieland et al. was gourd curare from the
middle Orinoco district, near Urbana, in Bolivar State, Venezuela, but in
the fourth paper (1941) results are recorded for curares from Colombia
and Venezuela, for which more precise details of origin are not available
and there is considerable difference in the nature and quantity of the
alkaloids in the various samples used. An examination has also been made
of the bark of Strychnos toxifera, and one of the alkaloids (toxiferine II) it
contains has been found in some of the curares examined. In all, ten
alkaloids have been obtained and characterised and, with the exception
of curine, they are all of quaternary type. They are named toxiferine,
dihydrotoxiferine, or calabash-curarine (shortened to C-curarine in
practice) according to type, and the variants within the type are distinguished by numbers, or numbers and letters, e.g., toxiferine I, toxiferine l i b .
Calabash curare, probably from the middle Orinoco region, has also
been investigated by Karrer and Schmid,19(a) who have isolated eight new
alkaloids in addition to Wieland's C-curarine I.
The following three products were obtained by Wieland et al. from the
early samples of curare from Urbana.
Calabash-curarine I. This alkaloid was first named toxiferine (1937),
as it was expected to be found in Strychnos toxifera bark ; when this bark
yielded a different alkaloid, for which the name toxiferine was more
appropriate, the name of the curare alkaloid was changed. Crystalline salts
have been prepared of which the chloride, C20H23ON2C1 or C20H21N2C1, H 2 0 ,
colourless needles, m.p. >350, [a] D + 70-73, and the aurichloride,
C20H23ON2, AuCl4, m.p. 223-4, have been analysed. Alternative formulae
are quoted for the chloride as it is still uncertain whether a molecule of
water is, or is not, present as water of crystallation. If moistened with
CURARE
ALKALOIDS
381
382
IBOQUINOLINE
GROUP
CUBABE
ALKALOIDS
383
ALKALOIDS OF G O U R D CURARE.
Colour Reactions
Formula
Name of Base
C-curarine I
C21H2lN2+
C20H21N2+
C-curarine I I I
Toxiferine I
C-curarine I I .
C-dihydrotoxiferine I
C-isodihydrotoxiferine I
3-4
Toxiferine I I .
^20A23i,(2
Toxiferine II
C20H23N2+ ( H 2 0 )
Toxiferine II''
C-toxiferine I I
>300
blue
bright yellow
yellow-green
yellow-green
blue-violet
189
brown-green
none
yellowish-red
carmine
270
carmine
none
yellowish-red
carmine
204
1-5
reddish-green
none
yellowish-red
carmine
185
3-4
brownish-red
violet
none
carmine
242
i n a c t i v e a t 500
50-100
Melting
point of
Picrate
violet
C20H23N2+ ( H 2 0 )
Cone. H 2 S0 4
H s SO, +
K.Cr,0,
yellow
0-3
Cone. HNO,
50 per cent.
H 2 SO.
green
C20H2lN2+(H2O)
^20*^23^2
roteney expressed as y
(0-001 mgm.)
5 (calc. ex picrate)
216
20-30
carmine
none
yellowish-red
carmine
210
C20H23N2(H2O)
100-150
carmine
none
yellowish-red
carmine
216
C20H23N2(H2O)
10
Vermillion
none
yellowish-red
carmine
215
1
to
CURARE
385
ALKALOIDS
13
386
isoQUINOLINE
GROUP
ERYTHRINA
C-aHjj'CfflHHBl-COaH
IcH
(II)
387
ALKALOIDS
1
Hlfegl
lB.0H2
r i\y L
U
(in)
CO
s1
HH
388
isoQUJNOLINE
GROUP
Karce of Alkaloid
Heme of Alkaloid
Potency:
nigra./kilo., frog
3.0
E r y t h r a l i n e . KBr
10
Erythroidine methiodiie
200.0
Erythreliiw. Mo I
SO
Sodium B-erythroidlnate
75.0
Erythramino, HBr
10
Dihydro-3-erythroidir.e, HC1
0.5
Erythramine. Mel
Sodium dihydro-B-erythroidinate
0.6
Dihydrosrythramine, HBr
B-Erythroidino, HC1
40
300
HSr
200.0
E r y t h r a t i n e . HBr
75
8-Tetrahydro-0-erythroidine, HBr
0.6
E r y t h r a t i n e . Mai
300
Dlhydroerythratine, HBr
100
a-T^etrshydro-P-arytftroidine,
.
.
In view of the fact that the conversion of tertiary into quaternary bases
quite frequently leads to the development of curarising action, it is surprising that in these four alkaloids the methiodides are much less active than
the parent bases. On the other hand, hydrogenation in this series may
have no effect on activity (cf. erythraline and its dihydro-derivative erythramine) or may enhance it (cf. jS-erythroidine and its dihydride) or may
diminish it (cf. erythramine and its dihydride).
Erythramine, C 18 H 21 0 3 N. This base occurs in various Erythrina
species but was first isolated by Folkers and Koniuszy from E. sandwicensis
and E. subumbrans along with hypaphorine. It has m.p. 104-5, or 103-4
(solvent-free) ; b.p. 125/3-9 X "lO"4 mm., [a.]fb + 227-6 (EtOH). It is
isolated as the hydriodide, orange-yellow needles, m.p. 249 (dec), [a]ff
+ 220 (H 2 0) ; the hydrobromide "has m.p. 228, fa]f,6 + 203-2 (H 2 0)
and the hydrochloride, B . HC1, 0-5H2O, m.p. 250 (dry, dec). The
oxygen atoms in erythramine are present as one methoxyl and one methylenedioxy group. Neither CMe nor NMe is present and the nitrogen atom
is tertiary, a methiodide, m.p. 96-8, [a]},8" + 176 (H 2 0) being formed by
the action of methyl iodide. Hydrogenation in dilute hydrochloric acid
at 2 atmospheres pressure in presence of platinic oxide produces a tertiary
dihydro-derivative, m.p. 89-90, of which the following salts were prepared :
hydriodide, m.p. 214-5 (dec), [a] D 0 ; hydrobromide, B . HBr . H 2 0,
m.p. 240; methiodide, B . M e l , 0-5H2O, m.p. 160-1. Erythramine
hydrobromide shows curare-like action in the frog at 7 mgm. per kilo. :
the methiodide and dihydroerythramine are respectively one-third and onetwentieth as active. 26 (For probable constitution see below.)
Erythraline, C 18 H 19 0 3 N. This alkaloid and erythratine were first
isolated from E. glauca Willd. but have also been obtained from other
species of the genus. 27 It has m.p. 106-7, [a]?/0 + 211-8 (EtOH) and
yields the following salts : B . HI, m.p. 252-3 (dec), [aff + 177 ( H 2 0 ) ;
B . HBr, m.p. 243, [a]27 + 216-6 (H 2 0). The oxygen atoms are present
as a methoxyl and a methylenedioxy group. The nitrogen atom is tertiary.
The methiodide, m.p. 185-7, on oxidation with permanganate yields
hydrastic acid methylimide (p. 164). On hydrogenation in very dilute
hydrochloric acid and in presence of platinic oxide erythraline absorbs
ETBTHBINA
ALKALOIDS
389
s\
<
(i)
\y
^
.ITCH 3
CO'
^2
CH2
H2C
(II)
CH2
MH
CH2
390
isoQUINOLINE
GROUP
M.p.
U1D
C16H14H(0Me)2(0H)
204-5
+248
B.HC1;
10
Erysonine
236-7
( variable)
+285-9
B.HC1;
100
Erysopine
Ci6Hl4N(0Me) (OH) 2
241-2
+265-2
B.HC1;
Erysovine
179-5
+232-4
Ne s a l t .
Name
Formula
Erysodine
Combined Erythrina Alkaloids. The sources of the " liberated " alkaloids
(see above) are now known to be, at least in two cases, the sulphur-containing
alkaloids erysothiopine and erysothiovine, which are esters of sulphoacetic
acid, HOOC . CH 2 . S 0 2 . OH, identified as the aniline salt, m.p. 187-9 ;
with erysopine and erysovine respectively. The sources of erysodine and
erysonine have not yet been isolated. These combined alkaloids are
believed to be sulphonic esters, of the type HO . OC . CH 2 . S0 2 . O . R,
where R is the alkaloidal residue.30
Combined Alkaloids of Erythrina spp.
Name
Formula
Erysothiopine
C 1 6 H 1 4 N (OMe) (OHII-O-SOj-CHj-COgH) ,H 2 0
Erysothiovine
Minimum p a r a l y s i n g dose:
mgm./kilo., frog
Corresponding
l i b e r a t e d base
M.p.
[a]D
168-9
+ 194
Na s a l t ;
erysopine
187
+ 208
Ha e a l t ,
erysovine
PHARMACOLOGICAL
ACTION
391
following figures for his " curarines " : protocurarine 0-24 ; tubocurarine
1- 0 ; curarine 0-34. King's tubocurarine chloride produced curare paralysis
in frogs at 0-5 mg. per kilo and the isomeric d-bebeerine methochloride had
about ^ t h of that activity ; the same author's protocurarine was effective
in frogs at 1-5 mg. per kilo. Figures for paralysing doses of the various
curare and Erythrina alkaloids isolated in recent years are given in the
foregoing chemical sections.
West has shown that curare varies qualitatively in action, some
specimens having a " lissive " action, defined as " the selective removal of
pathological rigidities without apparent diminution of voluntary power " ;
and Hartridge and West 32 found it possible to control tetany in parathyroidectomised dogs by the use of a curare chosen on this basis.
There has been considerable discussion on this subject 32(a) and the
difficulty of obtaining supplies of curare and of preparing a uniform and
standardised product, suitable for general clinical use, from this extremely
variable drug, did not make for rapid progress at first but a number of
papers have appeared on the treatment of conditions involving certain
types of muscular rigidity. 33 The results were sufficiently promising to
arouse interest in the possible therapeutic applications of curare and by
1940 preparations more suitable for extended clinical trial were made
available, such as extract of Chondrodendron tomentosum, freed from
disadvantageous components and biologically standardised, 34 d-tubocurarine chloride,35 jS-erythroidine hydrochloride and more recently
dihydro-/3-erythroidine hydrochloride. These products have been the
subject of clinical trials in spastic-paralytic and dystonic conditions, 36
for the control of convulsions in the shock therapy of psychiatric patients 37
and more especially as an adjunct to general anaesthetics to produce the
muscular relaxation desirable in some surgical operations. 38 Curare has
also been suggested as a means of diagnosis of Myasthenia gravis.39
These developments have naturally led to the investigation of methods
of estimating the curarising potency of curare, preparations of tubocurarine chloride and possible synthetic substitutes for the latter. As
already stated, chemical methods for curare and its preparations are being
developed (p. 374) and work is being done on biological tests. 40 ' a) Investigations are also in progress on the general pharmacology of the drug,40(6) and
particularly on its mode of action, and in general on the interactions among
acetylcholine, the choline-esterases, curare and physostigmine, the lastnamed substance and its modern analogues and possible synthetic substitutes (p. 550) having special interest as antidotes to curare. In the latter
connexion an unexpected development is the discovery by Halpern,
Benda and Bourdon 40(c) that the bis-(8-quinolyloxy)-l : 5-pentane diethiodide prepared by Bovet, Courvoisier, Ducrot and Horclois ** is not
only a potent curarising substance, but also possesses well-marked action
of the physostigmine type.
There is already a voluminous literature on the medical use of curare
of which several useful reviews have been written.40'"*'
Curine is generally stated to be of low toxicity, and not to exhibit
392
isoQUINOLINE
GROUP
393
CURARE ALKALOIDS
44, 221 (Chem. Abstr., 1942, 36, 1441); ROBERTS, H E C H T and JACKMAN, J. Pharmacol.
Exp. Ther., 1942,74,392. (7) Ber., 1928,61,1698. (8) J. Chem. Soc., 1935,1381; 1939,
1157 ; 1940, 737 ; 1948, 265 ; see also DUTCHER, J. Amer. Chem. Soc., 1946, 68, 419.
(8a) FOSTER, Analyst, 1947, 72, 6 2 ; (with TURNER), Quart. J. Pharm., 1947, 20, 228,
412. (9) Acta Med. Skand., 1931, 75, 7 ; Skand. Arch. Physiol,
1934, 68, 213.
(10) Arch. Pharm., 1897, 235, 660. (11) Nature, 1935,135, 469 ; see also Kew Bulletin,
1933, No. 8, 390. (12) Ann. Chim., 1829, [ii], 39, 24. (13) Jabresb., 1861, 767.
(14) Compl. rend., 1865, 60, 1346. (15) Annalen, 1878, 235, 660. (16) Abh. Kgl.
Sachs. Ges. Wiss., 1895, 22, 203 ; 1896, 24, 23 ; Arch. Pharm., 1897, 235, 660. (17) Ber.,
1934, 67, 55 ; cf. K I N G , Ann. Rept. Chem. Soc, 1933, 30, 249. (18) J. Amer. Chem. Soc,
1946, 68, 419 ; (with WINTERSTEINER), Science, 1943, 97, 467 ; cf. K I N G , Nature,
1946,158,515 ; J. Chem. Soc, 1947, 936. (19) W I E L A N D (with KONZ and SONDERHOFF),
Annalen, 1937, 527, 160 ; (with PISTOR), ibid., 1938, 536, 68 ; (with PISTOR and BAHR),
ibid., 1941, 547, 140 ; (with BAHR and WITKOP), idem., p. 156 ; cf. W I T K O P , Die Chemie,
1942,
J. Set,
1932, 48, 5 6 3 ; R A O
et al, Proc. Ind. Acad. Set, 1938, 7, A, 179 ; cf. CHAKRAVARTI et at, J. Annamalia
Univ., 1933, 2, 238 ; DEULOFEU, H U G and MAZZOCCO, J. Chem. Soc, 1939, 1841 ;
(with LABRIOLA), Anal. Asoc. Quim. Arg., 1941, 29, 121 ; GENTILE and LABRIOLA,
J. Org. Chem., 1942, 7, 1 3 6 ; DEULOFEU et al., ibid., 1947, 12, 4 8 6 ; FOLKERS and
KONIUSZY, J. Amer. Chem. Soc, 1939, 61, 1232 ; 1940, 62, 436, 1677 ; (with SHAVEL),
ibid., 1941, 63, 1544. (24) Proc. K. Akad. Weten. Amst., 1911, 13, 1177; J. Chem.
Soc, 1911, 99, 2068 ; CAHILL and JACKSON, J. Biol. Chem., 1938,126, 29, 627 ; PLUGGE,
Arch. exp. Path. Pharm., 1893, 32, 313. (25) FOLKERS (with MAJOR), J. Amer. Chem;
Soc,
U.S.P. 2,373,952.
(25a) MERCK
and
MAJOR, B . P . 543,187;
(256) MAJOR and FOLKERS (to MERCK & Co.), U.S.P. 2,280,837.
Pharm. Assoc,
Amer.
1946, 35, 48. (25d) UNNA, KNIAZUK and GRESLIN, J. Pharmacol, exp.
(28) FOLKERS
(with
KONIUSZY
(29) FOLKERS (with KONIUSZY), ibid., 1940, 62, 1677 ; (with SHAVEL and KONIUSZY),
ibid., 1941, 63,1544 ; (with SHAVEL), ibid., 1942, 64, 1892 ; cf. GENTILE and LABRIOLA."
(30) FOLKERS (with KONIUSZY and SHAVEL), J. Amer.
(31) W E S T , Proc. Roy. Soc Med., 1932, 25, 1107 ; Lancet, 1938, 234, 432 ; J. Physiol,
1938,91,437; THORNTON, ibid., 1938, 93, 40. (32) Brain, 1931, 54, 312, 508. (32a) See,
for example, W E S T , COLE, D A L E , B U R N , HARTRIDGE and others, Brit. Med. J., 1935,
i, 125.
(33) See, for example, COLE, Lancet, 1934, 227, 475, 1130 ; FLOREY, HARDING
and FILDES, ibid., p . 1036 ; MITCHELL, ibid., 1935, 228, 262 ; W E S T , ibid., 1934, 227,
1194 ; 1936, 230, 12 ; 1938, 234, 432 ; 1945, 249, 155 ; J. Physiol, 1938, 91, 437 ;
Arch, intern. Pharmacodyn., 1937, 56, 81 ; Annotation, Brit. Med. J., 1939, ii, 405.
(34) GRIFFITH, J. Amer. Med. Assoc, 1945,127, 6 4 2 ; cf. Ref. (18) ; BAIRD and ADAMS,
Proc. Mayo Clinic, 1944, 19, 200 ; " New and non-official remedies," J. Amer. Med.
Assoc, 1945, 129, 517. (35) MACINTOSH, Lancet, 1945, 249, 124 ; see also W E S T 3 S
(1945). (36) Brit. Med. J., 1939, ii, 405 ; 1942, ii, 2 2 4 ; BURMAN, Arch. Neurol. Psych%,
1939, 41, 307 ; J. Pharm. exp. Ther., 1940, 69, 143 ; DENHOFF and BRADLEY, New
Eng. J. Med., 1942, 226, 411 ; HARVEY et al, Trans. Amer. Neur. Ass., 1940, 66, 156.
(37) B E N N E T , J. Amer. Med. Assoc, 1940, 114, 322 ; Amer. J. Psychiat., 1941, 97,
1040 ; R O S E N , ZIKGLER and COMINOLE, J. Amer. Pharm. Assoc,
and B O R E N S T E I N , Psychiat.
ibid., p . 5 3 7 ; BROWN, ESSEX and MOEBSCH, Proc. Mayo Clinic, 1941,16,264 ; WttxiAMS,
394
GROUP
TSOQUINOLINE
Ohio State Med. J., 1941, 37, 849 ; HOBSON and PRKSCOTT, Brit. Med. J., 1947, i, 451 ;
DONOVAN, Lancet, 1947, 252, 634 ; R I S I N G and CARROL, J. Kansas Med. Set., 1946-7,
p. 297.
(38) G R I F F I T H a n d J O H N S O N , Anesthesiology,
1942, 3, 418 ;
DRIPPS
and
SARGENT, ibid., 1947, 8, 241 ; CULLEN, ibid., 1944, 5, 166 ; COLE, ibid., 1945, 6, 48 ;
GRIFFITH, Ref. (34) and Can. Med. Assoc. J., 1945, 52, 391 ; Lancet, 1945, 249, 74 ;
MALLINSON, ibid., p . 75 ; PRESCOTT, ORGANE a n d ROWBOTHAM, ibid., 1946, 251, 80 ;
G R A Y a n d H A L T O N , Proc. Roy. Soc. Med., 1946, 39, 400. (39) B E N N E T T a n d CASH,
Trans. Amer. Neur. Ass., 1942, 68, 102 ; Arch. Neurol. Psych., 1943, 49, 537 ; see also
Lancet, 1943, 244, 274. (40) (a) CHOU, Brit. J. Pharmacol., 1947, 2, 1 ; D E JALON,
Quart. J. Pharm., 1947, 20, 28 ; (with W E S T ) , Nature, 1947, 159, 841 ; W E S T , Quart.
J. Pharm., 1947, 20, 518 ; SKINNER and YOUNG, J. Pharm. Exp. Ther., 1947,91,144 ;
VARNEY, LINEGAR and HOLADAY, Fed. Proc, 1948, 7, 261. (6) See, for example,
BRISCOE, J. Physiol., 1938, 93, 194 ; COWAN, ibid., p . 215 ; HARRIS a n d H A R R I S , Proc.
Soc. exp. Biol. Med., 1941, 46, 419 ; 1944, 56, 223 ; MCINTYRE a n d K I N G , Science,
1943, 97, 69, 516 ; (with D U N N ) , J. Neurophysiol,
1945, 3, 297 ; GROSS a n d CULLEN,
Anesthesiology,
1945, 6, 231 ; COMROE a n d D R I P P S , ibid., 1946, 7, 260 ; HOLMES,
J E N D E N and TAYLOR, Nature,
Pharm.
exp. Ther.,
J. Physiol.,
J.
1948, 92, 236 ; (e) KOPPANYI and VIVINO, Science, 1944, 100,
Med. Bull., 1946, 4, 110 ; SCHLESINGER, Bull. New York Acad. Med., 1946, 22, 520 ;
ROBBINS and LUNDY, Ancesthesiology, 1947, 8, 252, 348 ; Report of a symposium on
d-tubocurarine chloride, Brit. Med. J., 1947, i, 451 ; MOERSCH, Dansk. Tids. Farm.,
1946, 20, 295. (41) Arch. exp. Path. Pharm., 1934, 174, 742 ; cf. W E S T , Proc. Roy.
Soc. Med., 1934-5, 28, 572 ; BRAZIL et al., Bol. Inst. Vital. Brazil, 1945, 5, 79 (Chem.
Abstr., 1947, 41, 3872) ; J. Amer. Med. Assoc, 1947, 133, 882 ; MARSH, SLEETH and
T U C K E R , Fed. Proc,
(42) CRUM
example, ING (with COWAN), J. Physiol, 1933, 79, 75 ; 1934, 82, 432 ; 1935, 84, 90 ;
(with WRIGHT), Proc Roy. Soc, 1931, B , 109, 337 ; 1933, B , 114, 48 ; (with BARLOW)
also PATON and ZAIMIS, Nature, 1948, 161, 718 ; ING, Physiol. Rev., 1936, 16, 527 ;
SIMON, Arch. int. Pharmacodyn.,
1926,
D.R.P.
59, 1209 ;
GLUCKSMANN,
571,294 ;
BOVET,
COURVOISIER,
DUCROT,
HORCLOIS, Compt. rend., 1946, 223, 597 ; 1947, 224, 1733 ; BOVET, D E P I E R R E a n d
LESTRANGE, Compt. rend., 1947, 225, 74 ; DEPIERRE, idem., p . 956. (44) J. Pharm.
exp. Ther., 1942, 75, 265, 270 ; CHASE, LEHMAN a n d RICKARDS, ibid., 1944, 82, 266.
See also HARVEY a n d MASLAND, ibid., 1941, 73, 304 ; P I C K (with U N N A ) , ibid., 1945,
83, 59 ; (with RICHARDS), ibid., 1947, 90, 1 ; MARSH and PELLETIER, ibid., 1948, 92,
127; LENORMANT, Compt. rend. Soc. Biol., 1941, 135, 1050. (45) Brit. J. Pharmacol.,
1946, 1, 265 ; 1947, 2, 241 ; Quart. J. Pharm., 1947, 20, 94 ; Nature, 1947, 159, 813 ;
Lancet, 1947, 252, 9 7 ; see also BURKE and LINEGAR, Fed. Proc, 1948, 7, 208.
(46) MALLINSON, Lancet, 1947, 252, 98.
ALKALOIDS OF IPECACUANHA
The roots of Cephcelis Ipecacuanha (Brot) A. Rich constitute the
Brazilian ipecacuanha of commerce and also that cultivated in the
Federated Malay States, Bengal and Burma. Carthagena ipecacuanha is
derived from Cephcelis acuminata Karsten collected in Colombia. Emetine,
the principal alkaloid of this drug, was first obtained by Pelletier and
Magendie 1 in 1817, but was first prepared in a pure state by Paul and
Cownley,2 who separated from commercial emetine the phenolic base,
cephaeline, and later obtained a third alkaloid, psychotrine. To these
Pyman 3 added emetamine and O-methylpsychotrine,
IPECACUANHA
ALKALOIDS
395
396
TSOQVINOLINE
GROUP
IPECACUANHA ALKALOIDS
397
398
isoQUINOLINE
GROUP
Emetine, C 29 H 40 O 4 N 2
Cephseline, C 28 H 38 0 4 N 2
Emetamine, C 29 H 36 0 4 N 2
Emetine
Oz&^F^h
Psychotrine
> . isoCephaellne
C
25 H 28 N 2 l 0 C H 3 ' s 0 "
25H28"N2<0CH3 ) 3 0 H
-<- O-methylpsychotrine
6
Z5ni*V0aiS>~
IPECACUANHA
ALKALOIDS
399
at 225-6 and 262 respectively, both of which yield the same iV-methylemetinemethine, C 32 H 46 0 4 N 2 (oxalate, B . H 2 C 2 0 4 . 7-5H20, hard, brilliant
prisms, m.p. 82-3), so that the methiodides appear to be stereoisomeric.
A^Methylisoemetinemethine, similarly obtained from isoemetine, gives
an oxalate, C 3 2 H 4 6 0 4 N 2 . H 2 C 2 0 4 . 4H 2 0, crystallising in diamondshaped prisms, m.p. 133-4 (dried at 100), [a] D + 4-2 (H 2 0), and a
methiodide, which crystallises (with 1 mol. of methyl iodide) from water
in silky needles, m.p. 178-800.20
Oxidation. On gentle oxidation, for example, with iodine (1 mol.) in
alcohol, emetine and woemetine, C29H40O4N2, are converted into O-methylpsychotrine, C 29 H 38 0 4 N 2 , whilst more vigorous oxidation of any of these
three bases, for example, with four molecular proportions of iodine, or by
boiling with ferric chloride yields a new mono-acidic base, RUBREMETINE
(dehydroemetine), C 29 H 32 0 4 N 2 , isolated as the hydrochloride (rubremetinium chloride 21 ), B . HC1. 6H 2 0, brilliant scarlet needles, m.p. 127-8
or 166-73 {dry). In rubremetine one nitrogen atom is no longer basic,
and the second has become quaternary.
Carr and Pyman's observation that on oxidation with potassium
permanganate in acetone, emetine yields 6 : 7-dimethoxywoquinoline-lcarboxylic acid and metahemipinic acid (the latter confirmed by Windaus
and Hermanns) 22 constitutes the first definite evidence of the presence
of an woquinoline nucleus in emetine and the allied bases. 23 In 1927,
Spath and Leithe 24 showed that emetine on gentle oxidation with dilute,
faintly alkaline solution of potassium permanganate gave l-keto-6 : 7dimethoxy-1 : 2 : 3 : 4-tetrahydrowoquinoline (corydaldine, p. 286), and
pointed out that unless the oxidation of emetine to 6 : 7-dimethoxywoquinoline-1-carboxylic acid as observed by Carr and Pyman implied an
unusual dehydrogenation, this new observation indicates the presence
of a corydaldine complex, and therefore of a second isoquinoline nucleus
in emetine. In support of this view it was found that on oxidation of emetine
the yield of m-hemipinic acid was 65 per cent, of that calculated for one
woquinoline group, whereas palmatine and papaverine each containing only
one isoquinoline group gave only 34 and 25 per cent, respectively, and that
further treatment of the by-products in the oxidation of emetine increased
the yield to 96 per cent, of the calculated m-hemipinic acid, allowance being
made for the ketonic base. The second soquinoline nucleus thus indicated
must contain the secondary nitrogen atom, since iV-benzoylemetine on
oxidation under similar conditions gave 3 : 4-dimethoxy-6-/S-benzamidoethylbenzoic acid. In cephasline the same nucleus probably contains the
free hydroxyl group, since cephseline ethyl ether, on oxidation, gave a
mixture of l-keto-6 : 7-dimethoxy- and l-keto-7-methoxy-6-ethoxytetrahydrowoquinoline. At the second stage of an Emde degradation emetine
produced some trimethylamine {cf. Karrer 21 ), indicating the presence of
a secondary nitrogen atom, but in the third stage only poor yields of a
nitrogen-free product were obtained. On the basis of these observations
the partial formula (I) was proposed for emetine by Spath and Leithe.84
Later in the same year Brindley and Pyman,16 proposed formulae for
400
JSOQVINOLINE
GROUP
CONSTITUTION
401
<J4H7
?H 8
CH
CH2
CH
CH2
CH
CH
MeO /
MeO
(II)
Z
JCH
CHM9
xaaii
CH,
C\ I M e
N/
E
/CH
OMe
,CH
CH' JC
II C |
PCI
OMe
>"W
,CH
H0
CH
!
]2
CHMs
CH
\,
HClv
\H
Xf
I
J
\0Ue
F
JOMe
CHMe
(V)
vinyl group ; a condition which can be regarded as existing in ring A of
O-methylpsychotrine. The latter is, therefore, represented "by (IV) with
a double bond at C1C9 and psychotrinc by (IV) with R H, and a
double bond at C1C9.
Emetamine reduces to woemetine by addition of four atoms of hydrogen,
but it seems unlikely that either of its ethylenic linkages occupies position
C1 to C9, since it is not found as an intermediate product in the oxidation
of O-methylpsychotrine to rubremetine, and does not itself yield the latter
on oxidation. As it is more feebly basic than O-methylpsychotrine, it is
assumed that ring B of woquinoline nucleus (A.B.) is unsaturated as in (VI).
Staub, 5 taking into account the similarity of berberine and rubremetine,
and having found that the bromide of the latter is oxidised by permanganate to dioxyrubremetine (dioxydehydroemetine), C 29 H 28 0 6 N 2 , m.p. >305,
suggested a modified formula for emetine (p. 402) with corresponding,
changes in the formulae of the associated alkaloids.
Ahl and Reichstein 3 have pointed out that though it is certain that
the structure of emetine includes one, and possibly two, 6 : 7-dimethoxytetrahydroisoquinoline nuclei, the suggestions so far made as to the nature
of the rest of the molecule are speculative. They investigated the Hofmann
degradation of JV-acetylemetine, m.p. 97-9. This forms a monomethiodide,
m.p. 21&-60, from which, by the action of silver oxide and potassium
hydroxide, followed by cautious thermal decomposition and reacetylation,
402
ISOQUINOLINE
GROUP
a.c/V'N
OHo
CH
Dioxydehvdroemetine (Staub)
HCf^
\C.0Me
Emetine (Staub)
THERAPEUTIC
USES
403
proved inactive in vitro at 1 in 5,000, and the best example of types B and
B', 9 : 10-dimethoxy-3-phenyl-5 : 6-dihydrobenzglyoxalocoline (B') was
active at 1 in 25,000 as compared with emetine, effective at 1 in
500,000.
The harmol derivatives (type C), in which R ranged from ethyl to
n-dodecyl, proved active in vitro, and reached a peak of activity at O-nnonylharmol, and in a second series in which R was modified by the
inclusion of a dialkylamino-residue, activity was further increased and
reached a maximum at O-A-di-n-butylaminoundeeylharmol (type C:
R = (C 4 H 9 ) 2 N(CH 2 ) n -).
The remarkable activating influence of the dialkylaminoalkyl side-chain
was still shown when the harmol nucleus was replaced by other basic
nuclei or even by a simple substituted amino-group, and out of an extensive
series of compounds of the general formula (D) a/c-tetra-n-amyldiaminon-decane proved to be the most active.
-[CHJan
X /\AoMe
1
H 0k
j
l
>
vA
2
ui^/
2
/\
rV
KeOrA
MeoL I
EN/
2
CH2
R<A
(C)
"
KB
&,
(D)
NRR'.[GH1
.NRR'
404
TSOQUINOLINE
GROUP
Cf. GLENARD,
Ann.
Chim. Phys., 1876, [v], 8, 277 ; and K U N Z - K R A U S E , Arch. Pharm., 1887, 225, 461 ;
1894, 232,466. (3) J. Chem. Soc, 1917, 111, 428 ; see also Am. and REICHSTEIN, Helv.
Chim. Acta, 1944,27,366 ; BUCK, J. Amer. Chem. Soc, 1934, 56,1769. (4) J. Chem. Soc,
1914, 105, 1599 ; cf. H E S S E , Annalen, 1914, 405, 1. (5) " Ein Jahrhundert chemischer.
Forschung ilber Ipecacuanha-Aklaloide,"
Zurich, 1927 ; Helv. Chim. Ada., 1927, 10,
826 ; ADDOR, Bol. Minist. Agr. Brazil, 1945, 34, No. 5, p . 1. (6) See also K E L L E R
and BERNHARD, Arch. Pharm., 1925, 263, 401. (7) B.P. 14,677 ; see also B.P. 17,483,
D . R . P . 298,678, B.P. 291,088 (1928), and Russ.P. 20,082 (Chem. Zent., 1931, ii, 3664).
(8) FIGDOR, Amer. J. Pharm., 1926, 98, 157, describes a micro-form of Dieterle's process,
Arch. Pharm., 1923, 261, 77 ; BLISS, J. Assoc. Off. Agric. Chem., 1927, 10, 359 ; LEGER,
J. Pharm. Chim., 1927, [viii], 6, 501 (ipecacuanha extracts) ; MADSEN, Dansk. Tids.
Farm., 1928, 2, 145 (ipecacuanha extracts) ; BAGGESGAARD-RASMUSSEN, W A E L and
CHRISTENSEN, Dansk. Tids. Farm., 1929, 3, 250 (drug and galenical preparations);
BAUER and H E B E R , Pharm. Zent., 1930, 71, 513 ; cf. B C C H I , Pharm. Zeit., 1933, 78,
448 ; KLYACHKINA and ZILBERG, Bull. Nauch. Issledov. Khim.-Farm. Inst., 1931, 103
(separation of secondary bases from emetine) ; DAVID, Pharm. Zeit., 1935, 80, 112] ;
1936, 81, 806 ; JERMSTAD, Norsk, farm. Tids., 1936, 44, 358, 388 ; EVERS and SMITH,
Quart. J. Pharm., 1938, 11, 758 ; Di GANGI and T R U P P , J. Amer. Pharm. Assoc, 1943,
32, 22 ; W H I P P L E and WOODSIDE, ibid, 1948, 37, 83 ; LOWDELL, Pharm. J., 1946,156,
141 ; 157, 153. (9) See, for example, Rept. Council Sci. Ind. Res. Aust., 1942-3,
p. 11. (9a) MELVILLE, Pharm. J., 1946, 157, 89 ; Quart J. Pharm. 1946, 19, 202;
CHOPRA and
M U K E R J I , Ind.
Med.
Gaz.,
1932,
GUHA and
J.,
1891,
MUKERJI,
Sci. and Cult., 1945, 11, 204 ; BAL and DATTA, ibid., 10, 448 ; 1946, 12, 200. (10)
F R I E S E , Pharm. Zentr., 1935, 36, 223 ; ORAZI, Rev. facultad. cienc. quim., 1946, 19, 17.
(11) Pharm. Zent., 1934, 75, 598. (12) Pharm. Weekbl., 1935, 72, 513. (13) Cf. PAUL
and COWNLEY, Pharm. J., 1894, [iii], 25, 3 7 3 ; KELLER, Arch. Pharm., 1911, 249,
519. (14) The melting-points of the ipecacuanha alkaloids and their salts are often
indefinite ; the first temperature mentioned is usually a sintering-point, and the second
the point at which the substance flows or decomposes. (15) PYMAN, J. Amer. Chem.
Soc, 1926, 48, 8 3 6 ; cf. PALKIN and W A L E S , ibid., 1924, 46, 1488 ; 1925, 47, 2005.
(16) B R I N D L E Y and PYMAN, J. Chem. Soc,
1927, 1067.
(17) PYMAN, ibid., 1918,
113, 224. (18) Cf. KARRER, Ber., 1916, 49, 2057 ; 1917, 50, 582. (19) First observed
in emetine by KELLER, Arch. Pharm., 1911, 249, 512. (20) PYMAN, J. Chem. Soc,
1917,
111,
445 ;
1918,
113,
234.
Cf.
K A R R E R , Ber.,
1916,
49,
2057 ;
and
HESSE,
ibid., 1917, 111, 428 ; cf. KARRER, Ber., 1916, 49, 2057. (22) Ibid., 1914, 47, 1470 ;
HERMANNS, Inaug. Diss. Freiburg i. Br., 1915. (23) Cf. DOBBIE and F o x , J. Chem.
Soc,
PYMAN (16).
(26)
(24) Ber.,
CHOPRA and
CHOPRA, Ind.
Med.
(25) Quoted b y B R I N D L E Y
Gaz.,
1942,
77, 65 ; ADAMS,
and
Trans.
Roy. Soc Trop. Med. Hyg., 1945, 38, 237 ; HARGREAVES, ibid., p . 244 ; Lancet, 1945,
ii, 68 ; DACK and MLOSHOK, Arch, intern, med., 1947, 79, 228. (27) DOBELL (with
LAIDLAW), Parasitology, 1926, 18, 206 ; (with LAIDLAW and BISHOP), ibid., 1928,
20, 207 ; see also BONNIN and ARETAS, Bull. Soc. Path. Exot., 1938, 31, 829 ; REGNIER
et al., Ann. Pharm. Franc, 1944, 2, 49 ; D E LAMATER and HALLMAN, Proc Soc Exp.
Biol. Med., 1947, 65, 26 ; BRACKETT and BLIZNECK, J. Parasitol., 1947, 33, 154. (28)
J E P P S and MEAKINS, Brit. Med. J., 1917, ii, 645 ; Low, ibid., 1915, ii, 715 ; W E N Y O N
and O'CONNOR, J. Roy. Army Med. Corps, 1917, 28, 473. (29) CHILD and PYMAN,
J. Chem. Soc, 1929, 2010 ; 1931, 36 ; COULTHARD, L E V E N E and PYMAN, Biochem. J.,
1933,27, 727 ; 1934,28,264 ; PYMAN, Chem. and Ind., 1937,56,789 ; for other synthetic
IPECACUANHA
ALKALOIDS
405
work in this direction see SUGASAWA et al., Proc. Imp. Acad. Tokyo a n d K I N G and
ROBINSON, J. Chem. Soc, 1938, 2119. (30) I R I Y E , Nisshin. Igaku, 1912, 1 1 , No. 9 ;
ACTON, Lancet, 1922, i, 126 ; H E N R Y and BROWN, Trans. Roy. Soc. Trop. Med. Hyg.,
1923-24, 17, 6 1 .
(31) (With
GOODSON,
GOBVIN, G O S S , K I B B Y ,
LOCK, N E A L
and
SOLOMON), Brit. J. Pharmacol., 1948, 3 , 49, 62. (32) Handb. Chemother., Teil 1
(Fischer, Leipzig, 1932), p p . 224-56. (33) Brit. Med. J., 1941, ii, 2 5 5 ; see also
symposium on amoebiasis, Trans. Roy. Soc. Trop. Med. Hyg., 1947, 41, 55. (34) J O N E S ,
Brit. J. Pharmacol., 1947, 2, 217. (35) Ibid., 1948, 3 , 44. (36) S. AJr. J. Med., 1937,
2, 10. (37) Arch. Dermal. Syphilol., 1942, 45, 550 (38) J. Pharm. exp. Ther., 1941,
71, 362.
PHENANTHRIDINE GROUP
ALKALOIDS OF THE AMARYLUDACEiE
From Narcissus pseudonarcissus L. Gerrard 1 isolated the alkaloid
narcissine, which was subsequently examined by Ewins. 2 Twenty years
later Morishima 3 described a supposed new alkaloid, lycorine from Lycoris
radiata Herb., and in 1913, Asahina and Sugii 4 suggested that lycorine
and narcissine were identical. This was confirmed by Gorter, 5 who found
the same alkaloid in the following Amaryllidaceous plants : Amaryllis
belladonna L ; Clivia miniata Benth 6 ; Cooperia Drummondii Herb.
(also in C. pedunculata by Greathouse and Rigler 7 ), Crinum asiaticum
L., 8 C. giganteum Andr., C. pratense Herb, (also in C. scabrum, by Reichert 9 ),
Cyrtanthus pallidus Sims.; Eucharis grandiflora Blanck. ; Eurycles
sylvestris Salisb., (also in E. amboinensis by Oliveros and Santos 1 0 ) ;
Hymenocallis littoralis Salisb. ; Sprekelia formosissima Herb. App. 11
(Ungernia Sewertzovii Rgl. by Norkina and Orekhov 12) and (U. tadshicorum
Uved., by Juraschevski 1 3 ) ; Zephyranthes rosea Lindl and (Z. texana by
Greathouse and Rigler 7 ). The names in brackets in this list are those of
species in which lycorine has been recorded by other authors than Gorter.
Lycorine may also be the alkaloid Robecheck l 4 found in Narcissus
orientalis, but N. poeticus L., according to Kolle and Gloppe,15 contains
narcipoetine, which may be identical with /jomolycorine. From Narcissus
Tazetta L. Spath and Kahovec 16 isolated tazettine, to which Kihara 16
has recently added suisenine. Kondo's " base VIII " 17 from Lycoris
radiata and " ungerine," obtained from Ungernia Sewertzovii Rgl. by
Orekhov and Norkina, 12 were eventually identified with tazettine. The
same authors 16 suggest that sekisanine may also be identical with tazettine.
In Cooperia pedunculata, Greathouse and Rigler 7 found a second alkaloid,
which may be ^A-lycorine. From Lycoris radiata Herb, there have been
isolated nine alkaloids, viz., lycorine, lycoramine, lycorenine and tazettine
and the minor bases, sekisanine, sekisanoline, </r-lycorine, /jomolycorine,
and base IX. From Buphane disticha Herb. (Hwmanthus toxicarius Herb.)
Tutin 18 isolated lycorine (narcissine) and three amorphous bases, one of
which was named buphanine ; the latter has not been characterised but
it is converted by potassion hydroxide into a crystalline substance,
buphanitine, which has been described.
Lycorine (Narcissine), C 16 H 17 0 4 N. The alkaloid crystallises in prisms,
m.p. 275 (dec), [a]2,6" - 129 (EtOH), and is best purified as the hydrochloride B . HC1. H 2 0, needles, m.p. 217 (dec), [<x]D + 43-0; the
picrate has m.p. 196 and the perchlorate m.p. 230 (dec). Lycorine
contains a methylenedioxy group and two non-phenolic hydroxyl groups
(diacetyl derivative, m.p. 215-6, [a] D + 31-5). On oxidation with alkaline
permanganate it furnishes hydrastic (4 : 5-methylenedioxyphthalic acid)
408
LYCORINE
407
and oxalic acids. On these grounds and an assumed resemblance to hydrastine, Gorter 6 proposed an woquinoline formula for the alkaloid. Kondo
and Tomimura 19 confirmed Gorter's results but did not accept his formula.
Kondo and Uyeo 20 found that lycorine on distillation with zinc dust
yielded phenanthridine, thus establishing a relationship with tazettine.
In the first stage of the Hofmann degradation of lycorine, the methine base
obtained is abnormal, the two hydroxyl groups being eliminated by loss
of water. The product obtained is lycorineanhydromethine, C 17 H 15 0 2 N,
m.p. 98-5, [<x]D 0. This on oxidation with permanganate yields two
acids, (a) C 1 7 H n 0 6 N . H 2 0, m.p. 252 {dec), and (b) C 1 6 H u 0 5 N, m.p. 288.
The former passes into the second on further oxidation with hydrogen
peroxide, indicating that it is an a-keto-carboxylic acid. Acid (b) loses
carbon dioxide on fusion and gives a neutral substance, C 1 5 H u 0 3 N, m.p.
238, which was shown to be 6 : 7-methylenedioxy-iV-methylphenanthridone (I), by comparison with a synthetic specimen. The position of the
carboxyl group in (b) could not be determined by synthetic methods but
is probably at C1 since dihydrolycorineanhydromethine, C 17 H 17 0 2 N,
m.p. 87-5 [picrate, m.p. 174 (dec.); methiodide, m.p. 236 (dec.)] on
distillation with zinc dust yields a mixture of phenanthridine, 1-methylphenanthridine and 6 :7-methylenedioxyphenanthridine, m.p. 142
[picrate, m.p. 257 (dec.)], the identity of the two latter being established
by comparison with the synthetic products. These results indicate for
lycorineanhydromethine formula (II).
In 1937 20 a formula of type (III) was put forward for lycorine, but the
location of the two hydroxyl groups and of an ethylenic linkage had still
to be determined. It seems certain these are in ring B, since the production
of hydrastic acid on oxidation precludes the presence of two hydroxyls in
rings A or C. In 1938 it was shown that lycorine produces two methiodides,
a-, m.p. 247 (dec), [a]2,0" - 46-1 (H 2 0), and p- B . Mel. H 2 0, m.p. 198
(dec.) or 281 (dry, dec), [a]2,0" + 128 (dry, H 2 0). Hofmann degradation
of either leads to the lycorineanhydromethine, m.p. 98-5, described above,
and this on catalytic hydrogenation gives the dihydrolycorineanhydro-
(I)
(ID
(ill)
408
PHENANTHBIDINE
GROUP
CO
Dlhydrolyoorlne
Dlhydrolyoorlaone
CO
Aldehydo-aold
Lycoramine, C 17 H 25 0 3 N. This base was first described as xjt-homulycorine, C 19 H 23 0 4 N (1932).22 It crystallises from acetone in plates,
m.p. 120-1, [a]27 98-15 (EtOH), yields a platinichloride, m.p. 245
(dec), a perchlorate, prisms, m.p. 138-9, and a picrate, m.p. 108-9. The
methiodide forms colourless prisms, m.p. 308. Lycoramine contains one
methylimino-group, one methoxyl group and two non-phenolic hydroxyl
groups (diacetyl derivative, m.p. 95). On oxidation with permanganate
it yielded oxalic acid, m-methoxyphthalic anhydride, and a neutral
substance, C 17 H 23 0 4 N, m.p. 253, [a]*8'5" + 73-65 (CHC13) which (a) still
contains the NMe, OMe, (OH)2 groups of lycoramine, (V) regenerates the
parent base on electrolytic reduction, (c) yields 1-methylphenanthridine
LYCOBENINE
409
/ \
H0
2
MeO.C
I
C
CH
IIV)
/ ,0H
\ C/HO\
HC
0Hj,.000H
CH.OH
|
CH
CHEt(COOH)
/CH.Et
Ma.O
I
X
me
CH
(VI)
CHg.OOOH
C0.0Hs
me
(IX)
(VIII)
(VII)
410
PHENANTHRIDINE
GROUP
M I N O R A L K A L O I D S O F T H E AMARYLLIDACE^E.
Base.
li HCI.
IS. Mel.
Picrate
M.p.
Derivatives
K,
M.p.
M.p.
190
- 222-4
(MeOH)
234
275
146
240
(dry)
205-8
(dec.)
278
193-4
AomoLyeorine,
C17H15N(OMe)2(OH)2
175
+ 65-1
(EtOH)
285
(dec.)
+ 86-2
256
D i a c e t y l - m . p . 173 (dec]
^r-Lycorine, 22
C14HnN(MeO)(OH)3
245
41-5
261
(dec.)
150
Triacetyl- , m . p . 98-101.
207-9
+ 114-6
211
(dec.)
287
Diacetyl- m . p . 72.
D i h y d r o - , m . p . 2 5 0 , [a] -
Sekisanoline,21
C1,H1,0N(CHa02)(0H)2
152
(dec.)
60-27
(CHC1 3 )
117-22
127-33
Suisenine,16
ClsHlsON(OMe)(CH202)(OH)
229
180
189
M.p.
Base IX,2'
C14Hn(NMe)(OMe)(OH)2
Buphanitine,18
CH2406N2, EtOH
Crinamine, 8
C 1 6 H 1 6 0 3 N (OMe)
24
Sekisanine,26
C16H15N(CH202)(OH)2
+ 100-4
Diacetyl-,
m.p.
275 ;
methine
b a s e s : a-, C 1 7 H 2 1 0 3 N , m . p . 270 ;
[a] - 184-8 ( M e O H ) . 0-, m . p . 2 7 5
I
57-14.
Diacetyl- m . p . 155.
B e n z o y l - , m . p . 196 ;
Oxidation
p r o d u c t , C12H1504N, m.p 244.
412
PHENANTHRIDINE
GROUP
K U F F N E R ) , ibid., p . 2446. (13) J. Gen. Chem., U.S.S.R., 1938, 8, 949. (14) Pharm J.,
1893, p . 183. (15) Pharm. Zent., 1934, 75, 237 ; according t o EHRHARD, Inaug. Diss.
Dorpat, 1893, this species contains lycorine. (16) Ber., 1934, 67,1501 ; cf. YAMAMOUCHI,
J. Pharm. Soc. Jap., 1902, 22, 986, and KIHARA, J. Agric. Chem. Soc. Jap., 1939, 15,
128. (17) (With TOMIMURA and ISHIWATARI), J. Pharm. Soc. Jap., 1932, 52, 51 ; (with
SPATH and K U F F N E R ) , Ber.,
cf.
3 6 ; (with KATSURA), ibid., 1934, 54, 194. (20) KONDO (with U Y E O ) , Ber., 1935, 68,
1756 ; 1937, 70, 1087, 1094 ; (with KATSURA and U Y E O ) , 1938, 71, 1529 ; (with
KATSURA), 1939, 72, 2083 ; 1940, 73, 112, 1424 ; KAMIO, J. Pharm. Soc. Jap., 1937,
57, 839. (21) KONDO and ISHIWATA, Ber., 1937, 70, 2427 ; J. Pharm. Soc. Jap., 1938,
Soc. Jap.,
(24)
KONDO and TOMIMURA, ibid., 1929, 49, 76. (25) Idem, ibid., 1927, 47, 82. (26) Okayama
Igakkahi Zasshi, 1933, 45, 2536. (27) Arch. int. Pharmacodyn.,
1935-6, 52, 129.
(28) " Medicinal and Poisonous Plants of S. Africa," 1932, p . 25.
QUINOLINE GROUP
Echinopsine. F r o m Echinops Ritro (seeds) a n d other Echinops s p p .
Greshoff 1 isolated this alkaloid, which Spath and Kolbe 2 have shown is
l-methyl-4-quinolone. Greshoff also obtained from the same source
fi-echinopsine, m.p. 135, a n d echinopseine.
REFERENCES
(1) Rec. trav. Chim., 1900, 19, 360. (2) Monats., 1922, 43, 469.
Dictamnine, C 1 2 H 9 0 2 N. This alkaloid was isolated b y Thorns 1 from
white d i t t a n y root (Dictamnus albus Linn.) along with trigonelline and
choline. I t crystallises in prisms, m.p. 132-3, and yields crystalline salts,
B . HC1, m . p . 195 ; platinichloride, m . p . > 250 ; aurichloride, m . p . 152 ;
picrolonate, m.p. 178 ; and picrate, m.p. 163. I t was subsequently found
in Skimmia repens, N a k a i b y Asahina, O h t a a n d Inubuse, 2 who showed
t h a t it contained one methoxyl group and was transformed by methyl
iodide at 80 into wodictamnine (lb: R = Me), m.p. 188, which contains
no methoxyl group, a change recalling t h a t of a- and y-alkoxyquinolines to
iV-alkylquinolones. 3 With benzoyl chloride and anhydride, it yields
A'-benzoylnordictamnine (lb:
R = Bz), m.p. 165, from which norJietamnine (lb: R = H), m.p. 248, is obtained b y hydrolysis. Dictamnine is oxidised b y permanganate in acetone t o dictamnal, C 1 0 H 6 O 2 N . OMe,
m.p. 259-60, a n d dictamnic acid, C 1 0 H 6 O 3 N . OMe, m.p. 260 (dec.); t h e
latter is converted b y hydrochloric acid into 2 : 4-dihydroxyquinoline and
since 4-hydroxy-2-methoxyquinoline-3-carboxylic acid is not identical
with dictamnic acid, the latter m u s t be 2-hydroxy-4-methoxyquinoIine-3carboxylic acid. Formula (la) was assigned to dictamnine and (I& : R = M e )
to wodictamnine. In a later paper Asahina and Inubuse 4 showed t h a t
dictamnal was converted b y hydrobromic acid in acetic acid into nordictamnal, identical with 2 : 4-dihydroxyquinoline-3-aldehyde. The latter
was synthesised and used t o prepare 0-dictamnine (needles, m . p . 225),
represented b y (II). Observations on t h e pharmacological action of
dictamine have been m a d e b y Kovalenko. 5
REFERENCES
(1) THOMS, Ber. deut. Pharm. Ges., 1923, 33, 68 ; (with DAMBERGIS), Arch. Pharm.,
1930,268,39. (2) Ber., 1930, 63, 2045. (3) KNORR.i&t'd., 1897, 30, 929, 937. (4) Uriel.,
1932, 65, 61. (5) FarmatHya, 1946, 9, No. 5, 20.
418
QUINOLINE
414
GROUP
C-OMe
OMe
,s\
\
0-0H
.MeO-C
(III)
HeffC
"80-0
C-0Me
(IV)
When treated with alcoholic alkalis the y-methoxyl group in skimmianine is replaced by the alkyloxy group of the alcohol used. 3 The
ethoxy-analogue, C 15 H 15 0 4 N, has m.p. 138, yields a picrate, m.p. 194, is
re-converted to skimmianine by boiling with methyl alcohol, with methyl
iodide yields isoskimmianine, and is oxidised to the ethoxy-analogues of
skimmianal, m.p. 212, and skimmianic acid, m.p. 225 (I : EtO in 4).
REFERENCES
(1) Arch. exp. Path. Pharm., 1904, 52, 83. (la) CHOPRA et al., Ind. J. Med.
1938,
26, 481.
(2) Ber.,
1930,
63, 2052.
Res.,
and
415
FAGAMINE
hyde (y-fagaraldehyde), m.p. 185, and thence to fagaric acid, m.p. 215,
which in boiling, dilute hydrochloric acid is decarboxylated and partially
demethylated to a substance, eventually synthesised by Berinzaghi,
Maruzabal, Labriola and Deulofeu,5 and shown to be 2 : 4-dihydroxy-8methoxyquinoline, m.p. 250. With methyl iodide at 100 y-fagarine is
converted into y-isofagarine (cf. dictamnine > isodictamnine, p. 413).
On the basis of these results y-fagarine is formulated as 8-methoxydictamnine (cf. la, p. 413) and y-isofagarine as 8-methoxyisodictamnine (p. 413,
lb with MeO at C8). The ethoxy-analogue of y-fagarine, EtO in position 4
of the quinoline nucleus, has m.p. 143 and forms a picrate, m.p. 161.
a-Fagarine, C 19 H 23 0 4 N, has m.p. 169-170 (dry), distils unchanged a t
170-570-001 mm. and is optically inactive. I t forms a hydrochloride,
m.p. 192-3, a hydrobromide, m.p. 186-8 (dec), a hydriodide, m.p. 190-2
(dec), a methiodide, m.p. 205 (dec), and a picrate, m.p. 208-9. Two
methoxyls, one dioxymethylene group and one methylimino group are
present. The base is not hydrogenated, in presence of platinic oxide, with
hydrogen at 4 atmospheres pressure, and is unchanged on boiling with
either dilute hydrochloric acid or alkali in alcohol. Distilled with soda-lime,
it yields methylamine and on oxidation by permanganate under acid
conditions it produces formaldehyde and m-methoxybenzaldehyde.
Provisional formula (V) has been suggested for the alkaloid.6
a-Fagarine is identical with fagarine-I on which de Espanes has
published a number of pharmacological papers 7 and Deulofeu et a/.6 have
suggested that it should be known in future as fagarine. I t is regarded
as a possible substitute for quinidine in the treatment of auricular fibrillation, 7 and arising out of this work iV-methyldibenzylamines have been
prepared by de Espanes and Weksler 7 and shown to be active in cardiac
iibriilation. A review of the chemistry and pharmacology of the alkaloids
of Fagar a coco has been published by Deulofeu.8
REFERENCES
(1) Invest. Labor. Quim. biol. Univ. nac. Cordoba, 1933, 1, 69 ; D E IPOLA, ibid., p. 94 ;
OLSACHER, ibid., p. 100. (2) J. Amer. Chem. Soc, 1942, 64, 2326. (3) J. Pharm. Soc.
Jap., 1941, 61, 91. (4) J. Ind. Chem. Soc., 1944, 21, 401 ; cf. MOOKERJI, Current Sci.,
1943, 12, 209. (5) J. Org. Chem., 1945, 10, 181. (6) DEULOFEU (with LABRIOLA,
ORIAS, D E E S P A N E S a n d T A Q U I N I ) , Science,
1945, 102, 69 ;
(with LABRIOLA
and
BERINZAGHI), J. Org. Chem., 1947,12, 217. (7) Compt. rend. Soc. Biol, 1937,126, 834 ;
1938, 127, 118, 233, 510, 512, 579 ; 128, 309 ; 1939, 130, 679 ; (with W E K S L E R ) , Proc.
Soc. Expll. Biol. Med., 1946, 63, 195 ; SCHERF, ibid. 1948, 67, 59, cf. VAN DONGEN,
Arch, internal. Pharmacodyn., 1941, 66, 41. (8) Arquiv. faculdade nacl. med. (Rio de
Janeiro), 1946, 1, 8 0 ; for preparation of a-fagarine see Bol. Soc. quim. Peru, 1947,
13, 29.
416
QUINOLINE
GROUP
417
GAL1P0LINE
m.p. 113-5, and yields crystalline salts, more soluble than those of cusparine.
The hydrochloride, B . HC1. 4HaO, forms leaflets, m.p. 165 ; the picrate
has m.p. 194; the aurichloride, B . HAuCl4, and platinichloride both
melt at 174-5. The methiodide, B . CH3I, forms yellow needles, m-.p.
146. Galipine contains three methoxyl groups. On oxidation with
chromic acid it yields veratric acid and a second acid, C 11 H 9 0 3 N . 2H 2 0,
m.p. 194, which was shown by Spath and Brunner 12 to be 4-methoxyquinoline-2-carboxylic acid. On destructive distillation with zinc dust,
galipine yields quinoline.
Galipoidine, C 19 H 15 0 4 N, m.p. 233, is sparingly soluble in most organic
solvents; it forms a platinichloride, B 2 . H 2 PtCI 6 . 2-5H 2 0, crystallising
in stout yellow prisms and decomposing at 158, and an abnormal aurichloride, (B . HC1)2. AuCl 3 . 1-5H20, m.p. 170 (dec), crystallising in
bright yellow needles.5
Galipoline, C19H1903N. A process for the extraction and separation
of the angostura bark alkaloids was described by Spath and Eberstaller, 13
and from the phenolic bases obtained Spath and Papaioanou 6 isolated
this alkaloid. It crystallises from water, has m.p. 193, contains two
methoxyl groups, and on methylation by diazomethane yields galipine.
From a spurious angostura bark, Troger isolated an unnamed alkaloid,
C 2a H 26 0 3 N 2 , m.p. 167, soluble in alkali or acid and giving a crystalline
perchlorate and methiodide. 14
Constitution of Cusparine, Galipine and Galipoline.
Troger and
Kroseberg 5 proposed formula (I) for galipine. The substance represented
by this formula, synthesised by Spath and Brunner, 12 was found to be
different from galipine, and assuming, on good grounds, that the acid
C u H 9 0 3 N . 2H 2 0, m.p. 194 (see above), obtained by Troger and Kroseberg 5
to be 4-methoxyquinoline-2-carboxylic acid, they synthesised cusparine
by condensing 4-methoxy-2-methylquinoline with piperonal to 4-methoxy2-^-3': 4'-methylenedioxyphenyl-Aa-ethinylquinoline (dehydrocusparine),
m.p. 186 (II:CH2CH2replaced by CH=CH), which on hydrogenation of the ethinyl group furnished cusparine (II) identical with the
(I)
Olto
CB
(III)
QUINOLINE
418
GROUP
252,
459.
(11)
T R O G E R and
B E C K E , ibid., 1913,
251,
246.
(12)
Ber.,
1924,
57,
1243. (13) Ibid., 1924, 57, 1687. (14) Pharm. Zent., 1928, 69, 209. (15) (With MARR),
J. Amer. Chem. Soc, 1935, 57, 729 ; (with PAPA), ibid., 1936, 58, 1701. (16) Compt.
rend., 1944, 218, 727 ; see also PORCHER, Ann. pharm. franc, 1945, 3, 140.
CINCHONA
419
C 16 H 18 ON 2
C 19 H 22 ON 2
C 19 H 24 ON 2 .
C 19 H 24 02-N 2
^20-^26'-'2-^' 2
*-'22"26"4^'2
C,8H4402N4
C40H46a,N4
Name
Paricine.
Cinchonine, cinchonicine, cinchonidine.
Cinchotine, cinchamidine, cinchonamine.
Cupreine.
Quinamine, conquinamine.
Quinine, quinidine, quinicine, epiquinine,
^nquinidine, A-quinine.
Hydroquinine, hydroquinidine.
Chairamine, conchairamine,
chairamidine,
conchairamidine.
Cusconine, concusconine, aricine.
Dicinchonine.
Diconquinine.
Ma
420
QUINOLINE
GROUP
QUININE
14
421
15
results. Morton
and Prideaux and Winfield
have investigated the
conditions under which cinchona alkaloids can be titrated accurately.
Useful analytical data are also provided by the determination of the
optical activity of the chief cinchona alkaloids under various conditions
by Andrews 16 and the record of optical crystallographic data for many
quinine salts by Shaner and Willard. 17
Quinine, C20H2iO^!2. Impure preparations of quinine were probably
obtained by Fourcroy in 1792, and by Vauquelin under the name " quina "
in 1809. In 1810 a Spanish physician, Dr. Gomes, obtained, by the addition
of caustic potash to an alcoholic extract of cinchona bark, a crystalline
substance which he named " Cinchonino." The basic properties of this
material were mentioned by Houtou-Labillardiere in Paris to Pelletier and
Caventou, who, inspired by the then recent observations of Sertiirner on
the existence of " organic alkalis " in nature, investigated " Cinchonino,"
and resolved it into two substances, quinine and cinchonine.18 The bases
were characterised by Pelletier and Dumas, 18 and the composition of
quinine was accurately determined by Liebig, Regnault and Strecker,
the two latter assigning to it its present formula.
The manufacture of quinine sulphate and other salts is described in
detail by Schwyzer, and useful information is also provided by Vetter. 19
The sulphate is the commonest salt and is the form in which quinine is
usually isolated from the total alkaloids of the bark and so is the primary
material used as a source of the alkaloid for the preparation of other salts
and derivatives. The commercial sulphate contains cinchonidine and
dihydroquinine, and may be purified by recrystallisation of, (a) the acid
sulphate, B . H 2 S0 4 . 7H 2 0, to constant specific rotation [a]J,5 216-5
(dry salt, c = M/40, H 2 0), or (b) the dihydrobromide, B . 2HBr . 3H 2 0,
which after recrystallisation till pure has [a]J>5 189-6 (dry salt, c = A//40
H 2 0). 2 0 Quinine is precipitated as a colourless powder by pouring an
aqueous solution of the acid sulphate so purified into excess of ammonia
solution with vigorous stirring to prevent co-precipitation of the neutral
sulphate. The washed, air-dry powder can be crystallised from boiling
benzene, when it separates in needles, containing solvent which is lost on
exposure to air, leaving a micro-crystalline powder, m.p. 173-5 (dry). When
precipitated in presence of ammonia, it is stated to pass gradually into
a crystalline, efflorescent trihydrate, B . 3H 2 0, m.p. 57, which changes to
B . 2H 2 0 in air, to B . H 2 0 when dried over sulphuric acid and becomes
anhydrous at 125 and then melts at 172-8. According to Hesse, 21 anhydrous quinine is obtained in colourless needles, m.p. 174-4 to 175, when
sodium carbonate is added to quinine sulphate dissolved in warm water,
or when the trihydrate is heated during eight days in dilute alcohol at
30. Anhydrous quinine is sparingly soluble in water (1 in 1,960 at 15
(Hesse), 1 in 1,667 at 20 (Sestini), 1 in 1,750 at 25 (U.S.P. XI), but
readily so in alcohol (1 in 0-6 at 25), ether (1 in 4-5 at 25, 1 in 188 of
pure, dry ether (Treadwell)), chloroform (1 in 1-9 at 25) or boiling
benzene. Ammonia readily forms supersaturated solutions with quinine.22
The alkaloid is lasvorotatory; the pure base, prepared as described above,
422
QUINOLINE
GROUP
QUININE
423
424
QUINOLINE
GBOUP
QUINIDINE
425
petroleum. The pure alkaloid has [a])?' -f 334-2 (dry base, c = M/40,
iV/10 H 2 S0 4 ) 4 1 ; + 323-8 (dry base, c = 2 in 1-8 per cent. HCl) has been
recorded by Butler and Cretcher 43 for quinidine isomerised from pure
quinine and + 266-7 (c = 2, EtOH) by Thron and Dirscherl.42 The
sulphate and the salts of other oxygenated acids show a blue fluorescence,
especially in dilute sulphuric acid.
Quinidine is alkaline in solution and behaves as a diacidic base forming
two series of salts. The neutral sulphate, B 2 . H 2 S0 4 . 2H 2 0, crystallises
from hot water in colourless prisms, soluble in water (1 in 98 to 100 at 15,
or 1 in 7 at 100), more so in alcohol or chloroform, and scarcely in ether.
It is dextrorotatory, [<x]D +184-17 (CHC13). The acid sulphate,
B . H 2 S0 4 . 4H a O, forms hair-like, colourless needles, soluble in 8-7 parts
of water at 10 : [a.]1/ + 247-8 (c = M/10, H 2 0) or + 256-4 (c = M/40,
JV/10 H 2 S0 4 ). The neutral hydrochloride, B . HCl. H a O, m.p. 258-9
(dry, dec), [<x]| + 200 (H 2 0), forms asbestos-like prisms, easily soluble
in alcohol or hot water, less so in cold water (1 in 62-5 at 10). The acid
hydrochloride, B . 2HC1. H 2 0, forms prisms, readily soluble in alcohol,
sparingly in water, chloroform or hydrochloric acid. The dihydrobromide,
B . 2HBr. 3H 2 0, crystallises well from water and has [a]J,5 + 223-0
(c = M/40, H 2 0). The neutral hydriodide, B . HI, is deposited as a
crystalline powder when potassium iodide is added to a neutral aqueous
solution of a quinidine salt, and, owing to its sparing solubility in water
(1 in 1,250 at 15) is the form in which quinidine is usually isolated and
estimated. Quinidine gives the thalleioquin reaction (p. 424), and is
fluorescent in dilute sulphuric acid. Unlike quinine, it is dextrorotatory,
gives a sparingly soluble hydriodide and a neutral sulphate soluble in
water or chloroform. Monnet has suggested the thiocyanate as a means
of estimating quinidine.43(a)
Quinicine (Quinotoxine), C20H21O2N2. This alkaloid was isolated by
Howard 44 from cinchona bark, but had been prepared previously by
Pasteur 45 by heating quinine acid sulphate, and subsequently by Hesse 46
in a similar manner from quinidine. It is also formed by heating quinine
in dilute acetic acid or water, and the product so obtained was named
quinotoxine. The identity of the two was established by von Miller,
Rohde and Fussinegger.47 The base is a bitter yellow alkaline varnish,
48
W D + 3 8 - 6 (CHCI3),
and is usually purified through the oxalate,
B 2 . H 2 C 2 0 4 . 9H 2 0, small prisms, m.p. 166-7, [a]f, -f 24, which is
sparingly soluble in water (1 in 120 approx.), and can be recrystallised
from chloroform or alcohol. The lower values, m.p. 149, [a] D +18-18
(alcohol-chloroform 1 : 2) recorded for this salt are due to the presence
of dihydroquinicine (Thron and Dirscherl 44 ). The acid tartrate, B . C 4 H 6 0 6 ,
is also crystalline. The hydrochloride, B . HCl, crystallises in aggregates,
m.p. 179-80, or leaflets, m.p. 180-2, [a] D + 16-26 or + 13-7.49
Quinicine Z-tropate, B . C 9 H 10 O 3 . H 2 0, crystallises from water in small
cream-coloured needles, m.p. 112-3 (hydrated) or 116-8 (dry), [] D +
8-71 (dry salt, c = 0-997, EtOH). 80 The benzoyl-derivative (Thron and
Dirscherl 44) crystallises from benzene or methyl alcohol and has m.p.
426
QUINOLINE
GROUP
CINGHONINE
427
428
QUINOLINE GROUP
from boiling water ( 1 : 25). The crystals which separate at 35, after the
third crystallisation are generally free from impurities, and cinchonidine
may be regenerated from them as described already. 58 Commercial
cinchonidine generally contains quinine, which may be eliminated by
crystallisation from boiling benzene (1 : 30) until the base is no longer
fluorescent in dilute sulphuric acid. It then still contains dihydrocinchonidine, which may be eliminated by fractional crystallisation from alcohol
(1:6), the middle fraction being the best, until the product gives a satisfactory hydrogenation test 41 or mercuric acetate test. 42
Cinchonidine crystallises in large trimetric prisms, m.p. 204-5, and
when purified as described has [*]]? - 178 (c = ilf/40, iV/10 H 2 S0 4 ).
The following figures also on record probably relate to cinchonidine
containing dihydrocinchonidine : 107-9 (alcohol-chloroform 1 : 2,
Lenz), 111-0 (EtOH, Rabe), 110-0 (c = 1, EtOH, Emde). It is
sparingly soluble in water (1 in 5,263 at 11-5 (Skraup) ) ; more soluble
in alcohol (1 in 16-3 of 97 per cent, alcohol at 13 (Hesse) ) ; or ether
(1 in 1,053 of dry ether at 11-5 (Skraup), 1 in 188 of ether, sp. gr. 0-72 at
15 (Hesse) ). Cinchonidine is not fluorescent in dilute sulphuric acid
solution, and does not give the thalleioquin reaction. It is a diacidic
base, and yields two series of salts. The neutral sulphate, B 2 . H 2 S0 4 ,
m.p. 205 (dry, dec), forms monoclinic prisms with 6H 2 0 from cold water,
or with 3H 2 0 from hot water, and is soluble in alcohol (1 in 72 at 25), or
water (1 in 63 at 25). The acid sulphate, B . H 2 S0 4 . 5H 2 0, has [a]J,5
133-6 (dry salt : c = M/40, H 2 0). The neutral hydrochloride,
B . HC1. H 2 0, m.p. 242 (dry), [a] D 117-6 (dry salt, c = 1-214, H 2 0),
forms monoclinic double pyramids, or silky prisms with 2H 2 0, from its
saturated aqueous solution. The dry salt is moderately soluble in water
(1 in 38-5 at 10), or ether (1 in 325 at 10), readily in chloroform. The acid
hydrochloride, B . 2HC1. H s O, forms large monoclinic prisms easily soluble
in water or alcohol. The dihydrobromide, B . 2HBr . 2H 2 0, crystallises
well from water and has [a]*5" 114-3 (dry salt, c = M/40, H 2 0). The
tartrate, B 2 . H 2 C 4 H 4 0 6 . 2H 2 0, [a] D 129-6 (Oudemans), 132 (Hesse)
137-7 (Koppeschaar), is a crystalline precipitate, sparingly soluble in
water (1 in 1,265 at 10), almost insoluble in sodium potassium tartrate
solution, and is the form in which the alkaloid is usually estimated.
Detection. Cinchonidine is distinguished from quinine and quinidine
by not being fluorescent in dilute sulphuric acid, and by not giving the
thalleioquin reaction and from cinchonine in being lsevorotatory and
more soluble in ether, and in the sparing solubility of its tartrate.
Hesse's " homocinchonidine " 69 was probably, according to Skraup, 59
merely an unusually pure cinchonidine.
Cinchotine (Hydrocinohonine, more correctly dihydrocinehonine,
Cinchonifine, ^-Cinchonine), C19H24ON2. This alkaloid occurs in commercial cinchonine to the extent of about 14 per cent. 60 and may be
prepared from this source by the mercuric acetate process,42 or more
conveniently by the hydrogenation of commercial cinchonine previously
freed from quinidine.*1
HYDROQUININE
429
QUINOLINE
430
6
GROUP
has [aft ' 152-5 (dry salt, c = M/40, H 2 0). The alkaloid forms a
crystalline benzoyl derivative, m.p. 102-7; with methyl iodide it gives
a methiodide, B . Mel. MeOH. It readily forms crystalline molecular
compounds with cinchonidine, quinidine or cupreine, and by heating
its acid sulphate at 140 or by von Miller and Rohde's acetic acid
process it is transformed into the isomeric dihydroquinicine (dihydroquinotoxine) sulphate, m.p. 174. On demethylation it furnishes
dihydrocupreine (p. 431).
Hydroquinidine (Dihydroquinidirw), C 20 H 26 O 2 N 2 . 2H 2 0. This base
occurs in the quinidine of commerce to the extent of 25 to 30 per cent,
and was isolated from this source by Forst and Bohringer.68 It can be
separated from commercial quinidine, after removal of any cinchonine
in the latter, by the mercuric acetate process,42 but is best prepared by
catalytic reduction of quinidine. 69 It forms thick tablets from ether or
long needles from alcohol, m.p. 169-5, [a]Jf + 299 (dry base, c = M/40,
N/10 H 2 S0 4 ), gives the thalleioquin reaction and is fluorescent in dilute
sulphuric acid. The sulphate, B 2 . H 2 S0 4 . 12H 2 0, forms thick, bottleshaped crystals or fine needles with 2H 2 0, soluble in 92-3 parts of water
at 16 ; the hydrochloride, B . HC1, m.p. 273-4 (dec, dry), [a]ff + 183-9,
occurs in prismatic plates, easily soluble in water ; the dihydrobromide,
B . 2HBr . 3H 2 0, has [a]1/ + 200-4 (dry salt, c = M/40, H 2 0 ) ; the
platinichloride, B . 2HC1. PtCl 4 , forms short, orange-coloured needles.
The base can be transformed into dihydroquinicine and on demethylation
yields dihydrocupreidine (p. 431).69
Cupreine, C 1 9 H 2 2 0 2 N 2 . 2H 2 0. Cupreine occurs, with quinine, in cuprea
bark derived from Rem/ijia pedunculata, a plant closely related to, though
distinct from, the cinchonas.70 Cuprea bark had ceased to be collected
commercially, and cupreine had become a museum curiosity, but the
bark was again collected during the war, and so cupreine may once
more become available. It was prepared by converting the total
alkaloids of the bark into neutral sulphates. The product that separated
first was the sulphate of HOMOQUININE, a molecular compound of quinine
and cupreine, C 20 H 24 O 2 N 2 . C 19 H 22 0 2 N 2 . 4H 2 0. Homoquinine crystallises
from ether in needles, plates or prisms, m.p. 177 (dry), [a] D 235-6
(dil. HC1), becomes anhydrous at 125, is soluble in chloroform or
alcohol, less so in ether. The sulphate, B . B ' . H 2 S0 4 . 6H 2 0, forms short
hexagonal prisms from hot water; a solution of the sulphate in dilute
sulphuric acid poured into excess of sodium hydroxide solution with
constant stirring gives a precipitate of quinine, the cupreine remaining in
solution, from which it can be recovered as base by the passage of carbon
dioxide. Cupreine crystallises in concentrically grouped prisms, becomes
anhydrous at 120, and then melts at 198, [a]^" 175-5 (dry; EtOH).
It is sparingly soluble in ether or chloroform, readily in alcohol or solutions
of caustic alkalis, but not in ammonia, and gives the thalleioquin reaction.
Cupreine is a diacidic base : the neutral sulphate, B a . H 2 S0 4 , forms colourless anhydrous needles, m.p. 257,48 soluble in 818 parts of water at 17; the
acid sulphate, B . H s S 0 4 . H 2 0, crystallises in prisms and is soluble in
HTDROCUPBEINE
431
432
QUINOLINE GROUP
Physiol, 1947, 22, 42, 6 1 3 ; ALLEN, Pharm. J., 1948,160,202. The following references
describe developments in the countries named : (56) Belgian Congo, Pharm. J., 1944,
152, 163 ; 1945, 155, 260 ; 1947, 158, 135 ; D E N I S , Meded. Vlaam. Chem. Ver., 1945,
7, 151 (Chem. Abstr., 1947, 41, 3261). Central and S. America, STEERE, Science, 1945,
101, 177 ; ANON, Pharm. J., 1944,152,163. Bolivia, DE SOUZA, Chem. Abstr., 1947, 41,
3925. Brazil, KRUG and CARVALHO, Rev. Brazil Farm., 1942, 23, 38 ; WASICKY, Rev.
brasil. quim., 1944, 18, 265, 322 (Chem. Abstr., 1945, 39, 1505) ; Bol. Oficina sanit.
panamericana, 1945, 24, 159 (J. Amer. Pharm. Assoc, 1945, 34, Abstr., p . 299).
Colombia, D E CALDAS et al., Rev. acad. Columbiana exact, fls. not., 1937, 1, 257, 326 ;
1938, 2, 67, 3 7 7 ; LITTLE, ibid., 1947, 7, 4 0 4 ; FIGUEROA, Bol. Inst. Nac Ilig.
Samper. Martinez, 1942, 5, 9 (J. Amer. Pharm. Assoc, 1944, 33, Abstr., p . 135) ;
Pharm. J., 1945, 154, 113. Costa Rica, Pharm. J., 1943, 150, 191 ; 1946, 156, 78.
Ecuador, MARTINI and GANDARA, Bot. Gaz., 1945, 107, 184 (Chem. Abstr., 1946, 40,
1633) ; STEERE, Bull. Torrey Bot. Club, 1945, 72, 464 (Brit. Abstr., 1946, A iii, 247);
Pharm. J., 1945, 154, 195 ; 1946, 157, 111. Mexico, SOBERON and PELAEZ, Ciencia
(Mex.), 1946, 7, 221. Peru, Pharm. J., 1945, 154, 113 ; 155, 96 ; 1946, 156, 261 ;
HODGE, Carib. Forest, 1946, 7, 79 (Chem. Abstr., 1946, 40, 2932; see also ibid., 1948,
42, 2059). China, HSING, L O and Li, J. Chem. Eng. Chin., 1942, 9, 32 (Chem. Abstr.,
1946, 40, 2929). India, Pharm. J., 1944, 153, 202. Philippine Islands, MARANON and
BARTLETT, Nat. Applied Sci. Bull. Phil., 1941, 8, 111 ; SIMPAO, Rev. Phil. Med. Farm.,
1941, 32, 80. San Thom, COSTA, Noticias farm., 1940^11, 7, 173. Soviet Russia,
KURSANOV and KRIUKOVA, Biochimia, 1939, 4, 562 ; ALEKSEEVA, Sovet Nauka, 1940,
No. 7, 138 ; TAMARSKAJA, J. App. Chem., U.R.S.S., 1940, 13, 291 ; EFIMENKO, Soviet
Plant Ind. Rec, 1940, 2, 151 ; KAPTSIONEL, Chem. and Drugg., 1945, 144, 244.
Tanganyika, J. Trop. Med. Ilyg., 1942, 45, 126 ; Ann. Rept. East African Ind. Res.
Board, 1944 ; Repts. E. African Agric Res. Inst. Amani, 1942-5, H.M. Stationery
Office, London ; Pharm. J., 1947, 158, 36. (5c) " H i s t o r y of t h e Cinchona Project
of Merck and Co., Inc. and Experimental Plantations, Inc., 1934-1943," by
F . ROSENGARTEN, J r . ; see also " Performance records of individual trees and clones
of Cinchona in Guatemala," by J . R . SHUMAN (review in Science, 1947, 105, 557).
(5d) STEERE 8(6); see also P R O y CASTILLO, Bol. Soc. Quim. Peru, 1944, 10, 1 1 6 ;
HOCKING, Science, 1945, 101, 484. (5e) Pharm. J., 1946, 157, 142 ; 1947, 158, 191,
305. (6) GAGE, Trans. Roy. Soc. Trop. Med. & Hyg., 1925, 18, 348. (7) HOWABD
and CHICK, Year-book Pharm., 1923, p . 639 ; HOOPER, ibid., 1929, p . 186 ; GOODSON
and H E N R Y , Quart. J. Pharm., 1930, 3, 238. (8) Cf. GOODSON and H E N R Y , ibid.,
1932, 5, 161. (9) Malaria Commission, Health Organisation, League of Nations
(1931), CH/Afofaria/Nos. 158 a n d 167/1 ; (1932), CH/MalariafNo.
1 8 3 ; Quart.
Bull. Health Org. League of Nations, 1933, 2, 250 ; 1934, 3, 825 ; GIEMSA, Riv.
Malariol., 1933, 12, 7 0 ; GROOTHOFF and H E N R Y , ibid., p . 87 ; WATTEEZ, Bull. Inst.
433
CINCHONA ALKALOIDS
Roy. Col. Belg., 1933, 4, 852 ; SABATUCEI, Scienza farm.,
Med.
Gaz.,
1934,
Med.
J.,
1934,
1933, 1, 2 4 1 ; E D I T .
9, 2 6 ;
Ind.
SLATINEANU, CIUCA
et al., Bull. Soc. Path. Exot., 1934, 27, 723 ; Asiatic Rev., 1939, 35, 777 ; PABVULESCU,
CONSTANTLNESCO and B O E B I U , Arch. Roum. Path. Exp., 1934, 7, 523 ; BERMOND,
Bull. Sci. Pharmacol., 1934,41, 614 ; MABANON, P E B E Z and RUSSELL, Philippine J. Sci.,
1935, 56, 2 2 9 ;
1935, 5, 39 ; E D I T . ,
E.
African Med. J., 1944, 2 1 , 289 ; RAYMOND, ibid., p . 291 ; 1946, 23, 9 6 2 ; BABANGEB
and THOMAS, Biochem. J., 1943, 37, 342 ; CHAYANOV, Farmatsiya, 1939, No. 7, p . 19 ;
KAPTSIONEL, Ref.
(56);
F I G U E R O A , Ref.
(56);
Y E A G E B , R E I T L E E and
MCDANIEL,
J. Amer. Pharm. Assoc, 1946, 35, 337 ; KNOPPEES and NIEUWENHUIJSE, Arch, internal.
Pharmacodyn., 1946, 73, 260 ; APPLEZWEIG, J. Amer. Chem. Soc, 1944, 66, 1990 ;
(with RONZONE), Ind. Eng. Chem., 1946, 38, 576. (10) (a) Identification of Cinchona
Bark, WAGG, Quart. J. Pharm., 1938,11, 443. (6) Identification of Cinchona Alkaloids,
K O F L E B and MULLEB, Mikrochemie, 1937, 22, 4 3 ; WAGENAAB, Pharm. Weekbl., 1939,
76, 1544; MABTINI, Mikrochimie ver. Microkhim. Acta, 1940, 28, 235 ; FULTON, Ind.
Eng. Chem., 1941, 13, 848 ; KEENAN and WARREN, J. Amer. Pharm. Assoc, 1945,
34, 3 0 0 ; SUMEEFORD, Bull. Georgia Acad. Sci., 1945, 3, 5 ; Bull. Nat. Form. Cttee.,
1947, 15, 90. (c) Extraction and Separation of Alkaloids, BEGUIN, Pharm. Acta
Helv., 1939, 14, 109 ; ROSENTHALEB and JALCINDAG, ibid., 1941, 16, 149 ; B U C H I
(with F U C H S ) , ibid., 1942, 17, 1 ; (with GKAETZA), ibid., p . 73 ; NICHOLS and SHAH,
J. Amer. Pharm. Assoc, 1939, 28, 526 ; H U S A and PACENTA, ibid., 1941, 30, 635 ;
BELCOT and RAPEANU, Curierul Farm., 1940, No. 1, p. 1. Chromatographic Methods
HEILBBON et al., B.P. 558,320 ; KRASNOVA, J. Appl. Chem., U.R.S.S., 1945, 18, 86.
(d) Estimation of Total Alkaloids, S E L F and COBFIELD, Pharm. J., 1931, 127, 7 4 ;
Quart. J. Pharm., 1930, 3, 410 ; ALLPOET and F E I E N D , ibid., 1938, 11, 450 ; STEENON,
Bull. Soc Chim. Belg., 1932, 41, 85 ; GSTIRNEE, Pharm. Zeit., 1933, 78, 706 ; JEEMSTAD,
Norsk. Farm. Tids., 1936, 44, 302, 309, 3 2 3 ; WOJAHN, Apoth. Zeit., 1939, 54, 783,
1224 ; EFIMENKO, J. Appl. Chem., U.R.S.S., 1940, 13, 1405 ; E D E R and RUCKSTUHL,
Pharm. Acta Helv., 1943,18, 396 ; LJUNGBERG, Svensk. Farm. Tid., 1946, 50, 197, 219,
237; DALMA and RODRIGUEZ, Arch. farm. bioquim. Tucuman, 1S47, 3, 145 (Chem.
Abstr., 1948, 42, 322). (e) Estimation of Specific Alkaloids. (1) Physical Methods
KRANTZ, J. Amer. Pharm. Assoc, 1930, 19, 1299. Spectrophotometry
Methods
FABKE, Bull. Soc. Chim., 1925, [iv], 37, 1304 ; VAN AEKEL, Pharm. Weekbl., 1938, 75,
485 ; CAROL, J. Assoc. Off. Agric Chem., 1942, 25, 524; 1943, 26, 238; cf. LOUSTALOT
and PAGAN, ibid., 1947, 30, 153 ; EFIMENKO, J. Appl. Chem., U.R.S.S., 1940, 13, 1405 ;
STIMSON and R E U T E B , J. Amer. Chem. Soc, 1946, 68, 1192. (2) Chemical Methods
PINXTEREN, Pharm. Weekbl., 1929, 66, 919 ; VETTEE, Festschrift, E . C. Barrel, Basle,
1930, p . 541 ; H E R D , J. Amer. Pharm. Assoc, 1942, 31, 9 ; E D E R and RUCKSTUHL,
Pharm. Acta Helv., 1943,18, 396 ; SCHULEK and K O V A C S . Z . anal. Chem., 1941, 121, 21
(Vinyl cinchona alkaloids); ZELIGSON and SIN'KOVSKAYA, J. Gen. Chem., U.R.S.S.,
1945, 15, 9 5 7 ; CHBISTENSEN, GOTTLIEB and R E I M E R S , Dansk. Tids. Farm., 1947, 2 1 ,
221, 231. (11) A L I E N ' S " Commerical Organic Analysis," 5th edition, vol. 7 (London :
J . & A. Churchill; Philadelphia : P . Blakiston's Son & Co. Inc.). (12) Bull. Health Org.
League of Nations, 1934, 3, 342. (13) Quart. J. Pharm., 1930, 3, 238 ; 1932, 5, 161.
(14) Pharm. J., 1926,117,168. (15) Analyst, 1930, 5 5 , 5 6 1 ; cf. E V E R S , Year-book Pharm.,
1921, 327 ; LIVEBSEDGE, ibid., 1922, 425 ; and PEDERSEN, Dansk. Tids Farm., 1938,12,
161. (16) ANDREWS, Ind. Eng. Chem. [Anal. Edit.], 1942,14,543; (with W E B B ) , ibid.,
1941, 13, 222. (17) J. Amer. Chem. Soc, 1936, 58, 1977. (18) P E L L E T I E B (with
CAVENTOU), Ann. Chim. Phys., 1820 fii], 15, 291, 1337 ; (with DUMAS), ibid., 1823,
24, 169. (19) " D i e Fabrikation der Alkaloide," Berlin, 1927; VETTEB, Festschrift,
E . C. Barrel, Basle, 1936, p. 542. (20) T U T I N , Pharm. J., 1909, [iv], 29, 6 0 0 ; E M D E .
Helv. Chim. Acta, 1932, 15, 3 5 7 ; BUTTLE, H E N B Y and TBEVAN, Biochem. J.. 1934,
28, 426. (21) Annalen, 1890, 258, 135 ; cf. MALQUORI and COVELLO, Ann. Chim. Appl.,
1935, 25, 647. (22) DUNCAN, Pharm. J., 1905, 74, 438. (23) R A B E et al., Annalen,
1910, 373, 85. (24) H E S S E , ibid., 1875, 176, 205. (25) OUDEMANS, ibid., 1876, 182,
44 ; SCHOOBL, Pharm. Weekbl., 1926, 63, 469 ; LIQUIER, Compt. rend., 1926, 183,
1 9 5 ; L A P P , ibid., 1932, 195, 2 4 8 ; 1933, 196, 9 7 0 ; Arch. phys. biol., 1932, 10, 42;
434
QUINOLINE GROUP
Brill. Soc. chim., 1935, [v], 2, 1 4 0 7 ; DIETZEL and S6LLNER, Arch. Pharm., 1930, 268,
629 ; A N D R E W S , Ref. 10 (e) (1). (26) R A B E a n d MARSCHALL, Annalen,
1911, 382,
360 ; a n d J E T T E a n d W E S T , Proc. Roy. Soc., 1928, A, 121, 299. (26a) STUART, P O W E L L ,
R O S E a n d B I B B I N S , J. Amer. Pharm. Assoc, 1939, 28, 90. (266) GRUSSNER, GATZIF I C H T E R a n d R E I C H S T E I N , Helv. Chim. Acta, 1940, 23, 1 2 7 6 ; K U H N a n d W I E L A N D ,
Ber., 1940, 73, B , 971 ; ibid., 1941, 74, B , 218. (26c) STAHL a n d K U E V E R , J . Amer.
Pharm. Assoc. ,1942, 31, 154. (26d) R A O a n d SESHADRI, Proc. Ind. Acad. Sci., 1940,
11, A, 289. (27) See, for example, COWNLEY, Pharm.
ibid., 1927, [iv], 65, 264 ; BEAL and SZALKOVSKI, J. Amer. Pharm. Assoc, 1933, 22,
1219 ; W A L E S , ibid., 1934, 23, 793 ; WARREN, ibid., 1934, 23, 874. (28) J. Pharm.,
1884, [v], 7, 291. (29) Zeil. Anal. Chem., 1885, 24, 362. (30) Pharm. J., 1884-85,
[iii], 16, 358. (31) J. Pharm. Chim., 1904, [vi], 19, 427. (32) Cf. PAUL, Pharm. J.,
1885, [iii], 16, 361 ; HOOPER, ibid., 1886, [iii], 17, 61 ; H E S S E , ibid., 1887-88, [iii], 18,
517. (33) See, for example, HOWARD, Pharm. J., 1896, [iv], 3, 505 ; (with CHICK),
ibid., 1925, [iv], 61, 125 ; T U T I N , ibid., 1909, [iv], 29, 600. (34) J. Pharm., 1887, [v],
15, 5. (35) Zeit. Anal. Chem., 1888, 27, 549. (36) Arch. Pharm., 1903, 241, 54 ; MERZ
and HOFFMANN, ibid., 1938, 276, 388 ; see also ZELIGSON et al., Ref. (10(e)(2), and
REIMERS and GOTTLIEB, Dansk. Tids. Farm., 1947, 21, 45. (37) Cf. H A R T , J. Soc.
Chem. Ind., 1921, 40, 72T ; SALOMON, Ber. Deut. Pharm. Ges., 1919, 28, 273 ; E I S E N BRAND, Arch. Pharm., 1931, 269, 65. (38) See, for example, FUHNER, ibid., 1906, 244,
6 0 2 ; COMANDUCCI, Chem. Soc. Abstr., A, 1910, [i], 581 ; 1911, [i], 317 ; CHRISTENSEN,
Ber. Deut. Pharm. Ges., 1915, 25, 256 ; 1916, 26, 249 ; WELLER, Ber., 1921, 54, 230 ;
HARGREAVES, J. Amer. Pharm. Assoc, 1926, 15, 100, 7 5 0 ; 1936, 25, 9 7 5 ; MIKO,
Brit. Chem. Abstr., 1928, A, 1146 ; PAVOLINI, Boll. Chim. Farm., 1931, 70, 795 ; MONTI
and CIRELLI, Gazzetta, 1934, 64, 947 ; 1936, 66, 38 ; 1937, 67, 621.
(39) J O R G E N S E N ,
J. pr. Chem., 1876, [ii], 14, 230 ; ZIMMERN, Compl. rend., 1926,182, 1082. (40) ACTON
and K I N G , Biocehm. J., 1921, 15, 53 ; WAGENAAR, Pharm. Weekbl., 1929, 66, 177, 197,
2 5 0 , 2 6 1 ; 1934,71,316; STERKINand HELFGAT,Biochem. Zeit., 1929,207, 8 ; MONNET,
J. Pharm. Chim., 1933, [viii], 18, 94 ; CANALS a n d PEYROT, Compt. rend., 1934, 198,
746 ; G R E E N , Ind. Med. Gaz., 1929, 64, 614 ; F I E L D and K A N D I A H , Trans. Roy.
Trap. Med. & Hyg., 1935, 28, 385 ; K Y K E R , W E B B and ANDREWS, J. Biol.
1941,
Soc.
Chem.,
K A Y E , Milit. Surg., 1943, 93, 133 ; CLAZKO, U.S. Naval Mil. Bull., 1943, 41, 529 ;
B R O D I E and U D E N F R I E D , J. Biol. Chem., 1945, 158, 705 ; MARSHALL and R O G E R S ,
Biochem. J., 1945, 39, 258. (41) B U T T L E , H E N R Y and T R E V A N , Biochem. J., 1934,
28, 426. (42) Annalen, 1935, 515, 252. (43) J. Amer. Pharm. Assoc, 1933, 22, 414.
(43a) J. Pharm. Chim., 1935, 22, 112. (44) J. Chem. Soc, 1871, 24, 61 ; 1872, 25,
101. Confirmed b y THRON a n d DmscnERL, Annalen, 1935, 521, 48. (45) Jahresb.,
1853, p . 473 ; process improved by VON MILLER and R O H D E , Ber., 1894, 27, 1279 ;
1895, 28, 1056 ; cf. HOWARD a n d CHICK, Pharm. J., 1917, 99, 143. (46) Annalen,
1875, 178, 245 ; 1888, 243, 148. (47) Ber., 1900, 33, 3214 ; cf. B I D D L E , ibid., 1912,
45, 526 ; and R A B E a n d MCMILLAN, ibid., 1910, 43, 3308.
J. Soc. Chem. Ind., 1909, 28, 53. (49) HEIDELBERGER a n d JACOBS, J. Amer.
Soc,
Chem.
1919, 4 1 , 817. (50) K I N G a n d PALMER, J. Chem. Soc, 1922, 121, 2584. (51)
Ber., 1925, 58, 544, 554. (52) Pharm. J., 1917, 99, 1 4 3 ; 1923, 111, 9 3 ; see also
JOHNSON, J. Amer. Pharm. Assoc, 1937, 26, 1227, 1233. (53) Ibid., 1941, 30,
52. (54) BACHSTEZ a n d D E CARO, Arch. exp. Path. Pharm., 1932, 164, 314. (55)
Annalen, 1935, 521, 48. (56a) (With K O L B E and HOCHSTATTER), ibid., 1932, 492, 242 ;
(with H O T E R ) , J. pr. Chem., 1939, 154, 66 ; (566) Ber., 1908, 41, 67 ; (with K I N D L E R ) ,
ibid., 1918, 5 1 , 466 ;
ibid., 1931, 64, 2498. (57) SKRAUP, Monats., 1899, 20, 579 ; cf. H E S S E , Annalen, 1888,
243, 149 ; 1893, 276, 103. (58) H E S S E , ibid., 1880, 205, 196. (59) Ber., 1877, lfrj
2156 ; Annalen, 1880, 205, 203 ; 1883, 243, 148 ; 1890, 258, 142 ; cf. SKBAUP, ibi&.t
1879, 199, 859. (60) H E S S E , Annalen, 1873, 166, 256 ; 1898, 300, 46 ; cf. F O R S T am*
B S H R I N G E R , Ber., 1881, 14, 4 3 6 ; 1882, 15, 520. (61) H E I D E L B E R G E R a n d JACOB*?
J. Amer. Chem. Soc', 1919, 41, 817. (62) KAUFMANN and H U B E B , Ber., 1918, 46, 291#f
cf. R A B E and KINDLEH, ibid., 1918, 51, 1860. (63) Helv. Chim. Ada, 1982, I S , #
435
CONSTITUTION
cf. R A B E tt at., Annalen, 1934, 514, 6 1 . (64) Ber., 1881,14, 1270 ; H E S S E , ibid., 1683;
Annalen, 1882, 214, 1. (65) SKITA and N O K D , Ber., 1912, 45, 3312. (66) Ibid., 1882,
15, 854 ; Annalen, 1887, 241, 257. (67) See, for example, German Patents 251,936,
253,357 (Chem. Soc. Abstr., 1913, [i], 85) ; 306,939 (ibid., 1918, [i], 546); also SKITA
and co-workers, Ber., 1911, 44, 2866; 1912,45,3312,3588; 1916,49,1597; KAUEMANN
and H U B E R , ibid., 1913, 46, 2913 ; F R E U N D and BREDENBURG, Annalen,
1914, 407,
43 ; HEIDELBERGER and JACOBS, J. Amer. Chem. Soc, 1919, 41, 8 1 7 ; 1922, 44, 1098.
(68) Ber., 1881, 14, 1954 ; 1882, 15, 520, 1656 ; cf. H E S S E , ibid., 1882, 15, 855, 3010.
(69) HEIDELBERGER and JACOBS, J. Amer. Chem. Soc., 1919, 41, 817. (70) P A U L a n d
COWNLEY, Pharm. J., 1881, 12, 497 ; 1884, [iii], 15, 221, 401 ; cf. HOWARD and
HODGKIN, ibid., 1881, [iii], 12, 528 ; J. Chem. Soc, 1882, 41, 66 ; W H I F F E N , Pharm. J.,
1881, 12, 497 ; H E S S E , Annalen, 1885, 230, 57. (71) H E S S E , ibid., 1887, 241, 281 ;
H E I D E L B E R G E R and JACOBS, Ref. 69. (72) GIEMSA and HALBERKANN, Ber., 1918, 5 1 ,
1325 ; K E L B E R , ibid., 1916, 49, 55. (73) GIEMSA and HALBERKANN, Ref. 72 ; H E I D E L BERGER and JACOBS, J. Amer. Chem. Soc, 1922, 44, 1091 ; SLOTTA and B E H N I S C H ,
Ber., 1933, 66, 360 ; 1935, 68, 754 ; B U T L E R , N E L S O N , R E N F R E W and CRETCHER, J.
Amer.
Biochem.
(75) J. Indian
436
QUINOLINE
GROUP
molecule, but for which the term quinuclidine was coined by Konigs. The
proximate decomposition products of this " second half" are distinguished by the occurrence in their names of " loipon " (from loipos, a
residue) or the prefix " mero " (from meros, a part).
OXIDATION OF CINCHONINE and QUININE. This oxidation proceeds in
two well-marked stages. In the first the nuclear structure is preserved and
changes occur in side or connecting chains only, whilst in the second scission
also takes place and the characteristic products of the two portions of the
nuclei appear. Both alkaloids, as already stated, can be hydrogenated to
dihydro-derivatives. Similarly, they can each add on a molecule of a
halogen, as in the formation of two dibromodihydrocinchonines,3 or a
molecule of a haloid acid, as in the formation of the chlorodihydro-bases,
each of which exists in two stereoisomeric forms,4 e.g., a-chlorodihydroquinine (anhydrous rhombs, m.p. 210 (dec), [a]f, 251-0 (c = 0-5,
.2V-HC1) ) and oc'-chlorodihydroquinine (needles, m.p. 194 (dec), [a]f,
168-1 (c = 0-5iV-HCl). That these addenda are due to the presence of
a vinyl side-chain is clear from the fact that each of the four alkaloids on
ozonisation is oxidised to formaldehyde and an aldehyde derived from
the alkaloid.5 Similarly, each of the four alkaloids on oxidation in the
cold with permanganate is converted into formic acid and an alkaloidal
substance containing one carboxyl-group. These two reactions in the
case of quinine (I) may be represented thus :
C
Ozoaisation,
13 H 21 0 2 N 2- 0H0
Qulnlnal
H-CS0
Formaldehyda
Oxidation by KMnO
C H 0 N -C00H
18 31 Z'Z
Quitenine
H-C00H
Fermlo Acid
QUININONE
437
438
QUINOLINE
GROUP
acid, instead of these intermediate ketones, the products of the two nuclei
are obtained. The following scheme illustrates roughly the relationships
of these products to the parent alkaloids. Cinchonidine and quinidine
yield respectively the same products as cinchonine and quinine :
Cinchonine, ^gH^CHg
By chromic acid
J,
Cinchoninone, 0 ^ 0 1 ( 1 )
By permanganate
*
Cinchotenine, ClaH200gN2(2)
By chromic acid
Cinchoninie acid, C^HyOgN (3)
Meroquinenine, CgH-gOpN
Cincholoiponic acid, CgH.gO^i
Loiponic acid, C^H^O JJ
439
CONSTITUTION
in water, and dextrorotatory, [oc]| + 30-1 (H g O). I t furnishes a nitrosoamine, a monoacetyl derivative and a diethyl ester (needles, m.p. 181).
On oxidation with permanganate it produces loiponic acid, C 7 H u 0 4 N,
and when heated with sulphuric acid, 4-methylpyridine and carbon
dioxide. Racemic a- and /J-cincholoiponic acids were synthesised by
Wohl and Losanitsch, 12 and were resolved into their components by Wohl
and Maag 13 by crystallisation of the brucine salts. Of these, /?-d-cincholoiponic acid proved to be identical with the acid obtained from cinchonine.
Loiponic acid, C 7 H u 0 4 N, obtained in small quantity by Skraup 14
by oxidising cincholoiponic acid with cold permanganate, forms irregular
prisms, m.p. 259 (dec), from hot water. It furnishes a diethyl ester, and
with acetic anhydride gives acetylloiponic acid anhydride, m.p. 161.
Konigs 15 first pointed out the isomerism of loiponic acid with hexahydrocinchomeronic acid (piperidine-3 : 4-dicarboxylic acid). The latter acid
was found to be a mixture of the cis- and irans-forms, and by treatment
with potash was converted wholly into the more stable of these forms.
Loiponic acid, on treatment with potash, is also changed into this stable
form, and so must be regarded as a labile modification of this acid. From
the facts recorded above, the oxidation products of the " second half " of
the four alkaloids must be represented by the following formulae 16 :
CHr-CH-CH-C00H
CHj- CH-0H.-000H
| 2 |
p |
CH CH-CH-CH
>
Ca CH-C00H
CH CH-C00H
p |
>
CH, CH-C00H
8
I 8 I
I8 I
I8 I
HHC^
MH CH
HHCHg
Meroqulaenlne
Clnehololponlo aold
Loiponic aold
Action of Phosphorus Pentachloride. The oxygen atom in cinchonine
and cinchonidine and the second oxygen atom in quinine and quinidine
are present as alcoholic hydroxyls, since all four alkaloids yield monoacyl
derivatives, are not soluble in alkalis, and on gentle oxidation lose two
atoms of hydrogen forming ketones (p. 437). When acted upon by
phosphorus pentachloride, this hydroxyl group is replaced by an atom of
chlorine, forming cinchoninechloride, C19H21N2C1 (needles, [a]{3 -f 56,
m.p. 72), cinchonidinechloride ([a]J3 + 78, m.p. 108-9), quininechloride,
C20H23ON2C1 (minute needles, m.p. 151, [a]J,5 -f 60, gives the thalleioquin
reaction), and quinidinechloride (crystals, [a]J>5 -f- 35, m.p. 131-2)
respectively 1 7 ; the specific rotations are for approximately 2 per cent,
solutions of dry base in 99 per cent, alcohol, and it is noteworthy that
they are all dextrorotatory, even in the cases of quinine and cinchonidine.
Action of Alcoholic Potash on the " Chlorides.'" The products formed
in these reactions were the subject of a series of papers by Konigs and
collaborators published in the period 1880-1900. When cinchonine- or
cinchonidine-chloride is heated with alcoholic potash a molecule of hydrogen
chloride is split off with the formation of CINCHENINE (cinchene), C19H20N2,
leaflets, m.p. 123-5. Similarly quinine- or quinidine-chloride is converted
into QUINENINE (quinene), CoHMON2, crystallising in trimetric prisms,
440
QUINOLINE
GROUP
2H20
C9H1502N +
C10H9N
Meroquinenine
Lepidine
(4-melhylquinoline)
2H20
C9Hl502N +
Meroquinenine
Cinchenine
C 2 0 H 2 2 ON 2
Quinenine
C 1 0 H 8 N(OCH 3 )
G-Methoxylepidine.
CjjHs
Ao
?<&<k0H
w
apoClnohenlne
6HS
C00H
W
apoClaohenlne apoClnohanlnlo
thrl ether acid ethrl ether
96*3 <
OE
OgHgH
Honoapoolnchenlne
CINCHENINE
441
<
I
C9H6N
C_H5
^-COOH
^5
00 H
^ S
C^N
Hamoapoc lnchenlne
ethyl ether
^ H
2 5
CgH6N
Homoapoelnehealnlo
acid ethyl ether
Quinolylphenetole
CgHgN
Quinolylphenol
In apocinchenine the hydroxyl group must, therefore, be in the orthoposition relative to the point of attachment of the benzene ring to the
quinoline nucleus. The relative positions of the two ethyl groups are
determined by the fact that apocincheninic acid ethyl ether on oxidation
with lead peroxide and sulphuric acid gives the lactone of hydroxyapocincheninic acid ethyl ether (I), which, on oxidation by sodium hypobromite, yields quinolylphenetoledicarboxylic acid (II).
>
<
C0
s.
(ID
The latter must have its two carboxyl groups in the ort/io-position to
each other, since it readily yields an anhydride and, on fusion with
resorcinol, gives a fluorescein. apoCinchenine must, therefore, be represented by one of the formulae I, II or III, of which Konigs considered (II)
the most probable, since it best explained the formation of nitroapocinchenine by the action of nitrous acid,22 position 5 (para to the HO
group) being then free for the entry of the N0 2 group. Kenner and
Statham 22 have, however, proved that (I) is correct by synthesising the
2'-methyl- and 2'-ethyl- ethers of 4-(4': 5'-diethyl)-phenylquinoline and
showing that these are identical with methylopocinchenine (oil: picrate,
m.p. 200 (dec.)) and ethylapocinchenine (m.p. 70-1, picrate, m.p. 17980) respectively.
(I) C9H6N . C 6 H 2 Et 2 . OH (CH6N : E t : E t : OH = 1 : 4 : 5 : 2)
(II) C9H6N . C6H2Et2 . OH (CjHgN : E t : E t : OH = 1 : 3 : 4 : 2)
(III) C9H6N . C6H2Et2 . OH (CH6N : E t : E t : OH = 1 : 5 : 6 : 2)
The facility with which the " second half " of the molecule furnishes
benzenoid derivatives recalls the similar behaviour of tropine and ecgonine
(Comstock and Konigs 17 (1892)) and several formula? representing cinchonine and quinine, and their isomerides as containing a quinoline ring
attached to a bicyclic ring system similar to that of the tropine group
have been proposed.23 The formula now accepted for cinchonine is due
QUINOLINE OBOUP
442
CH
CH
CH
CH-
OH-
CH
CH
CH
CH
CH.-H C-(OH)-CH^(T
I"
XH
CH--H CH^CHOHV
Rabe's 1908 formula accounts satisfactorily for the following characteristic reactions of this group of alkaloids. W h e n cinchonine acid sulphate
is heated dry, or the base is boiled with various reagents, or with water
alone, it is converted into a n isomeride, cinchonicine (cinchotoxine) (p. 451),
which m a y also be obtained in like manner from cinchonidine. Quinine
and quinidine, under similar t r e a t m e n t , give rise to quinicine (quinotoxine)
(p. 425), and the reaction also takes place with cupreine and with t h e
dihydrogenated derivatives of all five alkaloids. Cinchonicine and quinicine are keto-bases, and contain b o t h a secondary a n d a tertiary nitrogen
atom. W h e n treated with amyl nitrite t h e y form oximino-compounds,
which, with phosphorus pentachloride, furnish, in the case of oximinocinchonicine, cinchoninic acid and meroquineninenitrile, and in the case of
oximinoquinicine, quininic acid and meroquineninenitrile. 2 4 R a b e has-also
shown t h a t cinchonine and cinchonidine methiodides b o t h yield t h e same
methylcinchonicine (methylcinchotoxine). 2 5 These reactions are readily
explicable from the following formulae, in which Q represents the quinoline
residue C 9 H 6 N, and t h e * a t C 8 indicates the point a t which oximinosubstitution takes place 26 :
CH,
.CO.4
CH.-.CH. CH-
CH
2
CH,
CHr-H
CH.CHp.CN
2
/\
CH.-.CH.CH
CH,
I *
NH
CH.CHOH.tJ
Cinchonine
Cinchonicine
Meroquineninenitrile
+
CH^-HCH-CVQ
OlnohoBlaoif
H0-H0
Q-COCB
CHj-a CH0H
B - T l w l - *-QttUmoHdonoxl.
STEREOISOMERISM
443
Cinchoninone is also formed by the action of alkali on JV-bromocinchonicine, and, since cinchoninone can be reduced to cinchonine,*7 it is
possible in this way to reconvert cinchonicine into cinchonine and quinicine
into quinine.28 On the basis of all these results, Rabe 29 developed the
following general formula (I) for this group of alkaloids :
.CB
CH
HS~
N
0
CH
CHg^CH-CH-CH-CHjj
I
R-C6'
i
(I)
C
AH ^
CH
J'CH
e*
0-
CH
(II)
CHOH
C H - N CE-CH g Q
4*
T
T
CH;
-OH.
'2
(HI)
a-OH
Ruban
s'
CH
II
'CH
''OH
S
t
I
H.CHg.CHg.NH
t'CH
7CH
-OH.
-SCH
(IT) Hubatoian
444
QUINOLINE
GROUP
CH
CH
I
(CH, 3 ' 2
(
CH 2 -
CH.CH(0H)q
a and BIsoQulnlnes
CH*.CH:C
3*
CH
Ws
CHNH
CH2
CHg.CO.Q
BIsoQulnotoxlne
STEBEOISOMERISM
445
aluminium in an.alcoholic solution of sodium ethoxide yields dihydrocinchonine (cinchotine, [a]n + 190), dihydrocinchonidine (cinchamidine,
M D 98), and two new alkaloidal secondary alcohols having [a] D + 88*5
and -f- 48 respectively,-84 now known as epidihydrocinchonine and epidihydrocinchonidine respectively. Using these and other data referred to
above, King and Palmer, 35 in a discussion of the contribution of each of
the four centres of asymmetry, came to the conclusion that the final direction of rotation of the eight principal cinchona alkaloids is made up by
dextrorotation at C3 and C4, taken together, throughout both series, by
laevorotation at C8 and C9 in the lasvorotatory series and by dextrorotation
at C8 and C9 in the dextrorotatory series. Since then Rabe and collaborators 36 have shown that when any one of the eight cinchona bases is heated
with potassium hydroxide in amyl alcohol it undergoes epimerisation
about carbon atoms 8 and 9, yielding an equilibrium mixture of four
stereoisomeric secondary alcohols. Thus such treatment of quinine
yields a final mixture of the following bases :
Carbon atom 8
Carbon atom 9
Carbon atoms 3 and 4
Quinine
epi'Quinine
Quinidine
0pi'Quinidine
+
+
+
+
+
+
+
446
QUINOLINE
GROUP
of bases thus producible from the eight principal cinchona bases are shown
in the table below, in which the deoxy-bases have been included to
illustrate the effects of the disappearance of asymmetry in the case of
carbon atom 9. The constants given are those recorded by Rabe, 36 who
has also discussed the influence of configuration on basicity in this series.
The last six items in the table relate to ruban and rubanol. Ruban
has one asymmetric centre (carbon atom 8 of formula III, p. 443). RubanDirection of Rotation
[a]D
C'& C"
- 158-2
97-7
+ 43-3
+
+
+
+ 243-5
+ 2111
+ 102-4
+
+
+
+
+
Nil
168
80-82
113
- 111
29-9
+ 62-8
+
+
+
Nil
202 J
60-62
103-104"
+ 224-4
+ 179-3
+ 120 3
+
+
+
+
+
+
Nil
200
91'
82-83 J
Dihydroquinine
( + )-Dihydroquinine .
Deoxydihydroquinine.
epiDihydroquinine
- 142 5
+ 143-5
- 77-3
+ 32-5
168-169
171-5"
70
Oil
Dihydroquinidine .
( )-Dihydroquinidine
Deoxydihydroquinidine
ppiDihydroquinidine .
+ 237-5
- 237-7
+ 107-7
+ 73-7
+
+
+
+
Dihydrocinchonidine
Deoxydihydrocinchonidine .
epj'Dihydrocinchonidine
95
21-2
48-3
+
+
+
Dihydrocinchonine
Deoxydihydroeinchonine
epiDihydrocinchonine.
+ 2000
+ 1430"
+ 88-4
+
+
+
+
+
+
9-Hydroxyruban .
+ 132 5
+ 143
+ 80-5
Nil
Nil
Nil
+
+
+
Nil
Nil
Nil
Quinine
.
.
Deoxyquinine .
epiQuinine
Quinidine
.
Deoxyquinidine
epi'Quinidine
Cinchonidine
Deoxycinchonidine
epiCinchonidine
Cinchonine
.
Deoxycinchonine
ep (Cinchonine
Ruban.
9-Hydroxyruban .
Ruban.
149
131-8
78-4
c*
Nil
+
+
+
+
Nil
+
+
Nil
Nil
+
+
Nil
+
Nil
+
-
Nil
177
48
Oil
168-169
171
85-87
122
231-232"
52
106
208-26972
120
230-5
1180
Oil
1180
230-5
Oil
* As shown on p. 414, C* and C* taken together as a unit are in total effect dextrorotatory, but C* is dextrorotatory throughout the series and C* is laevorotatory.30^)
9rone furnishes, on reduction, four stereoisomeric rubanols (9-hydroxyrubans) corresponding to the two dihydro-cinchonines and -cinchonidinef
STEREOISOMERISM
447
( + +),
(
),
(-|),
(f-),
Prelog and Zalan 37(a) have investigated the spatial distribution about
positions C3, C4 and C8 and have shown that cincholoipon ethyl ester (V),
whether prepared from cinchonine or quinine, has [oc]^7" -f- 16-7 and
gives a hydrochloride [a]f,3 - 9-3 (EtOH) or 7-0 (H 2 0). The figures
found by Kaufman et al.37 were the reverse of these, viz., 17-2 for the
ester and -f 5-7 for the hydrochloride. The ester was degraded to ()-3methyl-4-ethylhexane (VI) in which the C3 of cincholoipon, and of the
cinchona alkaloids, is the only remaining centre of asymmetry. This
hydrocarbon belongs to the laevorotatory series, represented by the general
formula CHMe . C2H5R where R is an alkyl group with more than two
carbon atoms, and can be represented by the conventional projection
formula (VII). Cincholoipon was also converted by a series of mild
reactions, in which the configuration at C 3 and C4 was unlikely to be
altered, into the optically inactive cis-1 :2-diethylc?/cJohexane (VIII),
indicating that in cincholoipon and the cinchona alkaloids, the substituents
at C 3 and C* stand in the cis- relation to each other. The dextrorotatory
alkaloids cinchonine and quinidine form isomerides (p. 451) in which there
is ether formation between the substituents at C3 and C8 (see, for example,
formula B, p. 449), whereas this type of isomeride is not obtainable from
the laevorotatory alkaloids, quinine and cinchonidine. It is assumed,
therefore, that in the dextrorotatory bases' the substituents at C 8 and C 8
are both in the endo-position (X), but in the laevorotatory alkaloids the C s
substituent is in the endo- and the C8 substituent in the exo- position (IX).
QUINOLINE
448
CH2
CHj
4
CHCH 2 C0 2 Et
|l
(VI NH
2
CH2
s|
CHC 2 H 5
CH 3 CH 2 CHEt
3 I
CH 3 CHEt
(VI)
4
CHEt2
H
~ { - E
(VII) CH 3
GROUP
4
C H 2 CH 2 CHEt
t
I
,3
(VIII) CH 2 CH 2 CHEt
CH2 C H - - C
H2i
/CH
CH2
CHV
CH
k X
CH2
CH
H 2 L CH2 j /
TBANSFORMATION
PRODUCTS
449
products are niquine from quinine and niquidine and isoniquidine from
quinidine, which have been proved to be represented by formula (Ga). 44
This probably also applies to the a- and /J-cinchonhydrines derived from
cinchonine, though for these formula (Gb) was proposed by Leger 39 and
they have not been investigated recently (cf. Langer 43 ).
The least desirable of the three reactions is (b) as this results in the
formation of some chlorodihydro-base and adds to the complexity of the
mixture of reaction products.
II.
10. 3
u.
CH^.CHOHCHCHCHo
3
,
CH 2 :CHCCHCHCH 2
CH2
CH 3 .CHCHCHCH 2
CH 2
"CHo
CH 2
CHo-N
CH
9
I
CHOH
CH0H
(B) Hydroxydihydrobase
CH,
I "
CH 2
I
CHo-N
CH
2
I
?CH
I
Q
CH5.CHfHal).CHCHCH2
CH3.CH:C
CH 2
CH 3 . CHOH. CHCHCH 2
CH 2
I
CH 2
QH 2
CH2-H
CHCH 2
CH
CHp-N
CHOH
CH 2
CHP
CHg-liH
CH
CH2
CHOH
I
CO
(D) Halogenodihydro-base
(E) apo-Ba3e
i
CH3.CH:CH.CH
CH 2
CH3.CH:C
-CH.CH2.CH3
CHg
I
CH,
NH
(F) Hydroxydihydroquinicine
CH3.CH:C
CHCH 2
CH, I
I " CH 2
CH2|
CH
I
""CHOH
i
4
(Ga) Niquidine (0 & H)
CH 2 EHCH
I
CHOH
I
Q
CH2-N
C. OH
(H) hetero-Base
15
450
QUINOLINE
GROUP
In the cases of quinine and quinidine there is an additional complication, except for reaction (c), owing to partial de-methylation of the
methoxyl group, thus in the action of sulphuric acid on quinine there may
be four products of formula E, viz., the two geometrical isomerides
apoquinine and woapoquinine (for which Q is 6-hydroxyquinolyl) and their
methyl ethers, jS-isoquinine and a-woquinine respectively (for which Q is
6-methoxyquinolyl).
The results of this additional complication may be illustrated by a
comparison of the reaction products in the cases of cinchonine and
quinidine.
Typed
Product.
Formula E
apoCinchonine (attocinchonine)
a- and /?-Hydroxydihydrocinchonines.
a-isoCinchonine (cinchoniline)
/?-isoCinchonine (cinchonigine).
Ga
It will be seen from the foregoing that there is no systematic nomenclature for these compounds. Some of them have been isolated by several
workers 42 and with the impression that" they were new substances have
been given new names, 43 and this applies especially to the two wocinchonines and dihydrocinchonine. It will be noticed that instead of the two
geometrical isomerides required by formula (Ga) there are three cinchonhydrines. The a- and /S-forms are well-defined crystalline substances, but
the supposed y-form (see table, p. 452) is amorphous and its authenticity
doubtful. 39 Formula (E) requires two geometrical isomerides, but quinidine
provides three possible claimants for this representation. When one of
these apo-bases is hydrogenated the ethylidene group C H 3 . C H : is
converted into an ethyl group and C3 becomes a centre of asymmetry once
more as in the typical cinchona alkaloid (A) and a mixture of epimerides
about C 3 is produced. When this process is applied to opoquinidine
methyl ether, neotsoquinidine or ^r-quinidine, the hydrogenated product
in each case can be separated into dihydroquinidine and a new substance
epi-C3-dihydroquinidine. In all three substances therefore one end of the
ethylenic linkage must be at C3 and it is suggested that the unexpected
third substance, probably ^r-quinidine, has its ethylenic linkage at C3C*
11
10
11
10
TRANSFORMATION
PRODUCTS
451
10
Characters
C 19 H 22 ON 2
a-i'soCinchonine (C) * .
/3-i.soCinchonine (C)
apoCinchonine (E)
Cinchonicine (F f)
A-Cinchonine (H)
References
Orthorhombic
prisms ; \ Jungfleisch and L e g e r 3 " ;
m.p. 130-4, [cc]D + 5 3 - 1
Hesse, Annalen,
1893,
Clinorhombic or ortho276, 88; Skraup, Monats.,
rhombic crystals ; m . p . 1 1 9 0 1 ,
22,
1097;
Lippmann and Fleissner,
130-7 ; [a]J/ - 61-6.
ibid., 1893, 14, 371 ; see
Needles ; m.p. 216-8,
also, ref. 40.
[] + 150.
/
Needles ;
m.p.
58-9, Rabe 30 ; Roques,
Ann.
[a] D + 49-62.
Chim. Phys., 1897, [vii],
10, 234 ; von Miller and
Rohde, Ber., 1900, 33,
3214.
M.p. 179-80; [a]J, 8 +151. Suszko " (1933) ; Rabe,"
* The capital letters in brackets refer to the lettered formulae (p. 443).
t See notes on formulae, p. 449.
16z
QUINOLINE OBOUP
462
Name and Formula *
CltHONt
apoCinchonidine (E)
yS-Cinchonidine (E)
C 19 H 24 ON 2
Dihydrocinchonicine
(dihydrocinchotoxine) (F f).
a- Cinchonhydrine
(8-cinchonine) (Ga).
/3-Cinchonhydrine (Ga)
y-Cinchonhydrine (Ga)
References
Characters
MS^32^2^2
Prisms;
m.p.
[a]2 - 214-8.
isoapoQuinine
Aggregates of needles ;
m.p. 275 (dec.); [a]}f
Henry,
Solomon
and
- 261-7.
Soc,
Needles or prisms ; m . p . J- Gibbs, J. Chem.
172 or 185-90 ; [a] D
1935, 966.
+ 181-8 or + 208-6
(dry).
1
Hexagonal prisms ; m . p . Henry and Solomon (loc.
245, [a]J,5 - 12-6.
cit.).
Prisms, m . p . 260, [a]* 6 " Henry,
Solomon
and
+ 206-2.
Gibbs.30(a)
(E)
apoQuinidine (E)
isoapoQuinidine (C)
neoapoQuinidine (E-f) .
CH..O.N,
a-Hydroxydihydrocinchonine (B) .
J3-Hydroxydihydrocinchonine (B) .
Hydroxydihydrocinchonidine (B) .
Dihydrocupreicine (F -j-)
184 ;
* The capital letters in brackets refer to the lettered formulae (p. 449).
t See notes on formulae, p. 449.
TBANSFORMATION PRODUCTS
Name and Formula *
Niquidine (Ga)
isoNiquidine (Ga)
Niquine (Ga)
453
Characters
References
^i9rl26U2N2
Dihydroniquidine (Ga f)
e/)i-C 8 -Dihydroniquidine (Ga f)
a-Hydroxydihydroapoquinine (B)
-Hydroxydihydroapoquinine (B)
x-Hydroxydihydroapoquinidine
(B : Q = 6-Hydroxyquinolyl).
/3-Hydroxydihydroapoquinidine
(B : Q = 6-Hydroxyquinolyl).
a-i'soQulnine
(meihyl-isoapoquinine) 30(a) (E).
/3-isoQuinine (apoquinine methyl
ether), isoquinine, ^-quinine (E).
a-isoQuinidine (C)
* The capitial letters in brackets refer t o the lettered formulae (p. 449).
t See notes on formate, p . 449.
454
QUINOLINE
Name and Formula *
References
Minute
needles;
m.p.
180-1, [ajj,5" + 193-2.
M.p. 70 [a]}5 + 51.
Henry,
Solomon
and
Gibbs (loc. cit., 1935).
Domanski and Suszko,
Rec. Irav. chim., 1935, 54,
481.
(dihydroquino-
epi-C 3 -Dihydroquinidine (E f)
e^i-C s -Dihydroquinine (E | ) .
a-Hydroxydihydroquinidine =
methyl ether of a-hydroxydihydroapoquinidine (B ; Q =
6-methoxyquinolyl).
jS-Hydroxydihydroquinidine =
aMo-quinidine (B : Q = 6-methoxyquinolyl).
a-Hydroxydihydroquinine (B : Q =
6-methoxyquinolyl).
M.p. 167 ; B 2 . H 2 S 0 4 ,
prismatic needles, m.p.
218 (dec).
O i l ; [a]]?' - 33-8 (0-1 N,
H 2 S0 4 ) ; B . C 4 H 6 0 6 ,
needles, m . p . 192-4,
[a]l5 - 12 ( H 2 0 ) .
jS-isoQuinotoxine (F f)
Dihydroquinicine
toxine). (F f).
Characters
H 2 S0 4 ).
(H)
OBOUP
Chem.
Soc,
* The capital letters in brackets refer to the lettered formula; (p. 449).
f See notes on formulae, p. 449.
SYNTHESES OF CINCHONA ALKALOIDS
SYNTHESES
455
OH
/\
MeO.O
HO
I
0
OH
CH2
00
NH
>
MeO.C
II
OH
0 . OH
OH
N'
>
MeO 0
II
000H
I
0
OH
s\/\
||
HO
CH:CHPh
I
C
Oil
s\/\
\
IH
OH.
I 3
,a
OH
/\/\
OH
HO
0
OH
III
CH N N ^
MeO.C
IV
OH
II
HO
0
^OH
OH
X
JT
4S6
QUINOLINE
GROUP
Cerkovnikov and U s t r i c e v n (1938) starting from tetrahydropyran-4propionic acid (A: R = CH2 . CH a . C0 2 H), which was converted by
the Curtius-Schmidt method into 4-(2-aminoethyl)-tetrahydropyran
(A: R = (CHgJgNHg), and this with fuming hydrobromic acid at 100
CH.CO.OEt
CH.C0.0Et
H2C
CH 2
H2C
H2C
CH 2 ~
H2C
H22
CH
V2
(II)
(I)
(HI).
CH,
CH
CHg
H26N
' VH2
"H 2 C
H2C
A
JcH2^
|CH2
(VII) 0
(VIII)
CH.CH2.R
CH.CH,.C0.0Et
H2C
CH 2
(IV)
(V)
CH.CH2.CH20H
H2C
H 2 C C H CO
I
CH2
H 2 C! H 1CH,
CftjBr
H2CMCH.CO.OEt
N.CH2.C0.0Et
I
HpC-CH ~ CHp
(EC)
CH2
HpCCHCH2
CH?CH?Br
BrH2C
HC-CH-C0
H2C
|CH2
H2C
CH2
(VI)
CH,OEBCH
-CH 2
CH2
(CH2)2
ICH 2 ) 2
(A)
CH 2 0
CH2
(B) CH2Br
NH2
CH
CH2Br
(C) CH2
-CH2
SYNTHESES
457
saturated ester (XIV) and the latter hydrolysed to the acid, which on
treatment with sodium azide in sulphuric acid (Curtius-Sclimidt reaction)
is converted into l-amino-2-(tetrahydropyranyl-4)-butane (XV). This
with fuming hydrobromic acid gives l-bromo-4-(aminomethyl)-3-(/?'bromoethyl) hexane hydrobromide (XVI) which with N/10 sodium
hydroxide solution furnishes 3-ethylquinuclidine (XVII). The latter is a
(X)
R.CO C 2 H 5
+
( I I ) CH 2 Br.CO00 2 H 5
5E.0HEt.0H 2 .NH 2
H 2 c/ \oH 2
H 2 cl
H.CICgHj^CH.COgEt
(XIII)
IcH 2
R.0K(02H5).0H2.0O2Et(XIV)
HoC
OH
OH,
BrH2C
CH2Br
I
N
Ha0
(XV)
CHEt
0H 2
H,C
0H 2
(XVII)
(XVI)
0H 2 Br
(l.CO.CHBr
ft.00.0H
N
(0H2)2
(0H2)2Br
C!2
0H 2
(XVIII)
ft.C0.0H.BH2
CH
0H 2
0H 2
ttnila)
,-
0H 2
OH
I
0H 2
CH2
4.0H2.0H 2
0H 2
Q.CH 2 .CH 2
CH.
CHj
OHg
CH
CH2
(XX)
0H 2
C^
CH
(HX)
0H 2
(SHgOHCH2
(miib)
Br
Br
CH2 OH,
I I
f I
CHJJOH
(XVIIIo)
CH2
Q.0H 2 .CH 2
>
0H 2 NH
CH,
I
CH,
II
OHgCH
(XVIIId)
CH2
458
QUINOLINE
GROUP
00 - OH CH3
- HO CB - CH 0H 2
1
'
I
I
'
I
I
'
I
(cHoM
( x n i ) <CHa)2
tixin)
(CH2)2
I I I
I I I
I I I
U-CH:0
S ORg a-CH2-0fl H CHg
a-CHjJ'CH B CH2
ini)
BASES.
The
degradation
products
of
quinu-
459
SYNTHESES
8 1
CH OH
I t .
N=-CH
Et-C 0 0H-GHOH-0Cl,
2
3
OH
CH,
(CH 3 )g
CH 2 NBz
Et-CH
0H-00gEt
00-0.
0H 2
|
0H 2 NH
(Vila)
CHBr-CO-Q
Et-0H
CHo
Et-CH
(0H2)2
0H 2 N
(VIII)
fCHg
C H Z?
I2
|
CH-C0-Q
CHp^CHCHp
CH;,
NH
(IV)
CH 2
CHP
C0-Q
OH
CHP
II
j
(0H2)2
0H 2 N
(K)
j
CH-0HOH-4
CHCH,
I
CH
I
CHp
0 H 2 N H CH2-C0-(J
(XI) 9-Rubatoxanone
OH
I
CH 2
I }Hg)2 1JH2 or
CH 2 -NBr
(VII)
CH
Et-CH
I
CH 2
Et-CHOH
0H2
C0-Q
l , H 2 ^ CH^ - CHp
I * I
0H2NH
(VI)
jCHgCH CHp
0H 2
.CH-C0Et
CH
(CH2)2
Et-OHOH
I I
(0H2)
CH CH
I I
NCH
(III)
(V)
OH CH
I I
N=0H
(ID
(I)
Et-CH
E t - C 0CH=CH-C00H
"
CH
E
CH2N
CH-C0-Q
(XII) 9-Rubanone
0H2N
0H-0H0H- 0.
( m i ) 9-Rubanola
460
QUINOLINE GMOUP
of ethyl cinchoninate,6* and so obtained dihydroquinine and dihydroquinidine, and later on the corresponding ept-bases.
Rabe and his collaborators '* have also effected the re-conversion of
cinchonicine, quinicine and dihydroqujnicine into cinchonine, quinine and
dihydroquinine respectively, by treating them with sodium hypobromite,
forming the iV-bromo-derivative (VII) or the 8-bromo-derivative (Vila)
as first employed by Kaufmann and Huber 62 and produced by the action
of bromine in hydrobromic acid. Either bromo-derivative is converted
by alkali hydroxide into the corresponding quina-ketone (VIII), which is
then reduced to the mixture of stereoisomer ides of the dihydro-cinchona
base (IX) by means of aluminium powder and sodium ethoxide solution.
Later it was found that reduction can also be effected by catalytic hydrogenation with palladium in the case of the dihydro-bases, but when the
latter process is applied to the vinyl-containing quina-ketones the sidechain is reduced as well as the carbonyl group. 65
Using the ()-Aomocincholoipon produced as described, Rabe and
Schultze,66 by the same sequence of reactions, have produced ()-dihydroquininone (m.p. 98-9, [a]f, 70-0 (final value; EtOH)), which on
hydrogenation in presence of palladium gave a mixture of bases, of which
()-dihydroquinidine and (+)-dihydroquinine were isolated.
The
characters of these mirror-image isomerides of dihydroquinidine and
dihydroquinine respectively have been given already with the directions
of rotation at the centres of asymmetry C3, C4, C8, C9 (see table, p. 446).
Using the same method, Rabe and Riza 67 have synthesised 9-rubanone,
first prepared by Rabe, Kindler and Wagner, 68 by condensing ethyl Nbenzoylpiperidylpropionate with ethyl cinchoninate, hydrolysis of the
resulting /J-ketonic ester (X) to 9-rubatoxanone (XI, yellow crystals,
m.p. 30) and conversion of this into 9-rubanone (XII, yellow needles,
m.p. 85-6) vid the 8-bromo-derivative (cf. formula Vila). The quinaketone, like others of its class, becomes in solution a mixture of four ketoenol isomerides, and such a solution on hydrogenation furnishes the four
9-rubanols (XIII), particulars of which have already been given in the
table (p. 446). Similarly Rabe and Hagen, 37 as stated already (p. 447),
have prepared the four stereoisomeric 6-methoxy-9-rubanols (XIII; Q =
6-methoxyquinolyl).
The important role played by the quinicines (rubatoxanones, quinatoxines) in the syntheses of the dihydrocinchona alkaloids and the
possibility that such substances might be used for the preparation of
products approaching quinine in therapeutical interest, has led to the
production of a large number of quinolyl ketones of various types and the
corresponding secondary alcohols, and other derivatives obtainable from
them, of which mention may be made of Rubtzov's syntheses of several
isomerides of dihydroquinine.69
Of special interest in this connection are the quinolylpiperidylcarbinols,
of which items have been made by Rubtzov,69(0) and by Sargent et aZ.69'*'
The first substance of this type was synthesised by Ainley and King,6*'"'
viz., 4-{6-metli0xyquin:olyl)-*'pipmdylcrbind (XIV), C u ^ O ^ N , , m.p
SYNTHESIS
461
OF QUININE
(XV) :<2U
CH 8 (S CB2
(171)
CH2CHPrBH2
Q = 6~llethoxyquiaolyl
Rabe's general formula (p. 443) for the cinchona alkaloids was published in 1908 and a partial synthesis of quinine was effected by Rabe
and Kindler in 1918,84 but a complete synthesis of this alkaloid did not
become available until 1945 when Woodward and Doering described their
ingenious process.
SYNTHESIS OF QUININE. This required a parallel series of operations
\n which the still unknown substance Aomomeroquinenine (3-vinylpiperidine-4-propionic acid) replaced its dihydro-derivative, Aomocincholoipon,
for the final condensation with ethyl quininate. The first step was taken
by ProStenik and Prelog,70'") who converted cinchonine to cinchonicine^
462
QUINOLINE
GROUP
SYNTHESIS
OF
463
QUININE
C H *6
I
OH
mW
i)W
OH
(III)
C( Me): UOH
COgEt
CH. CH2.CH2.Q0gEt
HPC
CH.CH(Me).Iffie3I
H2I
(VI)
H2C:HC.HC
CHg-CHg-COgH
CH2
CH2
(VIII)
NH
CH2
CH2
CH2
(VII)
:AO
H2C:HC-CH -CH-CHp-CH-COI
~ I
CH2
C0 2 Et
CH2
CH2-MrC0-Ph
(IX)
OMe
464
QUINOLINE
GROUP
and contains neither a methoxyl nor a methylimino- group. The hydrochloride, B . HC1. H 2 0, has m.p. 166-7, [a] D + 102- 8 (H 2 0), the hydriodide,
m.p. 224, [a] D + 84-8 (EtOH) and the nitrate, m.p. 186-8, [a] D + 94-9
(H 2 0). The picrate crystallises from boiling water in small yellow needles,
m.p. 175-6, [a] D -f- 90-0 (M/40; acetone). Nitrosoquinamine is amorphous but forms a crystalline picrate, C 19 H 23 0 2 N 2 . NO . C 6 H 3 0 7 N 3 , m.p.
161, and a crystalline acetyl derivative, C 19 H 22 0 2 N 2 (NO)(CO. CH 3 ),
small yellow cubes, m.p. 137-141. Quinamine forms a monomethiodide,
m.p. 250-1, [a] D + 114-2 and a methochloride, m.p. 237-^0, [a] D
-f- 111-9, and on hydrogenation produces a dihydro- base, m.p. 184-5,
M D + 119-8, yielding a picrate, m.p. 176-8 and a monomethiodide,
m.p, 219-25. When refluxed with acetyl chloride in benzene the
alkaloid is converted into amorphous acetylapoquinamine giving a picrate,
c
f 9 H 2 1 ON 2 . CO . CH 3 . C 6 H 3 0 7 N 3 , m.p. 143-5, and yielding on alkaline
hydrolysis crystalline apoquinamine, C 19 H 22 0N 2 , m.p. 115-7, [a] D 0
(EtOH) or 32-9 (M/40; N/10-H 2 SO 4 ), which forms a hydriodide,
m.p. 207-9, a picrate, m.p. 172-4, and a methiodide, m.p. 219-20,
and on hydrogenation in alcohol with palladised barium sulphate as
catalyst gives rapidly a dihydro-derivative (picrate, m.p. 179-81) and
very slowly a tetrahydro-derivative (picrate, m.p. 175-7). The formation
of nitrosoacetylquinamine and the dehydration to apoquinamine in the
reactions described above, indicate that in spite of the two replaceable
hydrogens found by the Zerewitinoff method, quinamine probably contains
three such hydrogens, two as hydroxyl groups and one as a secondary
nitrogen. When either quinamine or apoquinamine is subjected to
prolonged ebullition in dilute acetic acid it is converted into quinamicine,
the apo'base being apparently first hydrated to quinamine. Quinamicine,
like the quinicines (p. 425) in general, could not be crystallised, but a
crystalline picrate, C 19 H 24 0 2 N 2 . C 6 H 3 0 7 N 3 , m.p. 203-5, [a] D 17-46
(M/40; acetone), 2 :4-dinitrophenylhydrazone, m.p. 239-40 and
oxime, m.p. 217-20, [a]p +82-2, were obtained and by the action of
methyl iodide, iV-methylquinamicine methiodide, C 19 H 23 0 2 N 2 . CH 3 . CH 3 I,
m.p. 275-6, [a] D - 39-8 (EtOH).
Quinamine differs from all the cinchona alkaloids previously examined
in not yielding a quinoline derivative on oxidation but instead is oxidised by
chromic acid to a vinylquinuclidinecarboxylic acid, C10H15O2N, m.p. 206-8,
[a] D + 57-9 (CHClj) isolated as a copper salt (C10H14O2N)2Cu . H 2 0 . The
acid, on treatment with diazomethane and distillation of the reaction
product, is decarboxylated to a base C9H15N (picrate, m.p. 143-6) which is
assumed to be 3-vinylquinuclidine, since it absorbs one molecule of hydrogen to form 3-ethylquinuclidine, identified as the picrate, m.p. 151-3,
which showed no depression of melting point on admixture with the
picrate of 3-ethylquinuclidine prepared by the method of Prelog et al.M
(1940). Assuming that the central . CHOH group is present in quinamine
and is attached to C8 of the quinuclidine nucleus as is usual in the cinchona
alkaloids, the oxidation acid must be 8-vinylquinuclidine-8-carboxylic
acid, and from the data given above the empirical formula of quinamine
MINOR CINCHONA
ALKALOIDS
465
HH
H2C-
466
QUINOLINE
QBOUP
Properties
Conquinamine,
C19H2102N2.
C. succirubra,
C.
Ledgeriana,
etc.
Triclinic crystals, m . p .
121, [ a ] D + 204-6
(EtOH).
Crystalline
salts.
Javanine
C. Calisaya
Rhombic plates.
var. Javanica.
References
H e s s e , Ber. 1877, 1 0 ,
2158;
Annalen,
1 8 8 1 , 2 0 9 , 62 ;
O u d e m a n s , ibid., p .
38.
C.
succirubra M . p . 136, a m o r p h o u s H e s s e , Annalen,
1873,
Paricine,
from
salts, [a]D 0.
166, 2 6 3 ;
Pharm.J.,
C16H18ON2. i H a O .
Darjeeling.
1 8 7 9 , [ i i i ] , 9, 9 9 3 ;
H o w a r d , ibid., p . 7 9 2 .
C. rosulenla
A m o r p h o u s ; m . p . 4 0 , H e s s e , Annalen,
1885,
Dicinchonine
and
[a]lf + 6 5 - 6 ( E t O H ) ;
(Dicinchonicine),
227, 154.
B . 2HC1, crystalline.
C.
succirubra.
C38H4402N4.
" Q u i n o i d i n e . " A m o r p h o u s , d e x t r o r o t a - H e s s e , Ber., 1877, 1 0 ,
Diconquinine
(Diquinicine),
2155.
tory.
H e s s e , Ber.,
2162.
1877, 1 0 ,
Properties
References
P r i s m s , m . p . 188, [ a ] D P e l l e t i e r a n d C o r r i o l , J.
Pharm.,
- 5 8 - 3 ( E t O H ) , + 14-5
1829, 15, 565 ; H e s s e
Annalen,
(
a
c
i
d
)
.
O
x
a
l
a
t
e
s
p
a
r
i
n
g
l
y
1
8
7
3
,
166,
259
;
1876,
1
8
1
, 58 ;
^ 2 3**2 6^-* 4^*2 *
soluble in water. Green
1877, 185, 310 ; Pharm. J., 1882,
colour w i t h nitric acid.
[iii], 12, 517 ; H o w a r d , J.
Chem.
Soc, 1875, 2 8 , 309 ; M o i s s a n a n d
Landrin, Bull. Soc. Chim., 1890,
[ i i i ] , 4, 2 5 8 .
Leaflets, m . p . 110 (dry), L e v e r k o h n , Rep. Pharm.,
1829, 3 3 ,
Cusconine,
357 ; H e s s e , Pharm. J., 1882, [ i i i ] ,
C23H2604N2. 2HaO.
[<x]D - 54-3 ( E t O H ) .
12, 507 ; Annalen,
1877, 185, 3 0 1 .
H e s s e , loc. cit.
Amorphous.
Cusconidine
Cuscamine
P r i s m s , m . p . 218.
\
H e s s e , ibid., 1880, 2 0 0 , 3 0 4 .
Cuscamidine .
Aricine
(Quinovatine),
MINOR CINCHONA
467
ALKALOIDS
Crystalline Form
Optical notation
Chairamine,
C22H2604N2. H 2 0 .
Conchairamine,
C 2 2 H 2 6 0 4 N 2 . H a O.
Needles or
prisms, m . p .
233 (dry).
Prisms, m . p .
120 (dry).
Chairamidine,
C22H2604N2. H 2 0 .
Amorphous ;
m.p. 126-8.
Conchairamidine,
C22H2604N2. H 2 0 .
Crystalline,
m.p. 114
(dry).
Colour Reactions
[<x]D
REFERENCES
(1) K I N G , J. Chem. Soc, 1946, 523. (2) Bee. trav. Chim., 1933, 52, 847 ; H E N R Y
and SOLOMON, J. Chem. Soc., 1934, p . 1924 ; cf. T H R O N and DIRSCHERL,
Annalen,
1935, 515, 255. (3) COMSTOCK a n d K O N I G S , Ber., 1887, 20, 2517 ; CHRISTENSEN, J. pr.
Chem., 1905, 71, 1. (4) GOODSON, J. Chem. Soc., 1934, 1095. (5) SEEKLES, Rec. trav.
Chim., 1923, 42, 69. (6) H E S S E , Annalen, 1875, 176, 232 ; SKRAUP, ibid., 1879, 197,
381.
(8)
K E R N E R , Zeit. Chem., 1869, p . 593 ; SKRAUP, Annalen, 1879, 199, 348 ; Monats., 1889,
10, 39 ; VON BUCHER, ibid., 1893,14, 598 ; GOODSON, H E N R Y and MACFIE, Biochem.
J.
1930, 24, 874 ; ANDREWS and CORNATZER, Elisha Mitchell Sci. Soc, 1943, 59, 177.
(9) F O R S T a n d BOHRINGER, Ber., 1882, 15, 1659.
3655. (11) Annalen, 1909, 364, 330 ; R E N F R E W a n d CRETCHER, J. Amer. Chem. Soc.,
1935, 57, 7 3 8 ; WOODWARD et al., ibid.,
i&ttt,1946, 68, 586. (12) Ber., 1907, 40, 4698. (13) Ibid., 1909, 42, 627. (14) Monats.,
1896, 17, 377. (15) Ber., 1897, 30, 1326. (16) Loc. cit. a n d KONIGS, ibid., 1902, 35,
1357 ; cf. R A B E a n d PASTERNACK, ibid., 1916, 49, 2753.
(17) COMSTOCK a n d K O N I G S ,
ibid., 1880, 13, 2 8 6 ; 1881, 14, 1854; 1884, 17, 1 9 8 6 ; 1885, 18, 1 2 1 9 ; 1892, 25,
1545 ; R A B E , Annalen,
K I N G , Proc. Roy. Soc., 1938, B , 125, 49 ; for corresponding bromides see BOHRINGER,
Ger. P a t . 592,540, 592,541. (18) COMSTOCK a n d K O N I G S , Ber., 1880, 13, 2 8 6 ; 1881,
14, 108, 1 8 5 4 ; 1884, 17, 1 9 8 4 ; 1885, 18, 1219. (19) KONJGS, ibid., 1894, 27, 900
QUINOLINE GROUP
468
Chem. Runs., 1945, 15, 324. (20) KONIGS, ibid., 1881, 14, 103, 1854 ; 1885, 18, 1219 ;
1894,
(21) COMSTOCK a n d K O N I G S ,
Ber.,
Alkaloide, p . 315 ; KONIGS, Ber., 1899, 32, 3599; 1907, 40, 2 8 7 3 ; AnnaUn,
347, 1 4 3 ; R O H D E a n d ANTONAZ, Ber., 1907, 40, 2 3 2 9 ; R A B E , Annalen,
1906,
1906, 350,
180 ; Ber., 1908, 41, 62. (24) R A B E and collaborators, AnnaUn, 1906, 350, 180 ; 1911,
382,
365.
2329 ; 1909, 42, 2182. (27) Ibid., 1907, 40, 3655 ; 1908, 41, 62 ; AnnaUn, 1909, 364,
330. (28) R A B E , Ber., 1911, 44, 2088 ; 1918, 51, 466 ; also p . 445 of this book. (29)
AmnaUn, 1909, 365, 353 ; 1910, 373, 85. (30) Ber., 1922, 55, 522 ; t h e earlier notation
is also due t o R A B E , AnnaUn, 1910, 373, 85 ; cf. KAUFMANN a n d H U B E R , Ber., 1913,
46, 2913, who reversed t h e order. (30a) H E N R Y , SOLOMON a n d GIBBS, J. Chem. Soc.,
1937,
AnnaUn,
. CH2: CH.
cf. R A B E ,
becomes
(34) Ger. P a t . 330,813 (Chem. Soc. Abstr., 1921, [i], 3 5 5 ) ; cf. KAUFMANN and H U B E R 3 3
and R A B E a n d K I N D L E R , Ber., 1918, 51, 466. (35) J. Chem. Soc, 1922, 121, 2578.
(36) (With IRSCHICK, SUSZKO, MULLER, N I E L S E N , K O L B E , VON R I E G E N a n d HOCHSTATTER,
AnnaUn,
1932, 492, 242 ; see also ibid., 1910, 373, 85 ; (with SCHULTZE), Ber., 1933,
66, 120 ; R A B E , ibid., 1943, 76, 251 ; cf. KAUFMANN and H U B E R , ibid., 1913, 46, 2913 ;
a n d KONIGS a n d H U S E M A N N , ibid., 1896, 29, 2185 ; FIEDZIUSKO a n d SUSZKO,
Arch.
Chem. Farm., 1935, 2, 139 ; SUSZKO and SZELAG, Bull. Inst. Acad. Pol., 1936, A, 403 ;
WOODWARD et al., Ref. 11. (36a) J. Amer. Chem. Soc, 1947, 69, 1700. (37) F o r
6'-methoxyruban-9-ols see R A B E (with K I N D L E R a n d W A G N E R ) , Ber., 1922, 55, 532 ;
(with H A G E N ) , ibid., 1941, 74, 636 ; (with SCHULER and Voss), ibid., 1943, 76, 318 ;
cf. PRELOG, S E I W E R T H , HEIMBACH-JUHASZ, a n d STERN, ibid., 1941, 74, 647 ; KLEIMAN
and WEINHOUSE, J. Org. Chem., 1945, 10, 562. (37a) Helv. Chim. Acta, 1944, 27,
535, 545 ; cf. K E N N E R , Chem. Soc. Ann. Repts., 1922, 19, 158 ; for a synthesis of dlcincholoipon and its ethyl ester, see STORK and MCELVAIN, J. Amer. Chem. Soc, 1946,
68, 1053. (376) (With Z E L L E U a n d H U B E R ) , Ber., 1913, 46, 1823. (37c) L E V E N E and
MARKER, J. Biol. Chem., 1931, 91, 405, 761 ; 92, 455 ; see also FREUDENBERG, " Stereochemie," 1932, pp. 679, 727, and E . FISCHER, Ber., 1891, 24, 2683. (38) Monats., 1899,
20, 425 (VON ARLT) ; 571,585; 1900,21,512,535,558; 1901,22,171,191 (HLAVNICKA) ;
253, 1083, 1097, 1103 ; 1902, 2 3 , 443 ( P E C S I S ) ; 455 ; 1903, 24, 119 (ZWERGER) ; 311 ;
KAAS, ibid., 1904, 25, 1145 ; 1905, 26, 119 ; KONIGS, ref. 40. (39) Ann. Chim., 1920,
[ix], 14, 59 (with a bibliography of the original papers on which the summary is based) ;
J. Pharm. Chim., 1936, [viii], 22, 558, 608 ; 1938, [viii], 27, 63 ; Bull. Soc. Chim., 1937,
[v], 4, 180 ; 1938, [v], 5, 183. (40) K O N I G S , AnnaUn, 1906, 347, 143 ; cf. R A B E a n d
BOTTCHER, Ber., 1917, 50, 127. (41) SKRAUP, Monats., 1893, 14, 428. (42) SKRAUP,
Monats., 1899, 20, 571. (43) JUNGFLEISCH and LEGER, Compt. rend., 1894, 118, 2 9 ;
L E G E R , 1919, 169, 797 ; cf. LANGER, Monats.,
HAUPT, ibid., 1898,19, 4 6 1 ; cf. LANGER, ibid., 1901, 22, 151. (44) GIBBS and H E N R Y ,
J. Chem. Soc, 1939, 240, 1 2 9 4 ; SOLOMON, ibid., 1941, 7 7 ; BUTLER, R E N F R E W a n d
CRETCHER, J. Amer. Chem. Soc, 1943, 65, 2038. (45) AnnaUn, 1934, 514, 61 ; Ber.,
1941,74,725 ; cf. SUSZKO and TOMANEK, Rec Trav. Chim., 1933,52,18 ; LUDWICZK6WNA
and SUSKO, Arch. Chem. Farm., 1935, 2, 196. (46) Ber., 1912, 45, 1800. (47) Ibid.,
1912, 45, 1805 ; cf. KAUFMANN a n d W I D M E R , ibid., 1909, 42, 1999, 3 7 7 6 ; 1911, 4 4 ,
2052, 2058 ; 1918, 51, 116 ; 1922, 55, 614 ; HALBERKANN, ibid., 1921, 54, 3079, 3090 ;
THIELPAPE, ibid., 1922, 55, 127 ; 1938, 71, 387 ; 1989, 72, 1432 ; KOELSCH, J. Amer.
Chem. Soc, 1944, 66, 2019. (48) Ber., 1931, 64, 2487 ; A I N L E Y and K I N O , Proe. Rot/,
Soe., 1938, B , 125, 60 ; CAMPBELL, TrpsON, E L D E R F I E L D , CAMPBEIX, C L A F P , G E N S L E * J
PHARMACOLOGICAL
469
ACTION
Annalen,
1886, 236, 69. (49) KONIGS, Ber., 1904, 37, 3244 ; (with BERNHART), ibid., 1905,
38, 3049 ; LOFFLER and STIETZEL, ibid., 1909, 42, 124. (50) Annalen, 1920, 420, 190.
(51) J. Chem. Soc., 1937, 1524, 1989; 1939, 1241 ; 1941, 476. (52) Annalen, 1937,
532, 69, 83 ; 1938, 535, 37 ; 1940, 545, 247 ; Ber., 1939, 72, 1325. (53) Ann. Chim.,
1882, [v], 27, 469. (54) Ber., 1894, 27, 1502. (55) Helv. Chim. Acta, 1919, 2, 338.
(56) J. Chem. Soc,
PRELOG a n d KOMZAK, ibid., 1941, 74, 1705; (with MOOR), Helv. Chim. Acta, 1942,
25, 1654 ; 1943, 26, 846 ; (b) STEVENS, B E U T E L a n d CHAMBERLIN, J. Amer. Chem.
Soc,
66, 1456 ; cf. PRELOG et al., Helv. Chim. Acta, 1945, 28, 182 ; (c) ROBINSON and W A T T ,
J. Chem. Soc, 1934, 1536 ; (with MATEJKA), ibid., 1932, 2019. (58) Ber., 1921, 54,
1343;
cf. R A B E a n d K I N D L E R , 1918, 5 1 , 1 3 6 0 ;
1 9 1 9 , 5 2 , 1 8 4 2 . (59) Ibid., 1933, 66, 120. (60) Ibid., 1918, 51, 1360; cf. Ger. P a t .
330,945 (Chem. Soc Abstr., 1921, [i], 360); and Ger. P a t . 268,830 (ibid., 1914, [i], 575).
(61) Ibid., 1916, 49, 2299 ; cf. Ger. P a t . 313,321 (Chem. Soc. Abstr., 1920, i, 7 8 ) ; for a
survey of such reactions see KOELSCH, J. Org. Chem., 1945, 10, 34. (62) KAUFMANN
and H U B E H , Ber., 1913, 46, 2913. (63) Ibid., 1919, 52, 1842. (64) Ibid., 1911, 44,
2088 ; 1912, 45, 2163 ; 1918, 51, 466. (65) R A B E et al., Annalen, 1932, 492, 252.
(66) Ber., 1933, 66, 120. (67) Annalen, 1932, 496, 151. (68) Ber., 1922, 55, 532.
(69) See, for example, KAUFAIANN, P E Y E R and K U N K L E R , ibid., 1912, 45, 3090 ; cf.
REMFRY and DECKER, ibid., 1908, 41, 1007 ; and Ger. P a t . 268,830 ; 280,970 (Chem.
Soc. Abstr., 1914, [i], 5 7 5 ; 1915, [i], 7 2 0 ) ; KAUFMANN, Ber., 1913, 46, 1823 ; H O W I T Z
and K O P K E , Annalen, 1913, 396, 38 ; R A B E a n d PASTERNACK, Ber., 1913, 46, 1026,
1032 ; (with KINDLER), ibid., 1917, 50, 144 (cf. Ger. P a t . 330,813, J. Soc Chem. Ind.,
1921, 40, 4 4 9 A ) ; RUZICKA, Helv. Chim. Acta, 1921, 4, 482, 486 ; KARRER, Ber., 1917,
50, 1499 ; RUBTZOV, J. Gen. Chem. U.R.S.S., 1939, 9, 1493 ; 1943, 13, 593, 702 (Chem.
Abstr., 1940, 34, 2850; 1945, 39, 705, 706); KOELSCH, J. Amer. Chem. Soc, 1946,
68, 146. (69a) RUBTZOV, J . , Gen. Chem. Buss., 1946, 16, 461 ; SARGENT and a team of
Workers, J. Amer. Chem. Soc, 1946, 68, 2688-2721 (12 papers); AINLEY and K I N G ,
Proc Roy. Soc, 1938, B , 125, 60 ; K I N G a n d W O R K , J. Chem. Soc, 1940, 1307 ; W O R K ,
ibid., 1946, 194, 197 ; 1947, 222. (70) (a) PROSTENIK and PRELOG, Helv. Chim.
1943,
Acta,
2308; (c) WOODWARD and DOERING, J. Amer. Chem. Soc, 1944, 66, 849 ; 1945, 67,
860; (d) FRITSCH, Annalen, 1895, 286, 1 0 ; (e) LINSTEAD, Chem. and Ind., 1937, 56,
510; ( / )
Compt. rend., 1853, 37, 162. (71) (a) Ber., 1872, 5, 265 ; 1877, 10, 2152 ; Annalen,
1873, 166, 217 ; 1879, 199, 3 3 3 ; 1881, 207, 288 ; D E V R I J , Pharm. J., 1874, 4, 6 0 9 ;
HOWARD, ibid., 1875, 5, 1 ; OUDEMANS, Annalen, 1879, 197, 48 ; (6) J. Chem. Soc,
1945, 524 ; {c) Ibid., p . 528. (72) Annalen, 1877, 185, 296, 323 ; 1884, 225, 211.
(73) Compt. rend., 1881, 93, 5 9 3 ; 1883, 97, 174. (74) TSCHUGAEFF, Ber., 1901, 34,
1824.
(75) BOUTROUX and GENVRESSE, Compt. rend., 1897, 125, 467. (76) HOWARD
and CHICK, J. Soc. Chem. Ind., 1905, 24, 1281 ; 1909, 28, 53. (77) Compt. rend., 1941,
212, 135 ; 1945, 220, 670 ; 221, 307.
PHARMACOLOGICAL
ACTION
OF THE CINCHONA
ALKALOIDS.
The
470
QUINOLINE
GROUP
CHCH2
<(H2
CH2N
10
(II)
CH2N
CH
CHo
<JH2
CH.CH(0H).<1
(III)
CHCH2
CH8
CCH 2 ] 2 J
CH2
CH?N
(IV) 0
CH
(V)
CH2N'
CHCH2
CH2 CH.
0H2
I
CHNH CO-Q
CH3-CH2-CHCH-CH8-CH2-CH(0H). ft
u
CH8
<o
CH.CH(0H).ft
I*
CH3.CH:CH.CHCH2
It
CH,
CH2N'CH.CH(OH). Q
CH.Q
CH2-CH-CH
(VII)
^1
CH2
CH.CH(0H).Q
I I
I
<
CHCH2
0H2
CH,. CHCH
CH3.CH:C
<jH2
CH2
(I)
II
CB3.CH2.CH- -CHCH2
ii
m>
CH2
NHCH.CH(0H).
CH2
CH,
I Z
<JH2
(IX) NH -CH.CH(0H).
(VIII) CH2-NH
^
ft nay t> Quinolyl, 6-mothoiyqulnolyl, or 6-alkoxyquliiolyl, u b s t l t u t d art position 4
Q U I N I N E E Q U I V A L E N T S O F CINCHONA B A S E S A N D T R A N S F O R M A T I O N P R O D U C T S .
Q=6-Methoxyquinolyl in
formulae (p.
449).
Quinidine
(0-5)
Quinine
(1-0)
Q=6-Hydroxyquinolyl in
formulae (p.
449).
Q = Quinolyl
tp. 449).
Cinchonidine
(0-5).
Cinchonine
(<0-2).
II
III
IV
VI
Dihydroquinidine
(0-5-1-0)
Dihydroquinine
(1-2)
a/>oQuinidine
methyl ether
(1-0)
oe-isoQuinine
(0-62).
/3-isoQuinine
(0-69)
a-isoQuinidine
(0-065)
0-isoQuinidine
(0-1)
y-isoQuinidine
(inactive)
a-Hydroxydihydroquinine
(0-54)
Niquidine
(1-45)
MoNiquidine
(105)
Niquine
(0-86)
8
1
Dihydrocupreidine
(0-68)
Dihydrocupreine
(0-92).
apoQuinidine
(0-4)
weoapoQuinidine
(0-46).
apoQuinine
(0-98).
woapoQuinine
(0-9).
isoapoQuinidine
(Oil)
a-Hydroxydihydrorapoquinine
(0-076).
/9-Hydroxydihydroapoquinine
(0036).
Dihydroniquidine *
(1-08).
Dihydroni(Juine *
(0-63).
* Formula VI
with
CH3.CH:CH.CH--v
CH 3 . C H 2 . CH a '.CH
Formula VIII
Formula IX
Dihydro(<0-2).
Dihydro
cinchonine
(<0-2).
Formula VII
Quinicines
Dihydroquini(inactive)
cinols (inactive)
(Q = 0 -methoxy(Q = 6-methoxyquinolyl).
quinolyl.
4-(6-Methoxyquinolyl)a-piperidylcarbinol
(Ainley and King),
(0-5).
472
QUINOLINE
QBOUP
PHARMACOLOGICAL
ACTION
473
.
.
.
.
.
C16 C20 ^21 ^22 ^23 ^24 ^25 ^26 ^27 ^zs
^29 ^30
0-98 1-18 1-10 1-72
1-6
1-18
0-69 1-23 1-47 1-21
0-98 0-75
0-92 1-05 1-87 1-50
1-43 1-6
.
6
3
26
7
34
9
40
10
11
5
13
Each of these three series has two maxima, one for odd and one for
even numbers of carbon atoms. It will be noted that in each the rise in
the homologous series is due to the lengthening of an aliphatic chain and
it is known that an alternation of some physical constants may occur in
a homologous series so constituted. There is a general tendency now to
attach greater importance to the physical and biochemical properties of
drugs as influencing modes of action, and possibly explaining some of the
many anomalies in the pharmacology of structurally related compounds.
The cases just cited might provide useful material for a physical and
biological investigation on these lines.
According to the table, saturation of the vinyl side-chain in quinine
or quinidine (I) s-(II) increases activity but reduces it in the case of
cinchonidine and has little or no effect on cinchonine.4 Addition to the
vinyl group of hydrogen chloride, a halogen,1'6' or the elements of a molecule
of water (I > V) * reduces activity. Oxidation of the vinyl group to
carboxyl as in quitenine (p. 436) abolishes it, though it is restored on
esterification of the carboxyl group,* but not by conversion of the latter
to the amide or methylamide. 7 Work 8 found that when the vinyl group
is oxidised to . CHO as in the conversion of quinine to quininal, activity in
scarcely affected, but reduction of the . CHO group to CH,OH, as in
11
5
25
474
QUINOLINE
GROUP
PHARMACOLOGICAL
ACTION
475
476
QUINOLINE GROUP
PHARMACOLOGICAL
ACTION
477
Acridine Derivative
2 - Chloro - 5 - (a> - diethylamino - a - methylbutylamino) 7-methoxyacridine.27 (Wiselogle, S.N. 390, Vol. II, 1344.)
Guanidine Derivative
Paludrine.
N -^-Chlorophenyl-NB isopropylbiguanide.
CI. PhNHC(: N H ) . NH . C( : NH) . NH . CHMe2.
Since the introduction of pamaquin and mepacrine much chemical
and biological work has been done on potential, anti-malarial drugs based
on quinoline or acridine and possibilities in these directions are fairly
well known. Paludrine is especially interesting as a drug of a new type
and its possibilities are in process of clinical exploration. The chemical
researches, which led to its discovery are described in a series of papers by
Curd and Rose with several collaborators ; 28 the biological side of the work
is dealt with in a second set of papers 29 by a team of workers, beginning
with two by Curd, Davey and Rose detailing the biological methods used,
and discussing fully the limits and difficulties met with in devising a
standard method of testing and in assessing anti-malarial activity.
Parts III to IX are concerned with the pharmacology of, and accounts of
clinical trials with, No. 8349, 2-p-chlorophenylguanidino-4-j3-diethyl1
478
QUINOLINE
GROUP
PHARMACOLOGICAL
ACTION
479
C 2 H 5 .0
HO.C2H4.0
(CH 3 ) 2 .CH.O
HO . CH 2. CH(CH3). 0
(HO.CH 2 ) 2 .CH.O.
Toxicity. Approx.
L.D.50 (mice) mgm.
4
7
4
7
9
Bacteriostatic
Concentration of Drug
1:8
1:3
1 :16
1 : 16
1:3
XlO5
X 10 5
X 10 5
X 10 s
X 10 5
Bracken et al. found that hydroxy ethylapoquinine and " sulphapyridine " (oc-sulphanilylaminopyridine) gave equal protection to mice
against virulent pneumococci, and the use of either chemical enhanced
the protective action of the other. 40 Dawson et al.*1 found from the
ophthalmoscopic and histological examination of the eyes of dogs that,
while massive doses of quinine or the apoquinine alkyl ethers (III) caused
destruction of the cells of the ganglionic layer, no damage could be detected
after similar dosage of /Miydroxyethylapoquinine. Maclachlan and his
colleagues 42 used the drug successfully in a large number of cases of
human pneumonia, and no visual disturbance was observed in any patient.
Hegner et al. found the drug as active as quinine in avian malaria, and less
toxic. 43 A resume of the literature on " Structure and Anti-pneumococcic
Activity in the Cinchona Series " has been published by Renfrew and
Cretcher.44
None of the quaternary salts of the cinchona alkaloids have given
promising results as pneumococcicidal agents, but quinine methochloride
and ethochloride have received some attention recently as curarising
drugs. 45
The alkyl ethers of dihydrocupreine (II) are known to exhibit local
anaesthetic action, which appears to be at a maximum at isoamyldihydrocupreine, but local anaesthetic action in this group does not depend on the
intact quinuclidine nucleus, since woamyldihydrocupreicine (VII) is more
potent than woamyldihydrocupreine (II), producing local anaesthesia in
the cornea of the rabbit at 1 in 2,000 compared with cocaine at 1 in 50.46
Of the other cinchona bases, the dextrorotatory forms cinchonine
and quinidine have been used as anti-malarial drugs in cases of idiosyncrasy to quinine, a subject to which Dawson " has given much attention. Quinidine is used to control auricular fibrillation, and its value for
this purpose in comparison with dihydroquinidine has been investigated
by several workers.48 Dawes has recently devised a method of testing
QUINOLINE GROUP
480
Dis. Bull.
Exp. Ther.,
1939, 36,
H I A T T , ibid., 1944, 81, 160 ; (with QUINN), ibid., 1945, 83, 101 ; MARSHALL, ibid., 1945,
85, 2 9 9 ; BRATTON, ibid., p . 103. (4) B U T T L E , H E N R Y a n d T R E V A N , Biochem.
J.,
1934, 28, 426 ; (with SOLOMON a n d G I B B S ) , ibid., 1938, 32, 47 ; cf. GOODSON, H E N R Y
a n d MACFEE, ibid., 1930, 24, 874 ; see also W O R K , ref. 8. (5) F O U R N E A U , T R E F O U E L ,
Pasteur,
Immunitats.,
STRUKOW, Arch. Pharm., 1933, 271, 359 ; CERKOVNIKOV et al., ibid., 1943, 281, 78 ;
Helv. Chim. Acta., 1943, 26, 1180. (6) Arch. Pharm., 1935, 273, 320. (7) COHEN and
K I N G , Proc. Roy. Soc, 1938,125, B , 49. (8) J. Chem. Soc, 1944, 334. (9) DIRSCHERL
and THRON, Annalen, 1935, 521, 48 ; cf. R A B E , "Configuration and Basicity," Ber.,
1943, 76, 251 ; for other effects due t o optical isomerism see GAUSE et al., Biol. J.
(Russ.), 1 9 3 8 , 7 , 7 6 3 ; CHOPRA et al., Ind. J. Med. Bet., 1938,26,279,289. (10) Nature,
481
PHABMACOLOGICAL ACTION
1944, 154, 550.
(11) K A U F M A N N , Ber.,
1913, 46, 1 8 2 3 ;
R A B E , PASTEKNACK
and
Soc,
Soc,
1938, 125 B , 60. (14) J. Chem. Soc, 1940, 1307 ; 1942, 401. (15) Ibid., 1940, 1315 ;
1942, 426. (16) MAGIDSON atfd RUBTZOW, J. Gen. Chem. (U.R.S.S.), 1937, 7, 1896 ;
RUBTZOW, ibid., 1939, 9, 1 4 9 3 ; for other variants see ibid., 1943, 13, 593, 702 ; 1946,
16, 461 ; R A J N E B et al., Arch. Pharm., 1943, 281, 78. (17) MARSHALL et al., J. Pharm.
Exp. Ther., 1942, 75, 8 9 ; see also MARSHALL, ref. 2 ( 6 ) ; COGGESHALL et al., Proc.
Soc. Exp. Biol. Med., 1944, 57, 286 ; J. Amer. Med. Assoc, 1945, 128, 7 ; TONKIN,
ref. 3 0 ; (with HAWKING), Brit. J. Pharmacol., 1947, 2, 221. (a) GLYN-HUGHES,
LOUKIE
and
Y O R K E , Ann.
Trop.
Med.
Parasit.,
1938, 32, 1 0 3 ;
CHRISTOPHERS
and FULTON, ibid., 2 5 7 ; (6) FULTON, ibid., 1940, 34, 5 3 ; (c) J. Chem. Soc, 1946,
1063; (d) ibid., 1947, 1 0 3 4 ; (e) J. Org. Chem., 1947, 12, 617. (18) KAISER,
Arch. int. Pharmacodyn., 1940, 64, 215 ; HAAG, LARSON and SCHWARTZ, J. Pharm.
Exp. Ther., 1943, 79, 1 3 6 ; K E L S E Y and OLDHAM, ibid., 1943, 79, 77, 8 1 ; (with
GEILING), ibid., 1943, 78, 3 1 4 ; 1945, 85, 1 7 0 ; (with GELLING and DEARBORN),
ibid., 1944, 80, 391 ; (with CANTRELL and G E I L I N G ) , ibid., 1944, 82, 349 ; BURTON and
K E L S E Y , ibid., 1943, 79, 70 ; C H E N and G E I L I N G , ibid., 1944, 82, 120 ; M E A D
and
KOEPFLI, J. Biol. Chem., 1944, 154, 507 ; P . B . MARSHALL, Nature, 1945, 156, 505 ;
155, 730 ; K E L S E Y , OLDHAM, CANTRELL and G E I L I N G , ibid., 1946,157, 440 ; ANDREWS
exp. Ther.,
Biochem.,
Nat.
Malaria Soc. (Tallahassee), 1943, 2, 53 (Trop. Dis. Bull., 1944, 41, 188); H I A T T and
QUINN, J. Pharm. Exp. Ther., 1945, 83, 103 ; DEARBORN and MARSHALL, ibid., 1945,
85, 202 ; CEITHAML and E V A N S , Arch,
biochem.,
(19) H E W I T T and
RICHARDSON, J. Infect. Dis., 1943, 73, 1 ; KEOGH and SHAW, Austral. J. Exp. Biol.
Med. Sci., 1944, 22, 139 ; CHRISTOPHERS, Trans. Faraday Soc, 1943, 39, 333 ; (with
FULTON), Ann. Trop. Med. Parasit., 1938, 32, 43 ; 1939, 33, 161 ; COGGESHALL and
MAIER, J. Infect. Dis., 1941, 69, 87,108 ; (a) E V A N S , Fed. Proc, 1946, 5, 390 ; (6) BALL,
ibid., p . 397 ; (c) H E L L E R M A N , BOVARNICK and P O R T E R , ibid., p . 400 ; cf. H A A S ,
J.
Biol. Chem., 1944, 155, 321 ; (d) W E N D E L , ibid., 1943, 148, 21 ; Fed. Proc, 1946, 5,
406 ; GINGRICH, Amer. J. Trop. Med., 1947, 27, 147. (20) For special aspects of this
campaign see COGGESHALL, J. Amer. Med. Assoc, 1943, 122, 8 ; Chem. Eng. News,
1943,21,1152; SHERNDAL, ibid., p . 1154 ; ELDERFIELD, ibid., 1946, 24, 2598 ; NAPIER,
New England J. Med., 1945, 233, 38. (21) FAIRLEY, Trans. Roy. Soc. Trop. Med. Hyg.,
1945,38,311 ; Army Malaria Research Unit, Oxford, ibid., 1945,38,128,133 ; SHANNON,
E A R L E , B B O D I E , TAGGART, B E R L I N E R et al., J. Pharm. Exp. Ther., 1944, 8 1 , 3 0 7 ;
F I N D L A Y (with MABKSON and H O L D E N ) , Ann. Trop. Med. Parasit., 1944, 38, 139, 201 ;
(with STEVENSON), ibid., p . 168 ; for comparisons of anti-malarial drugs, see NAPIER,
New England J. Med., 1945, 233, 38 ; B R I T . M E D . R E S . COUNCIL, Brit. Med. J., 1944,
ii, 664 ; SAPEBO, J. Amer. Med. Assoc, 1946, 132, 623 ; Colonial Medical Research
Committee Report, 1946-7, p . 58 (Cmd. 7151, Stationery Office, U.K.) ; GORDON,
D I E U A I D E , M A R B L E , CHRISTIANSON a n d D A H L , Arch. Intern. Med., 1947, 79, 365 ;
COATNEY a n d CLARK COOPER, Amer. J. Hyg., 1947,46,119 ; (with YOUNG a n d B U R G E S S ) ,
ibid., p . 132 ; (with YOUNG and M C L E N D O N ) , ibid., p . 84 ; (with YOUNG, BURGESS and
SMARR), ibid., p . 105 : a review of recent work on antimalarial drugs has been published
by BLANCHARD, Ann. Rev. Biochem.,
16
QUINOLINE GROUP
482
1322,1520,1524 ; 1935,1143,1421; 1943, 555, 557, 561 ; BARBER and WRAGG, ibid.,
1947, 1331 ; BOVET et al., Bull. Soe. path. Exot., 1934, 27, 2 3 6 ; MAGIDSON and
STRUKHOV, Arch.
Pharm.,
273, 320 ; CEKKOVNIKOV a n d PRELOG, Ber., 1941, 74, 661 ; (with STERN), Helv.
Chim.
Acta, 1943, 26, 1180; KRITSCHEVSKI a n d STERNBERG, Z. Immunitatsf., 1933, 80, 438
(biological); cf. SCHULEMANN, Deut. Med. Woch., 1935, 61, 305 ; SCHONHOFER, Zeit.
Physiol. Chem., 1942, 274, 1 ; DECOURT a n d SCHNEIDER, Presse Med., 1946, No. 36,
516. (25) LOEB, J. Amer. Med. Assoc, 1946, 132, 321. (26) MARCHOUX, Bull. Acad.
Med. (Paris), 1931, [iii], 106,183 ; TAREEVet al.,Med. Parasit. ParasiticDis. (U.R.S.S.),
1933, 2, 189 ; LEISERMANN, ibid., p . 210 ; MILOSLAVSKI, ibid., p . 215. (27) MAUSS
Woch., 1933, 12, 1276 ; Angem. Chem., 1934, 47, 633 ; Ber.,
1936, 69, 641 ; see also MAGIDSON and GRIGOROVSKI, ibid., p . 3 9 6 ; FELDMAN a n d
KOPELIOVITCH, Arch. Pharm., 1935, 273, 488 ; GUHA and MUKHEBJEE, J. Ind. Inst.
Sci., 1946, 28, A, 63 ; TSCHELINCEV a n d OSETBOVA, J. Gen. Chem. Russ., 1940, 10,
1978 ; BACHER et al., J. Amer. Chem. Soc, 1947, 69, 1534 ; B R O W N and HAMMICK,
Nature, 1947, 159, 612 ; ALPATOV a n d NASTUKOVA, ibid., 1946, 158, 838 ; DROZDOV,
Chem. Abstr., 1947, 41, 763 ; K I N G , GILCHRIST a n d TARNOKY, Biochem. J., 1946, 40,
Proc. iii ; DAWSON, ibid., xli. (28) Parts I, IV, X , J. Chem. Soc, 1946, 343, 362, 729 ;
(with DAVIS), P a r t I I , ibid., p . 351 ; (with DAVIS, OWEN and T U E Y ) , Parts V I and I X ,
ibid., pp. 370, 720 ; (with RAISON), P a r t V, ibid., p . 366 ; (with RICHARDSON), P a r t V I I ,
ibid., p . 378 ; (with BASFORD), P a r t V I I I , ibid., p . 713 ; (with LANDQUIST), P a r t X I I ,
ibid., 1947,154 ; CURD and RAISON, P a r t X I I I , ibid., p . 160 ; see also H U L L , LOVELL,
OPENSHAW a n d T O D D , P a r t X I , ibid., p . 41 ; (with PAYMAN), P a r t I I I , ibid., 1946,
357.
and X , p p . 139, 157, 208 ; various authors on No. 3349, Parts I I I t o I X ; ADAMS,
TOWNSHEND a n d K I N G , P a r t X I , p . 217 ; SPINKS and T O T T E Y , P a r t X I I , p . 220 ;
ADAMS, MAEGRAITH, K I N G , T O W N S H E N D , D A V E Y a n d H A V A R D , P a r t s X I I I , X I V ,
SLADEN, Brit. Med. J., 1946, i, 903 a n d ref. 29. (32) GAGE a n d R O S E , Biochem. J.,
1946,40, Proc. i i ; K I N G , WOOTTON and GILCHRIST, Lancet, 1946,250, 886. (33) SPINKS,
T O T T E Y a n d MAEGBAITH, Biochem. J., T946, 40, Proc. i. (34) BLASCHKO, CHOU a n d
W A J D A , Brit. J. Pharmacol,
MARSHALL, ibid., 1947, 160, 463 ; TONKIN, ref. 30 ; BLACK, Trans. Roy. Soc. Trop.
Med. Hyg., 1946, 40, 163 ; MADINAVEITA, Biochem. J., 1946, 40, 373 : acquired resistance t o paludrine, see BISHOP and BrRKETT, Nature, 1947,159, 884 and WILLIAMSON,
BERTRAM and LOURDS, ibid., p. 885. (36) MORGENROTH efal., Berl. Klin. Woch., 1911,
48, 1560,1979 ; 1916, 53, 794 ; 1917, 54, 55 ; Deut. med. Woch., 1914, 40, 538 ; 1918,
44, 729 ; Zeit. Hyg. Infekt., 1924, 103, 4 4 1 ; Biochem. Zeit., 1916, 79,- 257 ; see also
SCHAEFFER, ibid., 1917, 83, 269, and VON OETTTNGEN, " The Therapeutic Agents of the
Quinoline Group," New York, 1933. (87) Ber., 1919, 52, 906. (88) J. Amer. Chem.
Soe., 1919, 41, 2090 ; 1920, 42,1481, 2278 ; 1922, 44, 1078,1079; for biological teste,
PHARMACOLOGICAL ACTION
483
ibid., 1947, 69, 1952 ; cf. K A I S H I , Jap. J. Pharmacol. Soc, 1943, 32, 28 (Chem.
Abstr.,
Amer.
J. Med. Sci., 1937, 193, 543. (42) MACLACHLAN, JOHNSTON, BRACKEN (with
P I E R C E ) , ibid., 1941, 201, 367 ; (with CORRADO and BREAM), Trans. Assoc. Amer.
1945, 57, 262.
Phys..
34, 132. (44) Chemical Reviews, 1942, 30, 49-68 ; cf. Chemical and Engineering News,
1943, 21, 474. (45) HARVEY, Bull. Johns Hopkins Hosp., 1940, 66, 52 ; (with LANDIS,
MASLAND and WIGTON), Trans. Amer. Neur. Assoc, 1940, 66, 154 ; BENNETT, Amer.
J. Psychiat.,
LEHMAN,
CHASE (with YONKMAN), J. Pharm. Exp. Ther., 1942, 75, 265, 270 ; (with RICKAKDS),
ibid., 1944, 82, 266 ; MOLLER, Acta Pharmacol. Toxicol., 1946, 2, 383. (46) MORGENROTH, Ber. deut. Pharm. Ges., 1919,29,233 ; see also ALBRICHT, Arch. Int. Pharmacodyn.,
1938, 59, 94. (47) DAWSON a n d GARBADE, J. Pharm. Exp. Ther., 1930, 39, 4 1 7 ;
J.
Amer. Med. Assoc, 1930, 94, 7 0 4 ; DAWSON, Internat. Clinics, 1930, 2, Ser. 40, 121 ;
(with NEWMAN), J. Amer. Med. Assoc, 1931, 97, 930 ; (with SANDERS), ibid., 1932,
99, 1773 ; SANDERS, ibid., 1931, 97, 850 ; (with DAWSON and TOMLINSON), J.
Immunol.,
1933, 24, 173. (48) KIRCHMANN, Arch. exp. Path. Pharmacol., 1939, 192, 6 3 9 ; D E
BOER, Arch, internat. Pharmacodyn., 1939, 61, 246 ; VAN DONGEN and BIJLEMA, ibid.,
1939, 63, 90 ; WEISMAN, Amer. Heart J., 1942, 24, 545 ; RICHTER, Zeit. ges. exptl. Med.,
1942,110, 216 ; PASTORIUS, J. Pharmacol, exp. Ther., 1939, 66, 27 ; SCOTT, ANDERSON
and C H E N , ibid., 1945, 84, 184 ; G O L D , MODELL, OTTO and H U N L O N , Fed. Proc,
1946,
5, 179 ; ALEXANDER et al., J. Pharm. Exp. Ther., 1947, 90, 191. (49) D A W E S , Brit.
Med. J., 1946, i, 43 ; Brit. J. Pharmacol, 1946, 1, 90. (50) Quart. J. Pharm., 1941,
14, 16. (51) (a) Compt. rend., 1938, 207, 1252 ; 1944, 218, 425 ; C. B. Soc. Biol.,
1939, 130, 429 ; (6) ibid., 1943, 137, 134 ; cf. PROVINCIALI, Arch. ilal. sci. farmacol.,
1938, 7, 73 ; (c) C. R. Soc. Biol., 1940, 134, 510 ; 1941, 135, 263 ; (d) Bull. Acad. Med.
(Paris), 1938, 120, 25.
16%
INDOLE GROUP
Abrine, C12H1402N2. This substance is not well named as it is liable
to be confused with abrin, the toxic albuminoid product obtained from
the same source, jequirity seeds, Abrus precatorius L. It was isolated by
Ghatak and Kaul, 1 and is stated to melt at 295 0 , 1 or at 270-95, depending
on the rate of heating and to have [<x]f + 46 (0-5 N/HC1) or + 62-4
(0-5 N/NaHO). 2 The following salts have been prepared : 1 hydrochloride,
m.p. 221-5 (dec.) ; nitrate, m.p. 143 (dec.) ; picrate, m.p. 194 (dec),
though 186-7 has been recorded frequently. Abrine was shown
by Hoshino 3 to be d-a-methylamino-/J-3-indolylpropionic
acid,
C 8 H 6 N . CH 2 . CH(NHMe) . C0 2 H, which makes it a close relative of
tryptophan, C 8 H 8 N . CH2 . CH(NH2) . C0 2 H, and hypaphorine (p. 386).
This constitution has been confirmed by the syntheses of the dZ-form by
Gordon and Jackson * and Miller and Robson, 5 who record respectively
m.p. 297 and 245 for the melting-point of the synthetic base, and though
the m.ps. found for the picrate are in good accord, that for the hydrochloride (M. & R. : 192-3) does not agree with Ghatak's figure (see above).
Cahill and Jackson 2 have shown that when d-abrine and Z-tryptophan are
methylated and the resulting methyl ester methiodides,
C 8 H 6 N . CH 2 . CH(NMe3I) . C02Me,
are converted to the corresponding betaines, the product in both cases is
hypaphorine, the specific rotations found being + 113-7, + 113-9 and
+ 113-4 respectively. It follows that abrine, like trytophan and the
natural amino-acids in general, belongs to the Z-series, and in accordance
with the accepted notation 6 should be described as Z(+)abrine. It is of
interest to note that as a growth-promoting substance, tried in rats,
abrine is less effective than Z-tryptophan, and more active than dZ-abrine
whence it is suggested that d( )abrine would probably be inactive, in
growth promotion in the rat. 7
REFERENCES
(1) GHATAK (with KAUL), J. Ind. Chem. Soc, 1932, 9, 383 ; GHATAK, Bull. Acad.
Sci. U.P. India, 1934, 3, 295. (2) CAHILL and JACKSON, J. Biol. Chem., 1938, 226,
29 ; cf. (3). (3) Proc. Imp. Acad. Tokyo, 1935, 11, 227 ; Annalen, 1935, 520, 31.
(4) J. Biol. Chem., 1935, 110, 151. (5) J. Chem. Soc, 1938, 1910. (6) FREUDENBERG
and R H I N O , Ber.,
cf.
Hypaphorine (a-trimethyl-3-indolepropiobetaine).
See alkaloids of
Erythrina spp. (p. 386).
Gramine (Donaxine), C11H14NZ. This substance was first found in
barley mutants by von Euler and Hellstrom,1 and later in Arundo donax
484
GRAMINE
485
7, 673 ;
VON E U L E R and
ERDTMAN, Annalen,
1935,
520,
1 ;
ERDTMAN,
27. (4) Annalen, 1936, 526, 188. (5) Ber., 1937, 70, 567.
Amer. Chem. Soc., 1945, 67, 36 ; H O W E et al., ibid., p . 38.
Ber.,
1937, 139,
ibid., 1947, 69, 3140. (7) Proc. Soc. exp. Biol. Med., 1945, 58, 1. (8) Bull. Acad.
Polon., 1937, Classe med., 479 (see also Acta polon. Pharm., 1938, 2, 125);
MASHKOVSKII, Chem. Abslr., 1944, 38, 4 3 1 6 ; RAYMOND-HAMET, Compt. rend. Soc.
Biol., 1937, 126, 859 ; 1939, 130, 1218.
486
INDOLE GROUP
487
CALTGANTHINE
Barger et al.1 took the view that the alkaloid contains two tryptamine
residues, one represented in the degradation products by AT-methyltryptamine, and the other by methyl-3-carboline, and on this basis proposed
formula (II). Manske and Marion,2 on the contrary, regard 2V-methyltryptamine and 3-carboline as originating from the same moiety of the
molecule, the other half being represented by 4-methylquinoline, and on
this conception based formula (III).
Calycanine, C16H10N2 or C21H13(15)N3. This substance was first described
by Marion and Manske 6 as resulting from the dehydrogenation of calycanthine by selenium or distillation of the base with zinc, but was first
fully characterised by Barger, Madinaveitia and Streuli,7 who obtained
it in a number of reactions including the oxidation of calycanthine with
chromic acid in acetic acid. It has m.p. 296-7, or 310 after sublimation,
is a weak but remarkably stable base, contains one reactive hydrogen
atom and does not give the Ehrlich colour reaction. Both groups of
workers at first assigned to it the formula C^HjoNa, but Manske and
Marion 2 changed this to C 21 H 13 N 3 or C21H15N3. Barger et al.7 proposed
for it formula (IV) and Manske and Marion suggested (V) or (VI) based on
their formula (III) for calycanthine. Hargreaves 9 has made an X-ray
examination of crystals of calycanine and obtained evidence which,
(in)
(v)
(n)
488
INDOLE GROUP
REFERENCES
1888, 84, 382. (2) J. Amer. Chem. Soc, 1905, 27,
144, 1418 ; 1909, 31, 1305 ; 1911, 33, 1626 ; MANSKE and MARION, Can.
J. Res.,
1939,
17, B , 298. (3) Ber., 1925, 58, 2131. (4) Rec. trav. Chim., 1938, 57, 548. (5) J . Amer.
Chem. Soc, 1929, 51, 1836. (6) Can. J. Res., 1938, 16, B , 432 ; (with K U L K A ) , ibid.,
1946, 24, B , 224. (7) J. Chem. Soc, 1939, 510. (8) Can. J. Res., 1931, 4, 275. (9)
Nature, 1943, 152, 600. (10) Arch. int. Pharmacodyn., 1905, 15, 487. (11) J. Pharm.
Exp. Ther., 1911-12, 3, 441. (12) J. Amer. Pharm. Assoc, 1942, 31, 513 ; cf. RAYMONDHAMET, Compt. rend. Soc. Biol., 1941,135, 111.
HARMALA
ALKALOIDS
489
490
INDOLE
GROUP
HOoC.C^
O05H3N 2 (0H 3 )
Harmlnlc a c i d
VeO.C6H3.C5H3Ng( CH: CHPb)
HO
p 0 g H 3 B 2 { 0 H 3 )
Benzylideneharmine
EC-apoHarmine
MeO.CgHj.CgHjNg.COgH
norHarmlnecarboxyllc
acid
02N.C
JIeO.C6H3.C5H4N2
norHarmlne
l e o H l c o t i n l c acid
m - M t r o a n l a l c aold
HABMALA
ALKALOIDS
491
CH
HH
CH
CMe
NH
OMe
Amlnoharman
Harming
C.CH2.CH(NH2).C02H
"oxidation"19
CH
CH
HH
NH
CM8
(I) Harman
(II) Tryptophan
CH.COgH
oxidation'19
CH
(III) Condensation product
with formaldehyde
NH
CH
INDOLE
492
GROUP
NH
(VII) 3 - ( o r B)-Cartiollne.
norHarman
NH
(V) 7 - P y r i n d o l e
NH
CUe
(VI) apoHarmlne
HABMALA
ALKALOIDS
493
CH
CH
NH
C . CH 3
(XIIIiHarmallne
N.CO.CH.
N.CO.CH
(XVII)
(XVI)
494
INDOLE GROUP
with zinc dust yielded a product from which norhanuan (VII) was isolated.
The
.me process
yiuucBs may
may be
uc represented
repre&cutcu thus,
nius, the
m e methyl group attached to the
indole
nitrogen
being
lost
in
the
last
stage.
indole nitrogen being lost in the last stage.
(OK)
(VII)
(XVIII)
tOie
lux
NH
CH(0Me)2
MeO
(XVII)
NMe
(XX)
(XXI)
By a similar method the same authors 24 have prepared JV-methyltetrahydronorharmine (XVII), starting with 6-methoxyindole-2-carboxylic
acid, the acid chloride of which was condensed with methylaminodimethylacetal to give 6-methoxyindole-2-carboxydimethylacetalylmethylamide
(XX), and this on boiling with alcoholic hydrogen chloride gave 8-methoxy2-keto-3-methyl-2 : 3-dihydro-/?-carboline (XXI), which on reduction with
sodium in w-butyl alcohol yielded JV-methyltetrahydronorharmine (XVII).
Among other syntheses by the same authors may be mentioned those of
apoharmine 28 and harmaline. 29 The latter is of special interest, being
->
(XXII) C6H4(C0)2N.[CH2]3.CHAo.C02Et
(XXIII)
(XXIV)
C0gNa.C6H4.CO.NH.[CH2]3.CHAo.C08Ha
C0gH.C6H4.C0.NH.LCH2]3.CAo:N.NH.C6H4.0Me
(a),
-CO-.
C 6 H 4 <co>N-[CH
2 ] 3 .CAo:HN 2 -l'
(XXV)
->
JOMe
(b)
-CO
6H4<C0>N-tCH2]2
OMe
(XX7I)
NB
->-
^CO-MH
6H4\
I
^CO-HH
and
(XXVII)
Cite
HARMALA
ALKALOIDS
495
(232)
(XEXI)
M
(XXIII)
496
INDOLE
OBOUP
been ascribed to harmala seeds from the time of Dioscorides. They have
long been used as an anthelmintic in India and also as narcotics, and the
source of a red dye. Flury 36 and others have shown that harmine and
harmaline exhibit anthelmintic action.
Exact knowledge of the pharmacology of the alkaloids is largely due
to the work of Gunn and his collaborators. In a summary of his results
Gunn 36 states that in large doses harmine causes tremors and clonic
convulsions, the latter occurring without marked increase in spinal reflex
excitability and not being shown in frogs. With poisonous doses the
convulsions are followed for a short time by motor paralysis, due to
depressant action on the central nervous system ; respiration is paralysed
and in mammals there is a fall in temperature. Harmine induces a fall in
blood pressure chiefly due to weakening of the cardiac muscle. It arrests
the perfused heart in diastole and diminishes the contractions of most
forms of smooth muscle with the exception of the uterus, which, particularly in the rabbit, is made to contract powerfully. It is more toxic to
most protozoa than quinine. Harmaline (dihydroharmine) is about twice
as toxic to most laboratory animals as harmine, but the addition of two
atoms of hydrogen affects the degree of activity rather than its pharmacological character, as is also the case for tetrahydroharmine. The minimum
lethal doses of the three bases for the rabbit are in the following ratio :
harmine : harmaline : tetrahydroharmine = 2 : 1 : 3 . The character of the
action is still unaltered in tetrahydroworharman, but in changing the
ethers, harmine and harmaline, to the respective phenols, harmol and
harmalol, the capacity to induce clonic convulsions disappears, and the
two phenols cause a progressive paralysis of the central nervous system
without initial stimulation. The protozooicidal action is also much
reduced. In harmol alkyl ethers (homologues of harmine), the initial
stimulant action of harmine diminishes as the weight of the alkyl group
increases and at nonylharmol the action is purely depressant. Dilatation
of the coronary vessels of the perfused heart shown by tetrahydroharmine
is intensified with harmol, and is still more pronounced with the alkylharmols attaining a maximum at amylharmol. The harmala and cinchona
groups of alkaloids exhibit much similarity in action in spite of their
dissimilarity in chemical constitution, and it is suggested that in cases of
this kind the action must be due to a common chemical factor in the tissues
concerned.
Raymond-Hamet 36 has made a special study of the vascular action
of the harmala alkaloids and certain of their proximate derivatives,
including their influence on the pressor and other effects of adrenaline in
comparison with that of yobyrine and ketoyobyrine (pp. 505-6).
The possible therapeutic applications of these alkaloids as protozooicidal agents, coronary dilators 37 and ecbolics, and in nervous diseases,
for example in the treatment of post-encephalitic conditions, have been
discussed by a number of authors. 38 The alkylharmols, referred to above,
form part of an extensive series prepared by Coulthard, Levene and
Pyman,8* and tested by these authors for bactericidal properties and by
HARMALA
ALKALOIDS
497
Helv. Chim. Acta, 1927,11,164. (6) ZERDA BAYON, quoted by VILLALBA. 4 (7) VILLALBA
(loc. cit.) and J. Soc. Chem. Ind., 1925, 44, 205T. (8) LEWIN, Arch. exp. Path. Pharm.,
1928, 129, 133 ; Compt. rend., 1928, 186, 469. (9) ELGER, Helv. Chim. Ada, 1928, 11,
162 ; W O L F E S and R U M P F , Arch. Pharm.,
J.
PAarm.,1939,12, 30. (10) HASENFRATZ, Ann. Chim. Phys., 1927, [x], 7, 151. For other
processes including methods of estimation see ROZENFELD, Farm. Zhur, 1930, 183 ;
BOLOTNIKOW, ibid., 1931, 362 ; BUNTZELMAN, Bull. Nauch. Issledov Khim. Farm. Inst.,
1931, 7 1 , and ELGAZIN (JELGASIN), Khim. Farm. Prom., 1932, 128 ; ISMAILOV and
SHRAIBER, Farmatsiya, 1939, No. 6, 1. (11) O. FISCHER, Chem. Soc. Abstr., 1901,
[il, 405.
(12) FISCHER, Ber., 1897, 30, 2482 ; HASENFRATZ and SUTRA, Compt.
1934, 1636.
rend.,
and ROBINSON, J. Chem. Soc, 1919, 115, 933. For more recent demethylations of
harmine and harmaline see COULTHARD, L E V E N E and PYMAN
36
and
KONOVALOVA
and
1935, 273, 156. (14) FISCHER, Ber., 1897, 30, 2482. (15)
FISCHER
ibid.,
and
BOESLER,
1912,
45,
1934.
(16) FISCHER,
ANGERMANN
and
DIEPOLDER, ibid., 1914, 47, 99. (17) J. Chem. Soc, 1912, 101, 1778 ; HASENFRATZ
and SUTRA, Compt. rend., 1927, 185, 1048. (18) J. Chem. Soc, 1919, 115, 967 ; cf.
p. 933, where t h e genesis of t h e harmine formula is fully discussed. (19) J. Physiol.,
1903, 29, 451 ; cf. KERMACK, P E R K I N and ROBINSON, J. Chem. Soc, 1921, 119, 1617 ;
H A R V E Y and ROBSON, ibid., 1938, 97 ; (with M I L L E R , 1941, 153 ; JACOBS and CRAIG,
J. Biol. Chem., 1936, 113, 7 6 0 ; SNYDER et al., J. Amer. Chem. Soc, 1948, 70, 219,
222, 237. (20) Mortals., 1919, 40, 351 ; 1920, 41, 401. (21) Annalen, 1861, 120,
247. (22) Ber., 1879, 11, 1542. (23) TATSIU, J. Pharm. Soc. Japan, 1928, No. 555,
453 ; AKABORI and SAITO, Ber., 1930, 63, 2245 ; H A H N et al., ibid., 1934, 67, 2031 ;
Annalen,
BAYERLE,
Annalen, 1934, 513, 195 ; ASAHINA and OSADA, J. Pharm. Soc. Japan, 1926, No.
534, 629. (23a) J . Chem. Soc, 1929, 2924. (24) P E R K I N and ROBINSON, ibid., 1919,
115, 933 ; (with KERMACK), 1922, 121, 1877.
VALOVA and
ROBINSON,
OREKHOV, Arch.
ibid.,
1929,
Pharm.,
2942.
1934,
(25) Ibid.,
272,
(27) NISHIKAWA,
748.
(26) B A R R E T T , P E R K I N
PERKIN
and
ROBINSON,
and
ibid.,
1924, 125, 657. (28) (With LAWSON), ibid., 1924, 125, 626. (29) (With MANSKE),
ibid., 1927, 1. (80) Ber., 1930, 63, 122. (31) Arch. Sci. phys. not., 1904, [v], 17, 78.
(82) J. Chem. Soc,
498
INDOLE OBOUP
ROBINSON, ibid., 1988, 2013. (33) Ber., 1940, 73, 719. (34) Annalen, 1943, 554, 127.
(35) Arch. exp. Path. Pharm., 1910,64,105. For later results see SATO, Folia Pharmacol,
Japan, 1930,10, 13 ; KADOYAMA el al., Tohoku J. Exp. Med., 1931, 17, 1,10, 20, 25,
28 ; DA COSTA and RAYMOND-HAMET, Arch. exp. Path. Pharm., 1935,50,237. (36) Arch,
int. Pharmacodyn, 1935, 50, 379. For special contributions see Trans. Roy. Soc. Edin.,
1910, 47, [ii], 245 ; 1912, 48, fi], 83 ; (with ALLAN) Quart. J. Pharm., 1929, 2, 525 ;
(with Simonart) 1930, 3, 1, 218 ; (with MACKEITH), 1931, 4, 33 ; 1932, 5, 48 ; (with
HEATHCOTE) 1981, 4, 5 4 9 ; (with ELPHICK), 1932, 5, 37, 56, 63. F o r other papers on
the pharmacology of t h e harmala bases see K A D O Y A M A 3 6 ; L E W I N , Arch. exp. Path.
Pharm., 1928,129, 133 ; KBEITMAIR, Merck's Jahresb., 1929, 42, 9 ; RAYMOND-HAMET,
Compt. rend., 1929, 188, 1519 ; 1941, 212, 408 ; 1945, 221, 387 ; C. r. Soc. biol., 1941,
135, 69, 328 ; 1944, 138, 410 ; SETO, Folia Pharmacol. Jap., 1930, 11, 34 ; SATO,
Tohuku J. Exp. Med., 1935, 26, 161 ; SARGIN and W A S S I W E W A , Bull. Biol. Med. exp.,
U.R.S.S., 1937, 3, 94 ; AOYAMA, Mitt. med. Ges. Okayama, 1939, 51, 576, 1278 (Chem.
Abstr., 1942, 36, 6664 ; 1943, 37, 1185) ; B E E R , Arch. exp. Path. Pharm., 1939, 193,
377, 393 ; OVEJERO, Farmacoterap. act., 1946, 3, 842 (Brit. Abstr., 1947, A.iii, 4 0 6 ) ;
Euclides (Madrid), 1947, 7, 77 (Chem Abstr., 1947, 41, 5919). (37) See BRANWELL,
CAMPBELL and E V A N S , Lancet, 1933, 225, 69.
WORSTER-DROUGHT,
ibid., 1929, 217, 647 ; RUSTIGE, Deut. med. Woch., 1929, 55, 613 ; PINEAS, ibid., 1929,
55, 910 ; FISCHER, Munch., med. Woch., 1929, 76, 451 ; BERINGER, Merck's Jahresb.,
1929, 42, 1 6 ; L E GRAND and LAMELIN, Compt. rend. Soc. Biol.,
1930, 105, 9 4 3 ;
MARINESCO, K R E I N D L E R and SCHEIM, Arch. exp. Path. Pharm., 1930, 154, 301 ; R O S E N -
BERGER, Wien. klin. Woch., 1930, 43, 207 ; COOPER and GUNN, Lancet, 1931, 221, 901.
(39) Biochem. J.,1933,27,727.
(40) Ibid., 1934,28, 264. (41) Cf. G U N N and MARSHALL,
Proc. Roy. Soc. Edin., 1920, 40, 140 ; GOODSON, H E N R Y and MACFIE, Biochem. J.,
1930, 24, 888. (42) AESCHLIMANN and R E I N E R T , J. Pharm. Exp. Ther., 1931, 43, 417.
EVODIAMINE
499
(in)
Rutaaoarpla*
These formulse explain the scission products of the two alkaloids and
the conversion of evodiamine into rutsecarpine, and were accepted by
Asahina. 5 A partial synthesis of rutsecarpine was effected by Asahina, Irie
and Ohta, 8 who prepared the o-nitrobenzoyl derivative of 3-/J-aminoethylindole-2-carboxylic acid, and reduced this to the corresponding amine
(partial formula I), which on warming with phosphorus oxychloride in
carbon tetrachloride solution furnished rutsecarpine. This synthesis was
completed in 1928 by the same authors by the preparation,of 3-^-aminoethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide
on 2-keto-2 : 3 : 4 : 5-tetrahydro-3-carboline. An equally simple synthesis
was effected almost simultaneously by Asahina, Manske and Robinson, 9
who condensed methyl anthranilate with 2-keto-2 :3 : 4 : 5-tetrahydro-3carboline (for notation, see p. 492) by the use of phosphorus trichloride
(see partial formulae II). Ohta u has also synthesised rutsecarpine by
heating a mixture of 2-keto-2 : 3 : 4 : 5-tetrahydrocarboline with isatoic
anhydride at 195 for 20 minutes.
600
INDOLE
GROUP
In the synthesis of evodiamine effected by Asahina and Ohta, 10 Nmethylanthranilic acid was converted by ethyl chloroformate into Nraethylisatoic anhydride, which, on treatment with 3-/?-aminoethylindole,
furnished 3-j8-o-methylaminobenzoylaminoethylindoIe (III), and this with
ethyl orthoformate at 175-180 gave cW-evodiamine, m.p. 278, convertible
by boiling alcoholic hydrogen chloride into isoevodiamine, m.p. 147, as
shown above.
In a recent paper, Schopf and Steuer10(a) describe the synthesis under
physiological conditions of rutaecarpine from 4 : 5-dihydro-3-carboline
perchlorate and o-aminobenzaldehyde.
According to Raymond-Hamet, 12 evodiamine and rutaecarpine on
injection induce increased arterial pressure.
REFERENCES
(1) K L E I N and BABTOSCH, Osterr. Bot. Zeit., 1928, 77, 6.
(2) ( W i t h KASHIWAGI),
J. Pharm. Chim., 1916, [vii], 14, 54 ; (with MAYEDA) J. Pharm. Soc. Japan, 1916,
No. 416 (Chem. Soc. Abstr., 1921, i, 48). For a more detailed account see Acta phytochimica, Tokyo, 1923, 1, 67. (3) J. Amer. Pharm. Assoc, 1933, 22, 716. (4) J. Pharm.
Soc. Japan, 1935, 55, 90. (5) ASAHINA, ibid., 1924, No. 503, 1 ; and KERMACK, P E R K I N
and ROBINSON, J. Chem. Soc, 1921, 119, 1615. (6) ASAHINA and OHTA, J.
Pharm.
Soc. Japan, 1926, No. 530, 30 ; 1929, 49, 157. (7) (With F U J I T A ) , ibid., 1921, 863.
(8) Ibid., 1927, No. 543, 51 ; 1928, 48, 51 ; compare ASAHINA and ISHIMASA, ibid.,
1926, No. 534, 61. For another synthesis see ibid., 1927, No. 545, 541 (Jap. text).
(9) J. Chem. Soc, 1927, 1708 ; cf. MANSKE and ROBINSON, ibid., p . 240, and S E N and
R A Y , ibid., 1926, 646 ; (10) Ber., 1928, 61, 319, 869 ; J. Pharm. Soc. Japan, 1928, 48,
317 (Jap. t e x t ) ; 10(a) Annalen, 1947, 558,124. (11) J. Pharm. Soc. Japan, 1940, 60,
109. (12) Compt. rend., 1945, 220, 749.
YOHIMBINE
501
barks have appeared in commerce, which are not derived from P. yohimba,
Pierre, and have been examined. Among these is P. macroceras, Pierre
(Corynanthe macroceras (K. Sch.), Brandt), which contains inactive alkaloids and little yohimbine s and Pausinystalia paniculata, Welw., in which,
along with paniculatine, yohimbine is present, according to <itaymondHamet, 6 '"' as it is also in P. trillesii, Pierre, examined by Dupouy and
Beille.6'*' From Taberncemontana coronaria Br. Ratnagiriswaran and
Venkatachalan have isolated two alkaloids, tabernwmontanine, C 20 H 2e O 3 N 2 ,
m.p. 208-210, and coronarine, C 44 H S6 0 6 N 4 , 2-5H 2 0, m.p. 196-8 (dec.).6
Processes for the isolation and purification of yohimbine have been
described by Thorns,7 Feldhoff,8 Chemnitius,9 Schwyzer,10 RaymondHamet 6 and others. Some of these processes have been modified to
provide for estimation of the yield of yohimbine, usually as the hydrochloride, from the bark, or to facilitate the identification of this alkaloid
in commercial yohimbe bark, which is apt to vary both in quality and in
botanical origin. 11 According to W i t k o p n (1943) modern technical
yohimbine hydrochloride may contain a little isoyohimbine but no alloyohimbine.
Yohimbine (Quebrachine), C 21 H 26 0 3 N 2 , crystallises from dilute alcohol
in colourless needles, m.p. 234 (Spiegel, Warnat), [a] D + 50-9 (S); + 56
(EtOH, Fourneau), + 62-2 (EtOH, Witkop), or + 84-1 (pyridine,
Hahn 3 ), is readily soluble in alcohol or chloroform, sparingly so in ether.
The hydrochloride is crystalline, m.p. 295-300 (dry, dec), 286 (dec,
Witkop), [a]? + 105 (H 2 0); the nitrate, m.p. 269-270, forms colourless
prisms ; the thiocyanate separates from hot water in rectangular crystals,
m.p. 233-4 (Siedler); the tartrate, B . 6H 2 0, melts at 213 and remelts
at 278 (F). Yohimbine gives a methiodide, B . CH 3 I. H a O, m.p. 250.
It contains one methoxyl group and one alcoholic hydroxyl group yielding
a sulphuric ester, 12 m.p. 292-5. On acetylation it furnishes an 0-acetyl
derivative, m.p. 133, and an O : iV-diacetyl derivative, m.p. 183 ;
cf. Schomer u (1927).
When yohimbine is heated with potash solution it is converted into
potassium yohimbate, from which yohimbic acid (the forms yohimboic and
yohimboaic are also used and noryohimbine), C 2o H 24 O s N 2 . H 2 0 , is
liberated by acetic acid ; it crystallises from water in lustrous prisms,
m.p. 269 or 299 (dry, dec), [a] D + 138-8 (pyridine), and, on esterification
with methyl alcohol and its homologues, reproduces yohimbine and its
homologues, analysis of which by Field l a confirmed the view that
yohimbine is methyl yohimbate, and has the formula assigned to it by
Fourneau and Page. 8
For the detection and identification of yohimbine, Deniges l 3 uses a
microcrystallographic method ; the alkaloid in sulphuric acid gives with a
minute crystal of potassium dichromate violet streaks, changing to slateblue and finally green. With nitric acid, the hydrochloride gives a green
colour changing to yellow. Other characteristic colour reactions are described
by Rossi el al.u and others, mostly dependent on the coloured products
formed by indole derivatives with aldehydes in presence of mineral acids.
Crystals and
Solvent of
Crystallisation
m.p.
Wo
Py = pyridine
A = alcohol'
Salts
m.p. and [ot]D
in Water
B . HC1; 302-303
+ 103 to+106
Yohimbine (quebrachine) .
Needles;
234-235
mwoYohimbine
(woYohimbine).
Needles ;
238-240
+ 99 to 108 (Py)
+57-1 (A)
o-Yohimbine
Polyhedral:
MeOH or
EtOH + H 2 0
234-235
22 to 28 (A)
9-3 (Py)
/{Yohimbine .
235-236
y-Yohimbine
Leaflets : H 2 Oor
2MeOH
Leaflets: 3H,0
4- Yohimbine
Prisms ;
alioYohimbine .
Yohimbene
^-Yohimbine
.
Corynanthine, ex
- Pstudocinchona africana,
Chev.
Paniculatine
240 (dec.)
-28-3 (Py)
254
- 5 0 (Py)
Leaflets ; 1 or 3 B . H s O, 135-140;
H.O.
98-99 or
104-105
Rhombic leaflets
276 (dec.) .
72-7 or
-73-6 (Py)
Rhombic ;
Hexagonal;
2H 2 0
+ 26-6 (Py)
125 (A)
- 73 (Py)
B . 1-5,11,0
264-265
241-242
(dry)
+ 43-7 (Py)
42(A)
Acid Produced on
Hydrolysis, m.p. and MJ>
, Beferenco
No.
Yohimbio acid, B . H s O,
15
265-269 ; B (dry), 296-299
+ 133 to +138 (Py). Ethyl
ester: m.p. 190.
B . HC1; 298-300
isoYohimbio acid, B . HjO,
16
268-269; +146 to +147
+ 100 to +103-8
(Py). Ethyl ester: m.p.
243 (dec).
B . H C 1 ; 286 (de.) a-Yohimbio acid, 276 (dec.)
17
to 287 (dec); +47-6 to
+53-6 to +58
+56-9 (Py). Ethyl ester :
236, 6-7
B . H C 1 ; 292 (dec.) /3-Yohimbic acid, 257 or 270,
18
+ 27-7
+ 15-8 (Py).
B . HC1; 312 (dec.) y-Yohimbio acid, B . H s O, Hahn
and
+37-6
252 (dec); +89-5 (Py).
Schuch.1'
B . H C 1 ; 288 (dec.) S-Yohimbio acid, 253, +1-5 Heinemann."
18-6
(Py).
B . HC1: 275-279
alioYohimbio acid, B . H , 0 ,
19
(dec), +30-3
248-250, 79-5 (Py).
B . HC1. 3H0 ; 234 Yohimbenic acid, B . 2H t O,
230 (dec.) 17-1 (Py).
(dec), 8-8
Ethyl ester: 250-251.
B . HC1; 258
20
21
22
6a
YOHIMBfi
ALKALOIDS
603
504
INDOLE
GROUP
m.p. 238, and is converted by the action of acetic anhydride and fused
sodium acetate into a new apoyohimbine, m.p. 230.
Corynantheine. This alkaloid was found by Karrer and Salamon, 21
along with ^-yohimbine (table, p. 502) in residues from yohimbine manufacture, as an amorphous base, yielding a crystalline hydrochloride,
C 22 H 28 0 4 N 2 . HCl, m.p. 205, [a] D + 12-15 (H 2 0), soluble in chloroform.
It was compared by Raymond-Hamet 2 3 with the alkaloid which Fourneau
had found with corynanthine in Pseudocinchona africana (p. 500). The
two hydrochlorides had m.p. 200 and [a]}f + 7-6 or 7-2 (MeOH). Both
hydrochlorides were soluble in chloroform and gave blue colours with
Frohde's reagent and with Kiliani's reagent (ferric sulphate in sulphuric
acid). Raymond-Hamet's results indicate that the purified hydrochloride
has the composition, C 22 H 28 0 3 N 2 . HCl. a;H20 (x lies between l and 2).
The alkaloid contains two methoxyl groups, and on alkaline hydrolysis
yields corynantheic acid, C 21 H 26 0 3 N 2 , which crystallises from methyl
alcohol, has [a]21 + 7-53 (MeOH) and contains one methoxyl group.
Janot and Goutarel 22 have confirmed Raymond-Hamet's results and have
obtained crystalline corynantheine, C 22 H 28 0 3 N 2 , m.p. 115-6, [a]^
+ 28-1 to 28-8 (MeOH), yielding a hydrochloride, [a]B -f 43-8, and in
their 1941 paper state that Raymond-Hamet has also prepared
corynantheine hydrochloride, [a]i> -f- 40-5, from Pseudocinchona
pachyceras.
Corynantheidine, C 22 H 28 0 3 N 2 . This isomeride of corynantheine was
found by Janot and Goutarel (1944) in the residual, benzene-soluble
alkaloids of Pseudocinchona africana.22 It was isolated as the picrate,
m.p. 252, [a]J,5 152 (acetone). The base, B . COMe2, had m.p. 117,
[a]1/ - 142 (MeOH), or - 165 (solvent-free, MeOH); B . HCl. 2H 2 0,
m.p. 213, [aff 128 (MeOH), styphnate, m.p. 246, [a]1/ 138
(COMe2).
Corynanthidine, C 21 H 26 0 3 N 2 . This fourth crystalline alkaloid of Pseudocinchona africana, and a new isomeride of yohimbine, was also isolated by
Janot and Goutarel 22 (1945-46), who point out that it resembles Lillig's
cc-yohimbine (table, p. 502). It has m.p. 243-4, [a]*2" 11-5 (MeOH).
or 18-3 (pyridine), forms a hydrochloride, m.p. 288, [a]*2" + 57-4
(H 2 0), a picrate, m.p. 231-2, [a]2 -f- 6 (acetone) and a monoacetyl
derivative, m.p. 231-2. On hydrolysis it furnishes corynanthidic acid,
m.p. 322-3, [a]2 -f- 48-3 (pyridine) and on selenium dehydrogenation
yields yobyrine, tetrahydroyobyrine and ketoyobirine. Oxidation by the
Oppenauer process leads to a product different from the yohimbone
yielded by yohimbine and corynanthine.
Constitution of Yohimbine and its Isomerides. The yohimbe' alkaloids
are methyl esters of acids. Yohimbine, yohimbene, mcsoyohimbine
(isoyohimbine) and y-yohimbine (table, p. 502) are hydrolysed to four,
distinct, monocarboxylic acids, C 20 H 24 O 8 N 2 , each of which on decarboxylation by heating with soda-lime yields " yohimbol," ** long supposed to
be a secondary alcohol, C 1( JJ 8 40N 2 , but which Witkop u has shown to
be a ketone and has re-named yohimbone, CjjHjgONj, m.p. 807 (dec),
CONSTITUTION
505
606
INDOLE GROUP
Yohimbic acid
yohimbine
19H21S2(000H)
apoYohlrabio a o i i
0 19 H 16 B 8 (0O)
Ketoyobyrine
C19fi19M2-00pH
*~
a^oYohlrabine
+
Setrahydroyobyrine
Cj.8H22Na(CH0H)
Yohlabol
Yohimbone
-*
CigH-^iycoHCOOH)
Tetrahydroyobyrinecarboxylic acid
Cetrahydroyobyroneoarboxylio acid
19H16N2
Yobyrine
Yobyrone
507
CONSTITUTION
CH
HO
NH
\(010H1903)
Yohimbine
CH
HC"
CH
C.C0CB
I I
HC '
C
C0.C0H
(I)\H
BH
HCT
C00H
CH
C00H
I
H0,.C
C
( I I ) XH
-H.N0
NOp.C
( H I ) XCH
NH
508
INDOLE
GROUP
509
CONSTITUTION
s\
/s
/s
N,
BH
H2C
OH,
I "
3H
HH
(XVII)
HC)/\H2
CH-OH
(XVI)
H0pC-HC.k
yCH2
A
N /
OH-OH
^J
-*"
HO-CC
(XVIII)
CH
CH
Hahn and Werner 37 pointed out that this hydrolysis of " tetradehydroyohimbic acid " to harman and m-toluic acid implies that carbon
atom 14 appears as the methyl group of harman (XVII), and carbon
atom 21 as the methyl group of m-toluic acid (XVIII), and that this
precludes carbon atom 14 as the site of the hydroxyl group, as suggested
by Scholz. They preferred to place it at 17 with 18 or 19 as other possible
positions. In support of this view they condensed m-hydroxyphenylpyruvic acid with tryptamine hydrochloride and decarboxylated the product to 3-m-hydroxybenzyl-3 : 4 : 5 : 6-tetrahydronorharman (XX). This
reacts with formaldehyde, forming a product which, on treatment with
alkali, gives a hexadehydroyohimbol (XXI). When in this series of
operations m-hydroxyphenylpyruvic acid is replaced by the p-isomeride,
the formaldehyde condensation fails, and it is argued that as this is a
510
INDOLE
GROUP
QUEBBACHO
ALKALOIDS
511
512
INDOLE GROUP
feebly basic and does not form crystalline salts. It dissolves unchanged
in cold sulphuric acid, but addition of potassium dichromate produces a
brown coloration changing to green : perchloric acid gives a rose-red
colour and aldehydes such as piperonal or vanillin give a violet colour in
presence of hydrochloric or sulphuric acid. The alkaloid contains one
methoxyl group, and no evidence of a methylimino group could be got
by the Herzig-Meyer method, but the residue from this reaction contains
a new base, ASPIDOSINE, C19H26ON2, which crystallises from alcohol in
rectangular prisms or plates, m.p. 236-244-5, [a] D 16 (EtOH), and
gives intense colour reactions, rose-red with sulphuric acid, greenish-blue
with ferric chloride, and deep orange-red with sulphuric followed by
nitric acid. The hydriodide, B . HI, crystallises from hot water in octahedra, m.p. > 280.
When boiled with dilute hydrochloric acid, aspidospermine evolves one
molecule of acetic acid forming DEACETYLASPIDOSPEHMINE, C20H28ON2,
needles, m.p. 110-1, b.p. 210/l-2 mm., [a] D + 2-8 (EtOH). In sulphuric
acid it gives with nitric acid a violet, with potassium dichromate a deep
brownish-purple colour, and with ferric chloride a deep magenta tint.
The hydriodide, B . 2HI, crystallises from hot dilute hydriodic acid in
rectangular prisms, m.p. 235-243, and is very sparingly soluble in water.
The benzoyl derivative forms rhombs, m.p. 186-7 from alcohol, and the
dimethiodide, C20H28ON2, 2MeI, octahedra, m.p. 176-7. On acetylation
the deacetyl base is reconverted into aspidospermine. With nitrous acid
it forms a nitro-nitroso derivative, C20H26O4N4, m.p. 155-160 {dec),
which boiling hydriodic acid converts into aspidosine {see above). On
oxidation with chromic acid, aspidospermine yields a new base, C 15 H 24 0 2 N 2 ,
crystallising from ethyl acetate in stout prisms, m.p. 192-3.
Ewins suggests that deacetylaspidospermine is a secondary-tertiary
base, and that aspidospermine is a derivative of a reduced quinoline.
Quebrachamine, C19H26N2. According to Field,45 this alkaloid forms
rhombohedral leaflets from dry alcohol, has m.p. 147, [a] D 109-5
(acetone), and can be distilled in a high vacuum at about 240-250. The
sulphate, B . H 2 S0 4 . 2H 2 0, forms prisms, sparingly soluble in cold water :
the oxalate, B . H 2 C 2 0 4 , has m.p. 217 ; the picrate occurs in two forms,
yellow and red, m.p. 195-6. The base yields a monomethiodide, m.p. 234,
and a methosulphate, B . Me a S0 4 , m.p. 235. On oxidation with nitric
acid it gives a small yield of picric acid. Quebrachamine is unaffected by
cold sulphuric acid, but develops a blue colour on further addition of a
trace of an oxidising agent: it gives colour reactions {a) purple, (6) violet,
or (c) blue, with (a) Ehrlich's reagent, (b) vanillin and hydrochloric acid
and (c) Hopkins-Adamkiewicz reagent respectively. It behaves as a
monoacidic, tertiary base. The second nitrogen atom may be present as
an imino-group, while the scarlet picrate and the colour reaction with
Ehrlich's reagent may indicate the presence of an indole group.
Vallesine, CJOH^O^NJ, m.p. 154-6, sublimes at 130/0-05 mm.,
crystallises from actone or ether in asbestos-like clusters of needles and
has [a]^' 91 2 (EtOH). The hydrochloride, B . HC1, has m.p. 247-
PHARMACOLOGICAL
513
ACTION
251 and the oxalate, B . H 2 C 2 0 4) m.p. 233-4 (dec). The second nitrogen
is present as an N-formyl group and is neutral. The base does not give
an Ehrlich. colour reaction ; it contains one methoxyl, one methyl joined
to carbon but no methylimino group or replaceable hydrogen (Zerewitinoff).
It does not hydrogenate and on hydrolysis by standing in 2N-hydrochloric
acid it yields deformylvallesine, C l9 H 26 ON 2 , which closely resembles
deacetylaspidospermine, C20H28ON2, in physical constants. It has m.p.
107-8, [a]f + 7 2, forms a dihydriodide B . 2HI, m.p. > 280, and
on treatment with formylacetic anhydride reconstitutes vallesine. The
residues from the crystallisation of deformylvallesine from w-pentane on
similar treatment with formylacetyl anhydride gave a formyl derivative,
m.p. 148-154, from which a hydrochloride, C 21 H 28 0 2 N 2 . HC), m.p. 245250 (dec), resembling vallesine hydrochloride, and apparently identical
with formyldeacetylaspidospermine hydrochloride, was prepared.
Acetyldeformylvallesine had m.p. 208-210 and [a]|2 - 107 2 (EtOH).
It is physically indistinguishable from aspidospermine but satisfactory
combustion results could not be obtained. On treatment with benzoyl
chloride in benzene deformylvallesine yields a normal benzoyl derivative,
C26H30O2N2, m.p. 187-190, and a neutral substance C 26 H 34 0 4 N 2 , m.p.
203-5, in which deformylvallesine seems to have been benzoylated and
also to have absorbed the elements of two molecules of water (1948).41
PAYTA BARK. From this material Hesse 46 isolated two alkaloids
payiamine, C21H24ON2, amorphous and distinguished from its associated
base by not being precipitated from solution by potassium iodide, and
paytine, C 21 H 24 ON 2 . H 2 0 . The latter crystallises from alcohol, has
m.p. 156, [a] D 149-5, and yields a crystalline hydrochloride, B . HC1,
prisms from hot water : with perchloric acid it gives a magenta red
colour.
Pharmacological Action. Yohimbine lowers blood pressure, increases
the depth and frequency of respiratory movements and in toxic doses
paralyses respiration, death being due to this cause in mammals, the
heart remaining active for some time longer. It possesses local anaesthetic
properties and resembles ergotoxine and ergotamine in sympatholytic
action.47 Though quebrachine has been shown to be identical with
yohimbine, differences in pharmacological action have been noted. 48 The
other alkaloids of the group are stated to resemble yohimbine qualitatively
in action, but Raymond-Hamet has observed differences in the action of
aspidospermine.49 According to Edmunds, and Gunn, 80 yohimbine is the
most active of the group, closely followed by aspidospermine ; quebrachamine and aspidosamine are less gotent. Kreitmair 61 found a-yohimbine
less toxic than yohimbine, equally potent as a local anaesthetic and similar
in action on the genital organs of the dog. Various authors 62 have stated
that yohimbine exerts no oestrogenic activity. Rothlin and RaymondHamet 8S showed that /?-, 8-, meso- and aZto-yohimbines, yohimbene,
corynanthine and corynantheine are all to be regarded as true sympatholytic agents and that in this respect corynanthine is more active and
much less toxic than yohimbine. Raymond-Hamet also found that
r u n UK.
17
514
INDOLE
GROUP
corynanthine is more active on the genital organs of the dog M and that
on the rabbit cornea, the local anaesthetic action of yohimbine, cocaine
and corynanthine is of the order 2 : 1 : 0-25.55 Paris, Janot and Goutarel
state that corynantheidine is as effective in sympatholytic action as
either corynanthine or corynantheine, and less toxic than the former,
the M.L.D. being 0-55g./kg./mouse, against 0-25g./kg./mouse for corynanthine by subcutaneous injection.65(o)
Hesse and Langer S6 say that as a vasodilator yohimbine is the most
potent, followed by B- and a-yohimbines, yohimbene and aZZoyohimbine
in descending order. Yohimbine is principally used in veterinary medicine
as an aphrodisiac. 57
The sympatholytic activity of yohimbine, as indicated by its reversal
of the action of adrenaline, has attracted much attention from pharmacologists, particularly in regard to effects on blood pressure. 58 Much
work has also been done on the influence of alkaloids of the yohimbine
group on other responses to adrenaline. 59 Yonkman, Stilwell and Jeremias 60
have pointed out that some of these responses may be lost by the action
of sympathetic depressants, such as yohimbine, but may still persist under
electrical stimulation ; with larger doses of the depressant drug electrical
stimulation may also fail to evoke response. These two conditions are spoken of
as adrenolytic and sympatholytic respectively. Thus in their experiments on
cats, anaesthetised by urethane, it was found that yohimbine and ethylyohimbine are adrenolytic for the submaxillary salivation effect at doses of 2 to 7
mgm. per kilo, of bodyweight, and are sympatholytic for the same response at
4 mgm./kilo and 6 mgm./kilo respectively for the two drugs. For sympatholysis of the nictitating membrane response, the necessary doses are yohimbine hydrochloride 28 mgm./kilo or ethylyohimbine hydrochloride
15 mgm./kilo. The ethylyohimbine used in these experiments was the
least toxic of a series of yohimbic acid esters tried by Chase, Yonkman
and Young 61 in relaxation experiments on arterial muscle contracted by
adrenaline or ephedrine. The series included the allyl, allylamine, butyl,
phenyl and diethylaminoethyl esters, all of which acted as antisympatheticomimetic agents like yohimbine itself. According to Raymond-Hamet,
the diacetylation of corynanthine or yohimbine has little effect on their
power to invert hypertension induced by adrenaline. As a vasodilator
diacetylyohimbine is about as effective as the parent alkaloid and is less
toxic, 62 but according to Janot, Bovet and Montezin the mono- and diacetyl derivatives are respectively two and five times as potent as the
parent base. 62 Sympatholytic" activity is also shown by deoxyyohimbol
and by Hahn's synthetic hexahydroyohimbol. 63
Witkop ll tested in frogs for curarising action, quaternary derivatives
of yohimbine, apoyohimbine, yohimbine sulphuric acid ester, deoxyyohimbine, yobyrine, 2-(3'-tetrahydrowoquinoline)-3-ethylindole, harrnine
and harmaline. The methiodides were usually sparingly soluble and
methochlorides proved more suitable for tests. They were either
inactive or feebly active, a dose of 500y being required in most cases to
produce an effect. The most active of the series was 2-(8'-tetrahydro-
YOHIMBfi
515
ALKALOIDS
Rev. hot. appl. agr. trop., 1939, 19, 564 ; Compt. Bend., 1941, 212, 305 ; JANOT and
GOUTAREL, ibid., 1945, 220, 617 ; Bull. Soc. Chim., 1946, 535. (5) HERZOG, Ber. Deut.
pharm. Ges., 1905,15, 4 ; Pharm. Zent., 1908, 48, 967, 983 ; SMALL and ADAMS, Pharm.
J., 1922 [iv], 54, 283. (6) (a) J. Pharm. Chim., 1934, [viii], 19, 209 ; cf. Bull. Sci.
Pharmacol., 1926, 32, 21 ; 1937, 44, 54 ; (b) Bull. Soc. Pharm. Bordeaux, 1906, 45,
203 ; (c) Quart J. Pharm., 1939, 12, 174. (7) Ber. Deut. pharm. Ges., 1897, 7, 279 ;
(8) Pharm. Zeit., 1925, 70, 864. (9) Chem. Zeit., 1927, 51, 469. (10) " Die Fabrikation
der Alkaloide," 1927, p . 89. (11) See also SCHOMER, Pharm. Zent., 1921, 62, 169 ; 1922,
63, 385 ; Arch. Pharm., 1927, 265, 509 ; BRANDT, ibid., 1922, 260, 49 ; VOGTHERR and
K I N G , Pharm. Zeit., 1923, 68, 447 ; WITKOP, Annalen, 1943, 554, 83 (with PRUCKNER),
ibid., p . 127. (12) BARGER and F I E L D , J. Chem. Soc, 1915, 107, 1025 ; 1923, 123,
1038 ; F I E L D , ibid., 1923, 123, 3004 ; Ber., 1927, 60, 1009. Series of yohimbic acid
esters are also described b y WORRALL, J. Amer. Chem. Soc, 1933, 55, 3715 ; 1935, 57,
900. (13) Mikrochem., 1928, 6, 113 ; MARTINI, ibid., 1939, 26, 227. (14) Anal. Farm.
Bioquim., 1932, 3, 51 ; cf. PESEZ, J. Pharm. Chim., 1935, [viii], 22, 1 6 4 ; SHANER and
WILLARD, Mikrochem.,
HARVEY,
MILLER and ROBSON, J. Chem. Soc, 1941, 153. (15) SPIEGEL, Chem. Zeit., 1899, 2 3 ,
59, 81 ; Ber., 1903, 36, 169 ; 1904, 37, 1759 ; 1905, 38, 2825 ; F O U R N E A U a n d P A G E ,
Bull. Sci. Pharmacol., 1914, 21, 7 ; H A H N , Ber., 1927, 60, 1 6 8 1 ; (with BRANDENBERG),
ibid., p p . 669, 707 ; (with J U S T ) , 1932, 65, 715 ; WARNAT, ibid., 1930, 63, 2959 ; 1931,
64, 1408. (16) SPIEGEL, Ber., 1915, 48, 2077 ; 1926, 59, 2706 ; WARNAT, ibid., 1926,
59, 2388 ; 1927, 60, 1118 ; 1931, 64, 1408 ; H A H N (with BBANDENBERG), ibid., 1927,
60, 669, 709 ; (with STENNER), 1928, 61, 278 ; (with SCHUCH), ibid., 1929, 62, 2953 ;
1930, 63, 1638, 2961 ; (with J U S T ) , 1932, 65, 715 ; W I B A U T and VAN GASTEL, Rec Irav.
chim., 1936, 54, 85. (17) LILLIG, Merck's Jahresb., 1928, 42, 20 ; Ber., 1930, 63, 2680 ;
H A H N a n d SCHUCH, Ber., 1930, 63, 1641, 2961 ; H E I N E M A N N , ibid., 1934, 67, 15.
(18) H A H N a n d SCHUCH, ibid., 1930, 6 3 , 1638 ; H A H N a n d J U S T , ibid., 1932, 65, 714 ;
HEINEMANN, ibid., 1934,-67, 15. (19) WARNAT, ibid., 1926, 59, 2388 ; 1927, 60, 1118 ;
H A H N (with BBANDENBERG), 1927, 60, 669, 707 ; (with S T E N N E R ) , 1928, 6 1 , 278 ;
(with SCHUCH), 1930, 63, 1638 ; (with J U S T ) , 1932, 65, 714 ; H E I N E M A N N , 1934, 67, 15.
(20) H A H N (with BBANDENBERG), ibid., 1926, 59, 2 1 8 9 ; 1927, 60, 669, 707 ; (with
STENNER), 1928, 6 1 , 278. (21) KAKREB a n d SALOMON, Helv. Chim. Acta, 1926, 9,
17a
INDOLti GBOUP
516
1059 ; I T O , Zeit. Kryst. Min., 1927, 65, 303 ; (22) P E H R O T , Compt. rend., 1909, 148,
1465 ; FOURNEAU, ibid., p . 1770 ; 1910, 150, 976 ; (with F I O B E ) , Bull. SOC. chim.,.
1911, [iv], 9, 1037 ; (with B E N O I T ) , ibid., 1945, [v], 12, 934 ; RAYMOND-HAMET, Compt.
rend., 1934, 199, 1658 ; Bull. Sci. Pharmacol., 1933, 40, 523 ; 1935, 42, 416 ; SCHOLZ,
Compt. rend., 1935, 200, 1624 ; WAKNAT, Ber., 1927, 60, 1118 ; H A H N a n d SCHUCH,
ibid., 1930, 63, 1638 ; JANOT and GOUTABEL, Compt. rend., 1938, 206, 1183 ; 1943,
217, 71 ; 1944, 218, 852 ; 1945, 220, 617 ; Bull. Soc. Chim., 1941, [v], 8, 625 ; 1943,
[v], 10, 383 ; 1946, 535. (23) Compt. rend., 1933, 197, 860 ; Butt. Sci. Pharmacol..
1933, 40, 5 2 3 ; J. Pharm. Chim., 1935, [viii], 22, 306. (24) H A H N (with STENNER),
Ber., 1928, 6 1 , 278 ; (with SCHUCH), ibid., 1930, 63, 1638, 2961 ; D E W A R a n d K I N G ,
Nature, 1941, 148, 25. (25) MENDLIK and WIBAUT, Bee. trav. chim., 1929, 48, 191 ;
1931, 50, 91 ; W I B A U T a n d VAN GASTEL, ibid., 1935, 54, 85 ; B A R G E R a n d SCHOLZ,
Helv. Chim. Acta, 1933, 16, 1343. (26) Ber., 1927, 60, 1118. (27) Helv. Chim. Acta,
1927,10,577. (28) Rec.trav. chim., 1931, 50,109. (29) Ber., 1926, 59, 2391. (30) Ibid.,
1930, 63, 2997. (31) Ibid., 1932, 65, 717. (32) Ibid., 1927, 60, 1118. (33) J. Chem.
Soc, 1933, 614. (34) Helv. Chim. Acta, 1933, 16, 1343. (35) Ibid., 1935, 18, 923.
(36) Ber., 1934, 67, 686 ; cf. MAJIMA and MUBAHASI, Proc. Imp. Acad. Tokyo, 1934,
10, 341 ; cf. B A R G E E , Ber., 1934, 67, 1124 ; H A H N , ibid., p . 1211. (37) H A H N a n d
W E R N E R , Annalen, 1935, 520, 123 ; cf. H A H N a n d H A N S E L , Ber., 1938, 71, 2192 ;
PBUCKNER a n d W I T K O P , Annalen, 1943, 554, 127. (38) CLEMO and SWAN, J. Chem.
Soc,
1946, 617 ; see also SCHLITTLER and ALLEMAN, Helv. Chim. Acta, 1948, 3 1 , 1 2 8 ;
J U L I A N et al., J. Amer.
Int.
Cong. Chem., London, 1947. (39) FLORIANI, Ann. Farm. Bioquim., 1930, 1, 135.
(40) Rev. Cent. Estud. Farm. Bioquim., 1935, 25, 373, 423 ; Rev. Farm. (Buenos
Aires), 1938, 80, 47, 135 ; (Chem. Abstr., 1938, 32, 4281, 9394) ; cf. LABRIOLA,
Anal. Asoc. Quim. Arg., 1939, 27, 150. (41) Helv. Chim. Acta, 1939, 22, 547 ;
SCHLITTLER and ROTTENBERG, ibid.,
DEULOFEU,
de LANGHE a n d
LABRIOLA, Rev. Inst. Bad. Dept. Nacl. Arg., 1939, 9, 224 ; (with CARCAMO), J. Chem.
Soc, 1940, 1051. (42) Ber., 1878, 11, 2189 ; 1879, 12, 1560. (43) Annalen, 1882,
211, 249. (44) J. Chem. Soc, 1914, 105, 2738. (45) F I E L D , ibid., 1924, 125, 1444.
(46) Annalen, 1870, 154, 287 ; 1873, 166, 272 ; 1882, 211, 280. (47) MULLER, Arch,
int. Pharmacodyn., 1902, 17, 81 ; RAYMOND-HAMET, Compt. rend., 1925, 180, 2074 ;
Compt. rend. Soc Biol., 1925, 93, 1274 ; BARIETY and KOHLER, ibid., 1939, 131, 754 ;
W E G E R , ibid., 1927, 96, 801 ; W E I N B E R G , J. Pharm. exp. Ther., 1933, 47, 79 ; HAZARD,
Compt.
rend. Soc Biol., 1941, 135, 92 ; TOURNADE, CHARDON, CALLEJA, ibid., 1941, 135, 444,
446, 544 ; BULLIARD and Dos GHALI, Presse med., 1943, 51, 20 ; DIMITRIJEVIC , Chem.
Zentr., 1939, i, 4500. (48) NAVARRO, Rev. Univ. Nacl. Cordoba Arg., 1942, 29, 369 ;
cf. HUKUHARA, Folia Pharmakol. Jap., 1940, 29, 79. (49) Compt. rend., 1930, 191, 157.
(50) CUSHNY'S "Pharmacology a n d Therapeutics," 10th edit., 1934, p . 534. (51)
Merck's Jahresb., 1928, 42, 22. (52) Voss, Arch. exp. Path. Pharm., 1939, 192, 570 ;
BULLIARD a n d K F O U R I , Compt. rend. Soc Biol., 1943, 137, 666 ; SULMAN and BLACK,
Endocrinol., 1945, 36, 70 ; cf. FUGO and GROSS, J. Pharm. exp. Ther., 1941, 72, 16.
(53) Arch. int. Pharmacodyn., 1935, 50, 241 ; Arch. exp. Path. Pharm., 1935, 178, 305 ;
Compt. rend. Soc Biol., 1934, 117, 978 ; RAYMOND-HAMET, ibid., 1925, 92, 1420 ; 1931,
108, 1046 ; 1935, 118, 33 ; 1936, 121, 1 0 6 0 ; 1939, 130, 733 ; Bull. Sci. Pharmacol.,
1940, 47, 33. (54) Arch. exp. Path. Pharm., 1937, 184, 680. (55) Compt. rend. Soc.
Biol., 1935, 118, 774. (55a) Ibid.. 1945, 139, 663, 665. (56) Med. Klinik, 1931, 27,
1536. (57) For method of evaluation see GLASER and KONYA, Arch. exp. Path. Pharm.,
1936, 182, 219.
and WBAGGE, Austr. J. exp. Biol. Med. Sci., 1942, 20, 69 ; HAZARD et al., Compt. rend.
Soc. Biol,
1941, 135, 253 ; 1942, 136, 397 ; B A R I E T Y and K O H L E R , ibid., 1943, 147,
143 ; YONKMAN (with YOUNG), J. Pharm. exp. Ther., 1939, 6fi, 40 ; (with CHASE and
LEHMAN), ibid., 1941, 72, 6. (59) YOUNG, ibid., 1935, 54, 1 6 4 ; YONKMAN (with
YOUNG), ibid., 1938, 63, 40 ; (with SACHS), ibid., 1942, 75, 105 ; TOUBNADE, CHABDON
and CALLEJA, Compt. rend. Soc. Biol., 1942, 136, 144 ; RAYMOND-HAMET, ibid., 1942,
136, 170 ; 1944, 138, 743 ; HAZARD et al., ibid., 1947, 141, 123. (60) J. Pharm. exp.
ERGOT
ALKALOIDS
517
Ther,, 1944, 81, 111. (61) Proc. Soc. exptl. Biol. Med., 1939, 40, 308. (62) Compt.
rend., 1943, 216, 614 ; Compt. rend. Soc. Biol., 1943, 137, 292, 305 ; cf. JANOT, BOVBT
and MONTEZIN, ibid., p. 278. (63) RAYMOND-HAMET, Compt. rend., 1943, 217, 303 ;
1945, 220, 670 ; Bull. Acad. Med., 1939, [iii], 121, 274; cf. HAHN and WERNER. 3 '
(64) Compt. rend., 1943, 217, 181. (65) FOUBNEATJ, MADERNI and de LESTRANGE,
J. Pharm. Chim., 1933, [viii], 18, 185 ; for pharmacological tests see, for example,
DAELS, Arch. int. Pharmacodyn., 1939, 61, 113 ; HAZARD el al., ibid., 1939, 62, 30 ;
STERNE, BOVET and LENOIR, Compt. rend. Soc. Biol., 1939, 130, 207. (66) See, for
example, BACQ and FREDERICQ, ibid., 1934, 117, 806; Ross, Amer. J. Physiol., 1936,
116, 574 ; WIERZUCHOWSKI, Arch. int. Pharmacodyn., 1938, 59, 1 ; MOISSET, ibid.,
p. 482 ; HAZARD and MOISSET, ibid., p. 457 ; SHEN, ibid., p. 242 ; and Ann. Physiol.
Physicochim. biol., 1938,14, 621 ; MORRISON and LISSAK, Amer. J. Physiol., 1938,123,
404 ; KATZ and FRIEBEBG, ibid., 1939, 127, 29 ; H i i i and MEYER, ibid., 1939, 126,
305 ; LOMBROSO, Compt. rend. Soc. Biol., 1940, 133, 551 ; HAZARD and VAILLE, ibid.,
1943, 137, 716 ; BRUNAUD and GERMAIN, ibid., 1944, 138, 840, 842, 861, 862. (67)
NICKERSON and GOODMAN, J. Pharm. Exp. Ther., 1947, 89, 167 ; NICKERSON et al.,
518
INDOLE GROUP
ERGOT
ALKALOIDS
519
INDOLE GROUP
520
acid. I t will be shown later that this acid is a constant product of hydrolysis
throughout the six pairs of alkaloids and that the " ergotoxine " bases are
derived from this acid and the " ergotinine " bases from its isomeride isolysergic acid. To these two acids is ascribed their property of giving the same
group of indole colour reactions, viz., (a) a deep blue colour, with dimethylaminobenzaldehyde,44 (b) a purplish-blue colour when a drop of sulphuric
acid is added to a solution of one of the alkaloids in glacial acetic acid
containing a trace of ferric chloride, (c) a blue colour with glyoxylic acid
in presence of sulphuric acid, and (d) a yellow colour with nitric acid
containing a trace of sodium nitrite. These colour reactions are also
given by lysergic and wolysergic acids, and their amides, woergine and
ergine. The alkaloids also give similar absorption spectra, viz., a peak at
A 3,180 and a less pronounced inflexion with a maximum at A 2,420, the
former, but not the latter, being also shown by ergine. Salts of the alkaloids show a blue fluorescence in aqueous solution.
The following is a list of the known alkaloids, with their specific rotations,
as recorded by Smith and Timmis,45 or by Stoll, Burckhardt and Hofmann.19
Ergotoxine
Serie3
Specific!
Rotation*
Ergotoxine
Ergotinine
Series
Specific
Rotation*
Formulae
+ 466 \
- 286
Ergotinine
dt -Ergotinine
* 513J
Ergotamine
- 192
Ergotaminine
+ 463
Ergosine
- 193
Ergosinine
+ 522
^O^Os^
ErgooristinelS21
- 217
Ergoori8tinine
+ 460
Ergocornine
- 226
Ergooorninine
+ 512
Ergokryptine
- 2260
Ergokryptinine
+ 508
C 32 H 41 0 5 H5
+ 520
- 160
Ergometrinine
(pyridine
as solvent)
Ergoraetrine
[a]
iAfii
:for
33H355H5
35H395H5
31H395N5
19H232N3
EROOT
ALKALOIDS
521
622
INDOLE
GROUP
ERGOT ALKALOIDS
523
624
INDOLE GROUP
which crystallises from boiling methyl alcohol in needles, m.p. 240-2 (dec.),
[a]f + 408 or [o]g + 508 (c = 1 ; CHC13).
Ergocornine and Ergocorninine, C 31 H 39 0 5 N 6 .
Ergocornine was
prepared by fractional crystallisation of the di-(p-toluoyl)-Z-tartrates of
commercial ergotoxine by Stoll and Hofmann 19 (1943). I t crystallises
from methyl alcohol (1 in 20) in polyhedra, melts at 182-4 (dec.) and has
[a]f - 188 or [ a ] ^ - 226 (c = 1 ; CHC13). The following melting
points are recorded for its salts : hydrochloride, B . HC1, 223 (dec.);
hydrobromide, B . HBr, 225 (dec.); phosphate, 190-5; ethanesulphonate, 209 (dec).
The di-(p-toluoyl)- hydrogen J-tartrate,
B.C 2 0 H l g O 8 , melts at 180-1 (dec.) and has [a]f + 103 (c 0-2;
EtOH).
Ergocorninine formed from ergocornine on standing in aqueous alcoholic
potash crystallises best from boiling alcohol (1 in 15) in massive prisms,
m.p. 228 (dec), and has [o]f, + 409 or [a]X + 512 (c = 1 ; CHC13).
Ergometrine and Ergometrinine, C 18 H 23 0^r 3 . The isolation of these
alkaloids has been referred to already (p. 517). A method for the preparation of ergometrine has been described by Dudley, 63 and the following
characters are mainly those given by that author :
Ergometrine crystallises, with solvent, from benzene in needles or
from methyl ethyl ketone in prisms ; both forms have m.p. 162-3 (dec).
From ethyl acetate it crystallises at 4 in thin, solvent-free plates,
m.p. 160-1 (dec), and at atmospheric temperature on concentration in
vacuo in diamond-shaped plates, B . 0-5EtAc, m.p. 130-2 (dec), from
which the combined solvent is not removed at 100 in vacuo. By
crystallisation from acetone, Grant and Smith 54 obtained a second form
in long needles, m.p. 212 (dec), which appears to be the more stable,
since the form, m.p. 162-3, tends to pass into it on keeping. Ergometrine
has [a] D - 44 (CHC1S); + 42-2 or [a] 5461 + 62-6 (c = 1-7, EtOH) or
HSTi ~~ 1 6 ( = !> pyridine).65 The hydrochloride forms needles,
m.p. 245-6 (dec), [a]f + 63-0 (c = 0-87, H 2 0 ) ; the hydrobromide,
needles, m.p. 236-7 (dec), and the oxalate, needles, m.p. 193 (dec),
[JD + 55-4 (c = 0-59, H 2 0). Ergonovine (ergometrine) maleate is
official in the United States Pharmacopoeia XIII with the standard [a]f>B
+ 48 to 57 (c 1 ; H 2 0). The picrate exists in two interconvertible
forms : fine yellow needles (hydrated), m.p. 148 (dec), and ruby-red
prismatic columns (anhydrous), which decompose suddenly at 188-9.
On hydrogenation the base yields dihydroergometrine, m.p. 225-230
(dec).66
Ergometrininels crystallises from acetone in short, stout prisms,
m.p. 195-7 (dec), [a.]f + 414 (CHC13), [afijj; + 520 (c =* 1, CHC1S) or
-f- 413 (c = 0-7, MeOH). The hydrochloride, B . HC1, H 2 0, forms small
needles, m.p. 175-180 (dec.); the hydrobromide, B . HBr . HgO;. crystallises from aqueous acetone on addition of ether, in needles, m.p. indefinite
(180-190); the nitrate, B . HNO s , forms stout prisms, m.p. 235 (dec),
[ s ] f -f 282 (c = 0-98, H 4 0), from aqueous methyl alcohol on addition
of ether, and the perchlorate, needles which discolour at 810 and deoom-
moor
ALKALOIDS
526
INDOLE GROUP
of the remaining pairs of alkaloids, ergocristineergocristinine, ergokryptineergokryptinine, ergocornineergocorninine, have been hydrolysed by StoU, Hofmann and Becker 19 and the products identified, with
the result that these six alkaloids are shown also to be derivatives of
lysergic, or- isolysergic acid, and the differences between the pairs to lie
in differences in the amino-acids of the residual portions of the molecules,
the hydrolytic products of which for the whole series of ergot alkaloidal
pairs are shown in the following summary, in which ergotoxine ajid
ergotinine are placed with their presumed equivalents, ergocornine and
ergocristinine respectively, for the reasons already given. The names of
the substances actually hydrolysed to give these results are marked with
an asterisk :
Ergocornine * (ergotoxine)ergocorninine (^-ergotinine).
Dimethylpyruvic acid, d-proline, Z-valine 19 (1943).
Ergocristine *ergocristinine (ergotinine *).
Dimethylpyruvic acid,
d-proline, Z-phenylalanine.19' 62
Ergokryptine *ergokryptinine. Dimethylpyruvic acid, d-proline, lleucine.19
Ergotamine *ergotaminine. Pyruvic acid, d-proline, Z-phenylalanine.62,63
Ergosineergosinine.* Pyruvic acid, d-proline, Z-leucine.17
Ergometrine *ergometrinine.* l-( +)-/?-aminopropyl alcohol.16'62, 6*
This summary shows that of the six pairs of ergot alkaloids the first
five are peptides divisible into two sub-groups, which differ mainly in
having either dimethylpyruvic or pyruvic acid as a characteristic hydrolytic product. The sixth pair, ergometrineergometrinine, are acid amides
According to Stoll (1945),33'a' when ergocornine is treated with one
molecule of sodium hydroxide it is hydrolysed to lysergic acid amide
and the polypeptide.
Me 2 CH. CO. CONH. CH(CHMe 2 ). CON. CH(COOH). CH 2 . CH 2 . CH2
Dimethylpyruvyl
Z-valyl
d-proline
Synthetic experiments have established the constitution of the polypeptide and the succession of the amino-acids, proline being always at
the distal end and the second amino-acid in the middle.
Ergine and isoErgine, C16H17ON3. Ergine, first obtained by Smith
and Timmis, 60 crystallises from methyl alcohol in prisms, B . MeOH,
m.p. 135 (dec), or from aqueous acetone in colourless plates, B . 2H 2 0,
m.p. 115 (dec). It has [a]526 + 514 (c = 1, acetone) or + 598 (c = 1-5,
CHC13). Ergine is alkaline in reaction and yields well-defined salts,
B . HC1, plates, m.p. 255-260 (dec.); B . HBr, prisms, m.p. 260 (dec),
and B . HC104, slender needles, m.p. 225 (dec). It gives the same colour
reactions as the ergot alkaloids (p. 520) and still retains one methyliminogroup. On hydrolysis by alkali it yields 1 mol. each of ammonia and
lysergic acid, C 16 H 16 0 2 N 2 . Impressed by the high dextrorotation of
ergine, Smith and Timmis 85 applied to this base the methods used in the
isomerisation of dextrorotatory ergot alkaloids to the laevorotatory iso-
ERGOT ALKALOIDS
52?
528
INDOLE
GROUP
ro.p.
(dec.)
Name
d-Lysergic-i-(+)-/5-propanolamide *
(d!-ergometrine)
Z-Lysergic-d-( )-/?-propanolamide .
(i-ergometrine)
<M>ysergic-d-( )-$-propanolamide
Z-Lysergic-Z-(+)-/?-propanolamide .
<W*oLysergic-Z-( + )-0-propanolamide
(d-ergometrinine)
i-isoLysergic-d-()-/3-propanolamide
(J-ergometrinine)
d-i'soLysergic-d-()-/!-propanolamide
i-isoLysergic-Z-( + )-j3-propanolamide
Activity on
rabbit uterus
162
+ 90
10
162
- 89
00
220
220
196
- 11
+ 10
+ 414
10
196
- 415
'
195
195
+ 353
- 351
~~
9
10
11
d-Lysergicethanolamide
.
.
.
d-Lysergic-(+)-/3-butanolamide
d-Lysergic-/-( -j-)- 8-methy]-j8-pentanoIamide
95
172
130
- 10
- 45
- 38
0-3
1-3
0-3
12
13
14
d-Lysergic-d-norephedride
d-Lysergic-Z-norephedride
Z-Lysergic-Z-raorephedride
.
.
.
230 J
130
230 f
+ 14
- 17
16
005
10
00
.
.
.
.
.
.
.
.
.
In the fifth column of this table are recorded activities on the rabbit
uterus in situ in relation to that of ergometrine taken as unity, (a) illustrating the effect of stereoisomerism, derivatives of Wysergic acid being
inactive, (b) of three homologues (Nos. 9-11) of ergometrine, indicating
the existence of a peak of activity in the homologous series, and (c) of three
lysergic acid derivatives of d- or Z-norephedrine (Nos. 12-14) showing that
aliphatic amino-alcohols are not essential to this type of activity in the
group and also illustrating the effect of stereoisomerism on activity. As
an example of the necessity for caution in drawing conclusions from the
results of biological experiments it may be pointed out that d-lysergic(+)-/J-butanolamide (No. 10) has proved at least as active in clinical
trials as ergometrine itself, thus confirming the high activity found in
the pharmacological tests, but d-lysergic-Z-norephedride (No. 13), which
also ranked as high as ergometrine in these pharmacological experiments,
was inferior to it in clinical trials.
Several formulae for the lysergic acids have been proposed by Jacobs
and Craig and their collaborators.' The tetracyclic nucleus was suggested
in 1935. Its present form is shown by formula (2) and is based mainly on
the following considerations :
EBGOT
529
ALKALOIDS
Clfe
OMe
cMe
MsHC
CH2
630
INDOLE GROUP
ERGOT
531
ALKALOIDS
COQH
C00H
CH-C
me
\y
(II)
(i)
(III)
145-175, and in these and other characteristics agreeing with dZ-dihydrolysergic acid, derived from dZ-lysergic acid. Jacobs and Craig 74 have
also provided evidence for the view that the dimethylpyruvic and
pyruvic acids, formed in the hydrolysis of the ergotoxine and ergotamine
types are derived from a-hydroxyvaline, Me2CH . C(OH)(NH2)(COOH),
and a-hydroxyalanine, Me . C(OH)(NH2)(COOH), residues, respectively,
and on this basis have proposed the following formula for these alkaloids.
Stoll and Hofmann's recent results (p. 523) involve change of the name,
ergotoxine to ergocristine for this formula, as it is the latter which yields
phenylalanine on hydrolysis. For convenience of comparison the formula
of ergometrine, now the most important ergot alkaloid, is added.
CH3-CHC0.NH.CH,CH2Ph
NH
CH
Ergotoxine (R * CHMe2)
Ergotamine (R CH3)
74(<l)
Erffome t r i n e
Recently Hofmann
has found that when the azide hydrochlorides
of the lysergic and isolysergic acids, or of their dihydro-derivatives, are
boiled iri dilute hydrochloric acid, a Curtius reaction occurs and the
carboxyl is replaced by an amino-group. In this way he has prepared
the following amines. They melt with decomposition and the specific
rotations are for pyridine as solvent:
6-Methyl-8-aminoergolen, C15H17N8, m.p. 253, [a]f,+ 96; ex lysergic acid.
6-Methyl-8-aminowoergolen, C15H17N3, m.p. 198, [a]f + 249; ex
isolysergic acid.
These two are represented by formulae (2) and (1) respectively in the
632
INDOLE GROUP
Dihydroergotamine
Dihydroergosine
Dihydroergocristine .
Dihydroergokryptine .
Dihydroergocornine .
( )-Dihydro-d-lysergic
acid.
Dihydroergometrine .
Formula
M.p.
(dec.)
Salts or Derivatives
CtlHilOlN(
180
- 56
CMHO.N(
235
-41
C, 1 H 1 1 0 5 N 5
187
- 48
C,sH06N6
239
[ <
(pyridine)
ERQOT
533
ALKALOIDS
ITama
Dihydroergotaminins
M.p.
(dee)
laJD
(pyridine)
M.p.
(de^)
97
206
-7
+3
236
33H3705H5
Isomeride II
(pyridine)
Bihydroergosinine
^SC^Z^5^5
234
+108
223
Dihydroergooristinine
35H4l05 5
248
+109
175
+13
Dihydroergokryptinine
C32 H 4355
268
+126
226
+26
Dihydroergooorninine
31 415 5
264
+147
180
+32.
Dihydroergometrinine
C 1 9 H 2 5 0 2 1J 3
211
+8
212
+45
Formula
I*
M.p.
Dihydrolysergic
acid
II
w|
M.p.
LaJD
It.p.
ri 20
lajj)
Acid
280
-86
310
+17
318
-122
Hydrazide
C16H200N4
227
-23
260
+56
247
-123
16 182 2
Azide
Amide
Methyl Ester
16 19
H
01,
3
H
17 202 2
275
190
-48
0
-82
307
+17
-79
276
-131
187
-96
534
INDOLE GROUP
the total activity of the crude drug and its galenical preparations, but
the specific effects are associated with the alkaloids proper. These form
a series of pairs of isomeric amides, one member of each pair being derived
from lysergic acid and the other from z'solysergic acid. The lysergic acid
derivatives, typified by ergotoxine, are leevorotatory and highly active
pharmacologically, while those of isolysergic acid, typified by ergotinine,
are strongly dextrorotatory and though they may have the same kind of
action as their laevorotatory isomerides, are always less potent.
White 78 has shown that the lysergic acids themselves exhibit weakly
some, but not all, of the types of activity characteristic of the alkaloids
of higher molecular weight. Both acids produce a slight transitory
cyanosis of the cockscomb and cause ataxia and delayed miosis in the
cat and also relax the isolated rabbit intestine. On the whole, lysergic
acid appeared more active than the isomeride.
The simple amides of these two acids, isoergine (lysergic acid amide)
and ergine (isolysergic acid amide) also induce in some degree the same
type of pharmacological effect as the more complex ergot alkaloids. In
the cat both amides produced some of the " sham rage " symptoms, so
commonly seen with the larger ergot alkaloids and intracardially in
monkeys, ergine and woergine produced drowsiness, jerkiness and difficulty in maintaining sustained movement. In the fowl, intravenously,
1-2 mgm. per kilo of either amide caused cyanosis of the comb. Both
reduce the contraction of the isolated rabbit intestine and have little or
no sympathicolytic activity, but show an oxytocic effect on the isolated
guinea-pig uterus in concentrations of 1 to 50,000 to 1 to 100,000. In
contrast, ergosine, a typical laevorotatory ergot alkaloid, may be active
on the guinea-pig uterus in concentrations down to 1 : 6,000,000, while
ergosinine, its dextrorotatory isomeride, is only active in concentrations
of the order of 1 : 125,000 to 1 : 250,000. It is only among the alkaloids
larger than ergometrine that a true sympathicolytic activity is observed.
White's observations on the pharmacological activity of the lysergic
acids and their simple amides are of practical, therapeutic interest in view
of the possibility of preparing from natural supplies of these acids, partially
synthetic oxytocic substances of which a first series by Stoll and Hofmann 68
has been described (p. 528), including d-lysergic-( -f-)-/?-butanolamide,
already the subject of promising clinical trials. 79
Of the typical ergot alkaloids, six pairs (table, p. 526) are now known.
The first five pairs are more complex in structure than the sixth pair,
ergometrine and ergometrinine.
Of these twelve alkaloids, three are of practical, therapeutic importance,
viz., ergotoxine, ergotamine and ergometrine, and round them a vast
pharmacological and clinical literature has accumulated, but for the present
purpose it is sufficient to mention the results of comparisons which have
been made between the chief types of pharmacological action exerted by
ergometrine and the longer-known ergot alkaloids ergotoxine and
ergotamine.
Brown and Dale 80 have shown that ergometrine (a) produces central
PHARMACOLOGICAL
ACTION
535
INDOLE OBOUP
536
.
.
.
.
3-55
1-17
2-15
105
Dihydroergotamine.
Dihydroergocornine
Dihydroergocristine
Dihydroergokryptine
.
.
.
.
25-00
35-00
27-00
20-50
R
10
0-5
10
1-5
S
1-0
20
40
40
Dihydroergotamine.
Dihydroergocornine
Dihydroergocristine
Dihydroergokryptine
R
2-25
2-5
3-6
50
S
7-0
250
35-0
350
This simplification in the range of activity in the dihydro-bases provides possible new therapeutical applications, and clinical trials on these
lines are now in progress, particularly with dihydroergotamine. 82 '"'
Ergothioneine is under investigation as a possible remedy for thyrotoxicosis.82(6)
As cases of ergotism still occur in man and animals, mention may be
made of the recent investigation by Fitzhugh, Nelson and Calvery 83 of
the effects ot long-continued feeding of known percentages of ergot in the
diet of rats ; one of the numerous symptoms of chronic toxicity recorded
is retardation of growth in the early stages, this effect being increased
with diets low in protein.
Useful general articles on the pharmacology of the ergot alkaloids have
been published by Nelson and Calvery,8* White, 22 ' 78 and Barger, 85 and
monographs on ergotamine and the alkaloids of ergot by Stoll (1945). 8* *
EBGOT ALKALOIDS
537
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538
INDOLE GROUP
Pharm.,
SCHOU a n d
E L P H I C K , Quart. J. Pharm.,
152 ;
J.,
and
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Eng.
Chem.,
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Vos,
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ERGOT
ALKALOIDS
539
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LEGAULT,
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Reviews, 1938, 18, 297. (85) Heffter's Handb. exper. Pharmakol.,
Ergdnzungswerk,
Band V I , 1938, p . 84.
640
INDOLE
GROUP
ALKALOIDS
OF CALABAR
541
BEAN
,CH
Eto.C
C.CH-.C00H
II
II
HC
(I)\s
C.CO0B
HMe
EtO.fT
CH
C.Mo
II
HC
IIDXH
II
CH
Ittie
B07
I HO
C.lie
HO
C
(III)\a
II
OH
IMS
642
INDOLE OBOUP
CH
CH2
sf
\
1 l"> [
HC
1
\ H
\ / \
/\
HC
CH?
/ \
HC'
B| EtO eC|
\/\ f
CH
CH
Nile
NMe
Eserethole
CH
CH
/^
HC
1
TMe
CH
/ \
CH| S
/^
EC
C
| EtO ||
HC
C
/*
EC
|
HC.OH
\ CH/ \ NMe/
NIOlo
CH
| =
Z
CH-
NMe2
Eseretholemethine
plhydroeseretbole
CSo
C
II
HC
C
( 1 7 ) ^CH
MeC
I
HC
MJe
CH
^CHo
Z
NMa
NHMe.CO.O.C^
CHo
C
II
HC
C
(7)^CH
MeC
I
HC
NMe
TH
2
MMa
ALKALOIDS
KtO.tT
>,
0.[OBg]g.NHMe
B 0H
/
OF CALABAB
543
BEAN
BtO
Ota
Dlhyflroasarathole
traduction)
EtO
EtO
DlquaternarT p l c r a t e
(Pi = p i c r i c a c l a )
(VI)
Dehydroeseretholemethine
IVII)
formula (IV) for eseroline, and therefore of (V) for physostigmine, have
been definitely established by the syntheses effected by three groups of
workers.
King and Robinson, 25 in continuation of researches 26 on the synthesis
of indolenines, prepared dehydroesermetholemethine (VI: MeO replacing
EtO) by the following series of reactions : the p-methoxyphenylhydrazone
of y-phenoxypropylacetone was converted by boiling alcoholic sulphuric
acid into the indole (VIII), which with methyl iodide under pressure at
120 gave 5-methoxy-l : 2 : 3-trimethyl-3-/2-phenoxyethylindoleninium
iodide (IX), convertible by cold, aqueous sodium hydroxide into the
methylene-indoline (X). This in turn was oxidised by potassium permanganate to the indolinone (XI), which, on treatment with fuming
hydrobromic acid, gave (XII), and this, on re-methylation at 5 and
replacement of the bromine atom by a dimethylamino-group, gave
d-dehydroesermetholemethine (XIII), which in the form of a quaternary
salt was resolved into d- and Z-components, each of which gave a methopicrate, m.p. 132-3, but the Z-base methopicrate, on admixture with the
corresponding quaternary salt obtained by the degradation of physostigMeO.C
I
(vim Na
-C.[CH.],.0P!l
L
SB
Qlt
(EC)
o.[ca2]2.oph
(mi) >/
^m.
(ni)
544
INDOLE
GBOUP
C6H4^
(W)
6H4^
^.[CHjJj.CHlJe.CIUc.COgEt
>
OEt
>
NH.[CH],.UeC
>
I
CO
ZZ
HO.C.C
2
V^ IXTII)
/C0V
" H *SK' , l ' C a i 1 ""f
HO
(ITIII) H
in) iieso^vMto V^
*phth
= phtbaljl rwldue
\ e ^m VMm)
ALKALOIDS
OF CALABAR
BEAN
645
Me0-C
(XXII
(XXV)
(IXVII)
29
i a
546
INDOLE GROUP
limnl
CUe-CH.-CN
(xxni)
a to (CH 8 ) 2 - !i H 2
(XZWII)
(XXCTI)
(xxznn)
CH
T*
L.
(XXXV)
ALKALOIDS
OF CALABAR
5*7
BEAN
548
INDOLE GROUP
PHARMACOLOGICAL
ACTION
549
about 1 per cent, of the potency of physostigmine, and also show the same
types of activity as the parent alkaloid in other directions.
The three items in the reactions described above have all been varied
in experimental investigations. Hawkins and Gunter 55 have used benzoylcholine and acetyl-/?-methylcholine as substrates, in addition to acetylcholine, and have employed specific choline-esterase as well as the nonspecific type (2weudo-choline-esterase).65(a) Prelog, Junasz, Rezek and
Stern 55(6) have prepared the sulphur analogue of acetylcholine chloride,
viz. dimethyl-/}-acetoxyethylsulphonium chloride and shown that it
closely resembles acetylcholine in its behaviour with choline-esterase, but
is less active pharmacologically and acceleration of fission by the enzyme
is less. Zeller65(c) has dealt with types of choline-esterase and their
inhibition by various chemotherapeutic and pharmaceutical substances,
Vincent and Beaujard 55(d) have shown that many alkaloids exert this
inhibiting action though none is as potent as physostigmine, and Wright 55(e)
has found effective inhibitors for the choline-esterase of human blood in
phenanthrenedialkylamino-alcohols of the type Ar . CHOH . CH2 . NAlk 2 .
According to Schemer,55'-^ jS-naphthylquinoline methiodide is twice as
active in this respect as physostigmine and about equal to prostigmine {see
below). Probably the most interesting addition to inhibitors of cholineesterase is diwopropyl fluorophosphonate, on which there is now a considerable pharmacological literature. It is one of a series of toxic inhalants
of the type (RO) 2 POF, prepared by a team of chemists led by McCombie
and Saunders,58 and tested biologically by a group of workers directed by
Adrian.56(a) In the most potent items so far described, R is cj/cZohexyl, or
an unsubstituted, secondary, alkyl radical, such as Isopropyl or secbutyl.
Their miotic action was noticed owing to their effect on the eyes of the
chemists working with them and this led to their examination for physostigmine-like properties. They were found to be potent inhibitors of
choline-esterase in vitro, the more active of them causing inhibition at a
concentration of lO" 11 M. Inhibition by them, unlike that due to physostigmine, is progressive and irreversible and takes place with ordinary
esterases as well as with choline-esterase.
The miotic effect induced by physostigmine lends itself to investigation
of the interrelation of chemical constitution and pharmacological action,
and Stedman has devoted much attention to this subject. Eseroline is
devoid of miotic activity, so that the latter action in physostigmine must
be mainly due to the fact that it is a methylurethane, and, since activity
only becomes evident in the urethanes of phenolic bases or phenols with a
basic side-chain, a basic nucleus for the urethanes appears also to be
essential.
In the series NHR . CO . O . C 6 H 4 . NMe2 all the members tried in
which R is a methyl group were active, but when R is ethyl or hydrogen,
miotic action is reduced or may even disappear, thus the p- and mdimethylaminophenyl esters of ethylcarbamic acid (R = C a H s ) are
inactive but the o-ester is active, indicating that activity is also influenced
by the position and nature of the basic group. When the tertiary basic
550
INDOLE GROUP
PHARMACOLOGICAL ACTION
551
amino-group.
Preliminary pharmacological results were promising.
Chaikin 6 5 has recently investigated t h e stability in solution, under biological
conditions ( p H , 7-4 a n d t e m p . 38), of three compounds of this t y p e ,
P h . C : CH . C ( C H a . N ( B r ) M e 3 ) : C ( 0 . CO . N M e 2 ) . C H : CH,
a n analogue of prostigmine, shows marked inhibition for ^-cholineesterase, b u t is only slightly active towards true choline-esterase.
Physostigmine and certain of its analogues, especially ( X L I : R = Me),
have been used in t h e t r e a t m e n t of Myasthenia gravis, a condition in which
t h e motor nerve-endings are easily fatigued, so t h a t t h e victim after b u t
slight exertion m a y become immobile. A considerable literature has
accumulated on this subject since t h e original successful experiment b y
Dr. Mary Walker. 6 6 Pritchard has suggested on the lines indicated above
t h a t this disease m a y be due t o failure of t h e acetylcholine action in t h e
transmission of the nerve impulse. 6 7 Guanidine has also been considered
for trial in this condition 6 8 a n d dnsopropylfluorophosphonate, already
referred to, has been tried ; it appears t o be effective b u t has certain
disadvantages. 6 9
MeHN.CO.O.c/ Nj.CHMe.NMe,,
HC
CH
CH
(XL)
HC
HC
\.O.C0.KHMe
CH
^C^NMe3.S04Me
Mlotine
(XLI) H = Me, Ph o r H.
REFERENCES
(1) Annalen, 1864, 129, 115 ; 1867,141,913. (2) Jahresb., 1865, p. 456. (3) Arch,
exp. Path. Pharm., 1876, p. 401. (4) BoHMNGERand SOHNE, Pharm. Post., 1888, 21,
663. (5) EHRENBURG, Verh. Ges. Deut. Nat. Aerzte, 1893, 11, 102. (6) Apoth. Zeit!,
1904, 19, 891. (7) J. Chem. Soc, 1911, 99, 2148. (8) Bull. Soc. Chim., 1915, [iv], 17,
244. (9) Amer. J. Pharm., 1912, 84, 4 9 ; cf. GSTIRNER, Pharm. Zenl., 1932, 73, 465,
and IONESCO-MATIU and POPESCO, Bull. Soc. Chim. biol., 1935, 17, 671. (10) J. pr.
Chem., 1927, [ii], 116, 59 ; SCHWYZER, " Die Fabrikation der Alkaloide," Springer,
Berlin, 1927. (11) For other reactions for the detection of physostigmine see EKKERT,
Pharm. Zent., 1925, 66, 53 ; MOGRAGNATZ, Bull. Soc. Chim. biol., 1928, 10, 905 ; 1930
12, 34 ; WAGENAAR, Pharm. Weekbl., 1929, 66, 381 ; AMELINK, ibid., 1932, 69, 1121 ;
PESEZ, J. Pharm. Chim., 1942, [ix], 2, 303. (11a) J. Assoc. Off. Agric. Chem., 194,1,
2 4 , 8 1 5 ; E I X I S eta*.,./. Pharm.Exp. TAer., 1943,79,295. (12) PETIT and POLONOVSKI)
Bull. Soc. chim., 1893, [iii], 9, 1008 ; 1915, [iv], 17, 235 ; EHRENBERG, Verh. Ges. Deut.
Nat. Aerzte, 1898, [ii], 102.
Annalen, 1918, 401, 350 ; 1914, 406, 832 ; E i x i s , J . Pharm. Exp. Ther., 1948, 79, 364
552
INDOLE GROUP
cf. F U H N E R , Biochem. Zeit., 1918, 92, 347 ; MASSABT el al., Enzymologia, 1939, 7, 339.
(13) POLONOVSKI a n d NITZBERG, Bull. Soc. Chim., 1916, [iv], 19, 27, 46. (14) STRAUS,
ref. (12). Cf, however, H E R Z I G a n d L I E B , Mortals., 1918, 39, 285. (15) STEDMAN, J.
and B R U N N E R , Ber.,
(18) STRAUS
(12);
M.
and
M.
POLONOVSKI, Compt. rend., 1923, 176, 1480, 1813, 1896 ; 177, 127 ; 1924, 178, 2078 ;
179, 57, 178, 334 ; 1925, 180, 73 ; Bull. Soc. chim., 1923, [iv], 33, 970, 977 ; 1924,
[iv], 35, 1492. (19) Loc. cit. and ibid., 1918, [iv], 23, 335, 357. (20) Ibid., 1918, [iv],
23, 335, 3 5 7 ; Compt. rend., 1923, 176, 1480, 1896; 177, 1 2 7 ; 1924, 178, 2078.
(2.1) Quoted by STEDMAN and BARGER, J. Chem. Soc, 1925, 127, 247. (22) Ibid.,
1923, 123, 762. (23) BRUNNER, Ber., 1905, 38, 1359. (24) Compt. rend., 1924, 178,
2078 ; 179, 57 ; 1925, 180, 73 ; Bull. Soc. chim., 1925, [iv], 37, 744. (25) J. Chem.
Soc,
1932, 326.
ibid., 1933, 1472 ; K I N G , LIGUORI and ROBINSON, ibid., 1933, 1475. (27) Ibid., 1932,
1433 ; 1933, 270 ;
K I N G , LIGUORI and R O B I N S O N ,
ibid., 1934, 1416. (28) Ibid., 1934, 1416. (29) HOSHINO (with TAMURA), Proc. Imp.
Acad. Tokyo, 1932, 8, 171 ; (with KOBAYASHI), ibid., 1934, 10, 99, 564 ; 1935, 1 1 ,
416 ; (with KOBAYASHI and SHIMODAIRA) 1935, 1 1 , 192 ; (with TAMURA), Annalen,
1932, 500, 35 ; (with KOBAYASHI and K O T A K E ) , ibid., 1935, 516, 76, 81 ; (with SHIMODAIRA), 1935, 5 2 0 , 1 1 , 1 9 . (30) HOSHINO, KOBAYASHI and KOTAKE, ibid., 1935,516, 8 1 ;
KOBAYASHI, ibid., 1938, 536, 143 ; 1939, 539, 213. (31) J. Chem. Soc, 1935, 757.
(32) (With BOGGESS), J. Amer. Chem. Soc, 1934, 56, 1797. (33) Ibid., 1935, 57, 539.
(34) Ibid., 1935, 57, 563. (35) Ibid., 1935, 57, 755. (36) Bull. Soc. chim., 1915, [iv.],
17, 244. (37) Ibid., 1917, [iv], 21, 191 ; 1918, [iv], 23, 335, 356 ; (with DESGREZ),
Compt. rend., 1938, 207, 685 ; see also Atti. X. Cong, internal, chim., 1939, 3, 303, 306.
(38) Verh. Ges. Deut. Nat. Aerzte, 1893,11,102. (39) J. Chem. Soc, 1911,99, 2148. (40)
Apoth. Zeit., 1904,19, 891. (41) Pharm. Post., 1888,21, 663. (42) Pharm. Zeit., 1892, 37,
483. (43) Merck's Berichte, 1926,40, 37. (44) ARNSTEIN and SUSTSCHINSKY, cit. ROSSBACH
ibid., 1914-15, 6, 147. (47) Pfluger's Archiv., 1921, 189, 230 ; (with NAVRATIL), ibid.,
1926, 214, 689. (48) Arch. exp. Path. Pharm., 1930, 150, 1. (49) J. Physiol., 1930,
70, 338. (50) J. Physiol, 1934, 81, 305. (51) (With FELDBERG), ibid., 1934, 81, 3 2 0 ;
(with FELDBERG and VOGT), ibid., 1936, 86, 353 ; (with BROWN and F E L D B E R G ) , ibid.,
1936, 87, 394. (52) HENDERSON and WILSON, Quart. J. Exp. Physiol, 1936, 26, 83 ;
SCHWEIZER and WRIGHT, J. Physiol, 1937, 89, 165, 384. (52a) Brit. Med. J., 1938,
i, 1249, 1293, 1349.
EASSON, Biochem.
J.,
1932,
26, 2056 ; GLICK, J. Biol Chem., 1938, 125, 729 ; J. Gen. Physiol, 1938, 2 1 , 289, 431 ;
SANZ, Helv. physiol. pharmacol. Acta, 1944, 2, C. 29 ; STRELITZ, Biochem. J., 1944,
38, 86 ; B A D E R , SCHUTZ and STACEY, Nature,
1946, 157, 587 ; Biochem. J., 1946, 40, 343 ; HAWKINS and MENDEL, J. Cell. Comp.
Physiol, 1946, 27, 6 9 ; BODANSKY, Ann. New York Acad. Sci., 1946, 47, 5 2 1 ;
CHAUDURI, Ann. Biochem. Exp. Med., 1946, 6, 91 ; E L L I S , J. Pharm. Exp. Ther., 1947,
91, 370. (536) EASSON and STEDMAN, Proc. Roy. Soc, 1936, B , 1 2 1 , 1 4 2 ; R I N K E L and
PIJOAN, J. Pharm. exp. Ther., 1938, 64, 228 ; SACK and ZELLER, Science, 1943, 97, 449 ;
K R A Y E R , GOLDSTEIN a n d P L A C H T E , J. Pharm.
(53c) E A D I E ,
J. Biol. Chem., 1941,138, 597 ; 1942, 146, 85 ; E L L I S et al. 11(a); STRAUS, GOLDSTEIN
and PLACHTE, J. Gen. Physiol,
exp,
Ther., 1944, 81, 67. (53d) ECCLES, Nature, 1945,156, 680 ; with numerous references ;
CUNLIFFE, BARNES and BEUTNER, ibid., 1947, 159, 307. (54) J. Pharm. Exp. Ther.,
1943, 79, 309. (55) Biochem. J., 1946, 40, 192. (55a) MENDEL and R U D N E Y , ibid.,
1943, 37, 59. (556) Helv. Chim. Ada, 1942, 25, 907. (55c) Verh. Ver. Schweiz Physiol,
1942, 21, 4 3 ; Helv. Chim. Acta, 1942, 25, 216, 1099 (with BISSEGGER), ibid., 1943, 26,
1619; cf. BODANSKY (53a). (55d) Ann. pharm. franc, 1945, 3, 22. (55e) J. Pharm.
Exp. Ther., 1946, 87, 109. < 5 5 / ) C. B . Soc. biol, 1946, 140, 34. (56) Nature, 1946,
STRYCHNOS
553
ALKALOIDS
157, 2 8 7 ; SATJNDERS, Chan, and Ind., 1947, 117. (56a) Nature, 1946, 158, 6 2 5 ; cf.
MACKWORTH a n d W E B B , quoted by D I X O N a n d N E E D H A M , ibid*, p . 433.
(57) S T E D -
MAN, Biochem. J., 1926, 20, 719 ; 1929, 23, 17. (58) J. Chem. Soc., 1929, 609 ; 1931,
1126. (59) J.Pharm.exp.Ther.,
1931,41,259. (60) Biochem.J., 1931,25,1147.(61) Ibid.,
1933,27,1257. (62) J. Pharm. exp. Ther., 1937,60,198. (63) J. Pharm. exp. Ther., 1931,
4 3 , 4 1 3 ; AESCHXIMANN, Chem. and Ind., 1935,54 139 T ; (with STEMPEL), Barell Jubilee
Vol., 1946, 3 0 6 ; LEHMANN, ibid,, p. 3 1 4 ; see also M I E S , Arch. exp. Path. Pharm,
1938, 190, 658 ; F R I E N D and K R A Y E R , J. Pharm. exp. Ther., 1941, 72, 15 ; P E R L O W ,
ibid., 1939, 66, 66. For notes on clinical uses of drugs of t h e physostigmine type see
Lancet, 1938, i, 1119 ; Brit. Med. Journ., 1941, ii, 732 ; 1942, ii, 431 ; and for a general
account of these drugs, BARGER, Pharm. J., 1938, Oct. 29, p . 437. (64) (With LAMBERTON
and
WOODCOCK,
J.
Chem.
Soc,
1947, 1 8 2 ;
(with D A V I E S ,
JONES
and
LAMBERTON), ibid., p . 191. (65) J. Amer. Chem. Soc, 1941, 63, 308 ; GARDNER and
STEVENS, ibid., 1947, 69, 3086; CHAIKIN, ibid., 1947, 69, 1266. (66) Lancet, 1934,
i, 1200. (67) Ibid., 1935, i, 432. (68) MINOT, D O D D and R I V E N , J. Amer. Med. Assoc,
1939, 113, 553 ; Science, 1938, 87, 348 ; THOMPSON and T I C E , J. Pharm. exp. Ther.,
1941,
73, 455.
and
GILMAN, Amer. J. Med. Sci., 1946, 212, 641 ; GADDUM a n d W I L S O N , Nature, 1946,
159, 680.
564
S.
S.
S.
S.
S.
S.
INDOLE GBOUP
STBYCHNINE
555
the formula given above. For the extraction of strychnine and brucine
on a laboratory scale the finely ground Strychnos seeds may be mixed with
slaked lime and made into a stiff paste with water. This is dried at 100,
powdered, and exhausted with boiling chloroform. From this the alkaloids
are removed by agitation with dilute sulphuric acid, which is then filtered,
excess of ammonia added, and the precipitate extracted with 25 per cent,
alcohol, which dissolves the brucine and leaves most of the strychnine
undissolved. The latter is purified by recrystallisation from alcohol, in
which brucine is more soluble. For operation on a larger scale processes
have been devised by Watson and Sen,14 Schwyzer l S and Volck.16
Strychnine crystallises in colourless rhombs, m.p. 268-290, dependent
on the rate of heating, [a] D 109-9 (EtOH, 80 per cent.) 139-3
(CHC13).4 According to Loebisch and Schoop, it distils unchanged at
270/5 mm. The base is slightly soluble in water (1 in 6,400 at 25, 1 in
3,000 at 80) or ether (1 in 5,500 at 25), more so in 90 per cent, alcohol
(1 in 110 at 25 or 1 in 28 at 60), or benzene (1 in 150 at 25), readily so
in chloroform (1 in 6 at 25). The aqueous solution is alkaline and has a
bitter taste, even in a solution containing 1 part in 700,000. It behaves as
a monoacidic base ; the salts crystallise well.
Strychnine nitrate, B . HN0 3 , occurs in colourless shining needles,
soluble in water (1 in 42 at 25), alcohol (1 in 120 at 25), or chloroform
(1 in 156 at 25); lsevorotatory. The sulphate, B 2 . H 2 S0 4 . 5H 2 0, forms
colourless prismatic crystals, m.p. 200 (dry), and is soluble in water (1 in
31 at 25), or alcohol (1 in 65 at 25), less so in chloroform (1 in 325 at 25).
The hydrochloride, B . HC1. 2H 2 0, forms colourless, efflorescent, trimetric
prisms, soluble in cold water (1 in 35) or alcohol (1 in 80). The aurichloride,
B . HAuCl4, crystallises from alcohol in orange-yellow needles. The
hydriodide, B . H I . H 2 0, is sparingly soluble in water, as is also the
periodide, B . H I . I 2 , reddish-brown prisms from alcohol. The dichromate,
B . H 2 Cr 2 0 7 , is slightly soluble in cold water (1 in 1,815 at 18) and
crystallises from boiling water in orange-yellow needles. The tetrachloroiodide, B . HIC14, is a pale yellow, crystalline powder, m.p. 91 (dec).
The benzylidene derivative crystallises in pale lemon yellow leaflets,
m.p. 235-7, and on solution in sulphuric acid (60 per cent.) gives a deep
blue coloration with potassium dichromate. Strychnine TX-oxide, C 21 H 22 0 3 N 2 ,
m.p. 210-2, the preparation of which has been improved by Oesterlin,17
has been the subject of several investigations into its reactions, as have
also the N-oxides of three derivatives of strychnine, described later, viz.,
isostrychnine N-oxide, which is amorphous but yields a crystalline perchlorate, m.p. 149-150, strychninic acid N-oxide, C 21 H 24 0 4 N 2 , m.p. 232-4,
and neostrychnine oxide, C 21 H 22 0 3 N 2 , 3H 2 0, m.p. 179-180.
Strychnine is not coloured by sulphuric acid, even on warming. With
nitric acid it gives a yellowish coloration, and the residue left on evaporating
the liquid at 100 gives a reddish-purple colour with ammonia. A fragment
of the alkaloid in a drop of sulphuric acid gives, with a crystal of potassium
dichromate, manganese dioxide, eerie oxide or potassium permanganate
stirred in it, a series of colours, beginning with blue, which gradually passes
556
INDOLE GROUP
through violet and red to yellow.18 The only other alkaloids which
resemble strychnine in this respect are " curarine " and gelsemine. Certain
other alkaloids give a somewhat similar colour reaction, but most of these
are also coloured by sulphuric acid alone. Brucine gives a deep red colour
when oxidised, e.g., with nitric acid, and this is apt to obscure the colour
change produced by strychnine, so that if brucine is present it should
first be eliminated. Organic matter also masks the reaction, and may be
removed by warming with sulphuric acid and recovering the strychnine
by adding water and ammonia and shaking out with chloroform.19
Sulphuric acid containing ammonium vanadate gives with strychnine a
deep bluish-violet colour, changing to purple and finally to red. 20
Owing to its use as a vermin-killer and to its importance in toxicology,
a great deal of attention has been given to methods for the isolation of
strychnine from biological materials and the detection of minute quantities.
For critical reviews of such methods see Ainsworth Mitchell,21 Steyn, 11
Ward and Munch.22 A microchemical method for the differentiation of
strychnine and brucine has been described by Martini. 21
Brucine, C 23 H 26 0 4 N 2 . Brucine was first obtained in 1819 by Pelletier
and Caventou from Strychnos Nux-vomica bark, then supposed to be
derived from Brucea ferruginea. Its composition was determined by
Regnault. 13
Preparation. The mother liquors from strychnine manufacture are
concentrated and the alkaloids precipitated as neutral oxalates. * The
precipitate is dried and extracted with dry alcohol in which the strychnine
salt is the more soluble. The less soluble salt dissolved in water is decolorised
with charcoal, the alkaloid regenerated with ammonia and purified by
crystallisation as the sulphate. According to Saunders, pure brucine
may be obtained by slow crystallisation from a solution of the pure
hydrochloride in alcoholic ammonia. 23 A method of separation depending
on the greater solubility in water of strychnine hydriodide was employed
by Shenstone,24 whilst others have made use of the sparing solubility of
strychnine chromate for the removal of small quantities of this alkaloid
from brucine. For a large scale process see Schwyzer.15
Brucine crystallises from water or aqueous alcohol in monoclinic
prisms containing 4H 2 0, m.p. 105 or 178 (dry), [a] D 119 to 127
(CHC13) or - 8 0 - 1 (EtOH). The alkaloid is slightly soluble in cold
water (1 in 320), more so in boiling water (1 in 150), very soluble
in alcohol, chloroform, or amyl alcohol, sparingly soluble in ether
(1 in 134).
Brucine is a monoacidic base; the salts crystallise well and are
readily soluble in water. The hydrochloride, B . HCl, forms needles, the
hydriodide, B . HI, leaflets, sparingly soluble in water and the sulphate,
B 2 . H 2 S0 4 . 7H 2 0, long needles.
Brucine is easily distinguished from strychnine by not giving the
characteristic play of colours when oxidised with chromic acid in sulphuric
acid and by affording an intense red colour with nitric acid, which may be
distinguished from that given by morphine by cautiously adding stannous
STRYCHNOS
ALKALOIDS
557
chloride, when, in the case of brucine, the red colour changes to violet. A
series of other colour reactions has been described by Francois. 25
REFERENCES
(1) W I E L A N D and
OERTEL, Annalen,
1929,
469,
193.
Bull.
Inst. bot. Buitenz, 1902, No. xiv., p . 3. (3) J. Amer. Pharm. Assoc., 1914, 3, 1677,
(4) Helv. Chim. Acta, 1931, 14, 997. (5) For a more comprehensive list see W E H M E R ,
" Die Pflanzenstoffe," Vol. I I . , Jena, 1931. (6) VAN DEK W I E L E N (with L E COULTRE),
Pharm. Weekbl., 1939,75,1329; (with GROEN), ibid., 1939,76,3; E D E R and RUCKSTUBX.
Pharm. Acta Helv., 1944, 19, 23. (7) Pharm. J., 1883, [iii], 14, 2 9 2 ; GADREAU, J .
Pharm. Chim., 1927, [viii], 6, 145 ; KOLTHOFF and LINGANE, J. Amer. Pharm. Assoc,
1934, 23, 302. ALLEN and ALLPORT, Quart. J. Pharm., 1940, 13, 252. (8a) J. Pharm.
Chim., 1938, [viii], 28, 369 ; (86) Svensk. Farm. Tids., 1944, 48, 137 ; BROWNLEE,
Quart. J. Pharm., 1945, 18, 163 ; CHRISTENSEN, Dansk. Tids. Pharm., 1944, 18, 105.
(9) Dansk. Tids. Farm., 1942, 16, 11. (10) HADDOCK and EVERS, Quart. J. Pharm.,
1931, 4, 314 ; EVERS and SMITH, ibid., 1936, 9,397 ; cf. HALSTROM, Dansk. Tids. Pharm.,
1935, 9, 181 ; REIMERS, ibid., 1940, 14, 65 ; see also GARRATT, Analyst, 1937, 62,
538 ; MURRAY, J. Assoc. Off. Agric. Chem., 1937, 20, 638 ; H E R D , J. Amer. Pharm.
Assoc, 1942, 31, 9 ; BROWNLEE, Pharm. J., 1944, 152, 148 ; VAN DER W I E L E N and
GROEN. 6 (11) PORTNOW, Pharm. Zent., 1929, 70, 661 ; KOLL, Arch. exp. Path. Pharm.,
1931, 162, 307, 320 ; PRIESTLEY, J. Pharm. Exp. Ther., 1930, 38, 241 ; N U N N , Pharm.
J., 1932, 128, 145 ; STEYN, Onderstepoort J., 1935, 5, 139; 1938, 1 0 , 4 1 1 ; NAiDUand
VENKATRAO, Analyst, 1945, 70, 8 ; LABAT and KERGONOU, Bull. biol. pharm., 1937,
p. 4 5 7 ; TOFT, Acta Pharmacol. Toxicol., 1946, 2, 1 5 6 ; (with IPSEN), ibid., p . 167.
(12) FRANCOIS and SEQUIN, J. Pharm. Chim., 1928, [viii], 7, 3 3 1 ; ELMORE, J. Assoc
Off. Agric. Chem., 1926, 9, 224 ; WARD and CRABTREE, J. Amer. Pharm. Assoc, 1942,
31, 113. (13) Annalen, 1838, 26, 17 ; cf. NICHOLSON and ABEL, J. Chem. Soc, 1850,
2 , 2 4 1 . (14) J. Indian Chem. Soc, 1926, 3, 397. (15) " Die Fabrikation der AlkMoide,"
Berlin, 1927. (16) VOLCK, U.S. P a t . 1,548,566 (Brit. Chem. Abslr., 1925, B , 828).
(17) PICTET and MATTISSON, Ber., 1905, 38, 2782 ; POLONOVSKI, Bull. Soc
Chim.,
1927, [iv], 39, 1147; OESTERLIN, Ber., 1943, 76, 224 : (with IMOUDSKY), ibid., p . 574.
(17a) LEUCHS and SCHULTE, ibid., p . 1038 ; (with R U C K ) , ibid., 1940, 73, 731. (176) J.
Chem. Soc, 1932, 773. (18) MARCHAND, J. Pharm., [iii], 4, 200. (19) For other interfering substances, see MAMELI, Chem. Soc Abstr., 1915, [ii], 113. (20) GUERIN, J.
Pharm. Chim., 1914, [vii], 9, 595 ; cf. P O E and O ' D A Y , J. Amer. Pharm. Assoc, 1930,
19,1292. (21) "Allen's Organic Analysis," 5th edition, Vol. vii, pp. 777-799; MARTINI,
Mikrochemie, 1937, 23, 164 ; and for recent microchemical methods, see D E N I G E S ,
Bull. Trav. Soc. Pharm. Bordeaux, 1937, 75, 5 ; K L E I B S , Format, i Farmakol., 1937,
1, 16 (Chem. Abstr., 1939, 33, 5991) ; BERISSO, Anales Assoc Quim. Argentina, 1942,
30, 44. (22) WARD and MUNCH, J. Amer. Pharm. Assoc, 1930, 19, 954. (23) J. Amer.
Chem. Soc, 1928, 50, 1231. (24) J. Chem. Soc, 1881, 39, 456. (25) Bull. Soc. Pharm.
Bordeaux, 1930, 68, 156.
668
INDOLE
GROUP
STRYCHNOS
ALKALOIDS
559
560
INDOLE
GROUP
(I) q-Colubrlae
(II) B-Colubrlne
(III) Strychnlna
(IV) Brucine
(with RACK), ibid., 1940, 73, 731, 811 ; (with GUNDEKMANN), 1942, 75, 168 ; (with
FLAMMERFELD, VILLAIN and SCHONE), 1943, 76, 1065.
ROBINSON, J. Chem Soc, 1947, 1557. (3) J. Chetn. Soc., 1932, 2305 ; 1934, 595 ;
PRELOG and KOCOR, Helv. Chim. Acta, 1947,30,359. (4) Sci. Pap. Inst. Phys. Chem. Res.
Tokyo, 1939, 35, 415. (5) LEUCHS (with TESSMAR), Ber., 1937, 70, 2369 ; 1939, 72,
965 ; 1940, 73, 1392 ; (with SEEGER), 1939, 72, 495 ; (with Louis), 1939, 72, 1483,
1588 ; (with BOIT), 1940, 73, 99, 885, 1392 ; (with TEUBER), 1942, 75, 92/); (with
HWANG), 1942, 75, 168 ; (with TUSCHEN and MANGELBEBG, 1944, 77, 403.
(6) J.
Amer. Pharm. Assoc., 1914, 3, 1677. (7) VAN BOORSMA, Bull. Inst. hot. Buitens., 1902,
No. xiv, p. 8.
STBTOHNOS ALKALOIDS
561
C20H22ON(N(a)CO)
> C20H22ON(NH)(COOH)
The nitrogen atom included in the lactam group is non-basic and is
conveniently distinguished as N(a), the second and basic nitrogen being
written N(6).
In the conversion of strychnine to strychninic acid, Tafel 2 pointed
out that a second acid is formed, identical with Gal and Etard's 3 " dihydrostrychnine " and now known as wostrychninic acid. The preparation of
662
INDOLE
OSOUP
the latter has been improved by Oesterlin and Imoudsky, 8 who agree with
Tafel * that it crystallises as a monohydrate, C^H^OgNg. H 2 0, m.p. 247-8.
Leuchs and Schulte 3 give m.p. 245-8 (vac. dec.) and [<t]f 151/d
(N/NaOH). The acid forms a N-nitroso derivative, m.p. 243, which is
isomerised by hydrogen chloride in alcohol to a C-nitrosoisostrychninic
acid, decomposing at 238-240. Oesterlin was unable to effect condensation of the acid with o-toluenesulphonyl chloride, but according to Leuchs
and Schulte 3 it yields an O-acetylisostrychninic acid, C 2 3 H 2 6 0 4 N 2 . 5H 2 0,
m.p. 180-5 (diy) with acetic anhydride, though Siddiqui 3 states that the
product is an acetyk'sostrychnine, m.p. 196. Oesterlin 3 coupled the acid
with various diazonium salts. The derivative so formed with diazobenzenesulphonic acid, occurs in orange-red needles, m.p. 310 (dec), and
on reduction by stannous chloride in hydrochloric acid yields aminoisostrychninic acid, C 21 H 25 0 3 N 3 , decomposing at 240-5. The formation of
this azo-derivative is made the basis of a method for the detection and
estimation of small amounts of isostrychninic acid in strychninic acid.
isoStrychninic acid is not convertible into isostrychnine by any of the
ordinary methods (Oxford, Perkin and Robinson 3 ), but the reverse
process is feasible, and according to Bacovescu and Pictet 4 wostrychnine
(prismatic needles from benzene, m.p. 223-4, [a] D +24-1 to -f- 25-1
[EtOH]) is formed when strychnine is heated in water at 160-180, or better
with ammonia and methyl alcohol, and this with sodium ethoxide in
alcohol yields isostrychninic acid. woStrychnine, unlike strychnine,
contains a hydroxyl group and yields an acetyl derivative, m.p. 133-4
(Oxford et al.3) but which Leuchs and Schulte (1942) 3 describe as amorphous, and yielding a crystalline perchlorate, m.p. 206. According to
the same authors, t'sostrychnine forms with benzaldehyde a derivative,
which is abnormal in being colourless, and is named z'sobenzylidenestrychnine. It is amorphous, has [a]f, 655/d (CHC13), and can be
isolated as the crystalline sulphate, C 28 H 26 0 2 N 2 . H g S 0 4 , 5H 2 0, or perchlorate, m.p. 60-70 or 160-170 (dry).
When strychnine is treated with hydrogen bromide and red phosphorus
in boiling acetic acid, it is converted into a complex bromodeoxywostrychnine hydrobromide, (C21H21ON2Br)a;, which is hydrolysed by boiling
N-sulphuric acid to wostrychnine (see above), now distinguished as I, and
isostrychnine-II, m.p. 218-9, [<x]f 258 (EtOH), which with acetic
anhydride gives the acetyl derivative of isostrychnine-I (see above).
A similar study of the action of hydrogen bromide on brucine and the
resulting derivative of isobrueine is in progress (Leuchs and Schulte,
1942).3
Strychnine combines with methyl iodide, forming a methiodide, which
on successive treatment with silver sulphate and baryta gives methylstrychnine,* also formed when strychninic acid methiodide is treated with
silver oxide. 8 Methylstrychnine, C 2 2 H 2 6 0 8 N a . 2H 2 0, crystallises in long
prisms, is soluble in water, gives the characteristic colour reactions of
strychnine, and though not bitter, still exerts a physiological action like
that of strychnine. It behaves as a secondary amine, and gives a meth-
STRYCHNOS
563
ALKALOIDS
iodide, which on heating with silver sulphate and barium hydroxide yields
dimethylstrychnine, C 8 8 H 2 8 0 3 N 2 . 6H 2 0. 6 This base is also produced
from strychninic acid by conversion of the latter into the corresponding
methiodide, which in presence of caustic soda and methyl iodide furnishes
2V-methylstrychninic acid methiodide : this readily loses a molecule of
hydrogen iodide when warmed with silver oxide, forming the corresponding
betaine of N-methylstrychninic acid, usually called dimethylstrychnine.
The latter with nitrous acid yields nitrosodimethylstrychnine which
resembles nitrosodimethylaniline in giving dyes by condensation with
benzaldehyde, etc. Such behaviour is also characteristic of JV-methyltetrahydroquinoline, whence Tafel suggested that this base is the nucleus
of the strychnine molecule.6
In like manner wostrychninic acid furnishes methyh'sostrychnine,
C 22 H 26 0 3 N 2 . 7H 2 0 (needles from water), and dimethyh'sostrychnine,
C 2 3 H 2 8 0 3 N 2 . 3H 2 0 (microscopic needles, from water).
The formation of this series of alkylation products may be represented
by the following scheme :
OH,
/CO
*>! =
0 '
OHj-lJ
000H
Strychninic a o i d m e t h i o d i d e
Strychnine
00
C20H2gO^
U e t h y l e t r y o h n i n e (R=H).
D i m e t h y l e t r y o h n i n e (R=CH3)
olect.
^red'
Tetrahyqroatrychnina
_
dehyd.
fcsi'WW
elect.
red.
I cat.red.
Hexahydro strychnine
eleot.
red.
,)
dehyd,
|" e l e o t . r e d .
Dlhardrofltrychnin.
_^
T B21^24Q:W
H
DlhydrolBoatrychnlne
(0 H
a *4W
elect.
red.
elaet.red.
. pihydroatrychaldlne (A)
Dlhydroleoatryohnldlne{a)
I oat .rod.
Dlhydrolsoatrychnldlps (b)
-- gftrychnidlne
VsAfV
elect.red.
<-
'VWV
reduction
(EI and P)
StrjrohnoliMVReduction ( s o d l u n Deogatryolmlne
(0
i n anvl a l e o h o l )
"81'
aW
.W
e l e c t . Dlhydrotrychnolln
564
INDOLE GROUP
-*-
Stryohnine
CO
C2oH86N^|
->
Deoxystryohnine
CH 2
0 ^ 2 ^ !
Stryohnoline
""*'
,CH 2 0H
OsoBasO's
letrahyirostryohniM
-*"
.BH8
C2oHg201I^ I
Stryillinllln*
STBTCHNOS
565
ALKALOIDS
Strychnine
666
INDOLE
GROUP
NH>CO
Cacotheline
fil4H180N>
CO
>
CO
S t r y c h n i n e (R = H)
or
Brucine (H = Qsje)
29-<0i4H18Off)
\
NH.CO
C02H.OO.(Oj4H18OH)
and
HH 2
COgH
Wleland's C 1 ? acid
STBYCENOS
ALKALOIDS
567
.
.
.
.
(C13H18ON)(CON(a)C6H4C=)
(C13H18ON(CON(a)CH2CH2C^)
(C13H18ON)(CH2N(a)C6H4C^)
(C13H18ON)(CH2N(a)CHaCH2C^)
The following is an example of the application of this system of nomenclature. Strychnidine (p. 564) is oxidised by chromic acid to 2 : 8-diketo-
INDOLE GROUP
568
HC
C0-(C14H18(HJ)
C,(CuH180N)
Stryohnldine
CH*
CB5
CONlaJ^CH,
(a)NHCR2
2:3DiketonuoldJ,ne
Carboxyaponucldlne
14H180N)
:i(a,H^CH2
Nucidine
C0sH.(Ca4H180H)
CH(OH)(CuH180N)
U
CO
N(a)^CH
2-geto-3-hydroaynucldlne
STBYCHNOS
569
ALKALOIDS
(71)
N0 2
NH
IV)
H0 2
NH
(IT)
NOg
CH
CH
H C ^ \:.COgH
H(b
(vii)
E.C^
CO.COJJH
R.C
^HH
11
OH
(rail
K.
H.CO.CH,.
NH
.Ctf)
(II)
While this work was in progress Spath and Bretschneider showed that
strychnine, on oxidation with permanganate in alkaline solution, furnished
iV-oxalylanthranilic acid (VII), brucine yielding oxalyl-4 : 5-dimethoxyanthranilic acid, the latter observation providing confirmation of the
evidence previously adduced that the two methoxy-groups in brucine are
in the <w#io-position relative to each other as indicated by Lions, Perkin
and Robinson.34 The results so far considered indicate the presence in
brucine and strychnine of the complex (VIII), which can be extended to
(IX) if account is taken of the readiness with which carbazole can be
obtained from strychnine and brucine and certain of their derivatives by
decomposition with alkali 35 at temperatures ranging from 200 to 400.
Knowledge of the structure of the rest of the molecule is mainly due to
the results of the exhaustive study by Leuchs and his pupils of the oxidation
670
INDOLE GROUP
Brucine
oxidation by KMnO
Strychninonic acia
16H1?,N^IO)2(00) l O - O V 0 0 ^ '
,,
Bruclnonlc acid
0 18 H gl 0 2 (H-C0) 2 (00) (O-CHg-COgH)
reduction by sodium
amalgam
Strychnlnollo acid
O16H17(N-00)2{0K)H) (0-0H3-C0sH)
I
I
Bruclnolic acid
01gH2102(N-CO)|8(0K)H) (0-CHg-COgH)
alkaline hydrolysis
Strychninolone (a,b,o forms)
16B16 ( 1 , - 0 ! 2- G H 0 H
Bruclnolone (S forms)
18 H 202 (1, "' S~WE
g l y c o l l i c acid,
g l y c o l l l c acid.
STRYCHNOS
571
ALKALOIDS
[a]^ r 231-3 (acetic acid) and the dihydro-derivative, m.p. 227-9 and
[<x]D 88 (acetic acid). 37
Brudnolone, C gl H 22 0 5 N 2 . This substance is produced from brucine,
in the same way as strychninolone (see above) from strychnine, via brucinonie
acid, (MeO)2(C16H15)(NCO)2(CO)(0CH2COgH), (colourless prisms,
with 1H 2 0, m.p. 178-183 (corr.) or 266 (dry, corr., dec), [a]f 48-5)
and its reduction product brucinolic acid, C 23 H 26 0 8 N 2 , m.p. 250-1 (corr.,
dec), [<x]| 22, which in alkali decomposes into glycollic acid and a
mixture of brucinolone-a and brucinolone-i. The a-form has not been
isolated, but its existence is known by the formation of brucinolonic
acid (a) on further oxidation and the dihydro-derivative, m.p. 285-290
(dec), has been prepared by Prelog.36 Brucinolone-6 is obtained from the
crude mixture by purification through the hydrate or the acetyl derivative
(m.p. 253-4) and then has m.p. 270, [a]| 37. On reduction it gives
a mixture of (a) and (c) dihydrobrucinolones (Prelog,36 cf. Leuchs, Diels
and Dornov 37 ). Potassium hydroxide in alcohol converts it into brucinolone-c (cn/pfobrucinolone), which has m.p. 190-2, [a] D 151-1 (acetic
acid), yields an acetyl derivative, prisms (m.p. 272-4, [a] D 199-5),
and is reducible to dihydrobrucinolone-c, m.p. 180, [<x]D 78 (acetic
acid).38
The formation of strychninolone and brucinolone was first explained
by Fawcett, Perkin and Robinson, 29 who suggested that the loss of
glycollic acid from brucinolic acid must be due to the change, indicated
by (a) :
(a,)
CH-C-O-CH2-0OOH - *
C:G+H0-CH 2 -C00H
and that this implies the rearrangement (b) during the formation of
brucinonie acid from brucine, or strychninonic acid from strychnine.
lb)
CO
:G
^ C = CH-CH 2 -0CT
(II)
Nj(0H)-C0-CH2-0:
572
INDOLE
GROUP
Cv
:H-C0-CH 2 -C00H
_^.
:MH a n d
^
x
->
^
COOH
:cv
The nitrogen atom in this system must be N(a), since its associated CO
is followed by CH2and the double bond concerned must be that
formed in the conversion of brucinonic acid to brucinolone.40 The whole
change of groups in the conversion of acetylbrucinolone (I) through
acetylbrucinolonic acid (II) to curbine may therefore be represented by
the following extended formula;, in which the index figures above the
symbols correspond with the items in the graphic formulae (V) and (VI)
on p. 574 ; the unit in square brackets is the eliminated malonic acid.
(I)
n H l l ( 0 M e ) 2 (:H(6)-CQ-)
(II)
w
n
f
C i l B u t OMe >g ( : H ( 6 ) - C 0 - ) (GH-OAo) { :NU)-C0-CH a -CO0H)
0 n H n ( 0 M e ) 2 ( S(t)-C0-)
(-0-C0-5:)
:B CO-COoH
JiCH-CH
:BH
(C00H)p
0H-C00H
-CO-CHiCH-CH
(V)
N
Ci
CO'CHg'CHiC
N
C:
STRYCHNOS
.,
(VI)
ALKALOIDS
*.
G
573
10, . a n
a t y ':
:H(a)-CO-UH2'H'GH r
I
I
III
:'
If
'.
O'CHg-CHjC-CHg'Hfih
The first formulae for strychnine and brucine were suggested by Perkin
and Robinson in 1910 42 and were modified by these authors and their
collaborators, as further knowledge accumulated from the protean transformations to which the two alkaloids have been subjected.43 Formula (I)
indicates the views current up to 1939. Robinson and Leuchs were both
in agreement as to the main features of the structure to be assigned to
both alkaloids, but there was still discussion as to whether the . CH2 . CH2 .
chain, which begins at N(6) in ring D, has its second terminal at carbon
atom 4, as suggested by Menon and Robinson,44 at carbon atom 3, as
adopted by Leuchs,45 or at carbon atom 5, proposed by Blount and
Robinson,46' 47 as a possible alternative to C4. The latter authors have
pointed out that strychnine does not behave as a dihydroindole, as is
implied by the adoption of C3 as the second terminal. Therefore one of
the carbon atoms, <x or |3 in the indole nucleus, i.e., C4 or C5 in formula I,
must be attached by a carbon chain to N(6) and selection of C4 has the
advantage of providing the required tryptophan nucleus. The most
probable position for the second terminal was therefore C4, but this could
not be reconciled with the results of the action of bromine water on
2 : 3-diketonucidine, as recorded by Leuchs.45 This substance is produced
by the oxidation of strychnidine or brucidine 45(a) with chromic acid and
would be represented by (II) if the second terminal of the . CH2 . CH2 .
chain is at C4. When 2 : 3-diketonucidine (p. 568) is treated with bromine
water at 0 it forms, according to Leuchs, bromo-2 : 3-diketonucidine
hydrate, isolated as the perchlorate, C 17 H 21 0 4 N 2 Br . HC104, [a]^ + 98jd.
Leuchs assumed that the . CH 2 . CH 2 . chain in strychnine and brucine
had its second terminal at C3 and that carbon atom 4 had a free hydrogen
in the parent alkaloids, and in 2 : 3-diketonucidine, which was replaced by
a bromine atom in this reaction. On repeating the bromination experiment,
Holmes and Robinson 44 found that bromine was absorbed but were
unable to isolate any well-defined reaction product. In their repetition of
the experiment Leuchs and Grunow 45 confirmed the original experimental
data but gave a new interpretation of the results, which did not involve
bromine substitution at C4 in 2 : 3-diketonucidine. Though this change
of view provides no positive evidence for C4 as the second terminal of the
. CH 2 . CH 2 . chain, it eliminates the chief objection to it and left the
Menon and Robinson formula (IIIA) as giving the best all-round explanation of the reactions of brucine and strychnine up to that time.
In the following account of some reactions and derivatives of the two
alkaloids the Leuchs variation (IIIB ; note the different system of numbering adopted) is sometimes used for the convenience of readers, who may
need to consult original papers in which it appears, but there is no difficulty
I
INDOLE GROUP
574
JMi)
OH
CH,
CH
R-C
1
/),CH
V
CB
E
(I)
(II)
0H 2 -
R-C
CO
(III A.
f3
.CH
CH
R-0
CH2
R-0
r
6 CH
CH
",CH 2
S CH
N/5
( I I I B)
/* C H 2
\r/\
CH
0H 2
Strychnine,
-0H 2
CH 2
CH
CH-
CH
,CH
CH2
R-C
2:3-glketormoidlne
CH,
CH_
H2C
/* CH2
B r u c i n e . R=QMe
OH
CH
5CH
I M F
S t r y c h n i n e . R=H;
CH2
B *| C I D II
CO \
GH-
CH
H(t)
CO
0CH2
A I B I*; C *|I D |
&*>
R-C
CH,
CH2
.CHo-CHg
/
'I
0iiCH,
CH 2
S t r y o h n l n e . H-H ( l e u c h s )
in such formulfe. The changes which take place in the conversion, already
described (p. 572), of brucine into brucinolone and curbine are illustrated
by partial formulas (IV) to (VI) based on the Leuchs modification (III13),
which is also used in formulae (VII) to (IX), showing the structure and
interrelationships of the Hanssen and Wieland series of acids, C19, C17 and
C16, obtained by the oxidation of strychnine or brucine (p. 566). It will
be observed that the chain N(a) to N(6), referred to on p. 573, the evidence
CH,
CH
U
n
-HO
OH
(AKB) | " C I D
HC.
OH
'(JO*
HO'
I E I
OH
CO
(III)
>0H
CHg
"
00
COOH
^ 2
Bruoinonlo aold
Bruclnollo aoia CO*-i-CH-OH'
-HC
.OH,
N
'CH
>C0
m 1c 1D
OH.OH
HO
I E I
GO
-OH
m 1 cc 1
/ \ /
H
i
VO
-OH,
HO
HH
OH
ICH-OH
00
<s.
000H
COOH
(V)
(VI)
Sraolnolone
CH,
Carbine end Malonlo
80 Id
STBTCHNOS
575
ALKALOIDS
.'0^
CH
0
I B |
COgH
H
X
CH
CH
^OHj
C |
CH
NH
CH
0 I
CH
i
CO
OH
X
CH,
CH
V
CB
I
( V I I ) E a n a s e n ' s C, Aoid
CH,
CH
I 0 |
^CH
OOjH.OO.OH
DHj
CH
N
CH8
CH
^CH
C
f
NH
i
CH
\ < a
CH,
I
C
|
I K I F O H
I
0B
CH
y
i l r c H
OOOH.0H..CH
CO^.CH
CB
CO
N
CH
CHp
I
N
0-
(IX) Hanaaen'a C
2
Acid
INDOLE GROUP
576
~CH2
CH2
N(4)
VflH2
4
I
an
NW
H2C
3-CH
aCH
\.
CH2
(X) Strychnidins. R H
Brucidlne. R OMe
(Xla)
ostryohnldlno
(Robinson)
-0H 2
OH2'OMa
-OH
H2C
,CH
CH2
OHg
(XIH n f o S t r y o h n l d l n e
(Leuohe)
(XII)
MethoxyraethyldlhydroietfStryohnine
CH2
QJs
CH2-
CH2
-OHo
0H 2
CHp-OUa
-CH
HO
HO
OH
B
S
?H
0H 2
CH2
(XIII)
-CH 2
Uetboxyastbylc/tanotllijrdroatrysluiora
0H2
(XIV)
nioStryohnin*
-CB2
STBYCHNOS
ALKALOIDS
577
19
INDOLE
578
GROUP
(IT)
(XVI)
0H2-
(XVH)
-J3H 2
-A.
C&2
v\.
HoO.
(xrai)
CH
CHg
CH2
CH
BgC
-CH2
Cfi-g
(mi
-CHg
(XX)
The further degradation of the two des-bases (items (b) and (e), p. 577)
has been investigated by Achmatowicz 60 with results which are summarised
in diagram A, by-products being omitted for the sake of simplicity.
Both <fes-bases yield mono- and di-metho-salts, and the latter on,
digestion with sodium methoxide in methyl alcohol give the better yieldf
STBYCHNOS ALKALOIDS
579
DIAGRAM A
Dihydrostrychnidine-A,
C21H26OH2
drS-Base-D.
C22H280H2
I
H(6)Ue*Iiyl^0dihydro/t.S0stryehnidine
C22H28OD2
Dimethylae*strychnidine-D
C23H30OK2.n1.p.156-7
Dinethyliiwneostryohnidine
C23H30OH2.n1. p . 73-4
desa.z.aStrychnidiine-&
C21H2301J
and'
Dimethyla!eji>-tV/i^strychnidlneC23H300H2,m.p.ll3-4
^/xaStryohnidine-.6
C 21 H 23 0IJ
7 8 9
7 8
15
(a) . C H 2 . C H = C . C = C H 2 ; (b) . C H 2 . C H = C . C = C H . ;
3
(c) . C H = C H . C = C H .
For dimethyldesneostrychnidine the Achmatowicz formula has been slightly
modified t o ( X I X ) b y Holmes a n d Robinson. The third substance,
dimethyl&sstrychnidine-D yields both a dihydro- and a t e t r a h y d r o derivative and, unlike <fes-base-D, from which it is derived, does not
undergo internal alkylation when subjected t o the " hydrogenation "
process in acid solution : it is represented b y ( X X ) .
I n t h e final stage, when t h e dimethochloride of either dimethylctesbisneostrychnidine or t h a t of dimethylrfesstrychnidine-D is heated with sodium
methoxide in alcohol N (b) is eliminated as trimethylamine a n d there is
formed a mixture of t h e t w o desazastrychnidines, a a n d b, of which the
first is amorphous b u t yields a crystalline methiodide, m . p . 154-5, a n d
t h e second is crystalline, m . p . 109-110, giving a methiodide, m . p . 105-6.
E a c h yields a hexahydro-derivative, which m a y be a mixture of stereo
isomerides, a n d t h e difference between t h e forms a- a n d b- is probably t h e
result of dissimilar distribution of t h e three ethylenic linkages t h u s indi192
INDOLE GROUP
580
H02C-HJC-CH2
CH2
(XXII)
(XXI I I)
CH 2
(XXIV)
STRTGHN08
ALKALOIDS
581
INDOLE GROUP
582
<yu
cCHCM2N
r-T/H-T~ou
CO
1 1
CH2
CH
(XXV)
(XXVIl)
O-CHj-CH
CH2
CH
CH
I
CH
0CH 2
(xxvt)
STBYCHNOS
ALKALOIDS
583
because ^settdostrychnine
c
is a tertiary alcohol. These conditions limit choice among possible structures, of which six others considered, offer no advantage over (XXV) or
(XXVII). Dissection of (XXVII) and of the formula for cinchonine
(p. 443) into possible phyto-chemical units, on the lines suggested by
Robinson n in 1917, discloses a close structural similarity in the two
alkaloids, and this is even more striking in another strychnine formula
suggested somewhat later by Robinson 72 but which is now regarded as
unnecessary in view of further developments. Reference has already
been made to the difference in opinion regarding the location of the double
bond in the neo-bases (p. 575). It was found 1 (1946) that these substances
couple with diazonium salts in dilute aqueous acid, forming products
which are neutral and appear to be arylhydrazones. The reaction was
represented as follows :
: N . C = C . - * : N . C(OH) . C . N2< - > : NCO C : N2H<
and appears to be analogous with the characteristic oxidation of the
neo-bases to keto-amides by the addition of two oxygen atoms, as in the
oxidation, described by Briggs and Robinson,53 of methoxymethyldihydroneostrychnine (a) to the neutral ketone, methoxymethylc/iawodihydrostrychnone (b) in almost theoretical yield by perbenzoic acid. The two
processes may be represented by partial formulae of the units concerned
thus:
By ^-nitrobenzene
diazonium chloride
(a) M e N . C = C . CH . C H 2 . OMe
> MeN . CO N . N H . C 6 H 4 . NO a
I
By perbenzoic acid (20 added)
I
(6) MeN . CO .
II .
. C . CH . C H 2 . OMe
CO . CH . CH 2 . OMe by p-nitrophenylhydrazine
INDOLE GROUP
584
1886, 7, 83 ; T A F E L ,
Annalen,
1891, 264, 50 ; 1898, 301, 285. (3) GAL and ETARD, Bull. Soc. chim., 1879, [ii], 31,
98 ; cf. T A F E L , loc. cit. ; O X F O R D , P E R K I N a n d ROBINSON, J. Chem. Soc, 1927, 2391 ;
SIDDIQUI, J. Ind. Chem. Soc, 1940, 17, 152 ; OESTERLIN and IMOUDSKY, Ber., 1943,
76, 172, 374 ; LEUCHS and SCHULTE, ibid., 1942,75, 573,1522 ; 1943, 76,1038. (4) Ber.,
1905, 38, 2787. Cf. LEUCHS a n d N I T S C H K E , ibid., 1922, 55, 3171 ; O X F O R D , P E R K I N
and ROBINSON, J. Chem. Soc, 1927, 2391. (5) T A F E L , ref. (2), a n d Ber., 1890, 23,
2732.
(7) T A F E L ,
Annalen, 1892, 268, 229 ; 1898, 301, 285 ; cf. SIDDIQUI, Proc. Ind. Acad. Sci., 1940,
11, A. 2 6 8 ; J. Ind. Chem. Soc, 1940, 17, 152, 2 3 3 ; (with BASHEV and A L I ) , ibid..
1944, 2 1 , 285.
ROBINSON, J. Chem. Soc, 1927, 1589 ; OXFORD, P E R K I N and ROBINSON, ibid., p . 2389 ;
L E U C H S , Ber., 1944, 77, 675.
1929, 9 6 4 ;
CLEMO
and R A P E R , ibid., 1946, 891. (10) Ber., 1881, 14, 773. (11) J. Chem. Soc, 1885, 47,
139. (12) Ibid., 1930, 842. (13) MINUNNI and ORTOLEVA, Gazzetta, 1900, 30, 1, 39.
(14) LEUCHS et al., Ber., 1908, 41, 4393 ; 1909, 42, 2681 ; 1912, 45, 3686.
Cf. STOEHR,
ibid., 1885, 18, 3430 and LOEBISCH and SCHOOP, Monats., 1885, 6, 844. (15) See, for
example, CLEMO, P E R K I N a n d ROBINSON, J. Chem. Soc, 1927, 1597.
17, 2266, 2849 ; 1885, 18, 777, 1917. (17) OESTERLIN, ibid., 1943, 76, 224, 574. (18)
Annalen, 1854, 91, 76. (19) Ibid., 1899, 304, 24 ; cf. CLAUS (with R O H R E ) , Ber., 1881,
14, 765; with GLASSNER, ibid., 773. (20) Ibid., 1918, 51, 1375 ; 1922, 55, 724; 1929,
62, 1929 ; (with F . LEUCHS), 1910, 43, 1042 ; (with ANDERSON), 1911, 44, 2136, 3040;
(with OSTERBERG and K A E H R N ) ,
(with H E M P E L ) ,
(21) Ibid., 1887, 20, 451. (22) Ibid., 1922, 55, 2403. For further work on this reaction
and on the C 1 9 acid see LEUCHS, ibid., 1925, 58, 1729 ; 1929, 62, 1929 ; (with TAUBE),
1924, 57, 1092 ; (with BENDER and WEGENEB), 1928, 61, 2849 ; (with HOFFMANN),
1929, 62, 1258 and 2308; 1930, 63, 439 ; (with KROHNKE), 1929, 62, 2598 ; (with
STRYCHNOS ALKALOIDS
585
Louis), 1939, 72, 490. (23) Annalen, 1929, 476, 280 ; see also WIELAND and GUMLICH,
i&irf., 1930, 482, 52. (24) Ibid., 1929, 469, 216 ; 1930,480,39. (25) (With K R O H N K E ) ,
Ber., 1929, 62, 2176 ; 1930, 63, 1045 ; (with HOFFMANN), ibid., 1929, 62, 2303 and
1930, 63, 4 3 9 ; ' ( w i t h GRUNOW), 1937, 70, 2 5 7 ; (with B E Y E R ) , ibid., 628. (26) Ibid.
1930, 63, 2215.
(with OVERBERG), 1931, 64, 1007 ; LEUCHS, 1938, 71, 1525 ; (with Louis), 1939, 72,
2076.
(28) Annalen,
SIDDIQUI.7
FAWCETT, P E R K I N and ROBINSON, ibid., 1928, 3082. (30) Ibid., 1930, 830. (31) Ibid.,
1931, 773. (32) Ibid., 1932, 780. (33) Ibid., 1933, 486. (34) Ber., 1930, 63, 2997 ;
cf. L E U C H S , ibid., 1931, 64, 461 ; L I O N S , P E R K I N and ROBINSON, J. Chem. Soc,
127, 1158.
1925,
(35) See, for example, CLEMO, P E R K I N and ROBINSON, ibid., 1927, 1625.
(36) Ber., 1908, 41, 1711 ; (with SCHNEIDER), 1909, 42, 2494 ; (with R E I C H ) , 1910,
43, 2417 ; (with D I E L S ) , 1936, 69, 47 ; H O L M E S , OPENSHAW and R O B I N S O N , J.
Chem.
Soc, 1946, 908 ; PRELOG and SZPILFOGEL, Helv. Chim. Acta, 1945, 28, 1669 ; (with
BATTEGAY), ibid., 1947, 30, 366.
2494 ; (with R E I C H ) , 1910, 43, 2417 ; (with SCHWAEBEL), 1914, 47, 1552 ; 1915, 48,
1009 ; (with BENDIXSOHN), 1919, 52, 1442 ; (with NITSCHKE), 1922, 55, 3738 ; (with
D I E L S and DORNOV), 1935, 68, 106 ; cf. KOTAKE and MITSUWA, Bull. Chem. Soc
Jap.,
1936, 11, 231 ; J. Chem. Soc. Jap., 1938, 59, 1 4 6 ; LEUCHS, Ber., 1937, 70, 2031.
(38) LEUCHS, Ber., 1908, 41, 1711 ; 1938, 71, 2 2 3 7 ;
3703 ; (with BREWSTERI, 1912, 45, 201 ; (with PEIRCE), 1912, 45, 2653, 3412 ; (with
R A U C H ) , 1914, 47, 3 7 0 ;
(with
(43) FAWCETT, P E R K I N
and ROBINSON, ibid., 1928, 3082 ; P E R K I N and ROBINSON, ibid., 1929, 964 ; MENON,
P E R K I N and ROBINSON, ibid., 1930, 830 ; ROBINSON, Proc Roy. Soc, 1931, A, 130,
431 ; M E N O N and ROBINSON, J. Chem. Soc,
ROBINSON, ibid., 1932, 486. See also, especially for isostrychnine, OLIVERI-MANDALA
(and COMELLA), Gazzetta, 1923, 53, 619 ; 1924, 54, 516 ; CIUSA (with SCAGLIARINI),
1924, 54, 202 ; 1928, 58, 774. (44) M E N O N and R O B I N S O N , J. Chem. Soc, 1932, 780 ;
HOLMES and ROBINSON, ibid., 1939, 603 ; cf. L E U C H S , Ber., 1939, 72, 1588. (45) Ber.,
1932, 65, 1230 ; (with GRUNOW), 1939, 72, 679 ; (a) (with K R O H N K E ) , 1930, 63, 1045 ;
(with W E G E N E R ) , ibid., 2215; (with OVERBERG), ibid., 1931, 64, 1007. (46) BLOUNT
and ROBINSON, J. Chem. Soc, 1932, 2305 ; cf. KOTAKE and MITSUWA, Annalen,
1933,
505, 203 ; Sci. Papers Inst. Phys. Chem. Res. Tokyo, 1934, 24, 119, with reply by ROBINSON, J. Chem. Soc, 1934, 1490. (47) Ann. Rev. Biochem., 1933, 2, 4 4 7 ; (with
ACHMATOWICZ), J. Chem. Soc, 1934, 582 ; (with REYNOLDS), 1934, 592 ; 1935, 935.
(48) P E R K I N and ROBINSON (with CLEMO), ibid., 1927, 1 5 8 9 ; (with ACHMATOWICZ),
1932,
ibid., 1927, 1 6 2 7 ; (with ACHMATOWICZ), 1932, 775. (50) (With B E Y E R ) , Ber., 1935,
68, 292 ; cf. KOTAKE and YOKOYAMA, Sci. Papers, Inst. Phys. Chem. Res. Tokyo,
1937, 3 1 , 321.
1935, 936.
(52) P E R K I N , R O B I N S O N , ACHMATOWICZ
and CLEMO, ibid., 1932, 767 ; see also ref. (73). (53) BRIGGS and ROBINSON, ibid., 1934,
590. (54) BLOUNT and ROBINSON, ibid., 1932, 2306. (55) Annalen, 1912, 391, 88.
(56) P E R K I N , ROBINSON and SMITH, J. Chem. Soc, 1932, 1239. (57) Idem, ibid., 1934,
574; see also ref. (44). (58) Ibid., 1934, 581. (59) Idem, ibid., 1938, 1467. (60) Ibid.,
1938,
1472;
(with D Y B O W S K I ) , p . 1483.
ROBINSON,
ibid., 1935, 1685 ; ACHMATOWICZ a n d DYBOWSKI, ibid., 1938, 1488. (62) KOTAKE,
Proc Imp. Acad. Toyko, 1936, 12, 99 ; (with MORI and MITSUWA), Sci. Papers Inst,
Phys. Chem. Res. Tokyo, 1937, 3 1 , 129 ; CLEMO, J. Chem. Soc 1936, 1695 ; (with
METCALFE), ibid., 1937, 1518 ; SIDDIQUI, J. Ind. Chem. Soc, 1939, 16, 3 9 6 ; PRELOQ
and METZLER, Helv. Chim. Acta, 1946, 29, 1163. (68) OPENSHAW a n d ROBINSON,
J. Chem. Soc, 1987, 942 ; 1946, 912 ; (with HOLMES), 1946, 910 ; see also LIONS,
586
INDOLE
GROUP
Proe. Roy. Soc., N.S.W., 1938, 71, 192. (64) ROBINSON, Ann. Rev. Biochem., 1933,
2, 447 ; see afso ref. (3) and WIELAND (with JENNEN), Annalen, 1940, 545, 99; (with
THUX), ibid., 1942, 550, 287 ; (with HUISGEN), ibid., 1943, 555, 9. (65) Bex., 1933,
66, 951. (66) (With DORNOV), ibid., 1935, 68, 2234 ; 1936, 69, 1838 ;' (with HOHNE),
ibid., p. 2525 ; (with GRUNOW), 1937, 70, 257; (with BEYER), ibid., p. 629 ; (with
STEINBORN), 1938, 71, 1577. (67) LEUCHS, SEEGER and JAEGERS, ibid., 1938, 71, 2023.
(68) (With MABXERWEIN), Annalen, 1937, 527, 141 ; (with WILLE), ibid., 1937, 531,
268. (69) Experientia, 1945, 1, 197 ; Helv. Chem. Acta, 1945, 28, 1669 ; (with
KOCOR), ibid., 1947, 30, 359 ; 1948, 31, 237 ; see also WOODWARD, BREHM and NELSON,
J. Amer. Chem. Soc, 1947, 69, 2250. (70) Experienlia, 1946, 2, 28 ; Nature, 1946,
157, 438. (71) J. Chem. Soc., 1917, 111, 885. (72) Nature, 1947, 159, 263. (73)
CHAKRAVARTI and ROBINSON, J. Chem. Soc, 1947, 78.
see also Chem. and Ind., 1946, 264. For full paper see ROBINSON, PAUSACKER and
CHAKRAVARTI, J. Chem. Soc, 1947, 1554. (75) Helv. Chim. Acta, 1948, 31, 505.
(76) Nature, 1948, 161, 433. (77) Chem. and Ind., 1948, 156.
Vomicine,* C^H^C^Ng. 1 This alkaloid, obtained from residues of
strychnine manufacture, forms colourless needles from 80 per cent, alcohol,
or hexagonal prisms from acetone, has m . p . 282, [a]| 2 + 80-4 ( E t O H ) ,
is a weak, monoacidic base giving salts which are acid in reaction. T h e
hydrochloride, B . H C 1 . 3 H 2 0 , has m.p. 245 (dec), and, like the hydrobromide, hydriodide, sulphate a n d nitrate, is sparingly soluble in water.
The acetyl derivative has m.p. 204-5 (Part X X V I I ) . A dihydro-derivative, m . p . 290, is formed b y catalytic hydrogenation. The alkaloid gives
a stable red colour with chromic acid in sulphuric acid, and with nitric
acid a brown to orange-yellow t i n t develops slowly. Boiled with potassium
hydroxide in methyl alcohol a'n intensely green colour is produced, which,
on careful addition of hydrochloric acid, followed b y a few drops of ferric
chloride solution, changes to amethyst (Part VI). I t contains no methoxyl,
or methylenedioxy-group, a n d does n o t react with carbonyl group
reagents. I t h a s one replaceable hydrogen (Part X I I ) , probably as a
tertiary hydroxyl group, 2 contains a n aromatic ring, since i t c a n be
brominated a n d nitrated (Part X), resembles strychnine and brucine in
furnishing a n isonitroso-derivative and a .benzylidene derivative (yellow,
triangular leaflets, m . p . 280 (dec.) ), indicating the presence of a reactive
methylene group. I t does n o t react with methyl iodide, b u t yields a n
addition product with methyl sulphate which, on crystallisation from h o t
water, loses 1 mol. of methyl alcohol and forms vomicine methosulphate,
m.p. 272 (Parts I a n d X X I I ) .
CONSTITUTION. T h e fact t h a t vomicine occurs naturally with strychnine
suggests probable similarity of structure, a n d this is borne o u t b y t h e
parallelism of the reactions and derivatives of t h e two alkaloids, vomicinic
acid, deoxyvomicine a n d vomicidine, for example, being formed in t h e
same way and being analogous with the strychnine derivatives, strychninic
acid, deoxystrychnine and strychnidine respectively. The two nitrogenatoms, like those of strychnine, are distinguished as N(a) (lactam nitrogen)
a n d N(6) (basic nitrogen). As evidence for t h e structure of strychnine
h a s been given already, t h e discussion of t h e constitution of vomicine is
* See note underreference(1).
VOMIGINB
587
mostly concerned with the differences between the two alkaloids and
comparison of their analogous derivatives, and for this purpose it is
convenient to have at this stage the formula for (I) vomicine and partial
formulae for (II) wovomicine and (III) deoxyvomicine, oh which most of
the results of experimental work have been explained. It should however
be noted that a new formula for vomicine has been developed recently
and is briefly referred to in an addendum (p. 595). Two points should
be noted about the : N ( i ) . CH 2 . O group : (1) it is said to be the source
-022
CH2
9|0H2
<2H5)
CHOH
CH20H
OC
(II)
oVomicina (1943)
CH2
CB2
JSKH3
( I V ) B a s a 0 2 S H 3 0 02M8 ( 1 9 4 3 )
( I I I ) Deoiyvomiolne-(4 )
a
1
CH
1
SB
j2
CHj,
CH3
CB2
(V) Dlhydrodeoxyroraialne
(VI) TetrahydrodeoiyTomiolne
588
INDOLE
GROUP
1937 (the date of formula I) this terminal has also been placed at C6 and
C7 (Part XXVII). Similarly the ethyl group shown at C3 in formula I
has also been placed more recently at C4 (Part XXVII).
iso Vomicine, C 22 H 24 0 4 N 2 (Parts XXV and XXVII). When vomicine
is boiled with hydrogen bromide and phosphorus in acetic acid, a reversible
reaction, vomicine ^ isovomicine occurs. isoVomicine has m.p. 256
and [a] D + 260-3 (CHC13) : it contains two hydroxyl groups and forms
a mono- and a di-acetyl derivative, melting at 191-2 and 173 respectively ;
the lactam group is still present. On catalytic hydrogenation, isovomicine,
unlike vomicine, does not yield simply a dihydro-derivative, but gives a
mixture of products including a base, C22H30O2N2, (IV), m.p. 210, also
obtained by the hydrogenation of deoxyvomicine (Parts I and XV). In
the formation of deoxyvomicine (see below) by the action of hydriodic
acid and phosphorus in acetic acid on vomicine, there is simultaneously
obtained an iodo-compound, C 22 H 26 0 3 N 2 I, m.p. 223 (dec.), (Part XXIII),
which is also produced when isovomicine is subjected to this reaction,
though in this case no deoxyvomicine is formed directly, but is obtained
by the action of zinc dust and acetic acid on the mother liquors from which
the iodo-compound has separated. If in place of hydrogen iodide and
phosphorus in acetic acid there is used for this reaction potassium iodide,
phosphorus and phosphoric acid,2 wovomicine gives a 20 per cent, yield
of the colourless variety of deoxyvomicine, while vomicine, which gave a
60 per cent, yield of yellow deoxyvomicine under the former conditions,
now produces a new isomeride, neodeoxyvomicine (p. 591). No welldefined product has been obtained by the oxidation of zsovomicine with
chromic acid. On electrolytic reduction it furnishes wovomicidine,
C 22 H 26 0 3 N 2 , as a faintly pink, crystalline powder, m.p. 290 (dec.). On
the basis of these results and its relationship to deoxyvomicine (III),
formula (II) was assigned to isovomicine and (IV) to the base, C22H30O2N2,
as a reduction product of both isovomicine and deoxyvomicine
(Part XXIX).
Vomicinic Acid, C 22 H 26 0 6 N 2 . Vomicine, like strychnine, contains a
lactam group, and, on hydrolysis by potassium hydroxide in methyl
alcohol, yields vomicinic acid, which, in presence of alkali, autoxidises
rapidly, but can be isolated if the hydrolysis is conducted in an atmosphere
of nitrogen. The acid crystallises from dilute alcohol (20 per cent.) in
colourless needles, sinters at 164 and melts at 282 ; the latter is the
melting-point of vomicine, which is no doubt re-formed from the acid by
loss of water. The acid yields a nitrosoamine, orange-yellow prisms,
m.p. 190 (dec). Vomicinic acid furnishes dyes when treated with oxidising
agents in presence of dilute acid. This explains the ferric chloride colour
reaction referred to above, and all vomicine derivatives retaining the
lactam group give a colour reaction of this type when the lactam group
is opened and the product subjected to oxidation in acid ; bromovomicine
and bromodihydrovomicine are exceptional, the formation of a dye in
these cases being inhibited by the ^-orientation of the substituent bromine
atom in relation to the NH group (Part VI). Vomicinic acid cannot
VOMICINE
589
CO.CHg J
Strychnine
0
C(0H).CH2]
Vomicine
C00H.CH )
Vomlclnlo acid
590
INDOLE
GROUP
Vomicine, C 22 H 24 0 4 N 2 .
Deoxyvomicine, C 22 H 24 0 3 N 2 .
Dihydrovomicine, C 22 H 26 0 4 N 2 .
Dihydrodeoxyvomicine, C 22 H 26 0 3 N 2 .
Iododihydrodeoxyvomicine, C 22 H 25 0 3 N 2 I.
Vomicidine, C 22 H 26 0 3 N 2 .
Dihydrovomicidine, C 22 H 28 0 3 N 2 .
Base, L22xl30U2JN2.
Deoxyvomicirws, C 22 H 24 0 3 N 2 (Ref. 1, Parts I, XXVII, XXIX). Three
isomerides are known, which may for convenience of reference and description be distinguished as (a), (b) and (c), though (a) is usually called
" yellow," (6) is spoken of as " colourless," and (c) is named tieodeoxyvomicine. Deoxyvomicine-(a), or the yellow isomeride, is formed by the
action of hydrogen iodide and phosphorus in acetic acid on vomicine (I).
It has m.p. 211, [a.]f + 242 (CHC13), still contains the lactam group of
vomicine and two ethylenic linkages. In a variety of ways, e.g., by distillation in vacuo, or prolonged boiling in solvents, it is transformed into
deoxyvomicine-(&), the colourless form, which has m.p. 207 and [a]p
+ 209 fCHCl3). Both isomerides on catalytic hydrogenation produce a
mixture of hydro-derivatives of which one component, a base, C22H30O2N2,
m.p. 211, [a]*1" + 73 (CHC13), is common to both (Part XIV). This base,
represented by (IV), is also produced by the hydrogenation of isovomicine
(II). On ozonisation both deoxyvomicines yield acetaldehyde, but this is
produced more quickly and in larger quantity from the (b)- than the
(a)-form. The second ethylenic linkage in ring E (formula III) is placed in
the /}y-position to the CO group because deoxyvomicine-(fc) contains a
reactive methylene group giving a benzylidene derivative, m.p. 198-9.
Under the experimental conditions used for this reaction deoxyvomicine-(a)
isomerises to the (fr)-form and so gives the same derivative.
Both deoxyvomicines combine with hydrogen iodide to form iododihydrodeoxyvomicines, C 22 H 26 0 3 N 2 I. That from deoxyvomicine-(a) is
identical with the by-product formed in the conversion of vomicine into
deoxyvomicine-(a) by the action of hydriodic acid : it can only be isolated
as the hydriodide, C 2 2 H 2 5 0 3 N 2 I. H I . H 2 0, m.p. 214 (dec), and all attempts
to isolate the free iodo-ha.se result in de-iodination and the formation of
deoxyvomicine-(a). Reduction of this hydriodide, under special conditions,
by zinc dust in cold hydriodic acid, provides dihydrodeoxyvomicine-II,
C22H2603N2, m.p. 168, [*]f + 345 (CHC13), giving a hydrochloride,
m.p. 235 (dec). The iododihydro-base resulting from the addition of
hydrogen iodide to deoxyvomicine-(fc) is identical with the product of the
action of hydriodic acid on tsovomicine ; it has m.p. 220 and is also the
iodine analogue of the bromodihydrodeoxyvomicine, C 22 H 2B 0 3 N 2 Br,
m.p. 248 (dec), obtained by the action of hydrogen bromide on dihydrovomicine (Part XXV). Both the iodo- and bromo-compounds can be
dehalogenated by reduction and yield the same dihydrodeoxyvomicine-I,
CjjHjjjOjNj, m.p. 209, [a]^ + 248 (CHC18). This gives a benzylidene
VOMICINE
591
derivative, m.p. 222, and on catalytic hydrogenation forms two tetrahydrodeoxyvomicines, C 22 H 28 0 3 N 2 , A and B. Of these A has m.p. 246-7,
and [a]!1" + 210 (CHC1S), gives a methiodide, m.p. 222 (dec), and a
colourless, benzylidene derivative, m.p. 247, and can be electrolytically
reduced to tetrahydrodeoxyvomicidine-A, C ^ H J Q O J N ^ m.p. 250-1 (dec.).
The B-isomeride has m.p. 185-6 and [a] D + 270 (CHC13) and is
reduced electrolytically to tetrahydrodeoxyvomicidine-B, m.p. <* 200.
In considering these interrelationships with reference to formulae
(I to III) it should be remembered, as already pointed out, the second
terminal of the OCH2 group is not necessarily at C4 as shown in (I)
or at C3 as in (II) and (III), and similarly the location of the C a H 5 group
shown at C3 in (I) is doubtful. In the action of hydrogen iodide on
vomicine (I) ring F appears to be opened with the formation of a hydroxyl
group at C14 and an ethylenic linkage at C6C13, as in isovomicine (II).
Under more drastic conditions, hydrogen iodide is added at the ethylenic
linkage, C8C15, resulting in the formation of the two iododihydrodeoxyvomicines, which are regarded as epimerides about C8. The loss of hydrogen
iodide from these may occur in the direction C8 to C7, believed to give rise
to deoxyvomicine-(a), or C8 to C15 to form deoxyvomicine-(&) (formula I I I ) ;
the deoxyvomicines are therefore to be regarded as derivatives of isovomicine. The two dihydrodeoxyvomicines (V) are also regarded as
epimerides while the two tetrahydrodeoxyvomicines (VI) originating from
a single dihydrodeoxyvomicine-I are believed to owe their isomerism to
cis and trans arrangements about the junction of the homo- and heterocyclic rings (Part XXIX). Tetrahydrodeoxyvomicidine, the final stage in
this series of reactions, differs from the tetrahydrodeoxyvomicines (VI) by
the replacement of the lactam CO by CH2.
neoDeoxyvomicine, the third isomeride, is produced when vomicine is
heated under reflux with potassium iodide and phosphoric acid in presence
of phosphorus. It crystallises from alcohol in prisms, m.p. 312 (dec.),
retains the lactam group and the ethylenic linkage of vomicine and gives
a dihydro-derivative, m.p. 321, but cannot be acetylated.
Vomicidine, C 22 H 26 0 3 N 2 , obtained by the electrolytic reduction of
vomicine, crystallises from alcohol in needles or plates, m.p. 284 (dec),
yields an acetyl derivative, m.p. 229-230 (dec), and a benzoyl derivative,
m.p. 208-9, and gives a blue-violet colour with oxidising agents in acid
solution. It is a phenolic base (Part VIII), and good yields of the methyl
ether (needles, m.p. 295 (dec)) are obtained by the use of methyl iodide or
sulphate in presence of alkali in at atmosphere of nitrogen. Vomicidine
itself or the methyl ether, on heating with methyl iodide in alcohol, yields
the methyl ether methiodide (m.p. > 300, with sintering at 280), With
methyl iodide in a sealed tube at 100 vomicidine gives a dimethiodide,
and this, on treatment with diazomethane, is converted to the phenolbetaine,
C23H2803N2, which melts at 246 and then solidifies, being converted into
vomicidine methyl ether. The phenolbetaine with hydriodic acid yields
vomicidine-N(a) methiodide hydriodide, and this with diazomethane
yields the corresponding methyl ether methiodide. Vomicidine no longer
INDOLE
592
GROUP
contains the lactam group, but it still retains the ethylenic linkage, and
on hydrogenation yields some dihydrovomicidine, m.p. 296-8, which is
best prepared by electrolytic reduction of dihydrovomicine.
The conversion of vomicine to vomicidine is analogous with the reduction of strychnine to strychnidine, with the difference that the oxazoline
ring in vomicine is opened with the formation of a phenolic hydroxyl
group. The nitrogen atom (a) thereby becomes basic and vomicidine, like
strychnidine and brucidine, is readily oxidised to dyes; thus it and the
derivatives described above, except the phenolbetaine and the dimethiodide, give blue-violet colours on addition of ferric chloride to their solutions
in dilute acid (Part XIV). Vomicidine and the derivatives described
above may be represented by the following partial formulae :
0: =H(b)
OHg
Vomicine
OH
Vomicidine
0:
:N(b)
+M.0H
C&2.CBg-
Vomlcldlne-K(a)
methlodlde~
Vomloidlne
phenolb etalne
Vomloldlne dlmetniodide
593
VOMICINE
CH2
OH
II
OHOKe M e
CH0K
MMe
OHOUe J t M e ,
Q Pr XP," xXf
II)
Vomicine
(III U e t h y l v o , - a i o i n e - I I
( I I I ) B a s e C22H26O4N2
(IV) Kimettjlvcraiclfle-I
594
INDOLE
GROUP
595
VOMICINE
-CH2
I
H
H02C-
CH2
0H2
3H 2
(02H5)
(C,H=)
C
OH
-0
K20
0H2
HH
H2O
CH-
-0H2
CH2
(VIII)
Addendum.
(X)
(IX)
INDOLE GROUP
596
531,
268 ; X X
(with H O R N E R ) , 1938,
536,
89 ; X X I ,
H O R N E R , 1939,
540,
73 ;
PHABMACOLOOICAL ACTION
597
PYRROLIDINE
600
GROUP
but can be accommodated in type (II). The large lactone ring of (II)
explains the failure to regenerate carpaine from carpamic acid. Since
carpamic acid is not oxidised by chromic acid to a keto-acid, and is not,
like the pyrrolidylpropanols, 7 converted into a ketone when heated with
formaldehyde, it should be represented as a tertiary instead of a secondary
alcohol. As azelaic acid is the largest fragment produced on oxidation, a
chain of seven methylene groups is essential, and (III) is regarded as the
best method of meeting this condition as well as providing for a : CMe .
and a tertiary alcohol group, though (IV) has been considered as an
unlikely alternative. The attachment of the side-chain in the a-position
is in harmony with the failure of carpamic acid to give a colour reaction
with isatin. 8 Moreover, when carpamic acid is heated with hydriodic
acid and red phosphorus at 320, nitrogen is eliminated and a hydrocarbon,
C 14 H 28 or C14H30, is formed, which contains one : CMe . group instead of
the two which should be formed by the opening of a /^-substituted pyrrolidine ring. Similarly exhaustive methylation of carpaine, followed by
hydrogenation, leads in two stages to a lactone hydrolysed to an acid,
C 14 H 28 0 3 , also containing one : CMe . group.
A second basic substance isolated from papaw seed and named " carpasemine " has been shown to be benzylthiourea. 9
Pharmacological Action. Carpaine has been investigated by several
workers.10 It is essentially a heart poison, though not of the cardiac
glucoside type. It lowers the pulse frequency and depresses the central
nervous system. Five milligrammes per kilogramme body weight is said
to be toxic to rabbits. According to To and Kyu, it is a potent amcebicide.
REFERENCES
(1) Meded. uit's Lands. Plant., 1890, No. 7, p. 5. (2) Merck's Report, 1891, p.30.
(3) Arch. Pharm., 1893, 231, 184 ; 1897, 235, 332. (4) J. Chem. Soc, 1910, 97, 466.
(5) (a) (With GIRARDET), Helv. Chim. Acta, 1933, 16, 90 ; (6) (with W O R K ) , J. Chem.
Soc., 1937, 7 1 1 ; see also (with URUSHIBARA), ibid., p. 714 ; (with SHORT), ibid., p. 713 ;
(with H A R T SMITH), ibid., p. 718. (6) Ber. Deut. Pharm- Ges., 1914, 24, 123. (7)
H E S S , Ber.,
1913,
46, 4107.
(8)
GRASSMAKN and
Acad. Sci.,
VON A R N I M , Annalen,
1935,
519,
192.
MEYER, Arch. Physiol., 1903, 225 ; KAKOWSKI, Arch. int. Pharmacodyn, 1905, 15, 84 ;
Tu, Folia Pharmacol. Jap., 1925, 1, 32 ; K Y U , ibid., 1930, 10, 333 ; T o and K Y U ,
Jap. J. Med. Sci., 1934, 8, No. 1, 52.
PYRROLIZIDINE GROUP
The Senecio Alkaloids.
T h e botanical family Composite, until comparatively recently, was singularly free from recorded occurrences of
alkaloids. T h a t h a s been changed since t h e joint work of W a t t 1 a n d
Cushny 2 proved t h a t a liver disease of farm animals in S. Africa was
caused b y t h e alkaloids present in a Senecio species. Now, alkaloids of
the same t y p e , which are beginning t o be called " hepatotoxic " alkaloids,
have been isolated from m a n y Senecio spp., including t h e noxious weeds
" groundsel " a n d " ragwort," common everywhere. Similar alkaloids
have also been found in t w o genera, Heliotropium a n d Trichodesma, of
the Boraginacese a n d in several species of Crotalaria (Leguminosse). T h e
known alkaloids of t h e group a n d their recorded botanical distribution
are given in alphabetical order in t h e following list. Brief descriptions of
the less clearly defined alkaloids of t h e group are included in t h e list,
b u t those alkaloids which have been fully named and characterised are
described separately later as indicated b y page references.
A U R E I N E . S. aureus?
Subsequently identified with senecionine. 4
CAMPESTRINE, C 1 3 H 1 9 0 3 N, m . p . 93, a n d a second base, m . p . 215.
campestris v a r . maritima.5
CARTHAMOIDINE (p. 614).
S.
S.
carthamoides.
S. Jacobcea * L.
Heliotropium
S.
lasiocarpum
F . a n d M. 9
11
longilobus.
S.
othonme.16
601
602
PYRBOLIZIDINE
GROUP
SENECIO
ALKALOIDS
603
604
PYBBOLIZIDINE
GROUP
m.p. 234, []% 28-6 (H 2 0), a picrate, m.p. 180, which is soluble" in
water, and a methiodide, m.p. 255. The base contains two active hydrogen
atoms, and on hydrolysis furnishes retronecine (p. 607) and jaconecic acid,
C10H16O6, which has m.p. 182, [a]^5 -f 31-7, and contains three C-methyl
groups. 13
Jacodine, C18H2505N, m.p. 217, [a]7 - 109-6 (CHC13) yields a
nitrate, m.p. 215, [a]}/" 77-4 (H 2 0), and a picrate, m.p. 171. The
hydrolytic products are retronecine (p. 607) and an acid, C10H16O5, m.p.
136-7 (Barger and Blackie 4 ).
Jaconine, C 18 H 25 0 8 N . H 2 0, m.p. 146, b.p. 180/0-01 mm. (Barger and
Blackie 4 ).
Lasiocarpine, C 21 H 33 0 7 N, m.p. 94-95-5, [a] D 4 (EtOH). On
alkaline hydrolysis it furnishes heliotridine (p. 607) and angelic acid,
CH 3 . CH : C(CH3) . C0 2 H, and on hydrogenolysis the products are
(a) lasiocarpic acid, C 8 H 16 0 5 , m.p. 95-7, [a] D + 10-6 (EtOH), which is
unsaturated and contains one methoxyl and two hydroxyl groups, and
(b) a base, C 13 H 23 0 2 N, b.p. 123-5/8 mm., [<x]D + 3-8 (EtOH), which gives
a picrate, m.p. 157-9, and is hydrolysed to hydroxyheliotridane (p. 607)
and methylethylacetic acid. Lasiocarpine is regarded as angelyllasiocarpylheliotridine, both hydroxyl groups in heliotridine being esterified.9
Longilobine, C 18 H 23 0 5 N, m.p. 217-8 {dec), [a]f,5 - 79-2 (EtOH),
gives a methiodide, m.p. 249 (dec), and on alkaline hydrolysis yields
retronecine (p. 607) and longinecic acid, C10H14O5, m.p. 126-9."
Monocrotaline, C 16 H 23 0 6 N, m.p. 197-8 (dec), [a]?f - 55-7 (CHC13),
forms a hydrochloride, m.p. 184 (dec), [a]f? 38-4 (H 2 0), and a methiodide, B . Mel. 3MeOH, m.p. 205 (dec), [oc]f + 23-4 (MeOH). In boiling
aqueous barium hydroxide solution the alkaloid is hydrolysed to retronecine (p. 607) and monocrotic acid (p. 612), and on hydrogenation in
presence of platinic oxide in acetic acid the scission products are (a)
retronecanol (p. 607) and (b) monocrotalic acid 14 (p. 612).
Othosenine (otosenine), C 19 H 27 0 7 N, m.p. 221-2, forms a picrate,
m.p. 233-5. On hydrolysis with barium hydroxide solution it furnishes
an acid, C10H16O6, m.p. 180-2, possibly identical with jaconecic acid
(see above); the basic hydrolytic product was apparently decomposed in this
process. On acid hydrolysis othosenine yielded a substance, C10H13O4Cl,
m.p. 111-3, and othonecine, C 9 H 15 0 3 N, isolated as the hydrochloride,
m.p. 146-8. Othonecine contains one hydroxyl, one carbonyl and one
methylimino group but no methoxyl, and is regarded as probably a
derivative of N-methylpyrrolidine. On hydrogenation it is converted
into a reduced product, CgH^OaN, b.p. 105-7, characterised by a picrate,
m.p. 231-5, and an oxime, CgH^OgNjj, m.p. 179-181.15
Platyphylline, C 18 H 27 0 6 N. The constants recorded by Orekhov 17
are generally lower than those found by de Waal, 18 which are given in
brackets: base, m.p. 124-5 (129), [a] D - 45-09 (-56-4) (CHC13);
perchlorate, m.p. 222-3 (dec.) (244-5); picrate, m.p. 199-200, picrolonate, m.p. 205-6 (dec), aurichloride, m.p. 200-1 (dec.) and a methiodide,
m.p. 216-7, [a] D 81-27 (EtOH). Platyphylline contains one hydroxyl
SENECIO ALKALOIDS
605
606
PTSBOLIZIDINE GROUP
NEGINES
607
608
PTRBOLIZIDINE GROUP
609
NECINES
(I) of which one form (picrate, m.p. 116) is identical with d/-dihydro-de-Nmethylheliotridane and the other (picrate, m.p. 126) is diastereoisomeric
with, and convertible into, it by, dehydrogenation to the corresponding
pyrrole and hydrogenation of the latter in presence of copper chromite as
catalyst.
Ke.HC
CH
I
V
(I)
CH
2
me
CH 2
X
C H CH
Me.HC
CH
CH
2
H2C
N
CH2
( I I )XCHg X 0 H g
Me.HC
CH CHE
HgC
T*B
(IIIjNa^ NCH2
I
^
to
PTRROLIZWINE
610
GROUP
m.p.
()
96-5-98/] 8 m m .
(c)
95-6/15 m m .
Picrate
Oxime
Specimen
128-130
166-7
90-7 1 6 7 - 8
Mi>
Picrate,
m.p.
nil.
77-3 1 8 8 - 1 9 0
7 6 0 188-190
Picrolonate,
m.p.
m.p.
189-190
209-211
209-210
195
611
NEGINE8
u + Z-o
% fc
199-5. This still retains the initial ethylenic linkage and can be hydrogenated to heliotridane (II). The hydrochloride in water is oxidised by
ozone to 2-acetylpyrrolidinoacetic acid (XIV) hydrochloride, m.p. 180-1,
[ a ] f 4-4 (MeOH). In this the presence of the . CO . CH S group is
shown by a positive iodoform reaction and the formation of a 2 : 4-dinitro202
PYRROLIDINE
GROUP
phenylhydrazone, m.p. 199-201 (dec.); the hydrochloride on hydrogenation furnishes the related hydroxy-acid, 2-a-hydroxyethylpyrrolidinoacetic
acid, m.p. 186- 5-187- 5, [a] 28 ' 63-5 (H 2 0), which with diazomethane
forms the betaine (XV), itself an oil, but yielding a crystalline hydrochloride,
m.p. 176-7. The hydroxy-acid as hydrochloride, in acetic anhydride at
100, is converted into the lactone, characterised by the picrate, m.p. 169170, and a methiodide, m.p. 242-3. These results clearly indicate the
C1C2 position for the ethylenic linkage in retronecine, as shown in
formula (IV).
Rosmarinecine, C 8 H 15 0 3 N, derived from rosmarinine (p. 605), has
m.p. 171-2, [a]25" 118-5 (MeOH), gives a picrate, m.p. 175, and a
methiodide, m.p. 195. It is not hydrogenated in presence of Adams's
platinic oxide, and Richardson and Warren suggest that the third hydroxyl
group is at C2 (V : CH2 - CHOH at C2), which makes it a hydroxyplatynecine, a suggestion of some biological interest as platyphyllme, one of
the sources of platynecine, occurs with rosmarinine, by which it seems
sometimes to be replaced. Senecic acid is the acid component in both
alkaloids and occurs free in the plant. 20
Isatidine (p. 603) does not seem to be a derivative of 1-methylpyrrolizidine : its basic hydrolytic product, isatinecine, C 8 H 13 0 3 N, has m.p.
212-5, [a]2,0" + 22-4 (H 2 0) : it has two ethylenic linkages, no methylimino- or methyl to carbon group, does not behave as a tertiary base,
and gives well-marked pyrrole reactions. On these grounds it has been
suggested that it is a partially reduced pyrrole with a side-chain
. CH( : CH2) . CH2 . CH 3 at C2. (De Waal, 1941.)12
The Necic Acids. There appears to be much more variety among
the necic acids than among the necines, possibly because so little is known
about them. Most of them are described briefly under their appropriate
alkaloids, but there are at least four which need more detailed description.
Monocrotaline on alkaline hydrolysis yields retronecine and monocrotic
acid, C 7 H 12 0 3 , b.p. 145-6/18 mm., [a] D 0, which forms a ^-bromophenacylester, m.p. 78,and a methyl ester, b.p. 94-6/18 mm., characterised
by a 2 : 4-dinitrophenylhydrazone r m.p. 95-6 (see below). The acid gives
the iodoform reaction and is oxidised by sodium hypobromite to a mixture
of dl- and meso-aa'-dimethylsuccinic acids (I). These and other reactions
show that monocrotic acid is ajS-dimethyllsevulic acid (II) 1 4 , 37 and this
has been confirmed by comparison with a synthetic specimen of the
acid. The methyl ester of the synthetic acid forms a mixture of 2 : 4 dinitrophenylhydrazones, m.p. 108-9 and 121-2, into which the analogous
product, m.p. 95-6, first made from methyl monocrotate (see above), has
also been separated.
When monocrotaline is hydrogenolysed the acid scission product is
monocrotalic acid, C 8 H 12 0 5 , m.p. 181-2, [a]2,8" 5-33 (H 2 0), which
provides a methyl ester, m.p. 79-80, [<x]f 16-2 (EtOH), containing
one active H atom and a p-bromophenacyl ester, m.p. 162-3. It is a
lactonic acid, which on boiling with sodium hydroxide solution loses
carbon dioxide and produces oc/3-dimethyllaevulic acid (monocrotic acid, II).
NECIC ACIDS
613
This fact limits the range of structural formulae, which might be proposed
for crotalic acid, but does not simplify the problem of selection. Three
formulae have been considered of which the first and second were eliminated
after exploratory synthetic work and the remaining proposal (III) is now
under investigation. 37,38
CHrCHCOOH
I
CH3 CH COOH
(i)
CH,-CHC0CH3
<~
CHjCHCOOH
CH3CH -
C(0H)-CH,C0 2 H
>
CH3CH-C0
, (m)
(n.)
D - C O - R OC-0
H02C CHCH 2
H0 2 CC(:CHMe)-CH 2 -CH - C H 2
HC
C-CH 2
ICH
614
PTBBOLIZIDINE
GROUP
m.p. 92-5-94-5 , [<X|D 12 (H 2 0), is described as monobasic and containing one hydroxyl and one methoxyl group. It is oxidised by lead
peroxide in dilute phosphoric acid to 2-methyl-4-methoxy-3-pentanone,
b.p. 144-5, [a] D + 22-5, giving an oxime, m.p. 108-9, and a semicarbazone, m.p. 146-7, whose constitution was established by its reactions.
On this basis heliotric acid is believed to be 2-methyl-3-hydroxy-4-methoxypentane-3-carboxylic acid, C H 3 . CHMe . C(OH)(COOH) . CHOMe . CH 3 . 40
On the evidence available there is no reason to doubt that the " necylnecines " or parent alkaloids of this group are constituted normally, in
which case (VI; p. 613) probably represents a typical retronecine ester.
Toxicology. Senecio species are no longer used in modern medicine,6
and practical interest in them arises from the fact that they produce
disease in farm animals kept in pastures infested with them. Poisoning
cases in human beings have also occurred through the presence of Senecio
seed in food-grains, where the latter have been grown as crops in fields
infested by these noxious weeds. The resultant disease is variously
named in Canada, New Zealand, South Africa, Norway and elsewhere,
but it has one common feature, liver necrosis. Since the definite association
of this disease with Senecio alkaloids by Cushny 2 and Watt, 1 numerous
poisoning cases, especially in animals, have been recorded, 41 and many
toxicity trials have been made with single Senecio species.42 More recently
much detailed pharmacological work has been done by K. K. Chen 43 and
his colleagues on the various Senecio alkaloids. The alkaloids vary in
degree of toxicity and in details of pharmacological action, but the characteristic effect of the group is the production of liver necrosis, which is
usually central, but may be predominantly periportal as with pterophine
and carthamoidine. The latter alkaloid was isolated from Senecio carthamoides by Adams but has not yet been described chemically. Chen,
Harris and Rose 43 (1940) have noted that platyphylline, which seems to
be less prone to cause liver necrosis than its allies, has an atropine-like
action on the eye and the intestine, and Goldenhershel u has made a
detailed study of the alkaloid as a possible substitute for atropine and
concludes that at least as an antispasmodic in diseases of abdominal
organs it has advantages over atropine. It appears to be generally agreed
among the Russian workers that as a parasympathetic drug atropine is
from 20 to 30 times more potent than platyphylline.
Trachelantamine, according to Syrneva,44 has a weak atropine-like
action and also produces local anaesthesia. Its hydrolytic product, trachelantamidine, which is structurally identical with isoretroneeanol, yields a
p-aminobenzoyl derivative of which the crystalline hydrochloride, m.p.
230-2, is said to be as potent a local anaesthetic as cocaine hydrochloride.
The chloro-^r-heliotridane (p. 606) formed by the action of thionyl chloride
on trachelantamidine reacts with 6-methoxy-8-aminoquinoline to form
6-methoxy-8-(p$mioheliotridylamino)-quinoline,
MeO . Q . NH . CH 2 . CHCH2CH2NCH2CH2CH2. CH,
SENECIO
ALKALOIDS
615
1911, B , 84, 188 ; cf. J. S. Afr. Med. Res., 1920, 18, 346.
11
J.
J.,
Gewurz-pflanzen," 1924 (Chem. Zentr., 1925, ii, 1049). (7) D E WAAL, Onderstepoort J.,
1941, 16, 149-165.
571.
(8) ADAMS, CARMACK and ROGERS, J. Amer. Chem. Soc., 1942, 64,
(9) MENSCHIKOV, Ber., 1932, 65, 974 ; 1933, 66, 875 ; 1935, 68, 1051 ; (with SCHDANOWITSCH), 1936, 69, 1110. (10) MANSKE, J. Can. Res., 1939, B . , 17, 8. (11) Idem,
ibid., p . 1. (12) DE WAAL, Onderstepoort J., 1939, 12, 155 ; 1940, 14, 433 ; 1941, 16,
149.
(13) MANSKE, Can. J. Res., 1931, 5, 651 ; H O S K I N G a n d B R A N D T , New Zealand
J. Sci. Tech., 1936, 14, 638 ; BARGER and B L A C K I E . 4 (14) ADAMS and R O G E R S , J.
Amer. Chem. Soc, 1939, 61, 2815 ; cf. N E A L , RUSOFF and AHMANN, ibid., 1935, 57,
2560. (15) ZDANOVICH and MENSCHIKOV, J. Gen. Chem., U.R.S.S., 1941, 11, 835 ,
cf. KONOVALOVA (with GUREWITSCH and OREKHOV), Bull. Acad. Sci V.R.S.S. Ser. Chim.;
1936, 961. (16) D E W A A L and T I E D T , Onderstepoort J., 1940, 15, 251 ; RICHARDSON
and W A R R E N , J. Chem. Soc, 1943, 452. (17) OREKHOV and T I E D E B E L , Ber., 1935,
68, 650 ; (with KONOVALOVA), ibid., p. 1186, and J. Gen. Chem. U.R.S.S., 1938, 8, 273
(Chem. Abstr., 1938, 32, 5403) ; Bull. Soc Chim., 1937, [v], 4, 2037. (18) Onderstepoort
J., 1941, 16, 158. (19) MANSKE " ; ADAMS et al., J. Amer. Chem. Soc, 1942, 64, 2760.
(20) RICHARDSON and W A R R E N
16
1940, 15,
241 ; D E W A A L , ibid., 1941, 16, 156. (21) D E WAAL a n d PRETORIUS, Onderstepoort J.,
1941, 17, 181.
and
Chim.,
Compt rend., 1895, 120, 1120 ; MANSKE, Can. J. Res., 1936, 14, B , 6 ; BARGER and
BLACKIE. 2 2
1941, 11,
209; 1945,15, 225 ; MENSCHIKOV, ibid., 1947,17, 343 ; (with GUREWITSCH), idem, p. 1714.
(25) MENSCHIKOV and R U B I N S T E I N , Ber., 1935, 68, 2039 ; KONOVALOVA and OREKHOV
(1937). 15 (26) MANSKE, Can. J. Res., 1931, 5, 651 ; 1936, B . 14, 6 ; B A R G E R , SESHADRI,
WATT and YABUTA, J. Chem. Soc, 1935,11. (27) ADAMS and ROGERS, J. Amer. Chem,
Soc, 1941, 63, 537. (28) Ber., 1935, 68, 1555 ; Bull. Acad. Sci. V.R.S.S. Ser. Chem.,
1937, 1035. (29) J. Gen. Chem. Russ., 1937, 7, 1632. (30) (With SCHDANOVITSCH),
Ber., 1936, 69, 1799. (31) J. Amer. Chem. Soc, 1941, 63, 228. (32) Helv. Chim. Acta,
1944, 27, 531 ; cf. Ber., 1939, 72, 1101 ; Annalen, 1940, 545, 230 ; CLEMO and MELROSE,
J. Chem. Soc, 1942, 424, and GALINOWSKY and R E I C H A R D , Ber., 1944, 77, 138. (33)
(With ROGERS), J. Amer. Chem. Soc, 1941, 63, 537 ; (with CARMAQK and MAHAN),
1942, 64, 2593 ; (with HAMLIN), 1942, 64, 2597. (34) Ibid., 1944, 66, 257. (35) Ber.,
1909, 42, 2989. (36) J. Amer. Chem. Soc, 1943, 65, 2009. (37) ADAMS (with ROGERS
and SPRULES), ibid., 1939, 61, 2819 ; (with ROGERS and LONG), ibid., 2822 ; (with
LONG), ibid., 1940, 62, 2289. (38) (With WILKINSON), ibid., 1943, 65, 2203. (39) Arch.
Pharm., 1918, 251, 355. (40) MENSCHIKOV, J. Gen. Chem., V.R.S.S., 1939, 9, 1851
(Brit. Chem. Abstracts, 1940, A ii, 152). (41) Nature, Dec. 16th, 1920, p . 503 ; Lancet,
Oct. 23rd, 1920, p . 8 4 8 ; Nov. 27th, 1089 ; Dec. 18th, 1266. Useful accounts of t h e
causative plants and of the disease as i t occurs in S. Africa are given b y W A T T and
PYRROLIZIDINE GROUP
616
(42)
S T E Y N and VAN D E R
Pharm.
Exp. Ther., 1940, 68, 123 ; (with HARRIS and R O S E ) , platyphylline, seneciphylline and
lasiocarpine, ibid., p. 130 ; 1943, 78, 372 ; (with HARRIS and ANDERSON), integerrimine,
jacobine, longilobine, senecionine, spartioidine, ibid. 1942, 75, 69 ; monocrotaline and
retronecine, ibid., p , 7 8 ; isatidine, pterophine, sceleratine., ibid. 8 3 , ; riddelline,
ibid., 1943, 78, 372 ; carthamoidine, ibid., 1943, 79,133 ; 1946, 87, 382 ; general (with
R O S E , F I N K and HARRIS), ibid., 1945, 83, 265. (44) Klinicheskaya, 1943, 31, 56 (Amer.
Rev. Soviet Med., 1943, 1, 155); BABSKY, Compt. rend. Acad. Sci U.R.S.S., 1940, 27,
83 ; KOVYREV, Byull. Eksptl. Biol. Med., 1941, 11, 92 (Chem. Abstr., 1944, 38, 5597) ;
SYRNEVA, Farmakoli Toksihol., 1946, 9, 15, 45 (Chem. Abstr., 1947, 41, 6987); quoted
by MENSCHIKOV and GUREWITSCH, 2 4 (1947). (45) Amer. J. Clin. Path., 1945, 15, 407 ;
J. Amer. Pharm. Assoc, 1947,36,331. (46) MCCULLOCH,Science, 1940,91, 95 ; GROVES,
Wash. Agric. Exp. Stat. Bulltn., 1941, 410, 35. (47) NOVBLLI and de VARELA, Anal.
Asoc. Quim. Arg., 1945, 33, 176 (Brit. Abstr., 1917, A i i . , 219).
QUINAZOLINE GROUP
Vasicine (Peganine), C u H 12 ON 2 . This alkaloid was isolated from
the leaves of Adhatoda vasica Nees (Acanthacew) by Hooper, 1 and was
again prepared by Sen and Ghose.2 It was subsequently obtained by
Merck from Peganum Harmala (p. 488), and was investigated by Spath and
Nikawitz 3 under the name " peganine." According to Pallares, the watersoluble red pigment found in the bark of " Sangre de drago," on hydrolysis
by acid furnishes -peganine.3(a) Vasicine has m.p. 198 (dec.) or 211-12
(vac.), [<x]D 0, and yields crystalline salts ; hydrochloride, B . HC1. 2H 2 0,
m.p. 208 (dry) ; hydriodide, B . H I . 2H 2 0, m.p. 195 (dry); picrate,
m.p. 199 (dec.); and methiodide, m.p. 187.
Constitution. Ghose 4 suggested that vasicine is probably either
2-propyl-(or 2-wopropyl)-4-hydroxyquinazoline on the following grounds :
(1) it was converted by phosphorus pentachloride and oxychloride into
deoxychlorovasicine, CUHUN2C1 (greenish platelets, m.p. 136-7), which
on reduction furnished a base, C U H 12 N 2 . 0-5H2O, m.p. 87-8 ; B . HC1,
m.p. 255-6, subsequently named deoxyvasicine (p. 618) ; (2) it was
oxidised by potassium permanganate to 4-hydroxyquinazoline ; (3) on
fusion with potassium hydroxide it yielded acetic and o-aminobenzoic
acids. De and R a y 5 prepared 2-propyl- and 2-isopropyl-4-hydroxyquinazolines and found that neither was identical with vasicine, and a
reinvestigation by Ghose, Krishna, Narang and Ray 6 showed that the
permanganate oxidation product was 4-quinazolone (I). With acetic
anhydride vasicine gives an anomalous acetyl derivative, C13H,2ON3,
m.p. 165 (subsequently shown by Spath et al. to be iV-acetylpegadiene;
the normal O-acetylvasicine has m.p. 122). On the basis of these results
the Indian authors suggested formula (II) for vasicine and formula (III)
for tsovasicine, m.p. 164, an isomeride stated to be produced by the action
of alkali on the natural alkaloid. In their investigation of peganine
Spath and Nikawitz 3 came to the conclusion that their experimental data
were best accounted for by formula (IV). The chief new reaction concerned
is the formation from vasicine by oxidation with potassium permanganate
of 4-keto-3 : 4-dihydroquinazolyl-3-acetic acid (V), of which the methyl
ester (m.p. 152) is hydrolysed by potassium hydroxide solution to oaminobenzoic and aminoacetic acids, the latter being isolated in the form
of its benzoyl-derivative (hippuric acid).
The substance represented by formula (IV), viz., 4-hydroxy-3-allyl3 : 4-dihydroquinazoline, m.p. 130, was synthesised by Reynolds and
Robinson,7 and proved to be different from vasicine. Spath and Kuffner 8
established the identity of the degradation product (V), upon which formula
(IV) for vasicine was chiefly based by synthesis from isatoic anhydride,
which, on treatment with glycine ester hydrochloride and sodium methoxide, gave the substituted hippuric acid (VI), and this, on heating with
617
QUINAZOLINE
618
GROUP
formic acid gave (V). Narang and Ray 9 then proposed for consideration
two formulae (VII) and (VIII), of which (VII) was preferred, and at the
same time apparently accepted the identity of vasicine and peganine, of
NH.CHj.CCyte
2
CO
(IV)
which they had previously expressed doubt. 10 Formulas of the types (II),
(IV) and (VII) were rendered untenable by the work of Hanford, Liang
and Adams, 11 who showed that reduction of 3-allyl-3 : 4-dihydroquinazoline
(IX) (which is not identical with deoxyvasicine as it should be if vasicine
were (IV) ) or of its ketoderivative (IX : CO at 4) gave 3-allyl-l : 2 : 3 :
4-tetrahydroquinazoline (reduction of the linkage N L =C 2 in IX), which is
not identical with dihydrodeoxyvasicine, C n H 1 4 N g , m.p. 69-70 ; picrate,
m.p. 185, prepared by reduction of vasicine with sodium and amyl
alcohol. Dihydrodeoxyvasicine proved to be identical with " deoxytetrahydropeganine " previously prepared in this manner by Spath and
Nikawitz 3 from peganine.
N
x
CH.0H
IVIII) V
CH
/ 2.CH0H
I
CH.CH
VASICINE
619
.05^
(I)
in)
CHOH
I
f \ s
CH.
(XII)
COOH
(XIII)
(XT)
(XVI)\HOH
(mi)
\H.0H
(XVIII)
0H.OH ^
Vasicine (Peganlna)
QtJINAZOLINE
620
GROUP
tion of picric acid leads to precipitation of 2 : 3-cj/cZopentano-l : 2-dihydroquinazol-3-inium (XIX) picrate, m.p. 168-170. If, however, the reaction
mixture is treated with palladium-black and hydrogen, prior to the
addition of picric acid, deoxyvasicine (^9-pegene, XIII) is obtained, due
to a shift of two hydrogen atoms. I t is suggested that under natural
conditions o-aminobenzaldehyde might arise from tryptophan, and the
unknown aminohydroxybutyraldehyde (XX) required for a corresponding
biogenesis of vasicine from hydroxyornithine (XXI).
OHO
"g *f"2
CHO
(XIII)
CHo
IHZ)
(XX) CH0.CH0H.[CH2]2.HH2-<
C08H.CH(11H2).CH(OH).[CH2]2.HH2 (XXI)
4, 541. (6) J. Chem. Soc, 1932, 2740 ; Current Sci., 1935, 4,158 ; cf. MORRIS, HANFORD
1936, 196.
(7) Nature,
(9)
Chem.
and Ind., 1934, 53, 698 ; cf. J. Chem. Soc, 1935, 1277. (10) Current Sci., 1934, 2, 388.
(11) J. Amer. Chem. Soc, 1934, 56, 2780. (12) Ber., 1935, 68, 497 ; for a second synthesis see ibid., 1936,69,255. (13) J. Amer. Chem. Soc, 1935, 57, 9 2 1 ; MORRIS, HANFORD
andADAMS,tfcid.,p. 951. (14) Ber., 1935, 68, 935. (15) Ibid., 1935, 68, 699. (16) Ibid.,
p. 1384. (17) Ibid., 1936, 69, 255. (18) Ibid., p . 384. (19) Ibid., 1936, 69, 2022 ;
cf. SPATH and ZAJIC, ibid., p . 2449. (20) AnnaUn, 1936, 523, 1 ; cf. ibid., 1935, 518,
127.
(21) SPATH (with PLATZER), Ber., 1935, 68, 2221 ; 1936, 69, 387 ; (with K U F F N E R
and LINTNER), ibid., 1936, 69, 2052; (with K U F F N E R ) , ibid., 1938, 71, 1657; R A Y ,
NARANG a n d J U N E J A , Current Sci., 1935, 3, 352, 552 ; J. Chem. Soc, 1935,1277 ; B E R I ,
NARANG and R A Y , J. Ind. Chem. Soc, 1935, 12, 395 ; NARANG a n d R A Y , J. Chem.
Soc, 1936, 686, 1570 ; KONEK, Math, naturw. Anz. Vng. Akad. Wiss., 1936, 54, 452 ;
A H M E D , NARANG and R A Y , J.
Ind.
Chem. Soc,
(22) CHOPRA,
Med. Gaz., 1925, 60, 354. (28) Trans. Ukrain. Inst. Exp. Pharm., 1938, 1, 32.
Ind.
GLYOXALINE GROUP
ALKALOIDS OF PILOCARPUS
SPP. (JABORANDI)
Commercial Name
Name of Plant
P. Jaborandi
(Holmes).
Pernambuco
jaborandi.
P.
pennatifolius
(Lemaire).
P. microphyllus
(Stapf).
Paraguay
jaborandi
Maranham
jaborandi
P. racemosus
Guadeloupe
jaborandi
Ceara jaborandi
P. trachylophus
(Holmes).
P. spicaUts
(St. Hilaire).
Aracati jaborandi
Constituents
Amount of
Total
Alkaloid
per cent.
Pilocarpine
0 72'
isopilocarpine (?)
pilocarpidine
Pilocarpine
02-03
isopilocarpine
Pilocarpine
0-7G-0 78
isopilocarpine
pilosine
Pilocarpine
Amount of
Crystalline
Pilocarpine
Nitrate
obtained
per cent.
007
0 15 '
.
012
Not known
04'
fr Pilocarpine
i//-Jaborine
016'
921
622
!
GLYOXALINE
OBOUP
PILOCARPUS
623
ALKALOIDS
(I) C H 2 O C O
(II) CO
CH 2
and these lead to the following possible formula for pilopic acid :
CH(C2H5)CH . COOH
CH(C2H5)CH . COOH
II
(III) CH2
O CO
(IV) CO O CH2
As a substance of formula (III) should lose carbon dioxide on heating,
whereas pilopic acid is stable even at 200, it seemed probable that homopilopic acid is represented by (II) and pilopic acid by (IV). Jowett also
showed that pilocarpine, like isopilocarpine, yields /jomopilopic acid when
oxidised by permanganate. 16 In the oxidation of the two alkaloids the
two nitrogen atoms are eliminated as ammonia and methylamine.
From these and other experimental results Pinner and Schwarz 17
suggested that pilocarpine could be represented by formula (V), and
subsequently Jowett confirmed this by the preparation of a series of
disubstituted glyoxalines from wopilocarpine by distillation with sodalime,18 although he pointed out that the reactions of the alkaloid were
CO
(T)\r
CH2
OHIT
CO
6H2
CH-BKe^
(vi)\r
equally well accounted for by formula (VI), since it was then impossible
to decide whether the dialkylglyoxalines produced on distillation with
soda-lime were 1 : 4- or 1 : 5-derivatives.
The settlement of this point proved difficult, but the dimethylglyoxaline obtained by Jowett from wopilocarpine was finally shown
by Pyman 19 to be the 1:5-isomeride (b.p. 224-5; aurichloride, m.p.
OLTOXALINE GROUP
624
IT^
Me _C
>
II
(Til)
J*
tf^
(H)
J3H
HOgO.OBMe.HHUe
>
+ NH3
(Tin)
1W-CH-MB,
2
>
Me-GH-MHg
(I)
CH 3 .HH 2
NH 3
+ HCNSy
CMe-NMev.
||
X.SE
CH
N^
CMe-NMe^
||
JJCa
CH
YT
(XII)
(XIII)
There are two asymmetric carbon atoms in the pilopyl residue, and
the relationship between pilocarpine and wopilocarpine was assumed by
Jowett 2 1 to be stereochemical, whilst Pinner 22 took the view that they
might be structural isomerides dependent on the point of attachment of
the pilopyl residue to the glyoxaline ring. Definite experimental evidence
in favour of Jowett's view was provided by Langenbeck,23 who showed
(1) that the two alkaloids yielded different methiodides (examined as the
methochloroplatinates, m.p. 223-4 and 224-5, mixed m.p. 210), whereas
it is assumed 4- or 5-substituted glyoxalines should yield the same methiodide, 19 and (2) that on ozonisation the two alkaloids yielded two different,
well-defined methylamides, viz., Aomopilopic acid methylamide, m.p. 104,
MIS + 147-0, and Aowowopilopic acid methylamide, m.p. 53, [a]^56
+ 104-9 respectively. This evidence seemed to indicate clearly that the
difference between the two alkaloids is due to stereoisomerism in the
pilopic acid residue. This view has been confirmed by a series of syntheses
by Russian chemists,24 which may be summarised thus : Diethyl formylethylsuceinate ( I : R = Et) was reduced by aluminium in wet ether to
the ethylitamalates (II), which on heating gave a mixture of ethyl ethylparaconates (III) (ethyl pilopates or ethyl 2-keto-3-ethyltetrahydrofurane4-carboxylates), separable into two racemic mixtures :
(A) A liquid ester, C 9 H l 4 0 4 , b.p. 276-276-5/751 mm., which hydrolysed to an acid, m.p. 87-5-88-0, b.p. 184-5/7-5 mm., separable by
crystallisation of the strychnine salt into two acids, m.p. 105-5, having
I*]!2" 58-06 and + 58-92 respectively, the latter being identical with
an acid obtainable from Jowett's pilopic acid ( I I I : R == H), m.p. 104,
PILOCARPUS
625
ALKALOIDS
CHEtCH.COgR
CHEt
CH.C0oE
C0 g E
CO, ,R
[0
CH0
(I)
CE
CH2OH
CH.C0C1
CHEt
CO0CH 2
(IT)
(VI)
CH.CH.C0.CH o .Cl
CHEt-CH.CH-.CO.CHN,
| |
CHEt-CH.CO.CHN
C0-0-CH
(VIII) ex
,C0
CHEt-CH.CH.C0.CH.lT'
^C.H
2
|
|
2 \ c o ^ 6 4
CH
2
C0-O-CH
(VII) ex (IV)
(VI)
CHEt-CH. CH,.
Z CO. CH,.
2 HH,
2
+ \
C0-O-CH
2
|
(XI)
C0-0-CH 2
(X)
CHEt'-CH-r-CHgC-
-NR
CHEt-CHCH,
C0-O-CH,
CH
C0-O-CH
(mi)
CO0CH.
CO0CHg
(IX)
CHEt
(V)
CH. CHgOH
CO-I0CE
CHEt
(in)
(II)
CHEt
CO0CH
CH
\r
( H I ! ) Pllooarpldlne R = H;
I
OH
-HH
C.SH
(XII)
626
GLYOXALINE
GROUP
Characters of Nitrate
Synthetic Product
Starting Material
m.p.
H,
112-113-5 (dec.)
158-158-5
114-115
134-135
128-129
135-136
+ 27-63 1
+ 55-62 f
=
-
\
\
d-homoisopilopic
acid.
dl-htmuri&oxA] opic
acid.24fa)
di-Aomopilopic
acid.24(c)
b.p. or m.p.
WD
b.p. 160-8/
0-01 mm.
m.p. 74-2
50-98
m.p. 100-101
m.p.106107.24(i)
PILOCARPUS ALKALOIDS
627
CH.CH.C-MMev.
2
CH5
2
CH_
CO
CO
\ /
Nr
Pilosine
II
>H
CS.VT
CH-CH^-C-Mtev^
2
CH P
||
\ /
>H
C&VT
Pilosinine
GLYOXALINE
628
GROUP
Since pilosine can be recovered unchanged after boiling for a short time
with dilute alkali, it is regarded as allied stereochemically to isopilocarpine
rather than pilocarpine.
The foregoing formula has been confirmed by the synthesis of pilosinine
by Poljakova and V. A. and N. A. Preobrashenski,29 who followed the
process used for the synthesis of pilocarpine and the allied alkaloids (see
p. 625), starting with diethyl formylsuccinate to produce pilosinic acid,
PILOCARPUS
ALKALOIDS
629
(8) E V A N S ,
Analytical
Notes, 1906, p. 21 ; 1908, p . 20 ; 1909, p . 35 ; cf. CARE and REYNOLDS, Pharm. J.,
1908, (iv.), 26, 542 ; IMBESI, Arch. farm, sperim., 1938, 65, 113 ; TARAN, Farmaskaya,
1940, No. 5, 26. (9) JOWETT and PYMAN, J. Chem. Soc, 1912, 28, 268. (10) JDansk.
Tids. Farm., 1939, 13, 160. (11) JOWETT, Year-book Pharm., 1899, 36, 435 ; BOURCET,
Ann. Falsi/., 1929, 21, 23 ; SCHUPE, J. Assoc. Offic Agric Chem., 1941, 24, 757. (11a)
Quart. J. Pharm., 1947, 20, 234, 413. (116) Ibid., 1946, 19, 532. (12) J. pr. Chem.,
1928, 118, 20. (13) ROSENTHALER, Schweiz. Apoth. Zeit., 1924, 62, 124, 142. (14)
Pharm. Weekbl., 1930, 67, 285. (15) Bull. Soc. chim., 1922, [iv], 31, 1027, 1185, 1201,
1204. (16) J. Chem. Soc, 1903, 83, 438 ; cf. P I N N E R and collaborators, Ber., 1900,
33, 1424, 2357 ; 1901, 34, 727 ; 1902, 35, 204, 2443 ; 1905, 38, 2560. (17) Ber., 1902,
35, 2441. (18) J. Chem. Soc, 1903, 83, 442 ; (with POTTER), ibid., p . 464. (19) Ibid.,
1922, 121, 2616; cf. 1901, 97, 1820. (20) Ibid., 1925, 127, 581. (21) Ibid., 1903, 83,
438 ; 1905, 87, 7 9 4 ; cf. M. and M. POLONOWSKI, Bull. Soc chim., 1922, [iv], 31, 1314.
(22) Ber., 1905, 38, 1510. (23) Ibid., 1924, 57, 2072; 1932, 65, 8 4 2 ; J. pr. Chem.,
1928,
[ii], 119,
77.
(24)
PREOBRASHENSKI, Ber.,
1930,
63,
4 6 0 ; PREOBRASHENSKI et al., (b) 1935, 68, 847 ; (c) ibid., p . 844 ; (d) ibid., p . 850 ;
(e) N .
A.
ibid., 1933, 66, 1536; ( / ) ibid., 1187; (g) PREOBRASHENSKI, POLJAKOWA and
PREOBRASHENSKI, ibid., 1934, 67, 7 1 0 ; (ft) ibid., 1936, 69, 1314; (i) ibid., p . 1835 ;
Bull. Acad. Sci. U.R.S.S., 1936, 983 ; FREUDENBERG and K U H N , Ber., 1931, 64, 703 ;
(j) J. Gen. Chem. V.R.S.S., 1945, 15, 672 ; (k) ibid., 237. (25) W E L C H , J. Chem. Soc,
1931, 1370; D E Y , ibid., 1937, 1057. (26) Annalen, 1887, 238, 230. (27) J. Chem.
Soc, 1900, 77, 474 ; cf. PYMAN, ibid., 1912, 101, 2260. (28) Ber., 1925, 58, 513 ; see
also PAULY and ARAUNER, J. pr. Chem., 1928, 118, 33. (29) J. Chem. Soc, 1912,
101, 2260 ; cf. LEGER and ROQUES, Compt. rend., 1912, 155, 1088 ; 1*33, 156, 1687;
POLJAKOWA et al., J. Gen. Chem. U.R.S.S., 1939, 9, 1402. (29a) Ibid., 1947, 17, 1718.
(30) P E T I T and POLONOVSKY, J. Pharm.,
enterology, 1944, 2, 201. (32) MARSHALL, J. Physiol., 1904, 31, 123. (33) B U R N ,
quoted by Burtles, Pyman and Roylance, J. Chem. Soc, 1925, 127, 581 ; see also for
t h e pharmacological action of other substituted glyoxalines allied t o pilocarpine in
structure, LAIDLAW, quoted by PYMAN, ibid., 1912,101, 530 ; and for a description of
the group of alkaloids affecting parasympathetic nerves consult HENDERSON and
R O E P K E , Physiol. Reviews, 1937, 17, 373. (34) J. Gen. Chem. VM.S.S., 1941, 11, 459.
(35) Arch. easp. Path. Pharm., 1881, 13, 3 0 4 ; 1883, 16, 250. (36) J. Pharm. Exp.
Ther. Proc, 1941, 72, 20.
ALKALOIDAL AMINES
REFERENCE has been made already to the association with alkaloids
in plants of comparatively simple amines and amino-acids. Some of these
substances, e.g., acetylcholine and woamylamine, are physiologically
active, and there would be some justification for including them in a
work on plant alkaloids, and this also applies to such substances as arginine,
choline, betaine and other compounds of this type, but they are better
dealt with as a separate class of simple basic constituents of plants.
Special reference may be made to galegine, C 6 H 13 N 3 , isolated by Tanret 1
from the seeds of Galega officinalis and regarded by him as a 3-methylpyrrolidine derivative, but which was shown by Barger and White 2
to be a guanidine derivative of the following constitution:
Me2C : CH . CH 2 . NH . C(: N H ) . NH 2 .
REFERENCES
(1) Compt. rend., 1914, 158, 1182, 1426; Bull. Soc. chim., 1924, [iv], 35, 404.
(2) Biochem. J., 1923, 17, 8 2 7 ; see also SPATH (with PBOKOPP), Ber., 1924, 57, 474 ;
(with SPITZY), ibid., 1925, 58, 2273 ; and t h e following papers, mainly pharmacological,
MULUSR, Zeit. Biol., 1925, 83, 239; (with REINWEISS), Arch. exp. Path. Pharm., 1927,
125, 212 ; SIMONNET and TANRET, Conpt. rend., 1927, 184, 1600 ; 185, 1616.
SPHEBOPHYSINE
631
632
ALKALOIDAL
AMINES
J. Amer. Chem. Soc, 1942, 64, 187. (8) HILLER-BOMBIEN, Arch. Pharm., 1892, 230,
513 ; BLAU, Zeit. Physiol. Chem., 1908, 58, 153, Constitution, see GOLDSCHMIEDT,
Monats., 1912, 33, 1379 ; 1913, 34, 659 ; FRIEDMANN and GUTHMANN, Biochem. Zeit.,
1910, 27,491 ; JOHNSON and NICOLET, Amer. Chem. J., 1912, 47,459. Recent syntheses :
KANEVSKAJA, J.
pr.
Chem., 1929
[ii],
124,
48 ;
D E U L O F E U and
MENDWELZUA,
Ber.,
1935, 68, 783. (9) J. Gen. Chem. U.R.S.S., 1943,13, 801 (Chem. Abstr., 1945, 39, 1172) ;
(with BORODINA), ibid., 1947, 17, 1569 (Chem. Abstr., 1948,42,2245). (10) Farmakol
i Toksikol, 1941, 4, 105 (Chem. Abstr., 1944, 38, 1029).
633
HORDENINE
CgHg.CHg.CHjj.Cl
*-
CjHg.CHg.CHg.Mtog
- +
HO.CgH4.CH2.CB2.NHSg
Since then other syntheses have been effected7 of hordenine and its
homologues and derivatives.
According to Camus,8 hordenine is of low toxicity, but in large doses
it causes death by arrest of respiration. It is less active than adrenaline
but analogous in its action,9 resembling ephedrine rather than adrenaline.
Barger and Dale 10 found that the methiodide had a marked nicotine-
634
ALKALOIDAL
AMINES
(7) R O S E N M U N D , Ber.,
WINCKEL,
ibid., 1912, 45, 1004; E H R L I C H and PISTSCHIMUKA, ibid., 2 4 2 8 ; SPATH and SOBEL,
265, 3 8 9 ; VON B R A U N et at., Ber., 1912, 45, 2 5 0 4 ; 1914, 47, 4 9 2 ; 1924, 57, 913.
(8) Compt. rend., 1906, 142, 110, 237, 350. (9) RIETSCHEL, Arch. exp. Path. Pharm.,
1937, 186, 387 ; Klin. Woch., 1937, 16, 714. (10) BARGER a n d D A L E , J. Physiol.,
1910, 41, 19. (11) Compt. rend., 1939, 209, 67 ; see also BROOM and W A Y N E , J. Pharm.
Exp. Ther., 1946, 86, 83. (12) Biochem. J., 1926, 20, 719. (13) J. Physiol., 1938,
92, 422 ; cf. ibid., 1937, 90, 310.
EPHEDRA
ALKALOIDS
635
636
ALKALOIDAL
AMINES
EPHEDRINE
637
and the platinichloride, m.p. 186 (dec), form yellow needles. The
nitrosoamine has m.p. 92, and the dibenzoyl derivative m.p. 134.
On boiling with 25 per cent, hydrochloric acid ephedrine is partially
converted into ^-ephedrine. This change is reversible, an equilibrium
mixture of the two bases being formed, though according to Mitchell 30
the commercially desirable conversion of ^r-ephedrine into Z-ephedrine is
effected with more difficulty than the reverse process. Mitchell also
states that when ephedrine is heated with acetic anhydride at 70
for ten minutes it is converted into O-acetylephedrine, C 12 H 17 0 2 N. 2H 2 0,
m.p. 52 or 87 (dry), [x]f + 5 (EtOH) or + 7 (dry, EtOH), from
which neither a well-defined hydrochloride nor hydrobromide could
be obtained. Welsh,30(a) on the contrary, regards this substance as
N-acetyl-Z-ephedrine and finds that it forms with hydrochloric acid
an adduct, C 12 H 17 0 2 N . HCl, m.p. 106-7 (variable with rate of heating),
[a]f( + 5-6 (EtOH, 50 per cent.), which is acid in solution and in
which the acid can be titrated directly and quantitatively. N-acetyl(ZZ-ephedrine, similarly prepared, has m.p. 77-78-5 and yields a hydrochloride, which melts slowly from 100 to about 180. The latter,
on standing in acetone solution containing hydrochloric acid, is converted into 0-acetyl-(Z-ephedrine hydrochloride, m.p. 201-201-5 (dec),
of which a 2 per cent, solution has pH 5-0. On treatment with alkali in
excess it regenerates the N-acetyl derivative. The O-acetyl derivative
can also be obtained by heating N-acetyl-(ZZ-ephedrine hydrochloride for
70 minutes at 110 or by refluxing dZ-ephedrine hydrochloride with a mixture of acetic anhydride and acetyl chloride. It has not been possible to
prepare O-acetyl-Z-ephedrine hydrochloride by any of these methods,
owing apparently to the difficulty of inducing it to crystallise. When
N-acetyl-Z-ephedrine is heated at 110 it yields about 52 per cent, of
O-acetyl-tZ-i/i-ephedrine hydrochloride (see </<-ephedrine, below). The
mixed bases obtained by alkaline hydrolysis of the crude product of this
re-arrangement had [a]f, + 29-7 (H 2 0) as hydrochlorides, corresponding
to about 66 per cent, of i/i-ephedrine hydrochloride and 34 per cent, of
Z-ephedrine hydrochloride, calculated from the specific rotations of these
two salts. Hydrolysis of N-acetyl-Z-ephedrine by refluxing with dilute
hydrochloric acid produces d-i/r-ephedrine and Z-ephedrine hydrochlorides
in the proportion 62 to 38 : the inversion is stated to take place during
the shift of the acetyl group from N to O and not by the action of the
acid on Z-ephedrine.
Re-arrangement between amino-ester and hydroxy-amide forms in
derivatives of amino-alcohols are not uncommon and the mechanism of
this interchange in one series has been discussed by Phillips and Baltzly.30(6)
With potassium ferricyanide and sodium hydroxide solution ephedrine
forms benzaldehyde. A solution of the hydrochloride gives with copper
sulphate and sodium hydroxide solutions, a purple coloration extractable
by ether, leaving the aqueous layer blue. A solution of ephedrine base in
chloroform on standing is partially converted into ephedrine hydrochloride.30
638
ALKALOIDAL
AMINES
Much attention has been given to devising tests for (a) the identification
of ephedrine,31 (b) means of distinction between ephedrine and 0-ephedrine 31(o> and (c) the recognition of the dl-foim of ephedrine.31(W Ephedrine,
according to Kirkpatrick, 31 ^ is polarographically inactive.
0-Ephedrine, C10H15ON, crystallises from ether in rhombs, rn.p. 118-9,
[ s ] f -f 51-2 (EtOH), and, unlike ephedrine, is sparingly soluble in
water. The hydrochloride, B . HCl, crystallises in colourless, slender
needles, m.p. 181-2, [a]| + 62-05 (H 2 0), and, unlike the ephedrine salt,
is soluble in chloroform. The sulphate forms prisms, [<x]D + 52-5; the
oxalate, m.p. 218 (dec), unlike that of ephedrine, is readily soluble in
water; the aurichloride has m.p. 126-5-127-5. Nitroso-i/r-ephedrine has
m.p. 86, and dibenzoyl-^-ephedrine melts at 119-120. By Mitchell's 30
process <Z-i//-ephedrine yields an acetyl derivative, m.p. 103-5-104, [a]*0"
-f 110-4 (EtOH, 50 per cent.), which Welsh 30<a> has shown to be the Nacetyl compound (cf. ephedrine above). The hydrochloride has m.p.
about 180 with some sintering at 175 (m.p. variable with rate of heating)
and [oc]D + 93-3 (EtOH, 50 per cent.). On heating at 110 the N-acetyl
hydrochloride is converted into O-aceytl-d-^-ephedrine hydrochloride,
m.p. 179-5-181 (variable with rate of heating) and [oc]D + 98-6 (H 2 0).
In contrast to the effect on N-acetyl-Z-ephedrine (see above) of acid hydrolysis, the N- and O-acetyl-i/z-cphedrines produce only the original aminoalcohol, d-(^-ephedrine, on boiling with dilute hydrochloric acid. Identification tests for i/r-ephedrine and means of distinction from ephedrine
have been devised by various authors. 31(a)
Z-norEphedrine, C9H13ON, was isolated by Kanao l 5 from Ma-Huang
and by Wolfes 19 from European Ephedra. It forms a crystalline mass,
m.p. 51, b.p. 167-8/22 mm., and yields a hydrochloride, m.p. 173
(corr.), [a]| 33-14 (H 2 0), hydrogen Z-tartrate, m.p. 160 (approx.),
with some sintering at 130, [a]3,3" 34-64 ( H 2 0 ) ; platinichloride,
m.p. 221 (dec.); aurichloride, m.p. 188, ^-nitrobenzoyl derivative,
m.p. 175-6. The base synthesised by Nagai and Kanao 3 2 h a d [at.]'
- 14-56 (EtOH).
nor-d-^-Ephedrine, C9H13ON, was first isolated by Smith 1 7 from
Ma-Huang, and later by Wolfes 13 from Catha edulis, and was synthesised
by Nagai and Kanao. 32 It crystallises in plates, m.p. 77-8 (corr.), has
Mfiei +37-9 (MeOH), yields a sulphate, B 2 . H 2 S0 4 , hexagonal plates,
m.p. 295 (corr., dec), [a]f4^ + 48-7 (H 2 0), hydrochloride, prisms,
m.p. 178-9 (corr.), [a]*4" +42-1 (H 2 0), [a]J + 53-4 (H 2 0), oxalate,
needles, m.p. 235, and hydrogen tartrate, m.p. 149-151 (dry, corr.),
M2J* + 49-5 (H 2 0). The dibenzoyl derivative has m.p. 156-7 (corr.),
MMSI + 32-8 (MeOH), and on partial hydrolysis yields JV-benzoyl-nor-d-^ephedrine, m.p. 132 (corr.), [a]f + 67-2 (MeOH), which, in contact
with hydrogen chloride in acetone, is converted into O-benzoyl-nor-d-0ephedrine hydrochloride, needles, m.p. 244-5 (corr.), [ a ] ^ 87*6
(H 2 0), but which regenerates the ^-benzoyl derivative on recovery of
the base with sodium hydroxide solution.. Similar migrations of the acyl
group in this type of alkaloid have been recorded by Nagai and Kanao.3*
EPHEDRA
ALKALOIDS
639
640
ALKALOIDAL
AMINES
EPHEDRA
ALKALOIDS
641
(o)CH,
(I) C 6 H 5
(III) 66SS
(-)-gphedrlne
(l-Peoxrephedrln*
HO-C-B
(II) 0 6 H 5
C.H=
(IV)
C00H
(V)
()-V-Bphedrlne
642
ALKALOIDAL
AMINES
centre of asymmetry by formulae (I) and (II) for ephedrine and 0-ephedrine,
Leithe referring Doth to l-( )-a-phenylethylamine M (IV) and Freudenberg
and Nikolai correlating both with the natural amino-acid Z-(+)-alanine
(V).84 The crystal structures of the double tartrates of ^-cocaine with
ephedrine and N-methylephedrine have been investigated by Briickl,54
and of the hydrohalide salts of d-, I- and dl-forms of ephedrine, ^r-ephedrine
and N-methylephedrine by Gossner and Neff,64 with special reference to
the crystallographic relationships of d-, I- and dZ-forms.
Pharmacological Action. When ephedrine first became available in
1887 it was of interest mainly as a mydriatic and its later widespread use
dates from 1924, when Chen and Schmidt 65 recorded its similarity to
adrenaline in pharmacological action. In 1910 Barger and Dale 66 introduced the term sympathomimetic amines to describe substances exhibiting
this type of action, which includes the production of a rise in arterial blood
pressure, dilatation of the pupil, contraction of the plain muscle of the
orbit, a flow of saliva and tears not readily abolished by atropine, inhibition
of the tone and rhythm of the muscular walls of the mammalian intestine
and of the cat's urinary bladder. At the same time these authors prepared
and examined pharmacologically a series of aliphatic and cyclic amines,
the latter chiefly derivatives of phenylethylamine, and from the results
drew certain conclusions regarding the kind of molecular structure associated with sympathomimetic action. Since then there has been an
almost continuous output of papers dealing with the synthesis and pharmacological action of possible sympathomimetic chemicals. One result of
this activity has been to extend the range of therapeutic application of
drugs of this type as Gold 57 has pointed out in a recent review of their
clinical uses. Adrenaline is probably still the best all-round drug of this
type when action of short duration is required, but ephedrine and a number
of the synthetic drugs are especially useful in particular directions and
for these purposes can replace adrenaline. The action of ephedrine, unlike
that of adrenaline, is not potentiated by cocaine 68 nor reversed by sympatholytic drugs such as ergotoxine.59 The pressor and vaso-constrictor
activity is slower and less than that of adrenaline, but is more persistent
and, being more stable to metabolic conditions, ephedrine can be given
by mouth, whereas adrenaline has to be used by injection. It stimulates
the respiratory centre, increasing the depth of respiration ; reinforces
heart action and dilates the bronchi, more especially when they are in
spasm, hence its use in bronchial asthma. It contracts the uterus and
dilates the pupil. Large doses may cause hyperglycemia. Ephedrine also
has some analeptic action, 60 due to its central nervous stimulation, which
is the basis for its use in the treatment of depression by drugs and for the
relief of narcolepsy, though for this purpose its derivatives, deoxyephedrine
(methedrine) 61 and dZ-deoxynorephedrine (amphetamine);
C6H5 . CH 2 . CHMe . NH 2
seem to have advantages and the latter M has received particular attention
in this respect.
EPHEDRA ALKALOIDS
643
644
ALKALOIDAL
AMINES
tant members of the group. In the same symposium Beyer and Morrison
describe the systems which, in the course of animal metabolism, may play
a part in the deamination of amines resulting in their conversion into
inactive substances, e.g., the change of phenylethylamine into phenylacetaldehyde by the action of amine oxidase (tyraminase). An extensive
series of amines has been subjected in vitro to the action of such systems
under appropriate conditions and the rates of deamination found for the
amines show good correlation with t h e pressor activity, duration of action,
efficacy when administered orally, and proportion excreted unchanged in
in vivo experiments. The structural features in derivatives of phenylethylamine, which seem to promote resistance to deamination by such
systems are stated and discussed. The results of a recent investigation
of ten amines in similar fashion by Snyder, Goetze and Oberst have confirmed Beyer's * observations. 6 9 Randall and Hitchings, 7 0 using the
phenoloxidase system, tyrosinase, on a series of phenylethylamine derivatives, including secondary, tertiary and quaternary compounds, the 2-, 3and 4-monohydroxyphenylethylamines, and the 2 : 3- and 3 : 4-dihydroxyphenylethylamines, found t h a t where oxidation did occur, the results
indicated t h a t susceptibility to a t t a c k b y tyrosinase and the ability to
act as pressor agents appeared to depend primarily on different molecular
configurations.
Useful comparisons, over a range of pharmacological factors, of various
well-known, sympathomimetic amines have been made by Gunn, Tainter
and other workers, 7 1 which serve to indicate lines for the development of
special activity. Most of the drugs of this group produced recently are
still of the phenylalkylamine type, b u t divergence in structure is in progress, for example, in derivatives of pyridylalkylamines, 7 2 tetrahydroj'soquinolines, 73 naphthylalkamines, 7 1 indanamines, 7 5 indolylethylamines, 7 6
furfurylalkylamines, 7 7 iminazoles, of which 2-naphthyl-l'-methyliminazoline is an interesting item, 7 8 a-thienylalkylamines 77 and open-chain
amines, 7 9 such as 2-methylaminoheptane and 2-aminoheptane, and
various amidines. 8 0
Much attention has been given to development of drugs with improved
bronchodilator action. Diverging from the phenylalkylamine type there
is emerging a group of " anti-histamine " drugs, so-called because they
are intended to counteract the allergic and other effects believed t o be
due to the liberation of histamine, and are tested in the laboratory against
the effects of histamine administered b y " atomisation " or by injection.
A summary of the French work on this subject has been published b y
Bovet and Walthert, 81 from which it appears that two effective drugs are
N-benzyl-N-dimethylaminoethylaniline and N-p-methoxy benzyl-N-dimethylaminoethyl-2-aminopyridine; of the latter 0-1 mgm. per kilo of body
weight is stated to protect guinea-pigs against the effects of histamine
injected intravenously. Much work has also been done in the United
States on this subject, and among the drugs developed are alkamine
benzhydryl ethers of the type C 4 H 8 . CH(OR). C 6 H 5 in which R may be,
for example, dimethylaminoethyl or /J-piperidinoethyl. 82
Alkyloxy-
EPHEDRA
ALKALOIDS
645
Ind.
J.
Med.
Res.,
1928,
16, 889 ;
1931,
19, 177;
cf. K R I S H N A and
GHOSE,
Arch.
Pharm., 1930, 268, 6 3 6 ; Indian For. Rec, 1931, 16, Part I I . , 1 ; J. Soc. Chem. Ind.,
1929, 48, 67T ; R E A D and F E N G , J. Amer. Pharm. Assoc, 1928, 17, 1189 ; QAZILBASH,
Pharm. J., 1947, 158, 9 ; ANON., Chem. and Drugg., 1939, 130, 70 ; ARINO, Farmacog.
Madrid, 1943, 2, 101. (5) NIELSEN, MCCAUSLAND and SPRUTH, J. Amer.
Pharm.
Assoc, 1927, 16, 2 8 8 ; 1928, 17, 4 2 7 ; TERRY, ibid., 1927, 16, 3 9 7 ; BEASLEY and
HARRIS, ibid., 1942, 31, 171 ; R E A D and FENG, Proc. Soc. Exper. Biol. Med., 1927,
24, 819 ; cf. GROFF and CLARK, Univ. Calif. Publ. Bot., 1928, 14, 247, and CHAVEZ, Bol.
Soc. Quim. Peru, 1937, 3, 198 (Chem. Abstr., 1938, 32, 6326). (5a) L E BLANC and
H U M E , S. Dakota Agr. Exp. Stat. Ann. Rept., 1938, 4 0 ; H I N E R , ibid., 1940, 16 (Chem.
Abstr., 1941, 35, 1181 ; 1942, 36, 5320); CHRISTENSEN and H I N E R , J. Amer. Pharm.
Assoc, 1939, 28, 199; SIEVERS, J. Amer. Pharm. Assoc, 1938, 27, 1221 (cf. PERRONET
and CHATIN, J. Pharm. Chim., 1942, [ix], 2,19, and BLACK and KELLY, Amer. J. Pharm.,
1927, 99, 748). (6) Reports Council Sci. and Ind. Aust., 1941-2, 1942-3, p. 11. (7)
MASSAGETOV, FarmatiFarmakol,
1938, p . 17 (Chem. Abstr., 1940,34, 6765. (8) ALBERTI,
Boll. Chim. Farm., 1939, 78, 477 ; MULAS and SALIS, Arch. 1st., Biochim. Ital., 1939,
11, 315 ; CABBONI, Ricerca Sci., 1940, 11, 7 5 4 ; Ann. Chim. Appl., 1941, 31, 278, 281,
4 5 7 ; L A FLORESTA, Arch. Farm, sperim., 1939, 68, 6 6 ; 1940, 69, 4 1 ; Boll. Soc. ital.
Biol, sperim., 1940, 15, 501, 503 ; SIMON, Chem. Abstr., 1943, 37, 4532. (9) GHOSE
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646
157,
ALKAL01DAL
524;
MARSHALL, Pharm.
J.,
AMINES
(11) G U I X A N D a n d V I B D E N ,
J.
Chem. Soc., 1931, 2148. (12) GHOSH a n d D U T T , J. Jnd. Chem. Soc., 1930, 7, 825.
(13) Arch. Pharm., 1930, 268, 87. (14) Jnd. J. Med. Res., 1935, 22, 785 ; CHOPRA
and D E , Jnd. Med. Gaz., 1932, 67, 128. (15) J. Pharm. Soc. Japan, 1892, No. 120,
109 ; No. 121, 181 ; No. 127, 832 ; 1928, 48, 101 ; Annalen, 1929, 470, 157 ; KANAO,
Ber., 1930, 63, 95. (16) Merck's Jahresb., 1888, 1 ; 1893, 13. (17) J. Chem. Soc,
1927, 2056 ; 1928, 51 ; 1929, 2755 ; cf. NAGAI a n d KANAO, J. Pharm. Soc. Japan,
1928, 48 101. (18) CHEN, STUART and CHEN, J. Amer. Pharm. Assoc., 1931, 20, 339 ;
CHOU and M E I , Chin. J. Physiol., 1934, 8, 161. (19) Arch. Pharm., 1930, 268, 3 2 7 ;
SPEHR, Pharm. Zeit. Russ., 1892, 31, 65. (20) For other methods and comparisons of
methods, see WILLIAMS, J. Amer. Pharm. Assoc, 1928, 17, 4 3 0 ; H s u , ibid., 1930, 19,
817 ; H A Y D E N and J O R D A N , ibid., 1933, 22, 6 1 6 ;
Off.
Agric. Chem., 1929, 12, 2 9 0 ; P E Y E R and GSTIRNER, Pharm. Zeit., 1931, 76, 1440;
RYMILL and MACDONALD, Quart. J. Pharm., 1937,10, 463. (21) J. Pharm. Soc. China,
1943, 1, 27 (Brit. Abstr., 1944, B iii, 237), cf. MONNET and DURAND, J. Pharm. Chim.,
1938, [viii], 28, 145. (22) Pharm. J., 1944, 153, 178. (23) Chin. J. Physiol, 1927,
1, 397 ; see also CHEN, J. Amer. Pharm. Assoc, 1929, 18, 110. (24) Cf. JACKEROTT,
Dansk. Tids. Farm., 1939, 13, 53 ; 1942, 16, 134. (25) MORAW, J. Amer. Pharm.
Assoc, 1928, 17, 431 ; Amer. Pharm. Assoc. Lab. Bull. Natl. Form Commit., U.S.A.,
1939, 7, 3 3 7 ; ROSEN, ibid., 1940, 8, 353 ; GRANT, J. Assoc. Off. Agric. Chem., 1940,
23, 790 ; W E L S H , ibid., 1947, 36, 467 ; HILTY, J. Amer. Pharm. Assoc, 1944, 33, 28 ;
W E L S H , ibid., p. 96 ; 1947, 36, 373 ; SCHOEN, ibid., p . 116. (26) SANCHEZ, J. Pharm.
Chim., 1935, [viii], 22, 489 ; cf. FOURMENT and ROQUES, Bull. Sci. Pharmacol., 1937,
44, 372. (27) R E A D and F E N G , 3 (1927) ; PITTENGER, J. Amer. Pharm. Assoc, 1928,
17, 634; GITHENS, ibid., 1933, 22, 391. (28) CHEN and K A O , ibid., 1926, 15, 6 2 5 ;
E M D E , Arch. Pharm., 1930, 268, 83 ; R E A D , Trans. Far-East. Assoc. Trap. Med., 1927,
2, 537. (29) MOORE and TABERN, J. Amer. Pharm. Assoc, 1935, 24, 211 ; cf. J. Amer.
Med. Assoc, 1935, 104, 1707 ; R E A D , Chin. Med. J., 1937, 51, 69 ; cf. E M D E , Helv.
Chim. Acta, 1929, 12, 370 ; and JAROWSKI and HARTUNG, J. Org. Chem., 1943, 8, 564.
(30) J. Chem. Soc, 1940, 1153. (30a) W E L S H , J. Amer. Chem. Soc, 1947, 69, 128.
For early papers on acetylation of ephedrines see NAGAI, J. Pharm. Soc Jap., 1892,
No. 127, p . 832 ; SCHMIDT and CALLIESS, Arch. Pharm.,
SCHMIDT,
ibid., 1914, 252, 111. (306) J. Amer. Chem. Soc, 1947, 69, 200. (31) TSIANG and
BROWN, J. Amer. Pharm. Assoc, 1927, 16, 2 9 4 ; SIVADJIAN, J. Pharm. Chim., 1930,
[viii], 12, 266 ; 1931 [viii], 14, 61 ; cf. HARTUNG, CROSSLEY and MUNCH, ibid.,
193],
[viii], 13, 474 ; PESEZ, ibid., 1938 [viii], 27, 120 ; SANCHEZ 2 6 ; (a) CHEN, J. Amer.
Pharm. Assoc, 1929, 18, 110 ; F E N G and R E A D , ibid., 1933, 22, 1241 ; FOURMENT and
ROQUES
ae
; (6) CHEN, loc cit. ; ROSENTHALER, Zeit. Anal. Chem., 1931, 86, 61 ; P A R I S ,
Pharm. Weekbl., 1936, 73, 1526 ; (c) Quart. J. Pharm., 1946, 19, 534. (32) Annalen,
1929, 470,157. (33) J. Pharm. Soc. Japan, 1927, No. 540, 20 ; 1928, 48,145 ; Annalen,
1929, 470, 157. (34) J. Chem. Soc, 1929, 2754. (35) Arch. Pharm., 1906, 244, 246.
(36) Ber., 1889, 22, 1823. (37) Arch. Pharm., 1902, 240, 481. (38) SCHMIDT, ibid.,
1906, 244, 239, 241 ; E M D E , ibid., 1907, 245, 662 ; 1909, 247, 54 ; cf. GADAMER, ibid.,
1908, 246, 566. (39) FLAECHER, ibid., 1904, 242, 380 ; SCHMIDT, ibid., 1906, 244,
239 ; 1908, 246, 210 ; (with BUMMING), 1909, 247, 141 ; GADAMER, ibid., 1908, 246,
566; CAixnsss, Apothl Zeit., 1910, 25, 677. (40) Ber., 1911, 44, 8 2 4 ; cf. SCHMIDT,
Arch. Pharm., 1911, 249, 305 ; 1914, 252, 89 ; 1915, 253, 52 ; EBEBHABD, ibid., 1915,
253, 62 ; OGATA, J. Pharm. Soc. Japan, 1919, No. 451, 7 5 1 ; also DAVIES, J. Chem. Soc,
1932,1580; M C K E N Z I E , L U I S and MITCHELL, Ber., 1932,65,798. (41) See, for example,
SCHMIDT, Arch. Pharm., 1908, 247, 141 ; (with FLAECHER), ibid., 1905, 243, 73 ; (with
C A U J E S S ) , Apoth. Zeit., 1911, 26, 368. FOURNEAC, J. Pharm. Chim., 1904, [vi], 20,
481 ; 1907, [vi], 25, 593. For a critical survey of this early work see FOUBNEAU (with
KANAO), Bull. Soc. Chim., 1924, [iv], 35, 614 ; (with BENOIT), ibid., 1945, [v], 12, 987.
(42) Arch. Pharm., 1915, 253, 6 2 ; 1917, 255, 1 4 0 ; 1920, 258, 97. (43) Anal. Fis.
Quim., 1922, 20, 3 9 4 ; cf. FOUBNEAU, J. Pharm. Chim., 1904, [vi], 20, 4 8 1 ; 1907, 25,
593. (44) Monats., 1920, 41, 319 ; Ber., 1925, 58,197. (45) FOUBNEAU (with KANAO),
Bull. Soe. Chim., 1924, [iv], 35,614, critical risumi with bibliography; (withNicouTCH),
ibid., 1928, [iv], 43, 1232 ; (with TORRES), Anal. Fis. Quint., 1925, 23, 4 5 0 ; S P A T S
EPHEDRA ALKALOIDS
647
and KOLLER, Bar., 1925, 58, 1268 ; BOSSEBT and B R O D E , J. Amer. Chem. Soc., 1934,
56, 1 6 5 ; MANSKE and JOHNSON, J. Amer. Pharm. Assoc., 1928, 17, 1199 ; J. Amer.
Chem. Soc., 1929, 51, 580, 1906, 2 2 6 9 ; KANAO, J. Pharm. Soc. Japan, 1927, No. 540,
1 7 ; N A G A I a n d K A N A O , Annalen, 1929, 470, 157 ; cf. SPATH a n d BRETSCHNEIDER,
Ber., 1928, 6 1 , 3 2 7 ; K N O L L , H I L D E B R A N D T a n d K L A V E H N , B . P . 3 6 0 , 3 3 4 ; cf. U.S.P.
1,956,950 ; VON FODOR, Ber., 1943, 76, 126 (norephedrine); COUTURIER, Compt. rend.,
1938, 207, 3 4 5 ; STEVENS, J. Amer. Chem. Soc., 1938, 60, 3089 ; SAH, Ber., 1938, 71.
2300. (46) SKITA (with K E I L ) , Ber., 1929, 62, 1142 ; (with BAESLER), ibid., 1933, 66,
858 ; (with MEINER), ibid., p p . 974, 1400. (47) NEUBER&and HIRSCH, Biochem. Zeit.,
1921, 115, 282. (48) E M D E , Helv. Chim. Acta, 1929, 12, 365, 377, 384, 399 ; (with
SPANHAUSER), ibid., 1930, 13, 3 ; Arch. Pharm., 1930, 268, 90. (49) SCHMIDT, Arch.
Pharm., 1914, 252, 120 ; 1915, 253, 52. (50) (With SCHOEPFEL and BRAUN), J. Amer.
Chem. Soc, 1932, 54, 234 ; (with NIKOLAI), Annalen, 1934, 510, 223. (51) Ber., 1932,
65, 660. (52) Ibid., 1931, 64, 2827. (53) FREUDENBERG and R H I N O , ibid., 1924, 57,
1547. (54) BRUCKL, Zeit. Kryst., 1932, 81, 219 ; GOSSNER and N E F F , ibid., 1933, 85,
370 ; 86, 32 ; 1934, 89, 417 ; 1936, 93, 488 ; Neues. Jahrb. Min., 1935, 69, 347.
(55) J. Pharm. Exp. Ther., 1924, 24, 339. (56) J. Physiol, 1910, 41, 19. (57) Ind.
Eng. Chem., 1945, 37, N o . 2. Symposium on sympathomimetic agents : GOLD ;
clinical uses ; SCHOLZ, imidazole derivatives ; HARTUNG, j3-phenylethylamine derivatives ; TAINTER, pharmacological methods a n d objectives ; B E Y E R a n d MORRISON,
deamination of sympathomimetic amines ;
(61) HAUSCHILD,
Arch. exp. Path. Pharm., 1938, 190, 177 ; 1939, 191, 465 ; IVY and GOETZL, War Medicine (Chicago), 1943, 3, 60 ; use, as a pressor substance in surgery, see D O D D and
PRESCOTT, Brit. Med. J., 1943, i, 345 ; B U R N , Brit. Med. Bull., 1946, 4, 95 ; measurement of analeptic activity, see GOODWIN and MARSHALL, J. Pharm. exp. Ther., 1945,
84, 12 ; review of literature, HALEY, J. Amer. Pharm. Assoc, 1947, 36, 161, 301.
(62) GOLD " ; D A V I D O F F a n d R E I F E N S T E I N , Am. J. Psychiatry,
GUTTMANN, T R E V A N , R I C H T E R , R U D O L F , STROM-OLSEN, Proc
32, 391 ; New and Non-Official Remedies, U.S.A., 1945, 278 ; W A R R E N and W E R N E R ,
J. Pharm. exp. Ther., 1945, 85, 119 ; NEWMAN, ibid., 1947, 89, 106. (63) R E A D el ah,
Chin. J. Physiol, 1928, 2, 97, 435 ; 1929, 3, 81, 95 ; CHOPRA et al., Ind. J. Med. Res.,
1931, 19, 177 ; CHEN, Arch. Int. Med., 1927, 39, 404 ; (with W u a n d H E N R I K S E N ) ,
J. Pharm. exp. Ther., 1929, 36, 363 ; (with SWANSON, SCOTT and L E E ) , ibid., 1943,
79, 329 ; (with SWANSON and STELDT), ibid., 1945, 85, 70 ; EMILSSON, Acta Physiol.
Scand., 1942,3,275 ; BADGER, Nature, 1947,159,194; STEDMAN, ibid., p. 195. (64) Arch,
exp. Path. Pharm., 1931, 160,127 ; Med. u. Chem., 1936, 3, 383 ; cf. K I E S E , GARAN and
KRAUTWOLD, Klin. Woch.,1938,17, 967. (65) P A K and R E A D , Quart. J. Pharm., 1936,9,
235, 256; for action of methiodide see L E E , VAN ARENDONK and CHEN, J. Pharm. exp.
Ther., 1936, 56, 466.
1942, 75, 289 ; H A R T U N G . 6 ' (67) Anesthesiology, 1940,1, 6 9 ; J. Pharm. exp. Ther., 1940,
70, 283 ; (with BARBOUR), ibid., 1942, 76, 295 ; W E L S H and KEENAN, J. Amer. Pharm.
Assoc, 1941, 30, 1 2 3 ; see also EIDEBENZ, Arch. Pharm., 1942, 280, 49. (68) Brit.
Med. J., 1938, i, 713 ; (with KWIATOWSKI), J. Physiol,1938,
94, 87 ; 1939, 96, 385 ;
(with K . and J A N G , ibid., p . 104, cf. GRAHAM and GURD, J. Pharm. exp. Ther., 1941,
72, 48. (69) Ibid., 1946, 86, 145. (70) Ibid., 1944, 80, 7 7 ; cf. DULIERE and R A P E R ,
Biochem. J., 1930, 24, 239 ; ALLES, BLOHM and SAUNDERS, J . Biol. Chem., 1942, 144,
757. (71) HAUSCHILD, Arch. exp. Path. Pharm., 1938, 190, 1 7 7 ; 1939, 191, 4 6 5 ;
Klin. Woch., 1941, 20, 8 6 8 ; CRISMON and TAINTER, J. Pharm. exp. Ther., 1938, 64,
190; 1939, 66, 1 4 6 ; TAINTER, J. Amer. Med. Assoc, 1941, 116, 2769; GUNN, Brit.
Med. J~, 1989, i i , 155, 214 ; W A R R E N and W E R N E B , J. Pharm. exp. Ther., 1946, 86,
280, 2 8 4 ; R E I C H E B T a n d SCHMIEDER, Arch. exp. Path. Pharm., 1941, 198, 121.
648
ALKALOIDAL
AMINES
HUNT
and FOSBINDER, J. Pharm. exp. Ther., 1942, 75, 299 ; L E E , DINWTDDIE and CHEN,
ibid., 1947, 89, 83 ; NIEMANN and H A Y S , J. Amer. Chem. Soc., 1942, 64, 2288 ; BURRUS
and POWELL, ibid., 1945, 67, 1468 ; R I E G E L a n d WITTCOFF, ibid., 1946., 68, 1913.
(73) BUCK, ibid., 1934, 56, 1769, 1771 ; (with I D E ) , ibid., 1938, 60, 2101 ; 1940, 62,
425 ; H J O R T (with de B E E R and FASSETT), J. Pharm. exp. Ther., 1938, 62, 165 ; 63,
432 ; 1940, 68, 69, 73 ; FASSETT and H J O R T , ibid., 1938, 63, 253. (74) RAJAGOPALAN
and VENKARTACHALAM, Curr. Sci., 1944, 13, 232. (75) L E V I N , GRAHAM and K O L L O F F ,
./. Org. Chem., 1944, 9, 380. (76) RAYMOND-HAMET, C. R. Soc. Biol., 1941, 135, 1320.
(77) ALLES and F E I G E N , J. Pharm. exp. Ther., 194,1, 72, 265. (78) SCHOLZ " ; EMERSON
J. Pharm. exp. Ther., 1944, 82, 4 2 ; CRAVER, CHASE a n d YONKMANN, ibid., p . 2 7 5 ;
YONKMANN, R E N N I C K and SCHWERMA, ibid.,
1945, 84, 1 9 7 ;
H I L D , Schtveiz.
Med.
Woch., 1941, 71, 557. (79) AHLQUIST, J. Amer. Pharm. Assoc., 1943, 32, 151 ; J.
Pharm. exp. Ther., 1944, 81, 235 ; 1945, 85, 283 ; SWANSON and CHEN, ibid., 1946,
88, 10 ; FELLOWS, ibid., 1947, 90, 851 ; GAKENHEIMER and HARTUNG, J. Org. Chem.,
1944, 9, 85 ; ROHRMANN and SHONLE, J. Amer. Chem. Soc., 1944, 66, 1516 ; D U N K E R
and HARTUNG, J . Amer. Pharm. Assoc., 1941, 30, 619 (Review). (80) FASTIER, Nature,
1944,154, 429 ; GOODWIN and MARSHALL, J. Pharm. exp. Ther., 1945, 84,16. (81) Ann.
Pharm. Franc,
1944, 2, 43 ; BOVET, D E LESTRANGE and FOURNEAU, C. R. Soc.
Biol., 1939, 130, 1192. (82) LOEW (with KAISER and MOORE), J. Pharm. exp.
Ther., 1945, 83, 1 2 0 ; (with MACMILLAN and KAISER), ibid., 1946, 86, 2 2 9 ; E L L I S ,
Fed. Proc,
1946, 35, 30 ; ELIAS and MCGAVACK, Proc. Soc. exp. Biol. Med., 1946,
61, 133. (83) LOEW, KAISER and ANDERSON, J. Pharm. exp. Ther., 1946, 86, 7. (84)
LOEW, KAISER and MOORE, ibid., 1946, 86, 1 ; F E I N B E R G , ./. Amer. Med.
Assoc,
1946, 132, 702. (85) LEHMANN (with K N O E F E L ) , ibid., 1944, 80, 335 ; (with YOUNG),
1945, 83, 90 ; BURTNER and Cusic, J. Amer. Chem. Soc, 1943, 65, 262, 1582.
SINAPINE
CHgO .0
HO .C.
C.CH :CH.COOH
CELO.c'
HO.C
CH
649
C.CHlCH.CO.O.CHg.CHg.HIOHKCHjlj
CH
C.OCH
CUlCHj
Sinapic acid
Sinapine
660
ALKALOIDAL
AMINES
651
COLCHICINE
18
CH
C H 0 NV^^ICXHOH V^^NCHI
(I)
SyCH CO
JCO
( E l CH
CH
CH
V^^CI
H00CC,<^ICI
^ l S)im
HOOC-ck^C OCHj
i m ) CH
IJV) CH
652
ALKALOIDAL
AMINES
MeO^-
COLCHICINE
653
654
ALKALOIDAL
AMINES
H,C
MeO
MeO
OMe
OMe
H,C
CH2
' CHNH 2
Me0
MeO
OMe
ixrv)
CH 2 C0 2 H
MeO
NHAc
C02H
MeO
OMe
OMe
+
n OMe
IXVS)
COLCHICINE
665
R = H) and t'sodeaminocolchinol methyl ether is 9 :12 :13 :14-tetramethoxy-3 : 4 : 5 : 6 :-dibenz-.J3:6:7-cj/c/oheptatriene (XII). On this basis
and assuming absence of nuclear change during the first step of the
Hofmann process, colchinol methyl ether must be represented by (XIII).
Windaus's conversion of deaminocolchinol methyl ether into 9-methylphenanthrene has been paralleled by the production of the same hydrocarbon from 3 : 4 : 5 : 6-dibenz/eZohepta-l : 3 : 5-triene. This is the unsubstituted nucleus in formula (XI) proposed for deaminocolchinol methyl
ether, and the synthetic product resembles the latter in its behaviour
towards oxidising and reducing agents and in other respects (Cook,
Dickson and Loudon). 27
Support for this formulation has also been provided by Tarbell, Frank
and Fanta, 28 who found that deaminoiodocolchinol methyl ether
( X I ; R = I), C 19 H 19 0 4 I, m.p. 175-6, was oxidised by permanganate in
acetone, to two products (a) a dark red substance, C 18 H 15 0 6 I, m.p. 213,
probably 6-iodo-2 : 3 : 4 : 7-tetramethoxyphenanthraquinone (IX ; R = I)
and (b) a dibasic acid, C 19 H 19 0 8 I, m.p. 264-5 (XIV ; R = I), which was
hydrogenated to C19H20O8, m.p. 243-5. The iodo-acid dimethyl ester
(XIV ; R = I and 2C02H> 2C02Me) when boiled with sodium methoxide
in benzene gave a phenanthrol, m.p. 194-195-5, with OMe at positions
2 : 3 : 4 : 7 , C02Me at 10, OH at 9 and I at 6.
Cook 27 has suggested that colchicine itself may contain the 7-membered
ring B and Dewar 29 has proposed for the alkaloid formula (XV) with
(XVa) as a resonance form, mainly on the ground that the third ring (C)
in colchicine resembles in some of its reactions, stipitatic acid and presents
similar difficulty in interpretation of experimental results.
Cook 27 has pointed out that Dewar's 7-membered ring C receives
some support from Meyer and Reichstein's observation that colchiceine is
oxidised by periodic acid to a monocarboxylic acid, C 21 H 23 0 8 N, m.p. 238-9
(dec.), [a]pa 410-4 (MeOH, 60 per cent.), giving a crystalline silver
salt, m.p. 205-8 (dec), and a methyl ester, m.p. 98-100, [a]J,6 341
(acetone). Dewar's formula has also been invoked by Santavy 2 9 to
explain the formation of colchic acid, C 21 H 23 0 6 N, m.p. 262-6, when
colchicine, or Sorkin's isocolchicine (see below), is refluxed with sodium
methoxide in methyl alcohol, colchiceine remaining unchanged under like
treatment. Arnstein, Tarbell, Huang and Scott 2 9 also support this
formulation to explain the formation of an aldehydic substance in the
oxidation of hexahydrocolchiceine, C81C2906N, m.p. 205-5-6, which they
regard as a glycol (diacetate, m.p. 167).
Colchiceine (Acetyltrimethylcolchicinic acid), C 21 H 23 0 6 N . 0-5H2O, may
be prepared by heating colchicine with dilute sulphuric or hydrochloric
acid. It crystallises in colourless needles, m.p. 172 (dry), [a] D 253
(CHC13), is readily soluble in alcohol or chloroform, sparingly so in water,
and neutral in reaction. Its solutions in alkalis or acids are yellow. The
base gives a dark-green coloration with ferric chloride. According to
Sorkin,30 colchiceine on treatment with diazomethane produces a mixture
of colchicine and isocolchicine. The latter has m.p. 225 and [oc|D 807
666
ALKALOIDAL
AMINES
657
COLCHICINE
12,
227;
PEHROT,
Compt. rend.,
1936,
202,
1088;
KLEIN
1940,
Nos.
9, 10, p . 38.
and
POIAAUF,
V.R.S.S.,
1934, 24,
TUTIN,
J. Chem. Soc, 1915, 107, 835 ; PARTHASARATHY, Curr. Sci., 1941, 10, 446. (4) Monats.,
1888, 9, 870. (5) Ibid., 1883, 4, 162 ; 1886, 7, 557 ; 1888, 9, 1, 865 ; 1913, 34, 1181,
1327, 1339. (6) Ber. ungar. pharm. Ges., 1927, 3, 346. (7) J. pr. Chem., 1928, 118,
29. (8) Yearbook Pharm., 1923, 611 ; (8a) SEIBERT, Deut. Apoth. Zeit., 1943, 58, 7 1 ;
see also GILLET, Ann. pharm.,franc, 11)44, 2, 152. (9) Rev. Farm., 1930, 72, 187 ; see
also KIRKPATRICK, Quart. J. Pharm., 1946,19, 533 (polarographic). (10) Pharm. Zeit.,
1931, 76, 288.
(11) Pharm. J., 1932, 129, 236 ; BOYLAND and MAWSON, Biochem.
(12) Pharm. Acta Helv., 1983, 8, 92. (13) MERCK, Pharm. Zent., 1916,
H A R R I S , J.
Chem. Soc,
1944,
677 ;
MUHLEMANN and
J.,
TOBLER,
439,
(17)
p. 1875. (18) J. Chem. Soc, 1945, 176. (19) SHARP, ibid., 1936, 1234. (19a) Ber.,
1939, 72, 426. (20) Ber., 1938, 71, 245. (21) Compt., rend., 1940, 210, 490. (22) J.
Chem. Soc, 1940, 194. (23) Ibid., 1944, 322. (24) Ibid., 1944, 325. (25) Monats.,
1913, 34, 199. (26) J. Chem. Soc, 1911, 99, 2104 ; K E N N E R , ibid., 1913, 103, 613 ;
cf. TAURINS, J. pr. Chem., 1939,153, 192. (27) Chem. and Ind., 1945, 4 0 3 ; J. Chem.
Soc, 1947, 746. (28) J. Amer. Chem. Soc, 1946, 68, 502. (29) Nature, 1945, 155,
141 ; see also pp. 50, 479, and COOK, p. 479; SANTAVY, C. R. Soc. Biol., 1946, 140
932; Helv. Chim. Acta, 1948, 31, 8 2 1 ; ARNSTEIN et el., J. Amer. Chem. Soc, 1948,
70, 1669. (80) Helv. Chim. Acta, 1946, 29, 2 4 6 ; see also STEINEGGER and LEVAN,
Hereditas, 1947, 33, 385. (31) J. Physiol., 1908, 37, 50. (32) Arch. exp. Path.
Pharm., 1910, 63, 8 5 7 ; 1918, 72, 228 ; Heffter's Handb. exp. Pharm., 1920, 2, 498.
ALKALOIDAL
668
AMINES
(33) L I P P S , Arch. exp. Path. Pharm., 1920, 85, 2 3 5 ; BECK, ibid., 1932, 165, 2 0 8 ;
JACOBSON, Compt. rend. Soc. Biol., 1925, 93, 1178 ; TALBOTT, Bull. New York Acad.
Med., 1942, 18, 318. (34) DUSTIN, Butt. Acad. roy. Med. Belg., 1934, 14, 487 ; Lrrs,
Compt. rend. Soc. Biol, 1934, 115, 1 4 2 1 ; LUDFORD, Arch. exp. Zellforsch, 1936, 18,
411.
(35) Nature,
19J5, 135, 2 6 6 ;
Vet. J.,
1935, 9 1 , 88.
(36) B R U E S a n d COHEN,
Biochem. J., 1936, 30, 1 3 6 3 ; B R U E S , quoted by Cook and Engel, J. Chem. Soc., 1940,
198 ; BOYLAND a n d BOYLAND, Biochem.
PEYRON,
LAFAY and KoBozrEFF, Bull. Assoc, franc. Cancer, 1936, 25, 874 ; PEYRON, LAFAY and
POUMEAU-DELILE, Compt. rend. Acad. Sci., 1937, 205, 378 ; CLEARKIN, J. Path. Bact.,
1937, 44, 469 ; OUGHTERSON, TENNANT a n d HIRSCHFELD, Proc. Soc. exp. Biol.
Med.,
1937, 36, 661 ; Rep. Imp. Cancer Res. Fund, 1945-6, quoted in Nature, 1946, 157, 669 ;
LUDFORD, J. Nat. Cancer Inst., 1946, 6, 89 ; LETTRE et al., Zeit. physiol. Chem., 1944,
281, 58,133,139 ; DUSTIN, Nature, 1947,159, 794 ; LEHMANN, Experientia, 1947, 3, 223.
(37) LETTRE and FERNHOLZ, Zeit. Physiol. Chem., 1943, 278, 175 (Brit. Chem. and
Physiol. Abstr., 1944, Aii, 48 ; Aiii, 9 2 ) ; (with ALBRECHT), Naturwiss., 1941, 29, 390 ;
Chem. Zeit., 1943, 67, 52 ; MEYER and REICHSTEIN, Pharm. Acta Helv., 1944, 19, 127.
(38) Arch. Intern. Mid. exp., 1938, 13, 183. (39) MCPHAIL and WILBUR, J. Pharm.
exp. Ther., 1943, 78, 304 ; BARBER and CALLAN, Proc. Roy. Soc, B . , 1943, 131, 258 ;
BASTENIE and ZYLBERSZAC, Compt. rend. Soc. Biol., 1937, 126, 446, 891 ; ALLEN, SMITH
and GARDNER, Endocrinology, 1937, 21, 412 ; Amer. J. Anat., 1937, 61, 321. (40)
BRADLEY and GOODSPEED, Proc. Nat. Acad. Sci., U.S.A., 1943, 29, 295 ; DUSSBAU,
HITIER a n d FARDY, Compt. rend., 1943, 217, 7 0 4 ; BADENHUIZEN, Nature, 1941, 147,
577. (41) STEPHENS, Trop. Agric., 1940, 17, 23 ; HARLAND, ibid., p . 53. (42) SINNOTT,
BLAKESLEE and FRANKLIN, Genetics, 1941, 26, 168 ; DERMAN, ibid., p . 147 ; (with
BAIN), ibid., p . 147 ; TANG and Loo, Science, 1940, 91, 222 ; NEWCOMER, ibid., 1945,
101, 677; see also " Action and Use of Colchicine in the Production of Polyploid P l a n t s , "
J . L . F Y F E , Imperial Bureau of Plant Breeding and Genetics, Cambridge, 1939.
(43) SHMUK (with GUSSEVA), Compt. rend. Acad. Sci., V.R.S.S., 1939, 22, 411 ; (with
KOSTOV), ibid., 1939, 23, 263. (44) Compt. rend., 1939, 208, 1667 ; cf. GAVAUDAN,
GAVAUDAN a n d D U R A N D , C. R. Soc. Biol.,
Compt. rend., 1939, 208, 593. (45) Lloydia, 1947, 10, 65.
ALKALOID OF AMANITA
MUSCARIA
Muscarine was isolated from fly agaric {Amanita muscaria L.) by
Schmiedeberg and Koppe ] as a deliquescent syrupy base with a characteristic pharmacological action, arresting the frog's heart in diastole and
being antagonised by atropine. Further examination by Harnack, 2
showed that this preparation contained choline, which was eliminated as
far as possible as the aurichloride, C5H14ON . AuCl4, leaving a more soluble
aurichloride, C s H ] 4 0 2 N . AuCl4. To the alkaloidal chloride Harnack and
Schmiedeberg assigned the formula, (CH 3 ) 3 NC1. CH 2 . CH(OH)2, which
is that of a hydrate of the aldehyde corresponding to choline.
Me;jlf (OH) 0H2- CH2-0H -* MeglTfOH) CH2 H
Choline
Betaine aldehyde
MUSCABINE
659
nitric acid on choline and isolated " artificial muscarine " and a choline
nitrous ester, ( C H a ^ C l . CH 2 . CH a . ONO, produced in this reaction,
but the results of Ewins's investigation showed that " artificial
muscarine" (now also called synthetic muscarine, choline-muscarine,
pseudo-muscarine) is choline nitrous ester, and Dale, 7 working with
Ewins's material, found that it had the pharmacological properties attributed to " artificial muscarine." Several other attempts were made 8
by the synthesis of bases having the formula C5H1402NC1, and in other
ways to clear up the question but without success. Finally, King 9
isolated from fly agaric a base with, in higher degree, the pharmacological
action characteristic of Schmiedeberg's preparation. The process used is
complicated and for details the reader is referred to the original paper.
The mixture of choline and muscarine finally obtained is fractionated as
aurichlorides, the more soluble muscarine aurichloride being eventually
obtained by crystallisation from dilute hydrochloric acid containing a
little gold chloride as glistening leaflets with a gold content of 38-2 per
cent, corresponding to a molecular weight of about 210 for the base.
The yield was 0-12 gm. from 25- 5 kg. of fresh fungus. Of the pure muscarine
chloride made from this aurichloride, only ^ J Q mg. was required to stop
the frog's heart in diastole, as against -fa to -^ mg. recorded by Schmiedeberg and Harnack. King's results were extended by Kogl, Duisberg
and Erxleben, 10 who used a different method for the concentration and
isolation of the alkaloid. Muscarine chloride, C8H1802NCI, has [a]|
-f 1-57 (H 2 0) : the aurichloride, C g H 18 0 2 N . AuCl4 forms bright yellow
leaflets, m.p. 113-7, and O-benzoylmuscarine
platinichloride,
C 30 H 44 O 6 N 2 . PtClg, crystallises from dilute hydrochloric acid and has
m.p. 256-7. The same authors found that muscarine is unaffected by
dilute alkali in presence of nitrogen, is not hydrogenated in presence of
platinic oxide at room temperature and is stable in air at pH 9- 8 but not
at pH 4-0. It gives the Angelo-Bimini and Schiff reactions for aldehydes.
The chloride on distillation with silver oxide furnishes trimethylamine, an
unidentified volatile substance, m.p. 70, and d-<x/?-dihydroxy-w-valeric
acid, m.p. 72, [a]| + 18-0 (H 2 0), identified by direct comparison with
the synthetic Z-isomeride.11 The formation of a carboxyl group in this
Hofmann degradation is believed to be due to oxidation of an aldehyde
group by the silver oxide. Muscarine is therefore considered to be either
C 2 H 5 .CHOH.CH(NMe 3 OH).CHO or C 2 H 5 . CH(NMe 3 OH). CHOH. CHO,
the former being preferred on account of its serine-like structure and its
stability to alkalis.
Quaternary salts of the substances represented by these formulae
have been prepared by Kogl, Veldstra and van der Laan u as well as of
the next lower homologues, the substituted butyraldehydes, and the
methyl ethers of both series. Their pharmacological activities were
negligible in comparison with that of muscarine, but as six stereoisomeric
forms may be produced in each synthesis, the inactivity may be due to
stereoisomerism, just as in the case of threonine (a-amino-j8-hydroxybutyric acid) where West and Carter Xl found that only the d{) form is
660
ALKALOIDAL
AMINES
J.
Pharm. exp. Ther., 1914, 6, 147 ; SCELBA, Alti. R. Accad. Lincei, 1922, [v], 31, ii, 518 ;
GUTH, Monats., 1925, 45, 631. (9) J. Chem. Soc, 1922, 121, 1743. (10) Annalen,
1931, 489, 156. (11) Ibid., 1942, 552, 1 ; W E S T and CARTER, J. Biol. Chem., 1937-8,
122, 611 ; J . P. FOURNEAU (with CHANTALOU), Bull. Soc. Chim., 1945, [v], 12, 845 ;
E . FOURNEAU (with BOVET, BOVET and MONTEZIN), Bull. Soc. Chim. biol., 1944, 26,134 ;
1945, 26, 516 ; see also Ann.pharm.franc.,
1945, 3, 114 ; 1946, 4, 166, 172 ; PFEIFFER,
Science, 1948,107,94. (12) Ber., 1884,17,1139. (13) Ibid., 1893,26,464; 1894,27,165;
cf. VOET, Arch. int. Pharmacodyn, 1929, 36, 205. CLAUSE, Diss. Berne, 1884, p . 17 ;
MEYER, Arch. exp. Path. Pharm., 1893, 32, 111. (14) J. Pharm. Exp. Ther., 1929, 37,
193.
(17) Ibid., 1943, 79, 1. (18) W O R K , J. Chem. Soc., 1941, 190. (19) IMHAUSER, Arch,
exp. Path. Pharm., 1929, 145, 120 ; 1931, 162, 5 0 6 ; RAAB, Zeit. physiol. Chem., 1932,
207, 157 ; 1933, 216, 224 ; R E N Z , ibid., 1934, 230, 245 ; B E N E T and MAREK,
Compt.
rend., 1936,202,1219 ; WIELAND (with LYNEN), Annalen, 1937, 533,93 ; (with WITKOP),
1940,
543,
Ziwi), 1941,
543,
1 ; BEAUVILLAIN, BOILOT
SPP.
662
STEROIDAL ALKALOID
GROUP
SOLANIDINE
663
17
664
STEROIDAL
ALKALOID
GROUP
Aoetyl
derivatives
SO.
M.p.
(CHCIJ)
Sotes
M.p.
+16.5) Ex No.5 by
hydrogenation.
+21.9)
Sibydrosolanidinea, C^H^OH
1
Solanldan-3( B)-ol
220
+28.2
196
Solnidan-3( a ) - o l
211-2
+31.9
174-6
alloSolanldan-S( g)-ol
216-7
+27.9
140-1
alloSolanldan-3( a ) - o l
13-4
+34.5
140-1
210-2
+45.6
Solanidan-3-ons,
C , J _0H
A - S o l a n i d e n e - 3 - o n s , C H OH
2
3
7 A - ( o r A l-Solanldene, C27H43B
213-6
+89.0
165
+67.9
8 A -(<" A
145-6
+84.0
161-2
+33.1
140-2
+34.8
9
10
Solanidane,
)-allSolanldan8,Cg 7 H 43 I
c
27^45^
alloSolanldana, 0 2 7 H 45 H
+31.4) Ex No.6 by
hydroganatlon.
+45.2)
Ix So.l by
oxidation.
Ex solanidine
by oxidation.
Sx Bos.l & 2 by
l o s a of water.
Ex Hos.3 & 4 by
l o s s of water.
Ex Ho.7 by
bydrogenation.
Ex Ho.8 by
bydrogenation.
According to Rochelmeyer,20 (1939) in the formation of A4-solaniden3-one (solanidone, A 4 -solatubenone), C27H41ON, the ethylenic linkage of
solanidine moves from C6C6 to C*C6, and in the reduction of this
substance by sodium in alcohol only the carbonyl group is reduced, two
isomerides of solanidine, C 27 H 43 ON being formed, viz. the cis- (m.p. 204,
[a] D + 91-5) and trans- (m.p. 169, [a]D + 116-4) forms of A4-solaniden8-0I (A 4 -solatubenol, Rochelmeyer).
There still remains for consideration the nature of the heterocyclic
portion of the molecule, viz., rings e and / in formulas (I) and (II). In 1942
SOLANIDINE
665
666
STEROIDAL ALKALOID
GROUP
either formula I or II, Prelog and Szpilfogel proposed the new formula (III)
for solanidine, which is supported by the conversion of sarsasapogenin (IV)
to the stereochemieally corresponding dihydrosolanidine, viz. aZZosolanidan3-(j8)-ol, by Uhle and Jacobs.20*0' These authors started with the known
sarsasapogenic acid dioxime (partial formula V) which was hydrogenated
in methyl alcohol-acetic acid solution, with platinic oxide as catalyst, to
the amino-acid (VI), C 27 H 45 0 3 N, m.p. 143, [<x]f?' + 25-0 (EtOH). The
latter on melting forms the lactam (VII), C 27 H 43 0 2 N, m.p. 200-2, [a]f
+ 17-0 (EtOH), and this on hydrogenation produces one of the forms of
dihydrosolanidine (partial formula (VIII); complete formula III with
ethylenic linkage C5C6 hydrogenated), viz., a/Zosolanidan-3(j8)-ol,
m.p. 216-8, [a]ff + 27-3 (CHC18) [cf. item 3, table, p. 664).
Solasonine (solanine-s), C 45 H 73 0 16 N. This alkaloid was first isolated
by Oddo et al.23 from the tubers of Solanum sodomeum and was named
solanine-s to distinguish it from the solanine of potatoes. The name
solasonine was suggested by Rochelmeyer.22 The alkaloid " solancarpine,"
isolated by Saiyed and Kanga, 24 and also by Gupta and Dutt, 24 from S.
ccanthocarpus S. and W., has been shown by Briggs,25 and by Rochelmeyer 22
(1939) to be solasonine. Similarly the alkaloid " purapurine," prepared
by Levi from S. aviculare,2* has been identified by Bell and Briggs 25 with
solasonine.
The alkaloid has undergone changes in empirical formula, and that now
given is provided by Briggs, Newbold and Stace, 25 after a further investigation and a critical review of published work on this subject.
Solasonine crystallises from 80 per cent, alcohol with 4-5 H 2 0 and
then melts at 245-250 (dec), or from methyl alcohol in crystals with
0-5 H 2 0, m.p. 275-280, [a]26 - 53 to - 68-7 (EtOH) : the picrate has
m.p. 199-201, the picrolonate, m.p. 230-1 ; the hydrochloride forms
microscopic scales, m.p. > 265. The acetyl derivative melts at 135-8 and
on hydrolysis, by 70 per cent, hydrobromic acid in acetic acid, is stated to
yield (a) diacetylrhamnose, m.p. 75, (b) acetobromosolanidine-s and
(c) an acetylsolanidine-s-glucose galactose, m.p. 170, after discoloration
at 140, which is hydrolysed by potassium hydroxide in alcohol to solanidine-5-glucoside and galactose. The names of these hydrolytic products
are those given by Oddo and Caronna,10 and " solanidine-s " should be
replaced by solasodine. The formulae originally assigned to these products
need alteration to conform with the new formula for solasonine, but in
their review of this work Briggs et al. (1942) agree that Oddo's results
justify the conclusion that the sequence in the gluco-alkaloid is similar to
that in solanine (p. 661) and may be stated as
C 6 H u 0 4 O
C 6 H 10 O 4
OC6H10O4
-0-C27H42ON
Rhamnose
Galactose
Glucose
Solasodine
and not with two molecules of solasodine, one at each end, as proposed
by the Italian workers.
Solasodine (solanidine-s), C^H^OjN . H 2 0. This formula was first
used by Rochelmeyer 22 (1939) and was confirmed by Briggs, Newbold
and Stace.28 The alkaloid results from the acid hydrolysis, usually in
667
SOLASODINE
alcohol, of salasonine (see above) along with glucose, galactose and rhamnose.
It crystallises from dilute alcohol or dioxan, in nacreous scales, m.p. 197-8,
though this constant has been raised once to 200-5-202-5, [<x]jf 97-1
(MeOH)28 or 92-4 (C 6 H 6 ). 22 The following salts have been prepared:
picrate, m.p. 144 ; picrolonate, m.p. 234; hydrochloride, m.p. 314,
fa]2*" 70(MeOH); hydriodide, m.p. 293 ; tartrate, m.p. 222 ; oxalate,
m.p. 248. Solasodine contains two active hydrogen atoms, assumed to
be present as hydroxyl groups but only monoacyl derivatives are formed,
e.g., monoacetylsolasodine, C 29 H 45 0 3 N, m.p. 195, and 3 : 5-dinitrobenzoylsolasodine, m.p. 191-5-193. Rochelmeyer found that solasodine gives
Rosenheim's colour reaction with trichloroacetic acid, forms a sparingly
soluble digitonide, and on selenium dehydrogenation yields Diels's hydrocarbon, y-methyl/cZopentenophenanthrene, so it must belong to the
R-CH
CH2
R-CH
CH2
R-CH
II
II
CH2-N-CHCH2
CH 2 -N-C(0H)-CH 2
II
CH2
CH2
(IX) 50LANIDINE
R-CH
R-CH
2H 2
|l
CHfle
CH2
R'-CH
AitiHO
CH,
'
1
I
>
I
|
CH2 -NH(HX)-CH(0H)-CH2 "tHg - NH CH(OH) -CH 2
I
CHMe
(5E) SOLASODINE
CHMe
(X a ) S0LAS0DINE
CH2 .
I
I
*
CH2-NH(X) = C(0H)-CH2
CH2
(X)SOLASODINE
CHa
II
II
CHMe
CH2
(H fl )
CH2
CHMe
CH,
|
CHMe
(XT*)
TTRAHYDROSOLASODINE
steroid group and one of the hydroxyl groups should be in position 3 and
should be the one acylated, since the monoacetyl derivative does not
precipitate with digitonin. With methyl and ethyl iodides solasodine forms
only the hydriodide, described as quaternary ; with acetic acid and sodium
nitrite it produces with loss of water the quaternary nitrite, C 27 H 41 ON.
HN0 2 , m.p. 260-5-262-5 (dec), which on treatment with hot, dilute,
ammonia solution regenerates solasodine. This nitrite was first prepared
by Oddo and Caronna, who called it " azosolanidine-s " and regarded its
formation as an indication of a secondary amine group in solasodine 27
(1936). Briggs, Newbold and Stace z8 suggest that the behaviour of the
solasodine nitrogen atom is due to its association with the second hydroxyl
group of solasodine, either as a carbinol amine (X : R = steroid residue)
or more probably as a quaternary hydroxide (Xa : R = steroid residue).
This suggestion makes solasodine the quaternary hydroxide of solanidine
as formulated (IX) by Clemo, Morgan and Raper. In this connection it is
668
STEROIDAL
ALKALOID
GROUP
CHOH
>CO and the transfer of the ethylenic linkage, C5C6,
5
to C*C as in cholesterol to cholestenone, and the ultra-violet absorption
curve is in accord with these assumptions. 22 Similarly, solasodine is dehydrated by heating with hydrochloric acid in methyl or ethyl alcohol to
solasodiene, C27H41ON, m.p. 169-5-170-5, [a]2/ - 86-9 (CHC13), which
is also produced along with solasodine in the acid hydrolysis of solasonine.
The second ethylenic linkage formed in this reaction is placed at C3C4
being conjugated with the primary double bond, in a different ring, positions in accord with a maximum at 2,340A., log e 4-34, observed in the
ultra-violet absorption spectrum by Rochelmeyer,22 who named this
substance solanosodine (1939). It gives the Rosenheim colour reaction,
contains one active hydrogen atom (Zerewitinoff) and forms a hexahydroderivative, C27H47ON, m.p. 184-6, [<x]5 18, on hydrogenation in
acetic acid, under pressure in presence of platinic oxide.
Under similar conditions, but with palladised charcoal as catalyst,
solasodine forms a dihydro-derivative, C 27 H 46 0 2 N, m.p. 208-5-210-5,
[a]|6 63-5 (CHC13), and in presence of platinic oxide, a tetrahydroderivative, C 27 H 47 0 2 N, which is dimorphic, m.p. 292-5, and 285-291,
[oc]i-4-94(CHCl 3 ).
The salts of solasodine, except in the case of the nitrite already referred
to, are formed without loss of water and in their formation, as well as in
the production of hexahydrosolasodiene (dihydroc/ianosolasodane) and
tetrahydrosolasodine (dihydrocAanosolasodanol) it is suggested that
solasodine acts as the carbinol-amine (X) hydrogenation, e.g., taking place
as in (XI) to (Xlb), where R is the unsaturated, and R' the saturated
sterol residue, i.e., the ethylenic linkage is saturated first (R to R' in XI to
XI) and scission of the bridge between the two rings takes place by what
is described as a kind of Emde degradation.
Colour Reactions. Rochelmeyer (1939) 22 has provided a list of colour
reactions given by solasodine and solasodiene (solanosodine), with reagents
usually applied to the sterols, and Briggs et al.25 have found that when
concentrated sulphuric acid (1 mil) is carefully added to a solution of
solasonine or solasodine in hot alcohol (1 mil) a characteristic, intense,
greenish-yellow fluorescence is produced, a reaction which is not given by
solanine or solanidine. They have also found that intense colours are
formed when solasonine or solasodine is mixed with resorcinol, or one of a
variety of aldehydes, and boiled with concentrated hydrochloric acid.
Colours are also produced with this test by cholesterol, digitonin, jacobine
carbazole, pyrrole, or nicotine, the most intense colours being formed
with p-hydroxybenzaldehyde or anisaldehyde.
Solauricine, C 46 H, 3 0 1< N. From an alcoholic extract of the dried
SOLANUM ALKALOIDS
669
Mixture
H.p.
876
870
272
197
185
184
[a] D -80.4 as
631
232
base, -70.5ae
1980"
219*
Solaeonine
H. p.
Derivative
Glucoalkalold
Piorate
Picrolonate
Aglyoone
314.5-815
Hydrochloride
208-211 *
313-313.6 313.5-314
Botes
Solasodine has
hydrochloride;
solauricidine
Hydrtodide
288
285
886
Piorate
144
141
148
Picrolonate
238
234
838
as hydrochloride.
Tartrate
820
22SO
821
238
839
Oxalate
845-6
Aoetyl derivative
195
O-Mtrobenaoyl
2220
220
206.5-210.50
2L5-887.5
Dihydro-
197-803 "
This table shows that the similarity of the two aglycones is most
marked in their salts, but they do not appear to be dimorphic forms
giving identical salts, for the melting-points of the bases are unchanged
after sublimation, the rotations of the two bases in solution are different,
though those of the two hydrochlorides are identical within the limits of
experimental error, and all attempts at interconversion of the two bases
-670
STEROIDAL ALKALOID
GROUP
Solanocapsine
SOLANGUSTINE
671
672
STEROIDAL
ALKALOID
GROUP
(9) ZWENGER
and K I N D , Annalen,
1900, 25, 8 9 ;
ZEISEL and WITTMANN, Ber., 1903, 36, 3554 ; VOTOCEK and VONDRACEK, ibid., p . 4372 ;
and HEIDUSCHKA and SIEGER. 4 (10) Ibid., 1934, 67, 446. (11) Ibid., 1935, 68, 669,
(12) J. Soc. Chem. Ind., 1943, 62, 20, 48 ; cf. LAMPITT and GOLDENBERG, Chem. and
Ind., 1940, 59, 748 ; ROCHELMEYER, Chem. Zent., 1944, ii, 1188 and W O L F and DUGGAU,
J. Agric. Res., 1946, 73, 1 ; STREET et al., Ann. appl. Biol., 1946, 33, 1. (13) Biochem.
Zeit., 1937, 295, 44 ; cf. BRETON, Ann. pharm. franc, 1945, 3, 69. (14) Plant. Physiol.,
1937, 12, 79. (15a) ALBERTI, Zeit. Vnters. Lebens., 1932, 64, 260 ; WILLIMOTT, Analyst,
1933, 58, 431 ; FISCHER and THIELE, Oslerr. Bot. Zeit., 1930, 78, 325 (Chem. Zentr.,
1930, ii, 2164 ; cf. Monats., 1930, 56, 282) ; Pharm. Zent., 1931, 72, 545 ; Arch. Pharm.,
1937, 275, 521. (156) BOMER and M A T H S , Zeit. Vnters. Lebens., 1923, 45, 288 ; 1924,
47, 97 ; GRIEBEL, ibid., 1924, 47, 436 ; VALENTIN, Pharm. Zent., 1933, 74, 611 ; VON
FELLENBERG, Mitt. Lebens. Hyg., 1940, 3 1 , 85 (Brit. Abstr., 1946, C. 43). (16) Ber.,
1933, 66, 762 ; (with WALLENFELS), ibid., 1936, 69, 811. For a full account of work on
Diels's hydrocarbon see FIESER, " The Chemistry of Natural Products related t o
Phenanthrene," New York, 1937, p p . 159-166. (16a) J. Biol. Chem., 1943, 149, 451 ;
Science, 1943, 97, 122.
(18) B E R G E L
and WAGNER, ibid., 1933, 66, 1093. (19) Arch. Pharm., 1932, 270, 550. (20) DIETERLE
and ROCHELMEYER, ibid., 1935, 273 532, 539 ; ROCHELMEYER, ibid., 1936, 274, 543 ;
(with GEYER and SHAH), Ber., 1938, 71, 226. (20a) Helv. Chim. Acta, 1942, 25, 1306 ;
1944, 27, 390. (206) Ibid., 1943, 26, 2269. (20c) J. Biol. Chem., 1945, 160, 243. (21)
J. Chem. Soc, 1936, 1299. (22) Arch. Pharm., 1937, 275, 336; 1939, 277, 329. (23)
Gazzetta, 1905, 35, [i], 27 ; 1906,36, [i], 310 ; 1911, 41, [i], 490 ; 1914, 44, [i], 680, 690 ;
[ii], 181,191 ; Ber., 1936, 69, 283 ; see also ROMEO, ibid., 1905, 35, [ii], 579 ; SOLDAINI,
Boll. chim. Farm., 1905, 44, 769. (24) Proc Ind. Acad. Sci., 1936, 4A, 255 ; cf. P E N D S E
and D U T T , Ind.
J. Med. Res.,
Chem.
Soc,
1938, 15, 95 ; MANJUNATH and SHADAKSHARASWAMY, J. Mysore Univ., 1942, 3B, 117.
(25) BRIGGS, J. Amer. Chem. Soc, 1937, 59, 2 4 6 7 ; Nature, 1939, 144, 2 4 7 ; (with
ANDERSON), J. Chem. Soc, 1937, 1036 ; (with B E L L ) , ibid., 1942, 1 ; (with NEWBOLD
and STACE), idem, p. 3 ; (with B E L L and CARROLL), idem., p . 12 ; (with CARROLL), idem.,
p. 17. (26) J. Soc. Chem. Ind., 1930, 49, 395. (27) ODDO, Gazzetta, 1911, 41, [i], 534 ;
1914, 44, [ii], 191 ; (with CARONNA), Ber., 1936, 69, 283. (28) J. Chem. Soc, 1914,
105, 164. (29) Bull. Sci. Pharmacol., 1929, 36, 541. (30) J. Chem. Soc, 1936, 1537.
(31) Compt. rend., 1887 105, 1074. (32) J. Chem. Soc. Japan, 1921, 42, 16. (33) Bull,
Sci. Pharmacol., 1912,19,283. (34) Chem. News, 1911, 104, 2 ; cf. W E L L S a n d R E E D E R ,
ibid., 1907, 96, 199. (35) Pharm. Arch., 1940, 11, 23. (35a) (With MCMURBAY and
WALLER) J. Amer. Pharm. Assoc, 1944, 33, 300, 303. (36) D A L E , quoted by T U T I N and
CLEWEB, J. Chem. Soc, 1914, 105, 564. (37) Quart. J. Pharm., 1932, 5, 649. (37a)
Merck's Jahresb., 1939'53,45,52. (38) STABKENSTEIN, R O S T and POHL, " Toxikologie "
(Berlin, 1929), p . 122. (39) L E W I N , " G i f t e u n d Vergiftungen," p . 820. (40) POHL,
Heffter's Handb. d. Pharmakol., 1924, I I , 2, 1294.
ALKALOIDS
OF ACONITUM
673
8PP.
22
674
A.
A.
A.
A.
A.
A.
A.
A.
A.
A.
A.
A.
A.
STEROIDAL ALKALOID
GROUP
ACONITINE
675
676
STEROIDAL ALKALOID
GROUP
ACONITINE
677
loses acetic acid and forms pyroxonitine, C31H39O10N, m.p. 180, [a] D 127
(MeOH), which hydrogenates to the hexahydro-derivative, C31H45O10N,
m.p. 160-3. Alkaline hydrolysis deacylates oxonitine to oxonine,
C 24 H 37 O 10 N. 4H 2 0 [C19H19(OH)5(OMe)4(CO)(NH)], m.p. 175. Pentacetyloxonine, m.p. 246 [dec), []| 77-1 (CHC13), can be obtained by direct
oxidation of pentacetylaconine (Tamura 42 ). Pyroxonitine on alkaline
hydrolysis yields pyroxonine, C^HagOjN, m.p. 264 (dec).
When oxonitine is digested with hydrogen chloride, 6 per cent., in
methyl alcohol at 100, it loses carbon dioxide and is converted into a base,
C31H45O10N or C32H47O10N, m.p. 250, which contains one methylimino
and live methoxyl groups.
Brady 42 found that in the oxidation of aconitine by permanganate
there was formed a second product, C 21 H 29 0 9 N, m.p. 272. Jacobs, Elderfield and Craig 42 have also recorded the formation in this reaction of
oxoaconitine, C 33 H 43 0 12 N, or possibly C 34 H 46 0 12 N, m.p. 261, [<x]D 98
(CHC1,).
Nitric Acid. The most interesting product of this action was first
obtained by Brady 42 by the use of fuming nitric acid on aconitine. It
was described as a nitrosodicarboxylic acid, C 22 H 26 O u N 2) m.p. 205.
Suginome M obtained the same substance by the oxidation of mesaconitine
or oxonitine, but assigned to it the formula C 31 H 33 0 13 N 3 . It melted at
205, resolidified and then re-melted at 282 and had [a]|4 33-2.
Lawson a described three products of this kind, (a) C 29 H 33 O u N 3 , m.p. 186,
from aconitoline (p. 676), and (b) C 31 H 35 0 13 N 3 , m.p. 268 (dec), with
(c) C 31 H 36 0 14 N 3 , m.p. 263, both from aconitine under different conditions.
Jacobs and Craig 40 point out that though no deep-seated action takes
place in this oxidation several groups are involved simultaneously, mixtures
of reaction products are probably formed, which are not easily separated
and completely characterised, so that some confusion in results was to
be expected. They are convinced that aconitine, oxoaconitine (above),
oxonitine (p. 676) and aconitoline on oxidation by nitric acid all yield the
same product, a nitronitroso-compoxmd, C 31 H 35 0 13 N 3 , which crystallises in
four-sided prisms, m.p. 278 (dec), [a]|5 31 (EtAc), or in wedge-shaped
forms, melting to a resin at 180-200, re-solidifying on continued heating
and re-melting at 277-9. It is insoluble in sodium carbonate solutions
and is not an acid but may be a lactone or a : CH2 . N 0 2 derivative. It is
apparently formed from oxonitine or oxoaconitine by oxidative removal
of a molecule of hydrogen and introduction of a nitro group by replacement of a methoxyl group. Thus, Jacobs and Craig 40 were able to isolate
in this oxidation of oxoaconitine, an intermediate product, C 33 H 38 0 13 N 2 ,
in stout, colourless prisms, m.p. 180-190, [a]2,5" + 11-5 (EtAc), giving a
practically negative Liebermann nitroso-test. Oxonitine provided a
similar intermediate product, C 32 H S6 0 13 N 2 (or C 33 H 38 0 13 N 2 ), needles,
m.p. 288-9 (dec), [x]f + 14 (EtAc), giving no Liebermann test. This
nitration stage appears to be followed by a complicated oxidative cleavage
of a cyclic amide group with nitrosation of a liberated secondary basic
group, ending in the formation of the nitronitroso-compound, C 8 1 H g 6 0 l g N 8 .
678
STEROIDAL
ALKALOID
GROUP
JAPACONITINE
679
680
STEROIDAL
ALKALOID
GROUP
HYPACONITINE
681
682
STEROIDAL
ALKALOID
GROUP
PSEUDACONITINE
683
684
ACONITINE.
Aconitoline.
Nitromtroso
cpd.
PSETOACONITINE.
Chromic acid
product.
Nitric acid
product.
STEROIDAL
ALKALOID
GROUP
C34H47OuN
C 3S H 41 O 10 N
CslH85013N3
C 18 H 1 ,(NEt)(CHOH)(OH)(OMe) 1 (OAc)(OVe).
C, 8 H, 8 (KEt)(CO)(OH)(OMe) 8 (OAcKOVe).
Ca<H51018N
C35H16OnN
BIKHACONITINE
685
686
STEROIDAL
ALKALOID
GROUP
ATISINE
687
688
STEROIDAL
ALKALOID
GBOUP
diately reconcilable and the more important may be set out for convenience
of comparison as follows :
Lawson and Topps
Products
Bases
Neutral substance
Hydrocarbons
C 20 H 27 ON, picrate,m.p.indefinite.
C 21 H 31 ON, m.p. 180-190.
C 16 H 16 ON, m . p . 258-261.
C 20 H 29 N, picrate, m.p. 210-213.
Ci 6 H 1 6 N, tertiary, m.p. 83-5,
picrate, m.p. 221-3 ; B . M e l ;
m.p. 233-5.
C=CHN<
> CHCON<
since oxoisoatisine forms only a dihydro-derivative, C 22 H 35 0 3 N, m.p. 219223, [<x]o6 38 (CHC13), and reacts with only one equivalent of perbenzoic acid. With bromine it forms a bromo-derivative, C 22 H 32 0 3 NBr,
m.p. 172-5, [a]p* 73 (EtOH), while isoatisme forms a dibromide
hydrobromide, C^HgaOgNBrg, HBr, m.p. 212-5 (dec.) and dihydrooxoisoatisine is unaffected by this reagent. The change from atisine to
woatisine must involve one or both of the double bonds, since both yield
the same tetrahydro-derivative. One of the bonds involved must be that
adjacent to the nitrogen atom as woatisine is a weaker base than atisine.
The latter on treatment in benzene solution with Raney nickel catalyst
on alumina for ten hours yielded a base, C20Hg9ON, m.p. 145-150, giving
a hydrochloride, m.p. 230-5, [a]ff + 8 1 (H 2 0), and a picrate, m.p.
254-6. Twenty grams of the pale brown resin of the total alkaloid of
HETERATISINE
689
690
STEROIDAL
ALKALOID
GROUP
ibid., p. 1467; (with MOBIO), Annalen, 1929, 476, 203; cf. HENBY, Chem. Soc. Ann.
Rep., 1927, 24, 189. (2) J. Chem. Soc., 1900, 77, 49. (3) Arch. Pharm., 1885, 23, 162 ;
691
ACONITE ALKALOIDS
(4) Chem. Zent., 1890, ii, 148. (5) Ber., 1894, 27, 720. (6) Pharm. J., 1877, [iii], 8,
173. (7) J. Chem. Soc., 1879, 35, 387. (8) Arch. Pharm., 1909, 247, 243. (9) Ibid.,
1913, 251, 453. (10) COSTA and VALE, Noticias farm (Portugal), 1940, 6, 127 (Chem.
Abstr., 1940, 34, 6763). (11) GORIS and METIN, Compt. rend., 1925,180, 968,1132,1282 ;
GORIS, 1937, 205, 1007.
Ind. Pharm., 1945,1,6. (12a) MARION and EDWARDS, J. Amer. Chem. Soc., 1946,68, 2565.
(13) H E N R Y and SHARP, J. Chem. Soc., 1928, 1105. (14) MAJIMA (with SUGINOME a n d
MORIO), Ber., 1924, 57, 1461, 1472 ; (with MORIO), Annalen, 1929, 476, 171, 194, 203 ;
MORIO, ibid., p . 181 ; SUGINOME a n d SHIMANOUTI, ibid.,
HURUTA,
Jap. J. Med. Sci., [vii], 1940, 3 , 191. (15) DUNSTAN a n d ANDREWS, J. Chem. Soc,
1905, 87, 1 6 2 0 ; B A U E R a n d R A D J H A N , Pharm. Zent., 1931, 72, 145. (16) BEATH,
J. Amer. Pharm. Assoc, 1926, 15, 265. (17) MAJIMA and MORIO, Proc. Imp. Acad.
Tokyo, 1931, 7, 351 ; Ber., 1932, 65, 599. (17a) RITCHIE, Pharm. J., 1945, 154, 166.
(18) SCHULZE a n d B E R G E R , Arch. Pharm.,
ROGERS, J. Amer. Chem. Soc, 1936, 58, 533 ; 1937, 59, 2572 ; Ber., 1936, 69, 1962 ;
Science, 1938, 87,139; JACOBS and CRAIG, J. Biol. Chem., 1942,143, 611. (20) BRIMNER,
Schweiz. Apoth. Zeit., 1922, 60, 357. (20a) ROSENTHALER, Pharm. Acta Helv., 1942,
17, 194. (21) WEIDEMANN, Arch. exp. Path. Pharm., 1922, 95,166 ; see also JERMSTAD,
Chem. Zent., 1944, ii, 1198. (22) SCHULZE and BERGER, Arch. Pharm., 1927, 256, 524.
(23) Annalen, 1833, 7, 276. (24) Ibid., 1850, 74, 257. (25) Pharm. J., 1860, [ii], 8,
121. (26) J. Chem. Soc, 1875, 29, 1265 ; 1877, 31, 143 ; 1878, 33, 151, 318 ; 1879,
35, 387. (27) For a good historical account of t h e early investigations, see SCHULZE,
Arch. Pharm., 1906, 244, 136. (28) See, for example, CORNWELL and J O N E S , Pharm. J.,
1926, 117, 197 ; VAN BRONKHORST, Pharm. Weekbl., 1935, 72, 1058 ; GSTIRNER, Pharm.
Zent., 1932, 73, 465 ; BAKER and JORDAN, J. Amer. Pharm. Assoc, 1936, 25, 291 ;
LECOQ, J. Pharm. Chim., 1938 [viii], 28, 321. ROCHE LYNCH et al., Analyst, 1942,
67, 289 ; E D E R a n d RUCKSTUHL, Pharm. Acta. Helv., 1944, 19, 53. (29) See, for
example, SWANSON and HARGREAVES, J. Amer. Pharm. Assoc, 1927,16, 296 ; 1923,12,
957; 1924, 13, 1108 ; JAUREGUI, ibid., 1927, 16,1045 ; MUNCH et al.,ibid., 1929,18, 17,
S)86, 993 ; BRANDT, Arch. exp. Path. Pharm., 1930, 156, 203 ; D Y E R , Quart. J. Pharm.,
1930, 3, 626 ; GORIS, Bull. Sci. Pharmacol.,
ibid., 1934, 177, 74 ; FREUDWEILER, Pharm. Acta Helv., 1935, 10, 51 ; CHRISTENSEN
and NELSEN, J. Amer. Pharm. Assoc, 1940, 29, 97 ; H O P P E and MOLLETT, ibid., 1943,
32, 215. (30) Quart. J. Pharm., 1932, 5, 33. (31) CARR and KRANTZ, J. Amer. Pharm.
Assoc,
(32) See W R I G H T a n d L U F F
26
; JURGENS,
lnaug. Diss. Dorpat, 1885 ; DUNSTAN and co-workers, J. Chem. Soc, 1891, 59, 271 ;
1892, 61, 385 ; F R E U N D a n d B E C K , Ber., 1894, 27, 433 ; SCHULZE, Apoth. Zeit., 1904,
18, 783 ; 1905, 20, 368 ; Arch. Pharm., 1906, 244, 136, 165 ; 1908, 246, 281 ; DUNSTAN
and H E N R Y , J. Chem. Soc, 1905, 87, 1653. (33) TUTTON, ibid., 1891, 59, 2 3 3 ; cf.
WATANABE, Annalen, 1929, 476, 211. (34) J. Chem. See, 1893, 63, 994. (35) For
other tests see WAOENAAR, Pharm. Weekbl., 1930, 67, 165 ; MUNCH and PRATT, J.
Amer. Pharm. Assoc, 1934, 23, 968 ; VILANIL, Cron. Med., 1934, 510 ; SA, MAH, H O O ,
Sci. Rep. Tsing Una Univ., 1934, 2, 245 (Brit. Chem. Abstr., 1934, A, 1017) ; GIRARD
et al., J. Pharm. Chim., 1942, [ix], 2, 156 ; see also DENIGES, Compt. rend., 1944, 219,
059.
(36) DUNSTAN a n d CARR, J. Chem. Soc, 1895, 67, 459 ; cf. SCHULZE
3a
(1906).
(37) J. Amer. Chem. Soc, 1936, 58, 1059; cf. FREUDENBERG, Ber., 1936, 69, 1 9 6 2 ;
MAJIMA a n d TAMURA, Annalen,
Proc. Chem. Soc, 1896, p . 59 ; SCHULZE, Arch. Pharm., 1906, 244, 165. (39) SCHULZE
and LIEBNER, Arch. Pharm.,
J. Chem. Soc, 1894, 65, 178. (40) JACOBS and CRAIG, J. Biol. Chem., 1940, 136, 323 ;
(with ELDERFIELD), ibid., 1939, 128, 439. (41) LAWSON, J. Chem. Soc, 1936, 8 0 ;
MAJIMA a n d TAMURA, Annalen, 1940, 545, 1. (42) CARR, J. Chem. Soc, 1912, 101,
2241 ; BRADY, ibid., 1913, 103, 1821 ; BARGER a n d F I E L D , ibid., 1915, 107, 281 ;
MAJIMA and SUGINOME, Ber., 1925, 58, 2047 ; SPATH et al., ibid., 1930, 63, 2994 ; 1931,
64, 2201 ; H E N R Y a n d SHARP, J. Chem. Soc, 1931, 581 ; MAJIMA, SUGINOME a n d
SHIMANUKI, Ber., 1932, 65, 595 ; MAJIMA a n d T A M U R A , 3 ' TAMURA, Annalen, 1937,
533, 183 ; JACOBS, E L D E R F I E L D a n d CRAIG, J. Biol. Chem., 1939,128, 439 ; cf. JACOBS
Annalen,
692
STEROIDAL ALKALOID
GROUP
(45) P O P E ,
J. Chem. Soe., 1900, 77, 4 9 . (46) SCHMIDT a n d SCHWANTKE, Arch. Pharm., 1909,
247, 2 4 2 ; cf. WATANABE, quoted b y MAJIMA a n d MORIO, Annalen,
(47) J. Chem. Soc., 1878, 33, 151. (48) Ibid., 1897, 71, 350. (49) Ber., 1896, 29, 852.
(50) KONOVALOVA a n d OREKHOV, Bull. Soc. Chim., 1940, [v], 7, 95 ; J. Gen. Chem.
U.R.S.S., 1940, 10, 745. (51) J. Chem. Soc., 1928, 3094. (52) Arch. Pharm., 1913,
251, 453 ; 1916, 254, 567. (53) J. Chem. Soc, 1905, 87, 1636. (54) J. Pharm., 1896,
[vi], 4, 262. (55) Arch. Pharm., 1922, 260, 230. (56) Arch. exp. Path. Pharm., 1922,
95, 166. (57) On t h e authority of Dr. O. Stapf, Carr ha,s suggested t h a t t h e A. septenIrionaU Koelle, used b y Bosendahl (and b y Schulze a n d Weidemann), was probably
the true A. lycoctonum L., whilst t h e A. lycoctonum referred t o on p . 686 is really A.
vulparia Reichb. (58) Jahresb., 1866, p . 483. (59) Pharm. Zeit. Russland, 1884, 23,
313. (60) Arch. Pharm., 1913, 251, 8, with a bibliography and critical resume of early
work ; MARION a n d MANSKE, Can. J. Res., 1946, 24B, 1. (61) Blue Book, " Cinchona
Cultivation in East India," 1877, p . 133. (62) Arch. Pharm., 1879, 214, 193. (63)
Yearbook Pharm., 1879, 422. (64) J. Chem. Soc, 1896, 69, 1578 ; cf. GORIS. 1 1 (65)
Ibid.,
1937, 1640 ; cf. CHANDRASENA, ibid., 1933, 740. (66) JACOBS a n d CRAIG, J.
Biol. Chem. (a) 1942, 143, 5 8 9 ; (b) 1943, 147, 5 6 7 ; (c) 1942, 143, 6 0 5 ; (d) 1943,
1 4 7 , 5 7 1 ; (e) 1 9 4 4 , 1 5 2 , 6 5 1 ; ( / ) 1 9 4 7 , 1 7 0 , 2 0 3 ; (g) idem.,p. 515 ; (h) idem.,p. 189.
(67) Proc Roy. Soc, 1898, 62, 3 3 8 ; cf. MUNCH and GITTINGER, J. Amer. Pharm.
Assoc,
1938,
11, 84. (68) For special papers on the action of aconitine, see CORONEDI, " Tossicologia
dell'aconito e dei suoi alcaloidi," Florence, 1925 ; EKERFORS, Compt. rend. Soc. Biol.,
1928, 98, 795, 797. (69) CASH and DUNSTAN, Proc. Roy. Soc, 1901, 68, 379. (70) Idem,
ibid., 1905, 76, 468. (71) B E R N I , Arch. Farm, sperim., 1930, 50, 110. (72) BENIGNI,
Boll. Soc. ital. biol. sperim., 1929, 4, 399. (73) Quoted b y SCHULZE a n d BIERLING,
Arch. Pharm., 1913, 251, 48 ; for a recent pharmacological report on A. lycoctonum
see RAYMOND-HAMET, C. R. SOC. biol., 1943, 137, 675. (74) ROSENDAHL, quoted
by B O E H M . 6 6 (75) CASH, quoted b y JOWETT, J. Chem. Soc, 1896, 69, 1525 ; see also
RAYMOND HAMET, Compt. rend. Soc. Biol., 1938, 128, 479 ; Compt. rend., 1942, 215,
247.
DELPHINIUM
ALKALOIDS
693
viz. (a) the naturally occurring alkamines, atisine and heteratisine, and the
derived bases dihydroatisine, tetrahydroatisine and woatisine, and (b) the
hydrolytic alkamines, aconine and delphonine, and certain derivatives of
the latter, viz., the methochloride and methohydroxide, iV-methyl-desdelphonine, pyrodelphonine and oc-oxodelphonine. Based on these results
and the structural data accumulated from their previous work, they
suggest the annexed formula as an example
of a possible type of nucleus for these
alkaloids. This assumes relationship of
these alkaloids to the diterpenes, as indicated by the formation of pimanthrene
(1 : 7-dimethyl-phenanthrene) from staphisine (p. 699) and from hetisine (p. 689).2
While the hydrolytic alkamines, aconine
and delphonine, cannot be hydrogenated
and have therefore been regarded as saturated, their ultra-violet absorption spectra
as bases in solution and in common with
those of heteratisine and tetrahydroatisine, show a strong absorption within
the range 2,200 to 2,600 A, indicating unsaturation. With the bases in
acid solution there is a reduction in intensity and a shift in the position of
the absorption. It is assumed that these results arise from association of
points of unsaturation with the nitrogen atom. A similar range of absorption is shown by iV-methylpyrrole, as base in solution, but in this case
there is no shift in position on acidification.
Delphonine shows an unusually high basic dissociation constant, and
that of aconine is only a little less. In the case of tertiary vinyl cyclic
amines, which prove to be unexpectedly strong bases, Adams and Mahan 3
suggested that they exist in solution as equilibrium mixtures consisting
of the tertiary unsaturated base and a quaternary arrangement in which
the double bond has moved to the nitrogen, which may be represented
thus :
+
. .
. +
> C = CC= CNH< ^ > C = CCHC : N <
The assumption of these conjugated double bonds makes possible a tetracyclic nucleus which accords with the suggestion previously made by
the authors that these alkaloids might be structurally related to the
diterpenes. 2 It may also be noted that one of the nitric acid oxidation
products of pseudaconitine has been recorded as unexpectedly giving a
pyrrole reaction on destructive distillation.4
REFERENCES
(1) J. Biol. Chem., 1944, 154, 293. (2) CRAIG and JACOBS, ibid., 1944, 152, 645;
JACOBS and HUEBNER, ibid., 1947, 170, 189. (3) ADAMS and MAHAN, J. Aimer. Chem.
Soc, 1942, 64, 2588. (4) HENRY and SHARP, J. Chem. Soc., 1928, 1105.
ALKALOIDS OF DELPHINIUM SPP.
Delphinium spp., of which the larkspur is a familiar example, have
often been the cause of poisoning in cattle and a few have been used as
694
STEROIDAL
ALKALOID
GROUP
insecticides. This has led to the examination of some species but only to
establish the source of toxicity and in such cases there is little more recorded
than the presence and percentage of alkaloids, as for example in D. Andersonii,1 D. barbeyi 2 (1919), D. crassifolium,3^ D. chinense,3 D. formosum,3
D. geyeri,* D. glaucescens,2 D. glaucumf D. hybridum,3 D. rhinante,3 D.
subalpinum*
More work has been done on the alkaloids of D. bicolor, Nutt, D.
Menziesii, D.C., D. scopulorum, Gr. and D. Nelsonii,* Gr. which, according
to G. Heyl 4 (1903), contain a mixture of alkaloids, having pharmacological
properties akin to those of curare (Lohmann 4) and hence named " delphocurarine." From this material he isolated a crystalline alkaloid, C23H3307N,
m.p. 184-5, which contained methoxyl (18 per cent.).
Delphinium ajacis L. From the seed of this species Keller and Volker s
isolated two crystalline alkaloids which they named ajacine and ajaconine.
Their work was reviewed by Hunter, 6 who reported the presence of four
alkaloids, viz., ajacine, ajaconine and new alkaloids ajacinine and ajacinoidine (amorphous). Goodson 6 described ajacine in detail (1944) and
later reported the isolation of ajaconine and three more bases distinguished
as B, C and D. According to Hunter, lycoctonine (p. 686) is probably
also present.
Ajacine, C 34 H 46 0 9 N 2 . 2H 2 0. According to Goodson, the base crystallises from 70 per cent, alcohol in needles, m.p. 154, [a]f>2-|- 49-5 (EtOH)
or +30-8 (N/5HC1), and contains one ethylimino, two hydroxyl and
four methoxyl groups. On alkaline hydrolysis it yields lycoctonine,
C 26 H 39 0 7 N . H 2 0 (cf. Manske's formula, p. 686), and acetylanthranilic acid,
C 9 H 9 0 3 N. On acid hydrolysis ajacine furnishes acetic acid and anthranoyllycoctonine, C 32 H 44 0 8 N 2 (p. 687). Ajacine is therefore acetylanthranoyllycoctonine, which brings it into close relationship with lycaconitine (p. 686).
Ajaconine, C21H3103N (Hunter) or C22H3303N (Goodson), has m.p. 172,
[oftf - 119 (EtOH) (G) or [0c]],70 - 133 (CHC13) (H), forms a sulphate,
B . H 2 S0 4 . 7H 2 0, m.p. 113 or 231 (dry, dec), [x]f + 5-5 (H 2 0), an
acid oxalate, B . H 2 C 2 0 4 , m.p. 234-5, an amorphous picrate, m.p. 95-8,
and a methiodide, m.p. 134. Ajaconine is an A^-methyl base, contains
no methoxyl groups and absorbs one molecule of hydrogen in presence of
palladium-black.
Ajacinine, C 22 H 35 0 6 N, m.p. 210-1, [aft7" + 52 (CHC13), forms a
hydriodide, m.p. 169-170, and an acid oxalate, B . H 2 C 2 0 4 , m.p. 195
(dec.); the hydrobromide, m.p. 154-160, and pierate, m.p. 99-103,
have not been crystallised.
Ajacinoidine, C 38 H 66 0 12 N 2 , is amorphous, m.p. 120-6, [oc]8 + 46
(CHCI3), and gives an amorphous picrate, m.p. 125-30.
Base B, C19H2208(MeO)3(NEt)(AcO), m.p. 195, [a]*7" + 34 (EtOH)
or + 0 5 (N/6HC1), forms an aurichloride, B . HAuCl4 . 3H 2 0, m.p. 205.
The substituents are as shown in the extended formula. On hydrolysis it
yields acetic acid and base C (see below).
Base C, C1,HsB04(OMe)3(NEt), m.p. 206, [a]Jf + 57 (EtOH) or
DELPHINIUM
ALKALOIDS
695
696
STEROIDAL
ALKALOID
OBOUP
DELPHININE
697
698
STEROIDAL ALKALOID
GROUP
the acetyl and benzoyl groups and four methoxyl groups, but in neither
can the JV-methyl group be detected.
When delphinine is heated in methyl alcohol, acetic acid is liberated and
methylbenzoyldelphonine, C 32 H 45 0 8 N, formed. This has m.p. 173-5,
Mr?" + 27 (EtOH), and on oxidation with permanganate in acetone in
presence of acetic acid, is converted into methylbenzoyl-a-oxodelphonine,
C^H^OgN, which melts at 221-3, solidifies and re-melts at 236-7 and
has [a]|5 41-5 (MeOH). This product is also formed by the action of
hydrogen chloride (3 per cent.) in methyl alcohol on a-oxodelphinine (see
above). This replacement of an acetyl by a methyl group also occurs,
though less readily, when ^-oxodelphinine is heated at 100 in methyl
alcohol with hydrogen chloride (4 per cent.), the product being methylbenzoyl-jS-oxodelphonine, C 32 H 43 0 9 N, m.p. 182-5, [a]|5 + 27 (MeOH).
This kind of reaction was first recorded for aconitine (p. 675) and it serves
to emphasise the parallelism in reactivity, and probably therefore in structure, which exists between aconitine and delphinine and possibly between
the whole range of aconite and larkspur alkaloids.
Another example of this is the loss of acetic acid when delphinine is
heated in hydrogen at 200-215. Just as aconitine is so converted into
pyraconitine so delphinine yields pyrodelphinine, C 31 H 41 0 7 N, m.p. 208212, and similarly a-oxodelphinine, C 33 H 43 O 10 N, under like treatment
loses acetic acid and yields pyro-a-oxodelphinine, C 31 H 39 0 8 N, which
crystallises from methyl alcohol in needles, m.p. 248-250, after sintering at
238. This, on hydrogenation, forms a hexahydro-derivative, m.p. 183-5,
presumably by saturation of the benzoyl radical, which therefore leaves
unexplained the mechanism by which acetic acid is lost in this pyrolytic
reaction (cf. pyropseudaconitine, p. 683).
With nitrous acid at 100, delphinine, C 33 H 45 0 9 N, yields a nitrosoderivative, C33H44O10N2, m.p. 240-1, but is chiefly converted into
hydroxydelphinine, C 33 H 45 O 10 N, m.p. 180-2 (dec), [a]| + 7 (EtOH).
This is oxidised by permanganate to a third or y-oxodelphinine, C33H43O10N,
m.p. 226-9, [*]f + 40 (AcOH), which, like the a- and /S-forms,
can replace its acetyl by a methyl group forming methyl-benzoyl-ydelphonine, m.p. 184-8, [a]^ -f 5 (MeOH), closely resembling methylbenzoyl-/J-delphonine except in specific rotation.
The action of hydrochloric and nitric acids on delphinine and certain
of its derivatives has also been investigated (Jacobs and Craig,19 1940).
Addendum. In an important paper received too late for incorporation
in the foregoing account and of which only a brief summary can be given,
Jacobs and Huebner 19<0) have used a-oxodelphinine (I) as a primary
material for further investigations on the nuclear structure of delphinine
and the changes it undergoes are shown in the accompanying diagram.
It is pyrolysed to pyro-a-oxodelphinine (II), which is isomerised by hydrochloric acid in methyl alcohol to isopyrooxodelphinine, C 31 H 39 0 8 N (III),
m.p. 292-6, [a]|5 13 (pyridine), and there is also formed in this reaction
the chloro-compound, C2H3sOeNCla, already described by Jacobs and
Craig l8 (1940) and which is now represented by (IV). When this chloro-
699
DELPHININE
00-B:
OH
C19H22
OBz
C19H21
C12B21
CO-B:
CO-N:
OH
OH
OBz
019H81
OBz
*;
OAc
(01!e)4
(I)
{OMe ) 4
(II)
(0Me)4
.(III)
(Olfc)g
(IV)
OO'B:
CO-B:
OH
00-B:
CO'H:
OBz
OH
OH
OBz* -
OH
C19H21
C19H24
:0Me) s
O19H24
[0Me) 2
OAc
OH
OBz
C19H21
(01ie)2
(0Me)
OAo
OH
(OAo), 2
H
(V)
(VI)
(VII)
In t h i s t h e b e n z o y l group i s reduced t o
(VIII)
hexahydrobenzoyl.
700
STEROIDAL
ALKALOID
GROUP
are a hydrocarbon, C16H14, later (1944) proved to be identical with pimanthrene (1 :7-dimethylphenanthrene), and a hydrocarbon, C lg H 20 , m.p.
70-2, forming a picrate, m.p. 1434, subsequently shown by Huebner
and Jacobs to be a methylretene, viz., 1:3-dimethyl-7-?'sopropylphenanthrene, by comparison with a synthetic specimen, m.p. 73-6, picrate,
m.p. 145-6. The possibility that staphisine should be represented by the
doubled formula, C42H60ON2, i.e., by loss of a molecule of water between
two molecules, C21H31ON, is also discussed in this paper.
The following three alkaloids described by early workers on D. staphisagria are not well characterised : DELPHISINE, 1 5 m.p. 189; said to
resemble and to be isomeric with delphinine. DELPHINOIDINE, 15 C 25 H 42 0 4 N,
amorphous. STAPHISAGKOINE,16 C 40 H 46 O 7 N 2 , amorphous, m.p. 275-7.
Pharmacological Action. Delphinine resembles aconitine in its action.
In cases of poisoning death is due to respiratory paralysis accompanied by
cardiac and vasomotor damage. It also has an irritant action on the
skin. Detailed accounts of the pharmacology of various species of
Delphinium and their alkaloids are given by Boehm 21 and by Lewin 22
and cases of larkspur poisoning are described by Jakobsen, 23 Markwood 8
and Marsh, Clawson and Marsh.24 According to Williams, the insecticidal
properties of D. ajacis seeds are due to the oil and not to the alkaloids.25
Kuder 26 has published a general article on the botany, horticulture and
chemistry of the larkspurs.
REFERENCES
(1) MILLER, J. Amer. Pharm. Assoc, 1923, 12, 492. (2) BEATH, J. Amer. Pharm.
Assoc.,1918, 7 , 9 5 5 ; Wyoming Agric. Exp. Stat. Bull., 1919, No. 120, p. 55. (3) KELLER,
Arch. Pharm., 1925, 263, 274. (3a) E F R O S , Farmatsiya, 1946, 9, 22. (4) F . W. H E Y L ,
H E P N E R and LOY, J. Amer. Chem. Soc, 1913, 35, 880 ; G. H E Y L , Siidd. Apoth. Zeit.,
1903, 43, Nos. 28-30 (Chem. Soc. Abstr., 1903, i, 650) ; LOHMANN, Pfluger's Archiv.,
1902, 92, 398. (5) KELLER, Arch. Pharm., 1910, 248, 468 ; (with VOLKER), ibid., 1913,
251, 207 ; cf. HUNTER, Pharm. J., 1943, 152, 82, 95 ; Quart. J. Pharm., 1944, 17, 302.
(6) GOODSON, J. Chem. Soc, 1944,108 ; 1945, 245. (7) Canad. J. Res., 1938, B , 16, 57 ;
1946, B, 24, 1. (8) J. Gen. Chem., V.R.S.S., 1942, 12, 321, 329. (9) J. Amer. Pharm.
Assoc, 1924, 13, 696 ; 1931, 20, 454. (10) Ber., 1941, 74, 1031. (10a) J. Amer. Chem.
Soc, 1947, 69, 2010. (11) J. Lab. Clin. Med., 1924, 9, 326. (12) J. Chem. Soc, 1943,
139 ; 1944, 665. (13) J. Amer. Chem. Soc, 1936, 58, 684. (14) Ann. Chim. Phys.,
1833, 52, 352. (15) Pharm. Zeit. Buss., 1890, 29, 641 (J. Chem. Soc. (Abstr.), 1891,
60, 842). (16) Ber., 1899, 32, 1581, 1669. (17) Arch. Pharm., 1910, 248, 648 ; (with
SMECHEL), 1925, 263, 274. (18) Ibid., 1922, 260, 9. (19) J. Biol. Chem., 1939, 127,
361 ; 128, 4 3 1 ;
1940,
136, 3 0 3 ;
1941,
141, 6 7 ;
1944,
152,
645;
154, 2 9 3 ;
HUEBNER
and JACOBS, ibid., 1947, 169, 211. (19a) Ibid., 1947, 170, 209. (20) MARKWOOD,
J. Amer. Pharm. Assoc, 1927, 16, 928, gives crystal measurements ; for ultra-violet
absorption spectrum see BRUSTIER and VIGNES, Bull. Soc. Chim., 1945, [v], 12, 37. (21)
HEFFTER, " Handbuch der Exper. Pharmakol," 1920, 2, P t . I, p . 314 ; FISCHER and
HUBER, Heh). Phys. Pharmacol. Acta, 1944, 2, C. 38. (22) " Gifte und vergiftungen,"
p. 598, (23) Norsk. Mag. Laegevidensk, 1935, 96, 725. (24) Exp. Sta. Rec (U.S.A.),
1916. 35, 770. (25) Amer. J. Pharm., 1914, 86, 4 1 4 ; cf. JARETZKY and JANICKI,
Arch. Pharm., 1940, 278,156. (26) J. Chem. Education, 1947, 24, 418.
VERATRUM
ALKALOIDS
701
702
STEROIDAL ALKALOID
GROUP
CEVADINE
703
704
STEROIDAL ALKALOID
GROUP
JERVINE
705
23
706
STEROIDAL
ALKALOID
GROUP
violet absorption curve indicates that the isomerisation has not greatly
disturbed the chromophorically active feature of the jervine molecule,
nor the A"^-ketonic type of absorption. The hydroxyl group of jervine is
believed to be at C3 and it is considered that /^4-jervine may be a mixture
of 3-a and 3-jS epimerides, but as it does not give a sparingly soluble
digitonide separation was not attempted. The absorption spectrum of
A*-jervone is similar to those of A4-solanidone (p. 663) and rubijervone
(p. 708), but A4-jervone is more strongly absorbent and its formation is
taken to indicate a 3-hydroxy- A 5 -structure for jervine. On hydrogenation
in alcohol, in presence of platinic oxide, jervine yields dihydrojervine,
C 27 H 41 0 3 N, which crystallises solvent-free from acetone with m.p. 248251, [a]*f 82 (EtOH), forms a iV-acetyl derivative, C 29 H 43 0 4 N, which
melts at 157-9 and re-melts at 256-9, and a diacetyl derivative, m.p.
210-2. A tetrahydrojervine, m.p. 216-221, [ajff 18 (EtOH), is
formed when either jervine or its dihydro-derivative is hydrogenated in
acetic acid: its iV-acetyl derivative has m.p. 266-9 and the ultra-violet
absorption spectrum indicates that the carbonyl group is still present
though no oxime could be prepared. Jervine, on reduction by sodium in
butanol produces a so-called tetrahydrojervine, which is in reality
a-dihydrojervinol, C 27 H 43 0 3 N, m.p. 223-5, [a||7 - 107 (EtOH). When
dihydrojervine is similarly reduced, jS-dihydrojervinol, m.p. 286-9,
Mr?" ~~ 4 (EtOH), is formed, and this in turn can be hydrogenated in
acetic acid to tetrahydrojervinol, C 27 H 45 0 3 N, m.p. 293-6, [a]f,8 + 48-5
(EtOH), which is also obtained when tetrahydrojervine is reduced by
sodium in butanol. In these reactions it is thought that the A 5 -double
bond has been saturated in dihydrojervine, and that the carbonyl group
is reduced in the formation of the jervinols.
woJervine proved resistant to hydrogenation and in acetic acid
only a trace of a product, C 27 H 45 0 2 N (hexahydrodeoxywojervine), m.p.
163-5 or 218-220 (solvent-free), [a]f + 26 (solvent-free; EtOH), could
be obtained; in this reaction the double bonds seem to have been
saturated and the oxygen atom of the carbonyl or hydroxyl group lost;
the substance may equally well have the formula C 27 H 47 0 2 N. On reduction with sodium in butanol wojervine yields dihydroisojervinol,
C 27 H 43 0 3 N . H 2 0, m.p. 135-140, [ a ] f + 84 (dry ; EtOH). woJervine
changes rapidly in alkaline solution. On acetylation, A^-acetylisojervine,
m.p. 202-3, is formed and on further treatment, JV-aeetyh'sojervine
diacetate (triacetylwojervine), C 33 H 46 0 6 N, m.p. 192-3.
A formula is tentatively suggested for jervine, based on the formula
for sapogenin (IV, p. 665) with the following changes : CO at C12, ethylenic
linkages, A 5 and A 7 , and the oxygen of the six-membered heterocyclic ring
at the extreme right changed to NH. Alternative structures for the sidechain are also discussed, especially in relation to the isomerisation of
jervine to wojervine (p. 707).
On selenium dehydrogenation at 340 jervine, like cevine, yields three
types of products. 82
Bases. 5-Methyl-2-ethylpyridine.
VERATBUM
707
ALKALOIDS
708
STEROIDAL
ALKALOID
GROUP
VERATRUM
ALKALOIDS
709
710
STEROIDAL
ALKALOID
GROUP
(pyridine); it combines with acetone but the product could not be crystallised. Unlike its isomeride, woprotoverine can be hydrogenated, forming a
dihydro-derivative, which crystallises with solvent, e.g., C^H^OgN . 2MeOH,
slowly decomposes at 315-320 and has [<x]?? 49 (pyridine). The
products of selenium dehydrogenation of protoveratrine have been
described by Craig and Jacobs 40 (1942); they include the three acids
already mentioned as hydrolytic products, 5-methyl-2-ethylpyridine,
2 :5-dimethylpyridine, a base, C8H9ON, giving a picrate, m.p. 114-7,
with cevanthridine (p. 703) and probably cevanthrol. These products
indicate that protoverine has a ring structure similar to that of cevine.
Protoveratridine, C32H5109N. Poethke 4 has shown that, as Salzberger
suspected, this alkaloid does not occur naturally, but is formed from
germerine by loss of a molecule of methylethylglycollic acid in Salzberger's
process of extraction. It forms glancing crystals, m.p. 266-7 (dec),
and yields a crystalline hydrochloride, m.p. 243-5 (dec), picrate, m.p.
244-6 (dec), aurichloride, and platinichloride, m.p. 195 -200 (dec). On
alkaline hydrolysis protoveratridine yields Z-methylethylacetic acid, and
germine, also formed by the alkaline hydrolysis of germerine (see below).
The alkaloid gives a red colour with sulphuric acid and a carmine-red
colour with hydrochloric acid, an odour of isobutyric acid being developed
on warming.
Germerine, C 37 H 59 O u N. This alkaloid was isolated from Veratrum
album by Poethke, 4 who assigned to it the formula C ^ I ^ O n N , which has
to be altered to that given above to accommodate the new formula found
by Craig and Jacobs 40 for germine (see below). It crystallises from benzene
in leaflets, m.p. 193-5 (dec), [xff + 10-8 (CHC13), and forms wellcrystallised salts : hydrochloride, B . HC1. 2H a O, needles, m.p. 215
(dec); hydrobromide, B . HBr, needles, m.p. 212-3 (dec); acid sulphate,
B . H 2 S0 4 , leaflets; picrate, m.p. 186-7 (dec). The aurichloride is
amorphous. Germerine with strong sulphuric acid gives a colourless
solution which becomes carmine-red on standing or on warming, and with
Frohde's reagent it slowly produces a reddish-violet colour, whereas protoveratridine is at once coloured violet by this reagent. On alkaline hydrolysis germerine gives germine, i-methylethylacetic acid and methylethylglycollic acid. On standing with an aqueous solution of barium hydroxide
germerine is converted into protoveratridine (see above) by loss of 1 mol. of
methylethylglycollic acid.
GERMINE, C 27 H 43 O g N. This alkaloid is produced by the hydrolysis
of either germerine or protoveratridine, but it also occurs naturally
in white and green hellebores. It was first obtained by Poethke 4 and
has been investigated recently by Craig and Jacobs, 41 who have altered
Poethke's formula, CjgH^OgN, to that given above, which makes it isomeric with cevine (p. 702), a base it closely resembles in several respects.
Craig and Jacobs prepared their alkaloid by saponifying the mixture of
amorphous alkaloids left after the removal of all directly crystallising bases
from the total alkaloids of V. album, and separating it from the associated
alkamines, rubijervine, isorubijervine and isogermine so produced. Germine
VERATBVM
ALKAMINES
711
712
STEROIDAL ALKALOID
GROUP
suggested. Formula (II) explains the formation of the supposed hexanetetracarboxylic acid (COOH . CMe . CH 2 . COOH)2, resulting from the
oxidation of cevine (p. 704) or germine (p. 711) by oxidative scission of
rings (a) and (b) at the points indicated, but as it has since been found
(Huebner and Jacobs 27) that this acid has not the structure suggested
it is now thought that, as in rubijervine and worubijervine, in this
type of veratrum alkamine the normal sterol system of rings is also
present. Rings (e) and ( / ) account for the production of 5-methyl-2ethylpyridine and though the points of attachment have not been proved,39
their location at C16 and C17 is supported by the formula assigned to solanidine (p. 665), and this alkamine also yields 5-methyl-2-ethylpyridine on
selenium dehydrogenation.42
In the 1943 paper 43 a more detailed discussion of the formula is given
with a suggestion for a possible mode of formation for cevanthridine, and
for possible location of the hydroxyl groups, one of which in rubijervine and
isorubijervine is placed at C3, as in solanidine, to account for the formation
of sparingly soluble digitonides. This is also considered a certain position
for one hydroxyl group in the other veratrum alkamines. In cevine there
are possibly hydroxyl groups at C3, C21, C23 and C15. If the formation of
the hexanetetracarboxylic acid by oxidation of cevine or germine is
correctly interpreted, there cannot be hydroxyl groups at C1, C2 or C7.
There is at present no definite evidence as to the position of the ethylenic
linkage in these bases.
VERATRUM
ALKALOIDS
713
714
STBBOIDAL
ALKALOID
GROUP
VEBATBUM
ALKALOIDS
715
published in the Bulletin of the Imperial Institute, which also provides each
quarter a bibliography of insecticides of vegetable origin.48
REFERENCES
(1) The first systematic investigation of all three species was made b y W B I G H T
and L U F F : sabadilla, J. Chem. Soc., 1878, 33, 338 ; white hellebore, ibid., 1879, 35,
405 ; green hellebore, ibid., 1879, 35, 421. See also BOSETTI, Arch. Pharm., 1883, 221,
82 ; G. MERCK, Annalen, 1855, 95, 2 0 0 ; E . MERCK, Chem. Soc., Abstr., 1891, 60, 844.
(2) JACOBS and CRAIG, J. Biol. Chem., 1943, 148, 41. (3) SALZBERGER, Arch. Pharm.,
1890, 228, 462. (4) POETHKE, ibid., 1937, 275, 357, 571 ; 1938, 276,170. (5) SEIFERLE,
J O H N S a n d RICHARDSON, J. Econ. Entom.,
J.
Biol. Chem., 1944, 155, 565. (7) SAITO, BUU. Chem. Soc. Jap., 1940, 15, 22 ; JACOBS
and CRAIG, J. Biol. Chem., 1945, 160, 555. (8) Apoth. Zeit., 1906, 21, 41, 53. (9) " Die
Fabrikation der Alkaloide," Berlin, 1927. (10) " Die Pflanzenstoffe," Jena, 1929 :
SAITO. 7 (11) GSTIRNER, Pharm. Zeit., 1932, 77, 5 0 9 ; JACOBSEN, Dansk. Tids. farm.,
1935, 9, 302 ; KURSCHNER and IMMENKAMP, Pharm. Zent., 1936, 77, 458 ; DUCOMMUN,
Pharm. Acta Helv., 1936, 11, 322 ; NOVOSIL'TSEVA and MOGIL'SKII, Farmatsiya, 1945,
8, 30 (Chem. Abstr., 1947, 41, 3258). (11a) HUMMELSHEIM, Arch. exp. Path. Pharm.,
1933, 172, 2 2 7 ; CHRISTENSEN and MCLEAN, J. Amer. Pharm. Assoc, 1936, 25, 414 ;
VIEHOVER and COHEN, Amer. J. Pharm., 1939, 111, 8 6 ; COHEN, ibid., p . 240 ; W u .
BuU. Nat. Form. Comm. U.S.A., 1947, 15, 74. (116) MANCEAU et al., Ann. pharm,
franc., 1945, 3 , 11. (12) JARETZKY and JANECKE, Arch. Pharm., 1940, 227, 34, 8 2 ;
LINDEWALD a n d STREUBERT, Suddeut.
(13) SWANSON a n d H A R -
GREAVES, J. Amer. Pharm. Assoc, 1930, 19, 122. (13a) Dansk. Tids. Farm., 1945,
19, 222. (14) Annalen, 1877, 185, 224. (15) Ber., 1890, 23, 2700. (16) Cf. FREUND
a n d SCHWARZ, ibid., 1899, 32, 800. (17) MACBETH a n d ROBINSON, J. Chem.
Soc,
1922, 121, 1574. (18) FRANKFORTER, Amer. Chem. J., 1898, 20, 361. (19) HORST,
Chem. Zeit., 1902, 26, 334. (20) J. Biol. Chem., 1938, 125, 625. For previous papers
see, ibid., 1937, 119, 141 ; 120, 447 ; 1938, 124, 659.
Ber., 1904, 37, 1946 (with SCHWARZ), J. pr. Chem., 1917, [ii], 96, 236. (22) J. Chem.
Soc, 1935, 122 (with CROWFOOT), ibid., 1936, 414. (23) J. Biol. Chem., 1941, 139, 293.
(24) Ibid., 1939,129, 79 ; 1941, 139, 263. (25) CRAIG, JACOBS and LAVIN, idem, p . 277.
(26) J. Gen. Chem. Russ., 1934, 4, 875. (27) CRAIG and JACOBS, J. Amer. Chem. Soc,
1939, 61, 2252 ; J. Biol. Chem., 1940, 134, 123 ; 1941, 141, 253 ; H U E B N E R and JACOBS,
1947, 170, 181. (28) Ber., 1876, 9, 1115. (29) Ibid., 1919, 52, 1984. (30) Bull. Chem.
Soc Jap., 1934, 9, 15 ; 1936, 11, 168, 172. (31) J. Biol. Chem., 1943, 148, 51 ; 1947,
170,635.
J. Biol. Chem., 1943, 149, 451. (34) SCHOPF and HERRMANN, Ber., 1933, 66, 298.
(35) SEXTON, J. Chem. Soc, 1928, 2825 ; OPPENAUER, Rec trav. Chim., 1937, 56, 137.
(36) JACOBS and CRAIG, J. Biol. Chem., 1944,152, 641.
ibid., 1936, 114, 567. (38) J. Biol. Chem., 1945, 159, 617. (39) ROTHEN and CRAIG,
J. Amer. Chem. Soc, 1943, 65, 1102. (40) J. Biol. Chem., 1942, 143, 4 2 7 ; 1943, 149,
271. (41) Ibid., 1943, 148, 57. (42) CRAIG a n d JACOBS, Science, 1943, 97, 122 ; cf.
ROCHELMEYER, Arch. Pharm., 1936, 274, 543 ; 1937, 275, 336, a n d PRELOG a n d
SZPILFOGEL, Helv. Chim. Acta, 1942, 25, 306. (43) CRAIG and JACOBS, J. Biol. Chem.,
1941, 141, 253 ; 1943, 149, 451 ; (43a) 1945, 160, 243. (44) Helv. Chim. Acta, 1933,
16, 833. (45) Physiological Reviews, 1946, 26, 383 ; see also JAGUES, Rev. Can. biol.,
1946, 5, 246. (45a) WILLSON, Amer. J. Obstet Gyn., 1946, 52, 273. (46) J. Biol.
Chem., 1945, 159, 517 ; J. Econ. Entom., 1944, 37, 400 ; ALLEN, LINK, IKAWA and
B R U N N , ibid., 1945, 38, 293.
ibid., p . 564. (48) Bull. Imp. Inst., 1946, 44, 102, 124 ; 1947, 45, 156.
ANDERSON,
SPP.
THE barks of Alstonia species (Apocynaceae) had a considerable reputation throughout the tropics as effective anti-malarial drugs, which led to
their inclusion in the British Pharmacopoeia, 1914, and to their chemical
examination by various workers. The following is a list of the species
examined and of the alkaloids found. The figures in brackets are percentages of total alkaloids.
(1) Alstonia constricta F. Muell. Alstonine (chlorogenine), alstonidine,
porphyrine, porphyrosine (Hesse J ); alstonine, and three uncharacterised, amorphous bases A, B and C (Sharp 2) (0-4); alstonine
and alstoniline (Hawkins and Elderfield).2(a)
(2) Alstonia macrophylla Wall. Villalstonine, macralstonine, macralstonidine and base M (Sharp, 3 cf. Santos) (0-9).
(3) Alstonia somersetensis F. M. Bailey. Villalstonine, macralstonidine
(Sharp 3 ) (1-4).
(4) Alstonia villosa Blum. Villalstonine, base V (Sharp 3) (1-45).
(5) A. verticillosa F . Muell. Echitamine (Sharp 3) (0-27).
(6) A. scholaris R. Br. Ditamine, echitamine (ditaine of Harnack 4) and
echitenine (Hesse 5 ) ; echitamidine (Goodson 6) (0-16 to 0-40).
(7) A. spectabilis R. Br. Ditamine, echitamine, echitenine, alstonamine
(Hesse 7 ).
(8) A. angustiloba Miq. Echitamine (Goodson 6) (0-17).
(9) A. congensis Eng. Echitamine, echitamidine 6 (0-2 to 0-6).
(10) A. Gilletii De Wild. Echitamine. 6
(11) A. spathulata Blume. Echitamine 6 (0-06).
Most of these barks also contain considerable quantities of unnamed
and uncharacterised amorphous alkaloids. The barks fall into three
groups as sources of (a) alstonine, only found in A. constricta; (b) villalstonine, found in Nos. (2) to (4); and (c) echitamine, isolated from Nos. (5)
to (11). I t is unusual to find species belonging to the same genus divided
into such well-marked groups, in respect of their alkaloidal constituents.
Alstonine, C21H20O3N2. The base was first obtained crystalline by
Sharp. 2 It is unstable, and cannot be recrystallised without loss, but has
been obtained by precipitation, followed by trituration with water, as a
microcrystalline, yellow powder, B . 4H 2 0, sintering at 77 and decomposing
at 130, or from dry alcohol in pale yellow crystals, B . 1-25 H 2 0 , sintering
at 87 and decomposing at 254. It yields well-crystallised salts : the
sulphate, B 2 . H 2 S0 4 . 5H a O, forms stout, pale orange rods, m.p. 209
(dec.); [a] D + 118-6 (dry salt; H 2 0). Leonard and Elderfield m describe
two hydrated sulphates, viz. B 2 . H 2 S 0 4 . 2H 2 0, m.p. 195-6, [a]2,6 + 127
716
ALSTONINE
717
718
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
are similar, except that the latter shows an inflection at about 2,500 A,
which disappears in the case of hexahydroalstonol, C20Hgg02N2, m.p. 282-4
(dec), [a]f 78 3 (pyridine), which is formed by the reduction of
tetrahydroalstonine with sodium in boiling n-butyl alcohol. It gives a
picrate, m.p. 237-8 (dec), and an acetyl derivative, m.p. 95-6; in its
formation a carbomethoxy group is reduced to a primary carbinol group
and two atoms of hydrogen are added. The authors suggest that the data
so far provided indicate that alstonine has a /J-carboline nucleus with
substituents at positions 2 and 3, an unlocated carbomethoxy group and
a still unexplained residue, C6H10O.
Alstoniline, C 22 H 18 0 3 N 2 . This alkaloid was obtained by Hawkins and
Elderfleld 2(a) in working up A. constricta bark by a special process for
alstonine. It occurs in the anhydrous form as yellow-brown needles,
decomposing at 372, and as a monohydrate, B . H 2 0, also in yellow-brown
needles, decomposing at 356. Each form gives its own series of salts,
but the ultra-violet absorption curves of the two are similar so that the
hydration does not seem to imply a fundamental change in the ethylenic
linkage. The anhydrous form changes to the monohydrate on crystallation
from 95 per cent, alcohol.The following salts of the anhydrous form are described : sulphate,
B 2 . H 2 S0 4 , m.p. 260-4 (dec.); picrate explodes above 350 ; methiodide,
B . Mel, decomposes over a wide range.
The monohydrate gives the following salts:
hydrochloride,
B . HC1. H 2 0, fine-red needles decomposing over a wide range ; picrate
B . C 6 H 3 0 7 N 3 . H 2 0, m.p. 294 (dec). Attempts to obtain a methiodide
produced a new monohydrate, yellow needles, m.p. 189-190.
Alstoniline is susceptible to oxidation and in some reactions is recovered
as the oxide, C 2 2 H 1 8 0 4 N 2 . H 2 0 , m.p. 212-3 or 219-221-5 (dry), which
can be prepared by the aeration of the hydrated base in alcoholic solution.
Alstoniline monohydrate absorbs four atoms of hydrogen in presence of
platinic oxide, but on exposure to air during working-up, the reduced
product changes into alstoniline oxide. Alstoniline sulphate and hydrochloride absorb 8 and 4 atoms of hydrogen respectively, producing stable
products, m.p. 233-4 (dec.) and 231-2.
All Hesse's alkaloids accompanying alstonine are amorphous except
alstonidine,1 needles, m.p. 181, which also yields crystalline salts, but for
which no formula has been suggested.
Villalstonine, C40H50O4N4. This alkaloid, isolated by Sharp, 3 is a
colourless granular powder, sintering at 218 and melting at 260 ; it yields
well-crystallised salts. The hydrochloride, B . 2HC1. 4H 2 0, forms colourless needles, m.p. 270 (dec), [a] D + 56-3 ( H 2 0 ) ; the hydrobromide,
B . 2HBr . 4H 2 0, is similar and has m.p. 293; the sulphate,
B . H 2 S0 4 . 6H 2 0, crystallises with difficulty in prismatic rods, m.p. ;>310,
[]D + 52-94 ( H 2 0 ) ; the oxalate, B . H 2 C 2 0 4 , separates from alcohol in
colourless leaflets, m.p. 235 (dec), [a] D -f 55-6 (H 2 0). The base gives a
pink colour, changing to bluish-violet with vanillin and hydrochloric acid,
and a brown, changing through purple to blue with sulphuric acid.
ECHITAMINE
719
720
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
ARISTOLOCHIA
721
ALKALOIDS
constricta var mollis has been examined by Keogh and Shaw,12 and in its
action on isolated intestine, uterus, heart, circulation and striated muscle
is said to resemble quinine ; but in animal experiments showed little antimalarial action.
According to White, 13 alstonine sulphate causes contraction and
increased tone in isolated rabbit uterus and induces a fall in blood pressure
in the anaesthetised cat, which is unaffected by atropine.
Wakim and Chen 13(a) state that alstonine hydrochloride has about
two-thirds of the activity of quinine against Plasmodium lophurce in ducks
but is more toxic. Large doses have a deleterious action on the heart,
and fatal doses cause primary respiratory failure in anaesthetised cats,
dogs and rats. Villalstonine behaves similarly but is less active. 14 Echitamine, according to Trevan, 15 is toxic to mice in doses of 0-3 to 0-5 mgm.
per 20 gm., and acts by paralysis of the medulla. Raymond-Hamet l 6
has investigated the influence of echitamine on the effects induced by
administration of adrenaline : unlike ergotoxine, yohimbine and other
indole alkaloids, it exerted no sympathicolytic action, and he was unable
to confirm the atropine-like effect on the cardiac vagus attributed to it by
Harnack. 17
REFERENCES
(1) Annalen, 1880, 205, 360. (2) J. Chem. Soc, 1934, 2 8 7 ; 1938, 1353. (2a) J.
Org. Chem., 1942, 7, 573. (2b) Ibid., p . 556. (3) J. Chem. Soc., 1934, 1227 ; cf. SANTOS
and SANTOS, Bull. Univ. Phil. Nat. Appl. ScL, 1936, 5, 153. (4) Arch. exp. Path.
Pharm., 1877, 7, 1 2 6 ; Ber., 1878, 11, 2004; 1880, 13, 1648. (5) Annalen, 1875, 176,
326 ; 178, 49 (with JOBST) ; 1880, 203, 144 ; Ber., 1880, 13, 1841 ; cf. BACON, Phil. J.
Sci., 1906, 1, 1007. (6) J. Chem. Soc, 1932, 2626. (7) Ber., 1878, 11, 1546 ; Annalen,
1880, 203,170. (8) J. Chem. Soc, 1925,127,1640. (9) " Pharmacographia," Macmillan
& Co., London, 1879.
1934, 116,
1022; 1941, 1 3 5 , 1 5 6 5 ; Compl. rend., 1939, 209, 1013. (17) Arch. exp. Path.
1877, 7, 126.
Pharm.,
ALKALOIDS OF ARISTOLOCHIA
SPP.
The Aristolochias are used in medicine as tonics due to the presence
of bitter principles, though Hesse x suggested that A. reticulata Nutt, then
the serpentary root of commerce, might contain aristolochine, and the
view that the bitter constituents are of alkaloidal character has been
confirmed by Krishnaswamy, Manjunath and Rao, 2 for A. indica L.
Three apparently different bases have been isolated from this genus
of plants and named aristolochine. Pohl's alkaloid 3 was obtained from A.
clematitis L. and A. rotunda L. I t was assigned the formula C 32 H 22 0 13 N,
which Hesse s reduced to C 17 H 11 0 7 N, and is described as crystallising
from ether in yellow needles, m.p. 215 {dec), soluble in alkalis and giving
a green coloration with sulphuric acid. The same substance was obtained
by Castille * from A. Sipho He>it. and by Ryo s from A. debili. The former
states that it can be reduced to a colourless substance, Ci 7 H l s O r N, which
722
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
723
paralysis in frogs and mice : exerts some pressor action and increases the
rate of respiration in rabbits. Skeletal muscle is stimulated by small and
paralysed by large doses. In rabbits it causes hsemorrhagic nephritis and
an arsenic-like, gastro-intestinal irritation in dogs. Serpentary root is
used in medicine solely as a bitter tonic. Its appearance is, no doubt, the
foundation for the belief, common among natives of the tropics, than it is
an antidote for snake-venom.
REFERENCES
(1) Pharm. J., 1891-92, 51, 551 ; Arch. Pharm., 1895, 233, 684. (2) J. Indian
Chem. Soc, 1935, 12, 476 ; 1937, 14, 39 ; 1938, 15, 646. (3) Arch. exp. Path. Pharm.,
1892, 29, 282 ; cf. H E S S E , Arch. Pharm., 1895, 233, 684. (4) CASTILLE, J. Pharm. Belg.,
1922, 4, 569. (5) R Y O , Folia Pharmacol. Jap., 1927, 4, 123. (6) Pharm. Acta Helv.,
1943, 18, 243. (7) Buchner's Rep. Pharm., 1851, [iii], 7, 1.
ALKALOIDS OF CASSIA
ABSUS
Two alkaloids, chaksine and isochaksine, were isolated as carbonates
from the seeds of this plant by Siddiqui and Ahmed, 1 and the formula
C12H2102N3 was assigned to them. Both were described as quaternary
bases, forming salts, C12H20ON3X, by loss of water and chaksine sulphate
on treatment with barium hydroxide yields isochaksine. Later Kapur,
Gaind, Narang and Ray 2 suggested the new empirical formula C n H 2 1 0 3 N 3 ,
and Puri, Sharma and Siddiqui 3 found that the analytical results with
the benzoyl benzoate supported the C12 formula, but those for organic acid
salts were in better agreement with the C n formula. Chaksine has only
been prepared in an impure state, [a] D -f- 32 (EtOH). The iodide has
m.p. 168 (dec.); chloride, m.p. 178, bromide, m.p. 186; nitrate,
m.p. 220 (dec.) ; sulphate, m.p. 316 (dec.) ; picrate, m.p. 239-240 (dec.)
and platinichloride, m.p. 232 (dec). The hydrogen carbonate, B . HC0 3 ,
formed by adding a saturated aqueous solution of potassium bicarbonate
to the iodide in methyl alcohol, melts at 117-9 and is converted by the
action of benzoyl chloride, in presence of sodium hydroxide, into benzoylchaksine benzoate, C 2 6 H 2 9 0 4 N 3 .0-5H 2 O, m.p. 183-4, [a]?f 29
(CHC13), which is slowly dehydrated at 100 in vacuo to the anhydrous
form, m.p. 273, [a]jf + 15-9 (CHC13). A few preliminary degradation
experiments have also been made with chaksine.
isoChaksine forms a picrate, m.p. 184, a platinichloride, m.p. 172 (dec),
and a chloride, which loses a molecule of water at 90, forming a product,
m.p. 250-2 (dec). The carbonate, B 2 C0 3 , m.p. 128 (dec), is formed when
chaksine acid carbonate is heated in alcohol.
REFERENCES
(1) Proc. Ind. Acad. Sci., 1935,2A, 421 ; J. Ind. Chem. Soc., 1941,18, 589. (2) Ibid.,
1940, 17, 281. (3) J. Sci. Ind. Res. (India), 1946, 4, 701 ; see also AGGARWAI,, RAY and
ALKALOIDS OF DENDROBIUM
SPP.
The stems of these plants constitute the drug " Chin-Shih-Hu,"
used in China and Japan as a tonic and antipyretic. Some uncertainty
724
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
exists as to the species used, but Read gives the Chinese name as " Shik
Hu " and the source as D. moniliforme Sw., with D. monile Lindl. and D.
Macrae as quoted by other authors. From this drug Suzuki et al. isolated
dendrobine and an unnamed base. 1 They have also obtained dendrobine
from D. Linawianum, and recorded the presence of alkaloids in D. flaviflorum and D. toscensis and their absence from D. longicalcaratum.
Dendrobine, C 16 H 25 0 2 N, crystallises in colourless needles or prisms,
m.p. 134, [x]lf - 51-5 (EtOH) and yields well-crystallised salts : B . HC1,
m.p. 246 (dec), [a]*4" - 41 ( H 2 0 ) ; B . HI, m.p. 223 [dec), [aft** - 34-5
(H 2 0); aurichloride, B . HAuCl4, needles, m.p. 181 ; methiodide, B . Mel,
m.p. 231 {dec), [a]*5" 30-9 (MeOH). The base sublimes slowly at 50.
It contains a methylimino but no methoxyl group, behaves as a tertiary
amine and appears to be a y-lactone furnishing dendrobinic acid, C 16 H 27 0 3 N,
m.p. 227 {dec), [a.]f 27-5 (EtOH), which yields an unstable hydrochloride, an amorphous aurichloride, m.p. 85 (dec) and a crystalline
methiodide, m.p. 211 (dec). Methyl dendrobinate has m.p. 94, [a]J,4'5
17-5 (EtOH), and gives an acetyl derivative, m.p. 75.
Dendrobine methiodide is convertible into the methohydroxide,
m.p. 251 (dec). With cyanogen bromide cyanononlendrobine, m.p. 188,
was obtained, from which nordendrobine, m.p. 117-8, [a]},0" 21-6
(EtOH), was prepared via the carbamide. Dendrobine has also been
prepared by Chen and Chen,2 who record for certain of the salts, m.ps.
different from those given above, e.g., B . HC1, m.p. 193, B . HI, m.p.
284-5, but whose data are otherwise in agreement with those of Suzuki et al.
Chen et al.2 state that dendrobine produces moderate hyperglycemia,
diminishes cardiac activity in large doses, lowers blood pressure, depresses
respiration, inhibits isolated rabbit intestine and contracts isolated
guinea-pig uterus. It has a weak analgesic, antipyretic action. Chen
and Rose 2 found that the convulsions induced by injection of dendrobine
can be controlled by use of sodium isoamylethylbarbiturate : they appear
to be central in origin due to action on the cord and medulla.
REFERENCES
(1) (With KEIMATSU and ITO), J. Pharm. Soc. Japan, 1982, 52, 162 ; 1934, 54,
138, 146 ; (with KEIMATSU), 1932, 52, 183. (2) J. Biol. Chem., 1935, 111, 653 ; J.
Pharm. exp. Ther., 1935, 55, 319 ; LEE, VAN AHENDONK and CHEN, ibid., 1936, 56,
466 ; CHEN and ROSE, Proc. Soc. Exp. Biol. Med., 1936, 34, 553.
ALKALOIDS OF DICHROA
FEBRIFUGA
Dichroa febrifuga Lour, of the botanical family Saxifragaces, is a
Chinese anti-malarial drug known as Ch'ang Shan, of which the roots are
used. It was stated to contain two alkaloids, dichroine-A, m.p. 230
(dec), and dichroine-B, m.p. 237-8 (dec), of which the second proved
active in chick malaria, 1 but according to Tonkin and Work 2 neither
acid nor aqueous extracts gave alkaloidal reactions though they showed
considerable activity against a trophozoite-induced infection of P. gallinaceum in chicks.
DIGHROA ALKALOIDS
725
The roots and leaves have been re-examined by Koepfli, Mead and
Brockman, 3 who have isolated two alkaloids. Febrifugine, C 16 H 19 0 3 N 3 ,
m.p. 139-140, [a]|5 + 6 (CHC13), was obtained from both root and
leaves. It yields a dihydrochloride, m.p. 220-2 (dec), and is stated to
have about 100 times the activity of quinine against P. lophurce in ducks.
The second base, wofebrifugine, is isomeric with the first, has m.p. 129-130,
[ i ] f + 131 (CHC13), gives a hygroscopic hydrochloride and is convertible
into febrifugine by heat. Both alkaloids have almost identical ultra-violet
absorption spectra with maxima at 225, 266, 275 and 302 m/x and minima
at 250, 271 and 288 m/x, and there is evidence that two of the nitrogens are
in a quinazoline ring. The total alkaloidal content is about 0-1 per cent,
of the dry weight of the roots.
A further contribution to this subject has been made by the Chinese
workers 4 quite recently, in which they describe briefly five bases, of which
the three dichroines are interconvertible isomerides of the formula,
C 16 H 21 0 3 N 3 . The melting points of the salts are also decomposing points:
Dichroine-a, m.p. 136; sulphate, m.p. 230 ; B . HC1, m.p. 210.
Dichroine-, m.p. 146; sulphate, m.p. 224; B . HC1, m.p. 219;
B . 2HC1, m.p. 238.
Dichroine-y, m.p. 161; sulphate, m.p. 224; B . HC1, m.p. 219;
B . 2HC1, m.p. 238.
Dichroidine, C 18 H 25 0 3 N 3 , m.p. 213.
4-Ketodihydroquinazoline, C8H6ON2, m.p. 215.
They also state that analytical studies of the oxidation products of
dichroine-a indicate that the dichroines are quinazoline derivatives, as
already indicated by Koepfli et al. for their alkaloids. With the probable
exception of dichroine-a, these bases are active against malaria in chicks
in the descending order : dichroine-y (1), dichroine-/J (4); dichroidine ;
quinazolone (40); the figures in brackets are effective doses (mgm./kilo.).
There are also two neutral substances present, umbelliferone (dichrin-A)
and dichrin-B, m.p. 179-181.
REFERENCES
(1) JANG, FU, WANG, HUANG, LU and CHOU, Science, 1946, 103, 59. (2) Nature,
1945, 156, 630 ; WOBK, ibid., 1948, 161, 400 ; HOOPER, ibid., 1946, 157, 106. (3) J.
Amer. Chem. Soc, 194,7, 69, 1837. (4) JANG, FU, HUANG, WANG, Nature, 1948, 161,
400, with a list of prior publications from 1943 in China.
ALKALOIDS OF ERYTHROPHLCEUM GUINEENSE
G.Don.
This tree occurs widely distributed in Africa and the bark is known
under a variety of native names, e.g., " sassy bark " in West Africa,
where it was formerly used as an ordeal poison; in East and Central
Africa it is said to have been an ingredient in arrow-poisons. The" bark
was first examined by Gallois and Hardy 1 who isolated a toxic alkaloid,
erythrophleine, which- was examined by Harnack and Zabrocki 2 and
later by Harnack, 3 whose results differed from those of Gallois and Hardy
and were generally confirmed by Power and Salway.* Recently interest
726
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
in this and other species of the same genus has revived and a number of
chemical and pharmacological investigations have been made. Dalma 5
isolated from E. guineense bark, collected in forests at the mouth of the
Congo, four alkaloids, cassaine, cassaidine, norcassaidine, subsequently
shown to be cassaidine,14 and homophleine, which is amorphous. In a
second sample of bark from the same locality, but possibly derived from
a sub-species of E. guineense, Dalma found 0-1 per cent, of alkaloids of
which about one-tenth was cassaine, while in a third specimen from
central Congo forests 0-5 per cent, of amorphous base was isolated, which
appeared to be erythrophleine. Paris and Rigal 6 isolated from the bark
of E. guineense four alkaloids for which they record the following meltingpoints : (a) 105-6, picrate, m.p. 332-4 (dec.); (b) 114-6 ; (c) 105, and
(d) 112, and from the seeds two more : (e) 185-6, picrate, m.p. 277-8,
acetyl derivative, m.p. 123-4, and ( / ) m.p. 124.
These results seem to indicate a remarkable capacity for variation in
the alkaloidal components of Erythrophlceum guineense, or a need for
botanical investigation of the genus Erythrophlceum, and for care on the
part of chemists in making certain of the botanical authenticity of the
plant material they investigate.
Paris and Rigal state that the toxicity to guinea-pigs of E. couminga,
E. guineense, E. ivorense and E. Fordii decreases in that order. Laborde '
recorded the presence of an alkaloid resembling erythropleinein.E.commrcga,
a species found in Madagascar and the Seychelles, and in some of the
earlier papers on Dalma's alkaloids there are references to " madagascar,"
C 26 H 41 0 6 N, coumingine and coumingaine, of which coumingine has
been fully described. To these Schlittler has added coumingidine and
Ruzicka et alP have given a preliminary description of a third, welldefined, but still un-named alkaloid from this species, in which they have
also recorded the presence of cassaine and cassaidine.
Alkaloids closely resembling erythrophleine have been recorded in
the Australian species E. chlorostachys by Petrie, 8 in E. lasianthum of S.
Africa by Kamerman, 9 and in an unidentified bark from Mozambique by
Jacobsohn.10
All the erythrophleum alkaloids examined in detail so far are of the
same type, viz., acyl esters of either monomethylaminoethanol, e.g.,
erythrophleine and coumingidine or dimethylaminoethanol, such as
cassaine or cassaidine. The acyl substituents are complex, yield 1 : 7 : 8 trimethylphenanthrene on selenium dehydrogenation, and contain
at least one hydroxyl group, which may be acylated by an aliphatic
acid, e.g., coumingine forms three components on hydrolysis,
]8-hydroxyisovaleric acid, Me2 . C(OH) . CH2 . COOH, cassaic acid,
C17H27(CHOH)(CO)(COOH), and dimethylaminoethanol,
HO . CH2 . CH a . NMe2.
Erythrophleine, ^ H g j O j N .
This formula,' adopted by Blount,
Openshaw and Todd, u is based on analyses of the sulphate B . 0-5H.Ot,
and on the composition of the well-defined hydrolytic products, prepared
ER
YTHROPHLEINE
727
and characterised by these authors. The base has not been crystallised ;
the commercial sulphate is a cream-coloured, amorphous powder, but
a crystalline specimen has been mentioned by Chen et al.21 The salt
is readily soluble in water and in several organic solvents, including
benzene.11 The base contains one hydroxyl, one methoxyl and one
methylimino group, and gives a positive reaction for carbonyl with
2 : 4-dinitrophenylhydrazine. Harnack 3 first showed that erythrophleine
eould be hydrolysed by boiling with hydrochloric acid and described the
products as methylamine and amorphous, nitrogen-free erythrophleic acid.
Blount, Openshaw and Todd u investigated this reaction and found that
the best results were obtained by the use of iV/3-sulphuric acid under
carefully controlled conditions. The products are erythrophleic acid,
C 21 H 32 0 5 , and /3-methylaminoethanol; the latter was identified as the
picrate, m.p. 148, and the N-methyl-N-/?-hydroxyethyl-N'-a-naphthyIthiourea, m.p. 125. On this basis the formula of erythrophleine may be
extended thus : C 20 H 31 O 3 . CO . O . CH 2 . CH 2 . NHCH 3 .
Erythrophleic acid melts at 218, has [a]f, 40 (CHC13), contains
one methoxyl group and on hydrogenation, with platinic oxide catalyst,
takes up one molecule of hydrogen rapidlj-, to saturate one ethylenic
linkage, and a second molecule slowly, in reduction of a carbonyl group.
The methyl ester of the acid sublimes at 140/10'4 mm. as a white powder,
yielding a 2 : 4-dinitrophenylhydrazone, m.p. 219, crystallising in small
orange-red plates. On dehydrogenation with selenium at 270-300,
erythrophleic acid yields 1:7:8-trimethylphenanthrene, m.p. 143-4,
and a selenium compound, C19H16Se, m.p. 161-2. Erythrophleic acid
contains one hydroxyl group but no crystalline acyl derivative has yet
been obtained. The ultra-violet absorption spectrum (max., ca. 2210A;
log e, 4- 2) probably indicates an ajS-position of the double bond in relation
to the carboxyl group. From these data, and assuming that the formation
of 1 : 7 : 8-trimethylphenanthrene on dehydrogenation implies a diterpenoid structure, the partial formula I was suggested for this acid : the
positions of the methoxyl and carbonyl groups are still unknown and the
ethylenic linkage may be at C2C1 instead of C2C3 as shown.
The authors point out that erythrophleic acid may be a
methoxy-derivative of cassaic acid,
C20H30O4 (p. 728). Ruzicka, Dalma and
vx
Scott 1 3 (1941) have pointed out that
_//^S\/^\
formula I cannot be the basis of a general
T7
T
|
formula for the erythrophlceum alkaloids,
If
A.
JC"
because their degradation to 1 : 7 : 8-tri^/ M e \ /
JS-CH
me thylphenanthrene would then imply the
not r=0
I
I
migration of a methyl group from C8 to , o c a t t d {-Me j
\^Jrc<izH
C7 for which a substituent at C7 is essential.
These conditions do not obtain in cassanic acid (p. 728) although this acid
dehydrogenates to 1 : 7 : 8-trimethylphenanthrene.
Cassaine, C ^ H g ^ N . This alkaloid was first isolated by Dalma 6 and
was further examined by Faltis and Holzinger." According to Dalma it is
728
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
COUMINGINE
729
730
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
methyl ester, m.p. 150 ; oxidation product, diketocassenic acid, m.p. 249,
[oc]jf - 1 5 2 (EtOH), and its methyl ester, m.p. 132-3, [<x]f - 156
(EtOH).
From these results it was concluded that coumingine is an ester of
cassaine with an acid, which was later identified by Ruzicka, Dalma,
Engel and Scott 1 6 as /Miydroxywovaleric acid,
HO . C(CH 3 ) 2 . CH 2 . C0 2 H.
Coumingidine, C 28 H 45 0 6 N, or C 27 H 43 0 6 N. This alkaloid, found by
Schlittler 17 in the bark of E. couminga, is a secondary base and is best
isolated as the nitroso-derivative, m.p. 174-174- 5, from which it is
regenerated by the use of cuprous chloride.18 It has m.p. 160-1 and forms
a hydrochloride, m.p. 217-9; phenylthiocarbamate, m.p. 146, and
acetyl-derivative, m.p. 155, [a]| - 64-5 (EtOH).
Dihydrocoumingidine, obtained by catalytic hydrogenation, and
isolated as the perehlorate, m.p. 166-8, forms an acetyl derivative,
m.p. 115-116-5. On hydrolysis by iV/2-H2S04, coumingidine yields
monomethylaminoethanol, identified as the 3 : 5-dinitrobenzoyl derivative,
m.p. 195-196-5. When either acetyl- or nitroso-coumingidine is treated
with potassium carbonate in methyl alcohol, the amino-alcohol is split off
and the nitrogen-free hydrolytic acid is obtained as a methyl ester,
C 26 H 40 O 6 , m.p. 204-6. This, on treatment with potassium hydroxide in
methyl alcohol, gives an acid, C20H30O4, m.p. 209-211, of which the
methyl ester has m.p. 170-1 ; this acid is not identical with aWocassaic
acid (p. 728). The methyl ester, C26H40O6, still retains the ethylenic linkage
and its dihydro-derivative, C 26 H 42 0 6 , m.p. 162, on alkaline hydrolysis
furnishes an acid, C20H32O4, m.p. 232-4 (methyl ester, m.p. 114), which
in spite of its rather low melting-point is believed to be identical with ketohydroxycassanic acid (dihydrocassaic acid) for which Faltis and Holzinger12
recorded m.p. 229-235, while Ruzicka and Dalma 1 3 found m.p. 253-5.
Direct hydrolysis of coumingidine by acid or alkali proceeds less smoothly
than with other alkaloids of this group, but one of the products from
hydrolysis by alkali, or by oxalic acid, is cassaic acid.
An unnamed third alkaloid, C 25 H 39(41 )0 6 N, has been isolated by
Ruzicka, Plattner and Engel l 9 from E. couminga by chromatographic
fractionation of the residual alkaloids after removal of secondary bases by
nitrous acid v It has m.p. 149-151, and [a],r 47 (EtOH), and forms an
acetyl derivative, m.p. 100.
A summary of. work done on the Erythrophloeum alkaloids has been
published by Engel. 20
Pharmacology. It has long been known that erythrophleine possessed
local anaesthetic properties, and was the only alkaloid exhibiting action
of the digitalis type. This cardiac action has been confirmed by Chen,
Chen and Anderson, 21 who used a commercial, erythrophleine sulphate
described as crystalline. Santi and Zweifel 22 showed that this was also;
the case with Dalma's alkaloids which they arranged in the following
order of increasing toxicity : norcassaidine (now known to be cassaidine)
ERYTHROPHLWUM
ALKALOIDS
731
cassaine, erythrophleine, homophleine, coumingine. Cassaine is distinguished from t h e other four b y producing intense excitation. Trabucchi a
arranges t h e alkaloids in t h e following decreasing order of local anaesthetic
a c t i v i t y : (1) " madagascar," (2) homophleine, (3) erythrophleine,
(4) cassaine, (5) norcassaidine; percaine, used as a standard in these
experiments, came between (3) a n d (4). T h e first t w o are more irritant
locally. According t o Chen, Hargreaves a n d Winchester, 2 * t h e potency of
coumingine in t h e c a t is similar t o t h a t of scillarenA (a cardiac glucoside
of squill); t h e other alkaloids, coumingaine, cassaine, norcassaidine, are
less p o t e n t t h a n erythrophleine. They all produce emesis in cats. Acetylation reduces t h e cardiac activity, b u t raises slightly t h e emetic action of
cassaine. These authors add t h a t t h e Erythrophlceum alkaloids like other
cardiac drugs increase blood pressure in cats a n d stimulate rabbit intestine
and guinea-pig uterus. This has been confirmed b y further work of Santi
et al.,26 who p u t these activities, and also a vaso-constrictor action, in
approximately t h e following descending o r d e r : coumingine, erythrophleine, homophleine, cassaine, norcassaidine.
F u r t h e r work h a s been done b y various pharmacologists on several
of the special activities referred t o above, e.g., t h e action of erythrophleine
on the isolated uterus a n d intestine of the rabbit b y Rothlin and R a y m o n d H a m e t , 2 6 a n d t h e effects of cassaine, cassaidine, erythrophleine and
coumingine on t h e isolated mammalian heart by Maling and Krayer, 2 7
who s t a t e t h a t erythrophleic acid is devoid of a n y characteristic action
on t h e heart in a dose a t least 100 times as large as t h e minimal positive
inotropic dose of erythrophleine sulphate ; a similar result b y Chen is
quoted b y Blount et al.11 Ruzicka, P l a t t n e r a n d Engel 2 8 have prepared
a series of esters of dimethylamino- and diethylamino-ethanol with bile
acids a n d these have been tested pharmacologically as hydrochlorides.
They showed a slight a n d uncharacteristic digitalis action, and in some
cases local anaesthetic action accompanied b y marked local irritation.
Owing to their ready hydrolysis t h e oral dose m a y be ten times t h e
subcutaneous dose without causing toxic symptoms.
REFERENCES
(1) Bull. Soc. Chim., 1876, 26, 39. (2) Arch. exp. Path. Pharm., 1881-82, 15, 403.
(3) Arch. Pharm., 1896, 234, 561. (4) Amer. J. Pharm., 1912, 84, 337 ; cf. MAPLETHORPE, Pharm. J., 1923, 111, 85. (5) Ann. Chim. Appl., 1935, 25, 569; Helv. Chim.
Acta, 1939, 22, 1497. (6) Bull. Sci. Pharmacol., 1940, 47, 79. (7) Ann. Mus. Col.
Marseille, 1907, [2], 5, 305. (8) Proc. Linn. Soc. N.S.W., 1921, 46, 333. (9) S. Afr. J.
Sci., 1926, 23, 179. (10) Quoted by DALMA 5 (1939). (11) J. Chem. Soc, 1940, 286.
(12) Bar., 1939, 72, 1443. (13) Helv. Chim. Acta, 1939, 22, 1516 ; (with SCOTT), 1941,
24, 179E ; (with ENGEL, RONCO and BEBSE), ibid., 1945, 28, 1038. (14) Ibid., 1940,
23,753. (15) Ibid.,194,1, 24, 63. (16) idem.,p. 1449. (17) Idem, p. 319E. (18) JONES
and KENNEB, J. Chem. Soc., 1932, 713. (19) Experientia, 1945, 1, 160 (Chem. Abstr.,
1946, 40, 3760). (20) " Analytical and Synthetic Work in the Field of the Erythrophleum Alkaloids," Thesis, Zurich, 1945. (21) J. Amer. Pharm. Assoc., 1936, 25, 579 ;
1938, 27, 564. (22) Boll. Soc. ital. Biol, sper., 1936, 11, 758, 760; cf. DALMA, ibid.,
p. 791, and SANTI, Arch. exp. Path. Pharm., 1939, 193, 152. (23) Arch. Farm, sperim.,
1937, 64, 97. (24) J. Amer. Pharm. Assoc., 1938, 27, 9, 307; CHEN (with ROSE),
Proc. Soc. Exp. Biol. Med., 1942, 49, 351; (with ANDEBSON, HENDEBSON and MILLS),
732
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
ibid., 1943, 53, 200. (25) BoU. Soc. tad. Biol, sperim., 1937, 12, 720, 721 ; (with
PEIXIZARI), ibid., p. 723 ; (with ZWEIFEL), ibid., pp. 337, 724 ; CACCIAVULANI, ibid.,
p. 339; SANTI.22 (26) Arch. int. Pharmacodyn., 1939, 63, 10. (27) J. Pharm. exp.
Ther., 1946, 86, 66 ; cf. VAN DEB BERG, Acta brev. Neerland. Physiol. Pharmacol.
Microbiol., 1938, 8, 211. (28) Helv. Chim. Ada, 1944, 27, 1553.
ALKALOIDS OF FRITILLARIA
SPP.
FRITILLARIA
ALKALOIDS
733
alkaloid has two active hydrogen atoms but contains neither a methoxyl
nor a methylimino group. Wu 4 suggested that peimine may be a dihydroxy5
734
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
Buss., 1943, 13, 159. (3) "Chinese Medicinal Plants from the Pen Ts'ao Kang Mu,
A.D. 1596 " (Pekin, 1936). (4) CHOU and CHEN, Chin. J. Physiol., 1932, 6, 265 ; 1933,
7, 41 ; (with ROSE and ANDERSON), ibid., 1935, 9, 21 ; cf. Liu, CHANG and CHANG,
Chin. Med. J., 1936, 50, 249; CHI, KAO and CHANG, J. Amer. Chem. Soc., 1936, 58,
1306 ; 1940, 62, 2896 ; CHOU and CHU, ibid., 1941, 63, 2936 ; 1947, 69, 1257 ; Wu,
ibid., 1944, 66, 1778 ; CHOU, J. Amer. Pharm. Assoc, 1947, 36, 215. (5) JUNOSOV,
KONOVALOVAand OREKHOV, J. Gen. Chem. Russ., 1939, 9,1911. (6) Arch. int. Pharmacodyn., 1913, 23, 277. (7) Sci. Rep. Toko/at Imp. Univ., 1929, [i], 18, 323. (8) J. Chin.
Pharm. Assoc, 1940, 2, 235 (Chem. Abstr., 1942, 36, 1940); Liu, CHANG and CHANG.*
(9) Arch. int. Pharmacodyn., 1910, 20, 117. (10) Tohoku J. Exp. Med., 1935, 26, 825 ;
1936, 28, 26. (11) J. Amer. Pharm. Assoc, 1933, 22, 638. (12) Farmakol. i.
Toksikol., 1944, 7, No. 6, 51 ; 1945, 8, No. 6, 15 (Chem. Abstr., 1946, 40, 5848,
7411).
GARRY A
735
ALKALOIDS
ALKALOIDS OF GEISSOSPERMUM
VELLOZII
From " pereiro bark " of this species (also known as Taberncemontana
Icevis Veil.) used in Brazil as a febrifuge, Hesse isolated two alkaloids,
geissospermine and pereirine^1 and a third, vellosine, was found by Freund
and Fauvet. 2 Geissospermine has been investigated by Bertho et al.,3 whose
data are used in the following account.
Geissospermine, C10H50O3N4 . 1-5H20, crystallises from dilute methyl
alcohol, has m.p. 145-7 (dec), [al| 101-9 (EtOH), and on recrystallisation from ethyl acetate gives the dihydrate, B . 2H 2 0, m.p. 210-2 (corr.),
[<x]D - 108-2 (EtOH). The sulphate, B . H 2 S0 4 . 6H 2 0, m.p. 226 (dec),
[oc]D 84-2 ( H 2 0 ) ; oxalate, B . H 2 C 2 0 4 . 5H 2 0, m.p. 193 (dec.); and
dimethiodide, B . 2MeI. 4H 2 0, m.p. 261-2, |a]| 61-5 (EtOH), are all
well crystallised. The alkaloid contains one methoxyl group, a labile, basic
methylimino group and two active hydrogen atoms (Zerewitinoff). It gives
a colourless solution with pure sulphuric acid, a blue colour with sulphuric
acid containing ferric sulphate and a purple colour with nitric acid. For
a detailed study of the colour reactions, see Haymond-Hamet. 4
Bertho et al.3 have shown that geissospermine is hydrolysed by cold,
strong hydrochloric acid to two isomeric bases, C20H2602N2, presumably
by the scission of an ether linkage between the two halves of the molecule.
Base A discolours at 155, m.p. ~ 205 (dec), [<t]f 101 (EtOH), and
shows colour reactions similar to those of the parent base, which resemble
those of yohimbine and it is suggested that base A, the corresponding
half of geissospermine, and the minor alkaloid pereirine (p. 736) probably
have the same ring system as yohimbine. Base B, isolated as the hydrochloride, m.p. 159-160, is crystalline, m.p. ~ 160 (dec), gives no colour
736
with nitric acid, is free from methoxyl but contains one methylimino group
and forms a hydrobromide, m.p. 225-6 (dec), and a methiodide, B . Mel,
m.p. 230-1 (dec). The latter gives an amorphous monoacetyl derivative,
C22H2803N2 , Mel, decomposing at 237.
Geissospermine is converted by phosphorus and hydriodic acid in
boiling acetic acid to a deoxy-base, C20H26ON2, imp. 212-3 (dec), which
gives no colour with nitric acid and forms a methiodide decomposing at
246. The function of the third oxygen atom in geissospermine has not
been ascertained ; it gives no carbony 1 or hydroxyl group reactions.
Two of the nitrogens are tertiary and from the results of pyrolytic experiments the other two appear to occur in a pyridine and an indole nucleus.
The two active hydrogens are also still unexplained.
Distillation of geissospermine with zinc dust affords 3-ethylpyridine,
identified as the picrate, m.p. 126, and platinichloride, m.p. 183, and ah
indole base giving a picrate, m.p. 256-7 (dec). The mixed minor alkaloids
accompanying geissospermine, on distillation with zinc dust, gave (1) a base
forming a picrate, m.p. 128-130, and a platinichloride, m.p. 188-190,
which may be 2-methyl-6-ethylpyridine, and (2) a hydrocarbon, C 20 H 40 ,
m.p. 44-5 to 45-5.
Pereirine, C 20 H 26 ON 2 . 0-5H2O. According to Bertho and Moog3, this
amorphous alkaloid, m.p. 134-5, [a]f + 137-5 (EtOH), gives a
methiodide decomposing at 233-5 and a methyl ether, m.p. 195-7 (dec),
and is stable to dilute mineral acid. Bertho and Sarx 3 state that chromatographic examination shows the alkaloid has not been obtained pure.
Vellosine, C 23 H 28 0 4 N 2 , crystallises from hot alcohol in prisms, m.p. 189,
[oe]D + 22-8 (CHC13). The hydrobromide, m.p. 194-5, and the hydriodide,
m.p. 217-8, both crystallise with one molecule of water. Vellosine
contains two methoxyl groups and behaves as a monoacidic, tertiary base.
On heating with mineral acids it loses water, forming apovellosine,
C 46 H 54 0 7 N 4 . In physiological action it resembles brucine and is toxic to
rabbits in doses of 0-075 gm. per kilogramme of body weight.2
Raymond-Hamet 4 has published, with a bibliography, a critical
historical account of the botany and chemistry of pereiro bark, the botanical
source of which he suggests should be named Geissospermum Iceve (Vellozo)
Baillon. There seems to be some doubt as to whether vellosine was actually
obtained from this species.
REFERENCES
(1) Annalen, 1880, 202, 141. (2) Ibid., 1894, 282, 247 ; cf. HESSE, p. 266. (3) (With
VON SCHUCKMANN), Ber., 1931, 64, 2278 ; (with MOOG) Annalen, 1934, 509, 241; (with
SARX), ibid., 1944, 556, 22. (4) Bull. Sci. Pharmacol., 1937, 44, 449.
ALKALOIDS OF GELSEMIUM
SPP.
The existence of alkaloids in the rhizome and roots of the North
American plant Gelsemium sempervirens Ait (Loganiaceae) was first demonstrated by Wormley 1 and later a crystalline alkaloid, gelsemine, was
isolated by Gerrard. 2 Thompson 3 found in addition to gelsemine an
amorphous alkaloid, gelseminine. Gelsemine was later examined by
737
GELSEMINE
24
738
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
m.p. 328-330 {dec.); B . H N 0 3 , m.p. 285 (dec), and B . Mel, m.p. 301 -2
(dec). The dihydro-base on treatment with nitric and sulphuric acid at
7 forms dinitrogelsemine, C2oH20O2N2(NO2)2, m.p. 257-8 (dec),
[a]f + 6-6, of which the methiodide has m.p. 255-6 and [a]*8" 68-5
(MeOH). Marion 13 found that a mixture of bases and neutral products
is obtained when gelsemine is heated to 320 with either soda-lime or
selenium. The neutral products included 2 : 3-dimethylindole, characterised as the picrate, m.p. 154-5. The bases gave two picrates, m.p. 210
and m.p. 238 (dec), not yet identified.
Forsyth et al.8 pointed out that gelsemine is remarkably inert; they
were unable to repeat Moore's preparation of an acetyl derivative, to
obtain reactions with hydroxylamine, or to induce normal degradation of
the methiodide and they confirmed Moore's failure to induce reaction
with boiling alkali. By hydrogenation of gelsemine in dry acetic acid in
presence of Adams's platinic oxide catalyst they succeeded in preparing a
hexahydro-derivative, C2oH2802N2, m.p. 170, which forms a methiodide,
m.p. 296, and does not give the gelsemine colour reaction with sulphuric
acid and dichromate. On fusion with potash, gelsemine gave the amorphous base providing the picrate, m.p. 152, already referred to.
In view of the strychnine-like pharmacological action recorded for
gelsemine, Janot and Berton 8(a) have compared the ultra-violet absorption
spectra of the two alkaloids, which proved to be remarkably similar.
That of sempervirine was quite different and also unlike those of indole,
quinoline and cinchonamine, with which it was also compared.
Gelsemine dissolves in sulphuric acid, giving a colourless solution,
which on the addition of a crystal of potassium dichromate becomes red,
then violet and finally green. A solution in alcohol gives a pink colour
with dimethylaminobenzaldehyde in hydrochloric acid.
Addendum. Witkop 22 has shown recently that on distillation with zinc,
gelsemine yields skatole (3-methylindole) and two basic products, of which
the stronger has the formula C U H 1X N, forms a picrate, m.p. 185-7,
and is probably a dimethyh'soquinoline, not identical with the known
1 : 3 ; 1 : 4 ; or 3 : 4-dimethyKsoquinolines. The weaker base yields a
picrate, C 1 4 H U N . C a H 3 0 7 N 3 , m.p. 218-220. The formation of skatole
and a dimethyh'soquinoline implies simple breakage thus :C20H22O2N2>
C9H9N + C n H n N and it is suggested that gelsemine may have a structure
of the yohimbine type (XIV; p. 508), which in this reaction breaks across
ring C.
Sempervirine, C19H16N2 . H 2 0 . From the alkaline liquid, after removal
of gelsemine by ether, Moore 6 observed that amyl alcohol extracted two
amorphous alkaloids, of which the more basic was probably Thompson's
gelseminine. From this material crystalline sempervirine was obtained
by Stevenson and Sayre, 7 and later by Chou,9 but a formula was first
assigned to it by Hasenfratz.14 It forms yellow needles, m.p. 228, from
chloroform, or orange-yellow to brown-red crystals, m.p. 258-260,
from alcohol, [a] D 0, pK value > 10*6. The salts crystallise well:
B . HC1. 2H 2 0, yellow prisms, m.p. > 300 ; B . HBr . 2H 2 0, m.p. 825
SEMPERVIRINE
739
[xff+85.
Two varieties of Chinese gelsemium have been examined by Chou
et al., viz., " K o u - w e n " and " Ta-ch'a-yeh," 10 both said to be derived
from Gelsemium elegans Benth. The alkaloids found in " Kou-wen " are
as follows :
Koumine, C20H82ON2, rhombic prisms from acetone, m.p. 170, [a]jf
- 2 6 5 (EtOH); B . HC1, m.p. 255 (dec); B . HBr, m.p. 269 (dec).
Kouminine, amorphous, m.p. 115, fajp 0, yields a crystalline hydro2*2
740
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
PHARMACOLOGICAL
ACTION
741
26, 32 ; 1938,
27, 1208 ;
NEUGEBAUEB,
Apoth. Zeit., 1930, 45, 80 ; LYNCH and E V E E S , Analyst, 1941, 66, 108 ; FERREIRO,
These Pharm., Paris, 1940 (Chem. Abstr., 1947, 41, 136); W u , Bull. Nat. Form. Comm.,
1947, 15, 68. (12) J. Amer. Chem. Soc, 1940, 62, 1955 ; 1941, 63, 827. (13) Can. J.
Res., 1943, 21, B . , 247. (14) Compt. rend., 1933, 196, 1530 ; Bull. Soc. Chim., 1933,
[iv], 53, 1084. (15) Ber., 1893, 26, 1725; Arch. exp. Path. Pharm., 1893, 31, 49 ; cf.
CHEN, P A K and H o u 1 0 ; D E ESPANES, Compt. rend. Soc. biol., 1938, 127, 1002,
1176,1178; Risi, Zeit. Biol., 1939, 99,446. (16) Compt. rend., 1937, 205,1449. (17) J.
Amer. Pharm. Assoc, 1943, 32, 178. (18) Compt. rend. Soc biol., 1937, 126, 690, 1151 ;
(with ROTHLIN), ibid., 1934,117, 754, 859 ; 1941,135, 478 ; cf. CHOU." (19) Proc. Soc.
Exp. Biol. Med., 1931, 28, 7 7 9 ; Chin. J. Physiol., 1931, 5, 137, 181, 2 7 9 ; see also
CHEN (with CHOU and H o u ) , ibid., 1939, 14, 3 1 9 ; (with L E E ) , ibid., 1939, 14, 489.
(20) (With A N D E E S O N and BROWN R O B B I N S ) , Quart. J. Pharm.,
(21)
Compt. rend. Soc. Biol., 1938, 129, 3 8 6 ; (with CAHEN), Compt. rend., 1938, 206, 280.
(22) W I T K O P , J. Amer. Chem. Soc, 1948, 70, 1424. (28) Experientia, 1948, 4, 2 4 ;
Helv. Chim. Acta, 1948, 31, 588.
742
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
ALKALOID OF GENTIANA
KIRILOWI
This plant contains the alkaloid gentianine, C l0 H 9 O 2 N, m.p. 79-80, of
which salts have been prepared : hydrochloride, m.p. 171-2; nitrate,
m.p. 238-240; oxalate, m.p. 152-3; and methiodide, m.p. 190-1. On
catalytic hydrogenation, dihydrogentianine, m.p. 75-6, is formed. On
solution in alcoholic sodium hydroxide, gentianine forms sodium gentianate,
m.p. 132-4, from which the alkaloid is regenerated by acids. Oxidation
of gentianine by permanganate in acetone produces an acid, C 9 H 7 0 4 N,
m.p. 260-2 (dec), which on further oxidation by aqueous alkaline
permanganate, leads to pyridine-3 : 4 : 5-tricarboxylic acid. Zinc dust
distillation of gentianine yields pyridine. The alkaloid is regarded as
3-vinylpyridine fused at positions 4 and 5 with a cyclic lactone, which
may be of type (a) or (b) :
(a) CO . C . C . C . C . O
or
(b) CO . C . C . CMe . O
ALKALOIDS OF HOLARRHENA
1
SPP.
743
CONESSINE
Conessine C21H31(NMe)(NMe2)
norConessine, C23H38N2
Conessimine, C21Hsl(NH)(NMe2)
isoConessimine, C21H31(NMe)(NHMe)
Kurchine, C23H38N2
Conimine, C2IH31(NH)(NHMe)
Conamine, C21H31(NMe)(NH2)
Conanhimine, C21H31(NH)(NH2)
Conessidine, C81H32N,
Conkurchine, C21HS2N2
Conkurchinine, C26H36Na
Holarrhenine, C24H38ON2
Holarrhimine, C21H3l(OH)(NH2)2
Holarrhine, C20H38O3N2
Kurchicine, C20H36ON2
Lettocine, C17H2502N
Conessine .
isoConessine
isoConessimine .
Conimine .
Conessimine
isonorisoConessine
isoConimine
Isomerised by HjSO, to
isoConessine10
Methylated to
10
isonorisoConessine
isoConimine10
Conessine 66
Conessine
Conessine 6 10
isoConessine l0
isoConessine
Demethylated to
tsoConessimine
and
conimine.*
isonorisoConessine
and
isoconimine.11
744
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
base formed from this by the action of silver oxide, on distillation yields
trimethylamine, methyl alcohol and a crystalline product, 8 which Kanga,
Ayyar and Simonsen 12 showed was a mixture of two bases, of which they
isolated and characterised apoconessine, needles, m.p. 68-5, yielding a
picrate, m.p. 234 (Spath 13 ), and a methiodide, m.p. 283-5, which
reverts to apoconessine on treatment with silver oxide. Spath and
Hromatka 1 3 found that in the formation of apoconessine the methyl
alcohol arises from a secondary reaction, that apoconessine should be
represented by the formula C 23 H 35 N, and that it contains three ethylenic
linkages (hexahydroapoconessine, m.p. 69-70), one of which is originally
present in conessine, which yields a dihydro-derivative (see above), also
formed by the hydrogenation of dioxyconessine (Osada 14 ). The same
authors found that apoconessine methochloride was transformed by
sodium amalgam into trimethylamine and a hydrocarbon, C21H30, m.p.
74-6, [a]jf - 183-7 (pyridine), hydrogenated to C21H36, m.p. 56-8,
d52 0-9547, nf 1-50664, [a]}f + 14-5 (benzene).
The conclusion is drawn that conessine contains four hydrogenated,
carbocyclic rings with a ring containing one nitrogen atom attached. This
complex includes one ethylenic linkage resistant to reduction. The
nitrogen eliminated in the formation of apoconessine was originally in an
acyclic structure as an . NMe2 group. 4 Siddiqui and Sharma l S obtained
from conessine and woconessine hydriodides, ammonia and conessene,
C21H30, b.p. 185-19273 mm., [a\f + 35-0, which, like Spath and
Hromatka's hydrocarbon, contains three ethyleni* linkages, but is not
identical with it.
Siddiqui et aZ.15 have also investigated the nitration and the bromination of conessine, and its oxidation by permanganate and by chromic
acid, and have carried out various reactions with the products ; one
outcome of this work is the suggestion that the structure of conessine
includes the chain . CH : CH . CH2.
norConessine, C23H38N2, was obtained by Haworth 1 6 from the mother
liquors remaining from the isolation of conessine as the hydrogen oxalate.
It is a colourless, viscid oil, b.p. 238-240/0-7 mm., [a] D + 6-7 (EtOH),
yielding well-crystallised salts. The dihydrogen dioxalate separates from
alcohol or water in nodules, m.p. 225-7 (dec.); the dihydrochloride has
m.p. 340 (dec), and the dimethiodide forms pale yellow prisms, m.p.
310-2 (dec). With potassium iodate in presence of dilute sulphuric acid
norconessine yields dihydroxynorconessine, (^H^O^Ng, m.p. 264-6, and
the dimethiodide, on treatment with silver oxide, gives the corresponding
ammonium hydroxide which decomposes when heated under reduced
pressure into trimethylamine and the corresponding apo-base, aponorconessine, C22H33N, b.p. 190-2/0-2 mm. The latter furnishes a picrate,
m.p. 244-5, and a methiodide, m.p. 274-6, which could not be degraded
further. Dihydroxynorconessine decomposes on melting, forming a
vapour, which gives the pyrrole pinewood reaction. According to Bertho
(1989) norconessine is identical with kurchine (see p. 745).
Conessimine, C21H31(NH)(NMeg). This is one of four isomerides
HOLARRHENA
ALKALOIDS
745
746
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
has m.p. 152-3, [a]f 51-9 (EtOH), and forms a nitrate, B . 2HN0 3 ,
which colours at 180 and explodes on further heating, carbonate,
B 2 . H 2 C 0 3 , m.p. 149-150, dihydriodide, B . 2HI, m.p. 278 (dec),
sulphate, B 2 . H 2 S0 4 , and oxalate, B 2 . H 2 C 2 0 4 . The diacetyl derivative
forms a monohydrate, m.p. 182-3 (dec), and an alcoholate, m.p. 263.
Hydrogenation in methyl alcohol, with platinic oxide as catalyst, leads
first to dihydroconkurchine, m.p. 97-8, and eventually to tetrahydroconkurchine, m.p. 340-1 (hydrated) or 101-4 (anhydrous). Methylation
of these hydrogenated products, with formaldehyde and formic acid,
roduces conessine and dihydroconessine respectively (see p. 743). With
methyl iodide in boiling ethyl alcohol, conkurchine forms dimethylconkurchine dimethiodide, C2SH42N2I2, m.p. 277 (dec).
A normal
monomethiodide is only obtainable indirectly (see below). Conkurchine
condenses with aromatic aldehydes to form Schiff bases, and the salicylidene
compound, C28H36ON2, m.p. 244-5, [a]J,6'5 + 15-6 (CHC13) is recommended as a means of isolating the alkaloid from kurchi bark extracts.
With acetoin condensation involves two molecules of base and the product
formed is C 46 H 68 N 4 , m.p. 256-7 (dec), which is hydrolysed by dilute
nitric acid forming conkurchine nitrate. Neither acetaldehyde nor glycollic
aldehyde condenses with the alkaloid. Dihydro- and tetrahydro-conkurchine do not condense with aldehydes, and it is assumed that the
condensation requires an ethylenic linkage in the heterocyclic ring and
that conkurchine may contain in addition to the NH 2 group a. N H . C group
in equilibrium with . N : C < . A crude kurchi bark extract yielded 16-4 per
cent, of conkurchine, isolated as the salicylidene derivative.
In working up alkaloidal fractions from the original kurchi extract,
Bertho et al.6 isolated three substances : (a) m.p. 323, (b) m.p. 335-6, and
(c) m.p. 302-3 (dec), [a] D 34-87 (EtOH), which on solution in dilute
hydrochloric acid and re-precipitation by alkali remain unchanged, but on
recovery in like manner from solution in strong hydrochloric acid yield
conkurchine and, from solution in dilute nitric acid deposit, conkurchine
nitrate. They were at first regarded as " molecular associates " of conkurchine but are now thought to be due to the addition of the elements of
water to ethylenic linkages in conkurchine. Form (b) is the substance
formerly named " kurchenine " (1933). Form (c) is a " dihydrate,"
C2iH32N2 . 2H 2 0, of this stable type. It condenses with salicylic aldehyde
to form two salicylidene derivatives, (1) C28H40O3N2, m.p. 205-5 (dec),
and (2) C 28 H 38 0 2 N 2 , m.p. 205-5, described respectively as di- and monohydrates. From another high-melting fraction there was isolated as the
sparingly soluble nitrate, a base, C 23 H 38 N 2 , m.p. 87-8, provisionally named
" nitrate base I I . "
Addendum. In a later paper 2 8 (1947) it is shown that a normal
conkurchine monomethiodide, m.p. 266 (dec), can be obtained by
hydrolysing benzylideneconkurchine methiodide, m.p. 245"5, with
2NHCL This and the dimethylconkurchine dimethiodide referred to
above, as well as by-products formed with them, were subjected to a
number of reactions, the results of which provide material for a
HOLARBHENA
ALKALOIDS
747
748
(dec), [aft2" 27-2 (H 2 0), and aurichloride charring from 195 (Ghosh
and Ghosh ).
Lettocine, CuH^OgN, is a pale brown microcrystalline powder,
m.p. 350-2; it yields a crystalline hydriodide, B . HI, m.p. 256 (dec.) ;
picrate, m.p. 198, and is recovered unchanged from boiling acetic
anhydride. 18 Bertho suggested that it may be a condensed form of a Kurchi
alkaloid (p. 742).
Addendum. In a recent paper Bertho et al. have described a new
process for the isolation of kurchi alkaloids. From the final residue a
new base, C23H34N2, m.p. 129'5, was isolated as the carbonate, m.p. 91;
it provides the following salts: B, 2HI, 2H 2 0, (dec.) 174; B, 2HC104,
2.5H 2 0, m.p. 283, and a mono-acetyl derivative, m.p. 254. In a
second paper Bertho, Schonberger and Kaltenbom describe further
products obtained in the oxidation of conessine by chromic acid and by
potassium permanganate. 29
Pharmacological Action. According to the early work of Keidel,19
conessine is toxic, producing narcosis and finally death from paralysis of
the respiratory centre. Giemsa and Halberkann, 8 on the contrary, were
able to give comparatively large doses by mouth to dogs and to human
beings without producing narcosis, and Burn 20 found that, though both
conessine and holarrhenine induce narcosis in frogs, this effect is inappreciable in mammals. Both alkaloids produce local anaesthesia, but cause
necrosis on subcutaneous injection. Oxyconessine has no general or local
anaesthetic action, but produces a curare-like effect in frogs.
A later pharmacological investigation of conessine by Chopra, Ghosh,
Gupta and David 21 confirms Burn's results in general, and White 22
found that worconessine closely resembled its homologue in action, the
loss of a methyl group having but little qualitative effect on the general
activity. Kurchicine and woconessine show considerable similarity in
action to conessine, but kurchicine diminishes while isoconessine increases
the coronary outflow in the isolated rabbit heart. Findlay, quoted by
White, 22 found that Entamoeba histolytica grown on a buffered serum
medium, pH 7-2, was killed by emetine at 1 in 5,000,000 ; by conessine at
1 in 20,000; and by norconessine and dioxyconessine at 1 in 5,000.
Meissner and Hesse have made the interesting observation that conessine,
in common with harmine, oc-isoquinine, ethyl apoquinine and aminodihydroquinine, inhibits the growth of the tubercle bacillus in vitro.2*
Kurchi bark is principally used in India as a remedy for amoebic
dysentery, and in recent years there has been a revival of medical interest
in the drug in this connection.23 It is generally used in the form of a bark
extract but, in imitation of emetine bismuth iodide, " kurchi bismuth
iodide," consisting of the bismuth iodides of the mixed alkaloids of the
bark, has also been used.23(a) On the pharmaceutical side Datta and Bal
have studied the pharmacognosy of the bark 2 S and a method of alkaloidal
assay has been devised by Schroff and Dhir, 28 who have also described a
process for the preparation of kurchi bismuth iodide, a product for which
they, and also Mukherjee and Dutta, 27 have provided methods of assay.
LOLIUM ALKALOIDS
749
REFERENCES
(1) Tram. Med. Soc. Bombay, 1858, 4, 28 ; Pharm. J., 1865, pi], 6, 432. (2) Ibid.,
1864, p i ] , 5, 493 ; WARNECKE, Ber., 1886, 19, 60. (3) Ibid., p p . 78, 1682 ; see also
PARIS, Bull. Sci. Pharmacol., 1938, 45, 453 ; 1942, 49, 33. (4) J. Chem. Soc., 1919,
115, 163. (5) Trans. Roy. Soc. Trap. Med. Hyg., 1923-24, 17, 381. (5a) (With MISRA
and SHARMA), J. Sci. Ind. Res. (India),
1945, 3 , 555.
Soc.,
1934,11, 283 ; Proc. Ind. Acad. Sci., 1936, 3A, 249, 257 ; (with P I I X A Y ) , J. Ind. Chem.
Soc., 1932, 9, 553 ; BERTHO, Arch. Pharm., 1939, 277, 2 3 7 ; Annalen, 1944, 555, 214 ;
VON SCHUCKMANN, BERTHO a n d SCHONBERGER, Ber., 1933, 66, 786.
(6a) I R A N I , Curr.
Sci. (India), 1946, 15, 229. (7) ULBICI, Arch. Pharm., 1918, 256, 57. (8) GIEMSA and
HALBERKANN, ibid., p . 201. (9) J. Ind. Chem. Soc, 1934, 11, 787. (10) Proc. Ind.
Acad. Sci., 1935, 2A, 426 ; (with VASISHT), J. Sci. Ind. Res. (India), 1945, 3, 559.
(11) Proc. Ind. Acad. Sci., 1936, 4A, 283. (12) J. Chem. Soc, 1926, 2123 (bibl.); cf.
SIDDIQUI et at.11 (13) Ber., 1930, 63, 126. (14) J. Pharm. Soc. Japan, 1927, No. 546,
98 (German abs.), 680 ( J a p . text). (15) Proc. Ind. Acad. Sci., 1937, 6A, 191, 1 9 9 ;
1939, 10A, 4 1 7 ; J. Sci. Ind. Res. (India), 1946, 4, 435 ; (with VASISHT), ibid., p. 440.
(16) J. Chem. Soc, 1932, 631. (17) J. Ind. Chem. Soc, 1928, 5, 477 ; CHOWDHURYand
PEACOCK, ibid., 1937, 14, 4 8 6 ; GHOSH and BOSE, Arch. Pharm.,
PEACOCK and CHOWDHURY, J. Chem.,Soc, 1935, 734. (19) Inaug. Diss. GOttingen, 1878.
(20) J. Pharm. Exp. Ther., 1915, 6, 305. (21) Ind. Med. Gaz., 1927, 62, 132. (22) J.
Pharm. Exp. Ther., 1933, 48, 79 ; cf. BAKHSH, ibid., 1936, 58, 373 ; BERTHO, Arch,
exp. Path. Pharm., 1944, 203, 41. (23) BROWN, Brit. Med. J., 1922, i, 993 ; CAIUS and
MHASKAR, Ind. Med. Res. Memoirs, N o . 6, 1927 ; ACTON a n d CHOPRA, Ind.
Med.
1929, 64, 481 ; 1933, 68, 6 ; GHOSH, ibid., 1933, 68, 13 ; LEAKE, J. Amer. Med.
1932, 98, 195.
Gaz.,
Assoc,
Med.
Res., 1933-34, 21, 277 ; and BAKHSH, J. Pharm. Exp. Ther., 1936, 58, 361. (23a) GUPTA,
J. Proc. Inst. Chem. India, 1946, 18, 182. (24) Arch. exp. Path. Pharm., 1930, 147,
339.
(25) Ind. J. Pharm., 1945, 7, 123 ; cf. SCHROFP, B A L and D H I R , ibid., 1940, 2, 195.
(26) Ibid., 1939, 1, 20. (27) Science and Cult. (India), 1945, 10, 506.
Ber., 1947, 80, 316. (29) Annalen, 1947, 558, 6 2 ; 557, 220.
(28) BERTHO,
750
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
LUNASIA
ALKALOIDS
751
Sci. Tech.,
ibid., p . 159. (7) W H I T E and R E I F E R , ibid., 1945, 27, 38 ; CLAREand MORICE, ibid.,
p. 36 ; R E I F E R and W H I T E , ibid., p . 242. (7a) Arch. exp. Path. Pharm., 1892, 30, 203.
(8) N.Z. Journ. Sci. Tech., 1943, 24, 167.
ALKALOIDS OF LUNASIA
COSTULATA
752
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
ALKALOIDS OF LYCOPODIUM
SPP.
Recent interest in the alkaloids of the club mosses dates from 1934,
when Orekhov x called attention to Lycopodium annotinum as a source of
alkaloids. In the following year Muszynski 2 gave a preliminary account
of chemical and pharmacological work on the alkaloids of five European
Lycopodium species, and later Oficjalski3 recorded the toxicities of
Muszynski's alkaloids. Most of the recent work on the genus has been
done on American species by Marion and Manske, who distinguish their
alkaloids provisionally, by the letter L and a number, e.g., L13, a trivial
name being assigned when the individuality of an alkaloid has been clearly
established. The following list records the alkaloidal constituents of nine
Lycopodium spp. so far examined. Lycopodine has been found in all the
species except L. saururus. Nicotine occurs in four species. It has also
been found in one of the horse-tails, Equisetum arvense L., 8 and is the only
alkaloid so far found both in flowering plants and the pteridophyta, thus
establishing an alkaloidal link between the phanerogamia and cryptogamia.
(1) L. annotinum L. Annotinine (L7), lycopodine, obscurine (L6), (L8),
(L9), (L10), (Lll), (L12). (Manske and Marion.*)
(2) L. clavatum L. (European specimen.) Clavatine, clavatoxine, lycopodine (Achmatowicz and Uziebfo *). (American specimen.) Lycopodine, nicotine, (L13), (L18), (L19). Marion and Manske e suggest
that the American and European forms may be different varieties of
one species, or possibly distinct species.
LTCOPODIVM
BASES
753
754
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
LYCOPODIUM BASES
755
756
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
Res., 1944, 22B, 137. (7) Annalen, 1881, 208, 363. (8) Can. J. Res., 1942, 20B, 87.
(9) Ibid., 1946, 24B, 57. (10) Ibid., 1944, 22B, 53. (11) Ibid., 1946, 24B, 63. (12)
Compt. rend., 1886, 102, 1322. (13) Gazzetta, 1892, [i], 22, 49. (14) Rev. Cent. Estud.
Farm. Bioquim., 1931, 20, 534 (Chem. Zentr., 1932, i, 3452). (15) J. Amer. Chem. Soc.,
1942, 64, 968. (16) Can. J. Res., 1944, 22B, 1. (17) Ibid., 1942, 20B, 153. (18) Rev.
Soc. Arg. Biol., 1944, 20, 413 (Brit. Abstr., 1945, Aiii, 789). (19) J. Amer. Pharm.
Assoc., 1945, 34, 197. (20) Acta polon. Pharm., 1939, 3, 23 (Chem. Abstr., 1941, 35,
3766). (21) Can. J. Res., 1918, 26, 174.
ALKALOIDS OF MITRAGYNA,
ADINA AND OUROUPARIA
SPP.
These three Rubiaceons genera contain alkaloids about which comparatively little is known. Some of them, described as new, have subsequently
been identified with known bases. In the following list the superseded
names are shown in brackets :
Adina rubrostipulata K. Schumann. Mitraphylline x (rubradinine; Denis).2
Mitragyna diversifolia Hook. Mitraversine. 3
M. inermis Kuntze (M. africana Korth). Rhyncophylline (mitrinermine).4
M. parvifolia Korth. Unnamed, crystalline alkaloid.5
M. rotundifolia (Roxb.) Kuntze (M. diversifolia Hook). Rhyncophylline
and rotundifoline.6
M. speciosa Korth. Mitragynine,3 mitraspecine 7 and a base, or bases,
giving an amorphous picrate, m.p. 123-7. 8
M. stipulosa Kuntze (M. macrophylla Hiern). Rhyncophylline. 4
Ourouparia formosana Mats. Formosanine. 9
O. Gambir Baill. (Uncaria Gambir Roxb). Gambirine, uncharacterised. 10
0. Kawakamii Hayata. Hanadamine. 11
O. rhyncophylla Mats. Rhyncophylline and s'sorhyncophylline.12
The alkaloid crossoptine, which Blaise 16 isolated from Crossopteryx
kotschyana Fenzl, has been examined by Raymond-Hamet, who assigns
to it the following formula and constants : C22H2804N2, m.p. 218-9,
[a] D 24 (CHC13), and suggests that it is mitrinermine, which is now known
to be rhyncophylline. He also considers that the bark used was
probably derived from a Mitragyna sp.16
It is of interest to note that rhyncophylline occurs in two genera,
Mitragyna and Ourouparia. Raymond-Hamet 9 suggested in 1936 that
rhyncophylline, hanadamine and formosanine are chemically and pharmacologically related to the Mitragyna alkaloids and the first chemical
evidence of this is the identification of mitrinermine with rhyncophylline
(Barger el al.).e Millat has recently expressed doubt of this identification.
The formulae and chief characteristics of these alkaloids are summarised
in the table on p. 757.
Some progress has been made towards the determination of structure
in three of these alkaloids, mitragynine, rhyncophylline and rotundifoline.
The functions of the oxygen atoms, so far as known, are shown in the
extended formulae in the table. The bases are monoacidic and the second
nitrogen is non-basic and usually assumed to be present in an indole ring.
In rhyncophylline it is a secondary nitrogen as indicated by Zerevitinov
MITRAQYNA
game and Formula
ALKALOIDS
Physloal - Constant 8
of Base
Ultragynlne
c
i.8 H 81 I, s'0X)(0- CO-Ma)
amorph.. m.p.105-115
b.p.830-840/5 m.n.
Mitraphylllne
2OH233>E'0,te>
m.p.270;[a]J 5 -9.840
Ultravarslne
0 20 Il 19 0H 2 (Ue0) s (0H)
m.p.237
Mltraspacina
02sH27O2H2(0)te)3
m.p.244-5;
U]f-59-15
fihynoophylline
019H220K2(011s)(0-C0-Me)
m.p.208-9,
[a]S0-14.5
1soRhynoopnylllna
amorph., m.p.60-70,
[o.] S *8.3
Rotund Ifoline
19H202H2(CMe,(0-00'Be)
Formosanlne
<!2lH24<26)4'>2
m.p.233-4; Ia]J 5
+124
Hanadamine
019H2O0S2(0-0O-Me)(0H)
757
i
S a l t s
Pierate,817-223: B.Ha,m.p.243;
B.CgH40g, n . p . l 7 5 - 6 ( ^ ) .
methloalde, amorphous, m.p.211-5.
Plorate, m.p.166.
B.HC1. m.p.808-810.
Plorate io.p.l36-
B.HOIO4, m.p.l50(& ).
m.p.202-218; [a]j,
+ 91.3
B.EAuCl,,, m.p.l36(^ ) .
platiniohloride, amorph.,m.p.228-9.
758
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
(4) RAYMOND-
HAMET, Compt. rend., 1934, 199, 587 ; Compt. rend. Soc. Biol., 1934, 116, 1337 ; 1938,
128, 777 ; Arch. int. Pharmacodyn., 1937, 56, 303 ; (with PERKOT and LAKRIEU), Bull.
Sci. Pharmacol., 1930, 37, 4 0 1 ; (with PERROT and MILLAT), 1936, 43, 6 9 4 ; (with
MILLAT), J. Pharm. Chim., 1934, [viii], 20, 577 ; BARGER et al.s. (5) HOOPER, Pharm.
J.,
1907,
78, 453.
(6)
BARGER, D Y E R and
SARGENT, J.
Org.
Chem., 1939,
4, 418 ;
cf.
MILLAT, Ann. pharm. franc, 1946, 4, 27. (7) D E N I S Bull. Acad. roy. Belg., 1938, [v],
24, 653. (8) ING and RAISON, J. Chem. Soc, 1939, 986. (9) RAYMOND-HAMET, Compt.
rend., 1936, 203, 1383; Arch. Int. Pharmacodyn., 1939, 63, 336. (10) RAYMONDHAMET, Bull. Acad. Med., 1934, [iii], 112, 513. (11) KONDO and OSHIMA, J. Pharm.
Soc. Jap.,
Jap.,
1928, 48, 54 ; (with IKEDA), ibid., 1937, 57, 237 ; RAYMOND-HAMET, C. R. Soc. Biol.,
1934, 115, 255. (13) Fourth Rept. Govt. Laboratory, Bangkok, 1925, p. 5. (14) J.
Pharm. exp. Ther., 1932, 46, 251.
(15) Arch. int. Pharmacodyn., 1934, 48, 217.
(16) BLAISE, " Les Crossopteryx africains. Etude botanique."
These, Doct. Pharm.,
Paris, 1932 ; RAYMOND-HAMET, Bull. Sci. Pharmacol., 1940, 47, 194 ; cf. H E S S E ,
Ber., 1878, 11, 1546.
PIGRALIMA
ALKALOIDS
759
Chem.,
Pharma-
col, 1910, 17, 13. (3) Bull. Chem. Soc. Jap., 1931, 52, 815. (4) Compt. rend., 1941,
213, 386 (bibliography of early work).
ALKALOIDS OF ORIXA
JAPONICA
From the roots of this plant Terasaka x isolated four alkaloids of
which one, kokusaginine, resembles skimmianine (p. 414), which Obata 2
has found along with kokusagine in the fruits of the plant.
Orixine, C18H21(23)06N, has m.p. 152-5, [a]^7 + 83-3, and forms an
aurichloride, m.p. 155 (dec). I t is a weak, tertiary base, contains one
methylenedioxy and two methoxyl groups and is converted by hydrochloric acid in ether into isoorixine, m.p. 195, [a]| + 27-4. Dilute
hydrochloric acid under pressure produces orixidine, C 15 H 13 0 4 N, m.p. 195,
and a phenolic base, C 15 H 15 0 5 N, m.p. 113 (dec).
Kokusagine, C 13 H 9 0 4 N, m.p. 194, [a] D 0, aurichloride, m.p. 171,
picrate, m.p. 178 (157; Obata); contains one methoxyl and one
methylenedioxy group and is converted by methyl iodide at 100 into
isokokusagine, m.p. 247 (cf. skimmianine > ^soskimmianine, p. 414).
Kokusaginine, C14H13(16)04N. Crystallises in prisms, m.p. 171, forms
a hydrochloride, m.p. 225 (dec), and a picrate, m.p. 218 ; contains three
methoxyl groups (cf. skimmianine, p. 414).
Kokusaginoline, C 17 H 13 0 5 N, m.p. 283, contains one hydroxyl and two
methoxyl groups.
REFERENCES
(1) J. Pharm. Soc. Japan, 1931, 51, 99 ; 1933, 53, 219. (2) Ibid., 1939, 59, 136.
ALKALOIDS OF PICRALIMA
KLAINEANA
This Apocynaceous species is widely but sparsely distributed in tropical
Africa, where the seeds enjoy an undeserved reputation as a specific for
malaria. The drug is rich in alkaloids of which nine have been isolated
and characterised. 1
760
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
PIGRALIMA
Name
Akuammicine *
Pseudakuammicine
Akuammenine .
Akuammidine *.
Akuammfgine *.
Pseudakuammigine
Yield
on Seeds
percent.
C I .H0N,(0Me)
Ct.HMOlUOMe)
00064 1
00037 |
C If H0,N,(OMe)
CH0,N,(0Me)
C I1 H tl 0,N,(0Me>
CH0,N(OMe)(NMe)
00006
00340
00100
00170
CH0,N,(OMe)
CH n 0,N<0H)(0Me)(NMe)
CH0 J N(0H)(0Me)(NMe)
00107
O-5C0O
Akuammiline * .
Akuammine .
Akuammine hydrate
761
ALKALOIDS
Colour Reactions
Cone. HNO,
Piperonal + HCI
B r i g h t g r e e n , Magenta, changing
becoming
blue to
ultramarine
on dilution with blue on standing.
water.
YeUow
"\
Bright yellow
1
Brown, changing Pink, changing to
to yellow
/ a m e t h y s t on
None
1 standing.
Blood-red
1
Blood-red
/
762
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
Chalchupine-B, m.p. 240; picrate, m.p. 154-6; hydriodide, m.p. 258260 ; tartrate, m.p. 250-6. The colour reactions of A indicate that the
structure includes an indole group (Deger 3 ; Paris and Daza 8 ).
(4) R. monobasiana Stapf. (a false iboga, p. 768). Pharmacological
examination of an extract. (Raymond-Hamet. 4 )
(5) R. natalensis Sond. Several amorphous alkaloids (Rindl and
Groenewoud 5 ).
(6) R. serpentina Benth. Ajmalicine, ajmaline, ajmalinine, serpentine,
serpentinine (Siddiqui and Siddiqui 6 ). From a geographical variety of
the species, jAoajmaline, weoajmaline and unnamed alkaloids, m.p. 220
and m.p. 234 (S. Siddiqui 6 ). From the same species van Itallie and
Steenhauer ' isolated alkaloids B, C and A (rauwolfine) which may be
identical with Siddiqui's serpentine, ajmalinine and ajmaline respectively.
(7) R. vomitoria Afz. (sample from French Guinea). Ajmaline, isoajmaline, ajmalicine, ajmalinine and possibly serpentinine, cf. R. serpentina
(Paris 8 ).
The species which has received most attention as a drug is R. serpentina
for which Schroff and Bhatia and more recently Dutt et al. have devised
assay processes.9 Information regarding native uses of plants of this genus
will be found in short accounts published by Raymond-Hamet, 10 (who
uses the synonym Ophioxylum serpentinum Willd. for R. serpentina Benth.),
Lewin u and Watt and Breyer-Brandwijk.12
Ajmaline, C20H26O2N2. 3H 2 0. Regarded as identical with the rauwolfine
of van Itallie and Steenhauer (see below). It is only completely dehydrated
at 200, has m.p. 159-160, [a]??0 + 128 (CHC13), and yields crystalline
salts, B . HC1. 2H 2 0, m.p. 133-4; platinichloride, m.p. 217-8; picrate,
m.p. 126-7 or 223 (dry). The JV-benzoyl derivative has m.p. 214-6
(dec).
Methyl iodide converts it into methylajmaline hydriodide,
C 21 H 2 ,0 2 N 2 . HI, m.p. 230-1 ; the base recovered from this forms stellate
clusters of needles, m.p. 130-1. Ajmaline forms a dibromo-derivative,
m.p. 230 (dec.); an amorphous trinitro-compound, m.p. 238-258 (dec),
and a monosulphonic acid. On heating at 200, or on boiling with alcoholic
potassium hydroxide solution, it is partly converted into woajmaline
m.p. 265-6, [a];f + 72-8 (EtOH), which behaves as a diacidic base
B . 2HC1, amorphous, m.p. 238-240 (dec), [a]^" + 98-7 (H 2 0).
woAjmaline was subsequently found to occur naturally in a specimen oi
the drug collected in the Dun Valley (item 6, see above) along with a
third isomeride, weoajmaline, m.p. 205-7, which is convertible into isoajmaline by heating at 270 or by the action of alcoholic potash (Siddiqui 6 ).
The two oxygen atoms are believed to be present as a betaine group,
MAVWOLFIA
ALKALOIDS
763
764
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
BAVWOLFIA
ALKALOIDS
766
Advisory Sci. Board, Ind. Res. Fund Assoc, 1942, p . 71. (14) Ind. J. Med. Res.,
1944, 32, 183 ; J. Amer. Pharm. Assoc, 1947, 36, 416. For clinical trials see CHOWHAN,
Ind. Med. Gaz., 1940, 75, 382 ; GUPTA et al., ibid., 1943, 78, 547. (15) Ind. J. Med.
Res., 1944, 32, 177. (16) Bull. Sci. Pharmacol., 1936, 43, 364. (17) C. R. Soc. Biol.,
1940, 134, 94, 369. (18) Compt. rend., 1940, 211, 414 ; 1946, 223, 927. (19) Sci. and
Cult. (India), 1942, 7, 458. (20) GEILING, quoted by KOEPFLI. 1 (21) Arch. int.
Pharmacodyn., 1935, 51, 10. (22) Cardiologia, 1937, 1, 1. (23) Compt. rend., 1935,
201, 1050. (24) RAYMOND-HAMET, ibid., 1939, 209, 384, 599 ; C. R. Soc Biol., 1938,
129, 462 ; 1939, 132, 213. (25) CORNATZER el al., Elisha Mitchell Sci. Soc, 1944, 60,
167. (26) RAYMOND-HAMET, Bull. Acad. Med., 1939, 122, 30 ; C. R. Soc. Biol., 1941,
135, 627 ; 1944, 138, 40.
766
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
ALKALOIDS
OF THE STEMONACE&
767
(2)
Ibid., 1934,
54, 100,
SATOMI, 1939,
59,
184,
768
ALKALOIDS
OF UNDETERMINED
CONSTITUTION
(3) Chem. Soc. Abstr., 1913, i, 1033 ; Chem. Zent., 1913, i, 1823. (4) Ber., 1936, 69, 74.
(5) Compt. rend., 1932, 194, 386. (6) J. Pharm. Soc. Japan, 1934, 54, 96; 1939, 59,
177 ; 1940, 60, 149 ; 1941, 61, 111. (7) J. Atner. Pharm. Assoc., 1940, 29, 391.
ALKALOIDS OF TABERNANTHE
IBOGA
TAXINE
769
ALKALOIDS OF TAXUS
BACCATA
Taxine, G37H61Oi0N, is contained in the leaves, shoots and fruits of
the yew (Taxus baccata), from which it was first isolated by Lucas. 1 I t
was investigated by Marm,2 Hilger and Brande, 3 Amato and Capparelli,4
Thorpe and Stubbs, 6 Winterstein et al.,e Kondo et al.,1 Takahashi 8 and
Gulland et al.9
A phytochemical investigation of taxine in the yew has been conducted
by Kuhn and Schafer,12 who have devised special methods for the detection, estimation and purification of the alkaloid. Masson 13 states that
Taxus canadensis contains an alkaloid giving the colour reactions of taxine
but different from it in being crystalline and having m.p. 238-9 ; no
ephedrine was present.
Taxine is amorphous, as are also its derivatives, and special methods
have to be used in isolating it in a pure state. Gulland and Virden 9 have
shown that ephedrine is also present in the yew.
Taxine, in the purest form in which it has yet been obtained, has m.p.
121-4 after sintering at 115, [a]17 + 95-7 (EtOH). 9 It is soluble in
ether, chloroform or alcohol, but insoluble in water or light petroleum,
The salts are amorphous, including the aurichloride, m.p. 132-4 (two
forms, m.p. 90-105, 110, Kondo). The methiodide has m.p. 123-5,
and with alkali produces trimethylamine and a product, C 35 H 44 O 10 ,
m.p. 120-140. Taxine, on reduction, takes up four atoms of hydrogen
and forms a tetrabromide on addition of bromine. On oxidation with
permanganate, benzamide, benzoic acid, acetic acid, oxalic acid and
benzonitrile are stated to be produced. Cinnamic acid seems to be a constant product of the action of alkalis and acids on the alkaloid. Warmed
with dilute sulphuric acid for ten hours, taxine yields a crystalline compound, C n H 16 0N, which may be a /3-dimethylamino-/?-phenylpropionic
acid.' Winterstein and Guyer 6 suggest the following partial formula from
the observations so far made : NMe,. CHPh . CH, . CO . C, 4 H S 4 0 6 . OAc.
Callow, Gulland and Virden ' obtained evidence of the presence of four
replaceable hydrogen atoms and of a lactone group, thus accounting for
six out of the ten oxygen atoms required by the formula. The remaining
tun ui.
25
770
ALKALOIDS
OF UNDSTBBMINW
CONSTITUTION
1932,
52,
27,
36;
1934,
54,
117.
(9)
CALLOW,
GULLAND
and
VIRDEN,
J.,
Chem. Soc, 1931, 2138, 2148. (10) Quart. J. Pharm., 1932, 5, 205 (with a bibliography).
(11) Cf. NICHOLSON, 3rd Rep. Univ. Camb. Inst. Anim. Path., 1932-33, p p . 196-199 ;
WINTERSTEIN and IATRIDES. 8 (12) DeiU. Apoth. Zeit., 1937, 52, 1265. (13) Chem.
Abstr., 1942, 36, 7238.
MINOR ALKALOIDS
Acacia spp. According to White, the tops of A. floribunda Sieb., A.
longifolia Willd. and A. pruinosa Cunn. contain tryptamine (3-w-aminoethylindole), usually in association with ^3-phenylethylamine (N.Z. Journ.
Sci. Tech., 1944, 25, B, 157).
Alangium lamarckii Thw. The bark yields alangine, C 19 H 25 0 2 N,
m.p. 205-8 {dec), [a] D + 9 (EtOH), of which a hydrochloride, m.p. 264,
picrate, m.p. 84, methiodide, m.p. 201 (dec), and other salts have been
prepared. The base is monoacidic and tertiary, contains one methoxyl
group and possibly an alcoholic hydroxyl, but no methylimino group. 1
Pharmacological work has been done on an amorphous, alkaloidal preparation by Chopra and Chowhan,2 and on an injectable extract of the plant
by Raymond-Hamet 8 ((1) Parihar and Dutt, Proc. Ind. Acad. Sci.,
1946, 23, A., 325 (see also 1942, 16, A, 328). (2) Ind. J. Med. Res., 1934,
21, 507. (3) C. R. Soc. Biol, 1941, 135, 1011).
Anchusa officinalis L. Cynoglossine ; B . HC1, crystalline. Paralyses
peripheral nerve terminations. Consolidine ; gluco-alkaloid ; hydrolysed
to glucose and consolicine (also present as such). Paralyses the central
nervous system. The same alkaloids are also present in Echium vulgare L.
and Cynoglossum officinale L. (Greiner, Arch. Pharm., 1900, 238, 505).
Arachis hypogwa L. Arachine, C5H14ON2, with choline and betaine.
Yellowish-green syrup ; crystalline platinichloride, m.p. 216 ; and
aurichloride ; produces transient narcosis in frogs and rabbits with partial
paralysis (Mooser, Landw. Versuchs-Stat., 1904, 60, 321 (Chem. Soc. Abstr.,
1905, [i], 79)).
Argemone mexicana L. As a result of pharmacological and clinical
investigations in India it was established that certain outbreaks of epidemic
dropsy in that country were due to the consumption of mustard seed oil
containing argemone seed oil.1 Argemone seed contains berberine and
protopine (p. 169), but Mukherji, Lai and Mathur 2 isolated from samples
of the oils concerned, a colourless alkaloid, C 19 H 1S 0 4 N, m.p. 190, which
fluoresces blue in solution in alcohol, does not give the colour reactions of
protopine and is regarded as forming part of the complex molecule of
the toxic constituent. Argemone mexicana is also suspected of toxicity to
cattle, 8 but in such cases there is a tendency to regard the latex of the
plant as the source of the poison though the information available is
confusing ((1) Sarkar, Ind. Med. Gaz., 1939, 74, 752; Ann. Biochem.
Exp. Med., 1941, 1, 59, 271; Curr. Sci., 1942, 11, 239; Sen, ibid., 239;
Chopra and Pasricha (with Goyal, Lai and Sen), Ind. Med. Gaz., 1939,
74, 193; (with Banerjee), ibid., 1940, 75, 261; Lai, Das Gupta and
Adak (with Argawala), Ind. J. Med. Res., 1941, 29, 813 ; (with Mukherji),
ibid., p. 889. (2) Ibid., p. 861. (8) Hurst, " The Poison Plants of New
South Wales," 1942; 125).
FLAHI
OS..
771
26
772
MINOR
ALKALOIDS
MINOR
ALKALOIDS
773
774
MINOR
ALKALOIDS
in the paper ((1). Zeit. Physiol. Chem., 1936, 244, 229; (2). Helv. Chim.
Acta, 1948, 31, 1062).
Erythrwa centaurium. The plant contains 0-8 per cent, of alkaloids
from which erythricine, C1(fl90^, m.p. 81-3, has been isolated. It forms
a pierate, m.p. 122-4, oxalate, m.p. 151-2, nitrate, m.p. 114, hydrochloride, m.p. 165-6 (dec), and appears to be a lactone, hydrolysing to a
C10 acid and oxidising to a C9 acid (Feofilaktov and Ban'kovskii, Farmatsiya,
1946, 9, No. 5, p. 10).
Flindersia australis R.. Br. Flindersine, C 23 H 26 0 7 N 2 , m.p. 182-3
(dec), [a] D 0 ; pierate, m.p. 174 ; platinichloride, m.p. 262 (Matthes
and Schreiber, Ber. deut. Pharm. Ges., 1914, 24, 385).
Galanthus Woronovi (Amaryllidaceee). The leaves and bulbs contain
two alkaloids : galantine, C 13 H 13 N(OMe) 3 (OH). H 2 0, m.p. 132-3, or
160-4 (dry), [a] D 87; hydrochloride, m.p. 198-9, hydrobromide,
m.p. 201-3 ; perchlorate, m.p. 199-201. Galantidine, C13H15ON(CH202),
m.p. 235-8 ; hydrochloride, m.p. 197-9; hydrobromide, m.p. 213-213-5,
[a] D -f 32-3 ; methiodide, m.p. 232-3 (Proskurnina and Areshkina,
J. gen. Chem. V.R.S.S., 1947, 17, 1216).
Girgensohnia spp. G. diptera Bge. contains iV-methylpiperidine and
dipterine, CUH14N2, m.p. 87-8, [a] D 0 ; hydrochloride, m.p. 177-8,
pierate, m.p. 189-190, and picrolonate, m.p. 242-3, which was later
shown to be A^-methyltryptamine.1 G. oppositiflora Pall, contains JVmethylpiperidihe and girgensonine, C13H16ON2, m.p. 147-8, [a] D 0.
The latter forms a hydrochloride, m.p. 145-8, and a picrolonate, m.p.
192-4, and on hydrolysis by alkali yields piperidine, hydrocyanic acid
and j>-hydroxybenzaldehyde, indicating that it is 2V-piperidyl-p-hydroxyphenylacetonitrile, and this has been confirmed by comparison with a
synthetic specimen.2 ((1) Juraschevski and Stepanova, J. Gen. Chem. Russ.,
1939, 9, 2203 ; Juraschevski, ibid., 1940, 10, 1781. (2) Juraschevski and
Stepanova, ibid., 1946, 16, 141).
Hedyotis auricularia Linn. Contains hedyotine, C 16 H 22 0 3 N 2 , yielding
a hydrochloride, m.p. 245, nitrate, m.p. 252 (dec), aurichloride, m.p. 305310 (dec), and pierate, m.p. 265 (dec) (Dey and Lakshminarayanan,
Arch. Pharm., 1933, 271, 485). A different alkaloid was isolated in small
quantity by Ratnagiriswaran and Venkatachalam and named auricularine,
C 42 H 55 ON s . H 2 0 ; it has m.p. 201 (dec) and forms an oxalate, m.p.
>230 (dec), and a pierate, m.p. 217-8 (dec). A third base, giving a
hydriodide, which decomposed at 215-220, and amorphous bases were
also found (J. Ind. Chem. Soc, 1942, 19, 389).
Heliopsis longipes (A. Gray) Blake. This plant is the source of affinin
formerly believed to be derived from Erigeron affinis D.C. Affinin has
m.p. 160-2/0-3 mm. and n|7 1-5128 and has been identified as N-isobutyl-2 : 6 : 8-decatrienoamide. The substance is toxic to house flies at
a concentratiqn of 122-8 mgm. per c.c. of solvent (Acree, Haller and
Jacobsen, J. Org. Chem., 1945,10, 286, 449 \ !l947, 12, 781).
Helleborus viridis L. contains celliamine, CnH3sOgN, silky needles,
m.p. 127-181, tertiary base; no methoxyl group. SprintiUamine,
MINOR
ALKALOIDS
775
776
MINOR
ALKALOIDS
MINOR ALKALOIDS
in
778
MINOR
ALKALOIDS
ALKALOIDAL OCCURRENCES
779
780
MINOR ALKALOIDS
ALKAL01DAL OCCVMENCES
781
782
MINOR ALKALOIDS
ALKALOIDAL OCGUBBENCES
783
Cardiol. Mex., 1947, 17, 833; (Chem. Abstr., 1948, 42, 2730) ; Archiv. Biochem.,
1948, 16, 275.)
Vstilago mayMs. Alkaloids isolated from this maize fungus were named
ustilaginine and ustilagotoxine and are stated to resemble ergotinine and ergotoxine respectively. (Mas, Bol. Soc. Quint. Peru, 1938, 4, 3.)
Zanthoxylum budrunga. From the bark Khastagir isolated two alkaoids,
budrugaine, which chars above 180 but does not melt, and budrugainine, m.p. 155
(Curr. Sci., 1947, 16, 185 ; Chem. Abstr., 1948, 42, 326.)
INDEX
(Botanical names are printed in italics. Prefixes such as nor-, iso-, proto-, apo-, are
printed in italics and disregarded for indexing purposes.- Where more t h a n one
page number is given, a chief descriptive reference is indicated by t h e use of
heavier type.)
484
Alangine, 771
Abrotine, 772
Alangium lamarckii, 771
Abrus precatorius, 484
Alginine, 732, 734
Abuta spp., 371
Alkaloidal amines, 630
Acacia spp., 771
Alkaloids of undetermined constitution,
716
Acetylcholine, 262, 518
a-Alkyldihydrochelerythrines, 278
Acetylornithine, 170, 171, 172
Aloperine, 118, 150
Achillea spp., 779
Alstonamine, 716
Achilleine; achilletine, 779
Alstonia alkaloids, pharmacological action,
Aeolyctine, 686
Aconine, 673, 675, 679, 685
720
Aconines, nuclear structure, 693
Alstonia spp., 716, 718, 719, 720
Aconite alkaloids, 673
Alstonidine, alstoniline, 716, 718
Alstonine, 716
Aconitine, 673, 674, 775
oxidation products, 676
degradation products, 717
Aconitines, pharmacological action, 690
Alstyrine, 717
Aconitinone, 676
Amanita muscaria, 658
Aconitoline, 676
Amaryllidaceae, alkaloids, 406
Aconitum and delphinium alkaloids,
minor alkaloids, 411
interrelationship, 692
Ambaline, ambalinine, 777
Aconitum spp., 673, 674, 678, 680, 682, Aminodihydroquinine, 748
jS-Amino-4-ethylglyoxaIine, 671
684, 685, 686, 687, 689, 690, 695
Aminolaudanosine, 311
Actinodaphne spp., 319, 322
Ammodendrine, 35, 116, 139
Actinodaphnine, 322, 323
Ammodendron Conollyi, 35, 116
Acutumine, 268, 272
Ammothamnine, 116
Adenanthera pavonina, 779
Ammothamnus lehmanni, 116, 151
Adenocarpus spp., 779
Amcebicides, synthetic, 402
Adhatoda vasica, 617, 620
Amphiporine, 49
Adina spp., 756
Amphiporus lactifloreus, 49
Adlumia spp., 169, 210
isoAmylamine, 518
Adlumidine, 169, 172, 210
isoAmylputrescine, 630
pharmacological action, 212
Anabaseine, 45
Adlumine, 169, 171, 210
pharmacological action, 212
Anabasine, 35, 43, 44, 50, 53 _
Mgle marmelos, 414
Anabasis aphylla, 35, 43, 53, 118
Affinin, 774
Anacyclus pyrethrum, 2
Agmatine, 518
Anagyramide, 140
Aizoacem, 1
Anagyrine, 116, 137, 138, 140, 142,148,
Ajacine, ajacinine, ajacinoidine, ajaconine,
152
694
Anagyris faetida, 116, 140
Ajmalicine, 762, 763
Analgesics, synthetic, 263, 265
Ajmaline, 762 ; isoajmaline, 762, 764 ; Anamirta paniculata, 349
Anatabine, 35, 43, 46
neoajmaline, 762, 764
Anchusa officinalis, 771
Ajmalinine, 762
Andira spp., 631
Ajuga chia, 779
Andirine, 631
Akuamma alkaloids, 760
Angelic acid, 604
Akuammenine, 760
Angeline, 631
Akuapimicine, (J-akuammieine,
akuammidine, akuammigine,
Angostura bark, alkaloids, 415
0-akuammigine, akuammiline, 760
Anhalamine, 154
Akuammine, 760
constitution, 156
hydrate, 760
Anhalidine, 154, 156
pharmacological action, 761
Anhaline (Hordenine), 154,161, 633
78*
ABRHSTE,
EX
Anhalinine, 154, 156
Anhalonidine, 154,155, 160, 161
constitution, 157
Anhalonine, 154,155, 160, 161
constitution, 158
Anhalonium alkaloids, pharmacology, 160
Anhalonium spp., 154
Anhydroberberilic acid, 332
Anhydroecgonine, 97
Anhydrolupinine, 120
Anhydroxatine, 770
Anisomeks malabarica, 779
AT-(2-p-Anisylethyl)-jV-methylcinnamide, 330, 631
Annona atnbotay, 371
Annotinine, 752, 753, 755
Anodmine, 47
Anolobine, 317
Anonaceae, alkaloids, 317, 329, 349
Anona muricata, 317
Anonaine, 318
Anthorine, 673
Anthranoyllappaconine, 686
Anthranoyllycoctonine, 687, 694, 696
Anti-histamine drugs, 113, 197, 644
Anti-malarial drugs, synthetic, 475
Aphyllidine, 35, 53, 54
Aphylline, 35, 54, 138, 148
Aplopappus hartwegi, 779
Aporeidine, 173, 276
Aporeine, 173, 178, 275
Aporphine alkaloids, 232, 273, 284, 306,
314, 317, 319
interrelationships and syntheses, 309,
310, 811, 323
pharmacological action, 312, 316, 327
Apuleia molaris, 151
Arachine, 771
Arachis hypogtea, 771
Arariba rubra, 490
Archangelisia flava, 329
Areca nut alkaloids, 8
pharmacological action, 12
Arecaidine; arecaine, 10
Arecolidine, 12
Arecoline, 9, 12
Argemone spp., 169
Argemone mexicana, 771
Argemonine (protopine), 169
Aribine, 490
Aricine, 419, 465, 466
Aristidinic acid, 722
Aristinic acid, 722
Aristolic acid, 722
Aristolochia rumidfolia, 871
Aristolochia spp., 721, 722
Aristolochic acid, 722
WfoAristolochic acid, 722
Aristolochine, 722
Armepavine, 173,195, 276
Artabotrine, 317, 818
methyl ether, 819
Artabotrinine, 810
Artabotrys suaveolens, 817
Artarine, 880
785
786
INDEX
Benzoyloscine, 86, 88
Benzoylpseudaconine, 684
Benzoyltropine, 64, 93, 107
Benzoyl- ^-tropine, 100
pharmacological action, 106, 107
1 :2-Benzphenanthridine, 279
Benzylmethylamine, 636
Benzylmorphine, 217, 260
Benzylisoquinoline alkaloids, 182, 196
Berbamine, 329, 346, 350, 362
pharmacological action, 349
Berbamine methyl ether, 346, 356
Berberal, 332, 340
woBerberal, 332
Berberidaceae, 328
Berberilene, 337
Berberilic acid, 332
Berberinal, 333
Berberine, 162, 169, 170, 171, 287, 328,
329, 331, 344, 345, 631
Berberine, quaternary ammonium bases
from tetrahydro-derivative, 337
Berberine and related bases,
pharmacological action, 345
syntheses, 334
Berberineacetone, 333
e^nBerberine, 297
profoBerberine, 336
^-Berberines, 335
Berberinium hydroxide, 333
Berberinol, 333
Berberis spp., 328, 331, 346
Berberoline, 332
Berberonic acid, 507
Berberrubine, 329, 343
" Berbine," 336
Betaine, 518
Bicucine, 170, 209
pharmacological action, 212
Bicuculline, 169, 170, 171, 172, 209, 210
pharmacological action, 212
Bikhaconine, 685
Bikhaconitine, 674, 685
Bisbenzylisoquinoline alkaloids, 196, 346,
349, 352, 353, 783
characters and relationships, 358
Biscoclaurine alkaloids, 346
Bisdihydrodioscorine, 92
Bismatridine, 148
Bis-(8-quinolyloxy)-l : 5-pentane
diethiodide, 391
Bleekaria calocarpa, 781
Bocconia spp., 169
Boerhaavia diffusa, 772
Boldea fragrans, 325
Boldine, 325, 327
Bourreria verticiUata, 395
Boxwood alkaloids, 363
Brassica spp., 648
Bromocodide, 217
Bromomorphide, 217, 254
1-Bromosinomenine, 271
Brucea ferruginea, 556
Brucea javanica, 779
Brucidine, 576
EX
Carpyrine, 599
Carthamoidine, 601
Casealutine (i-isocorypalmine), 170, 291
Caseanine (/-tetrahydropalmatine), 170,
291
Casimiroa edulis, 772
Casimircedine, casimiroine, casimiroitine,
772
Cassaic acid, 728, 729
aHoCassaic acid, 728, 730
Cassaidic acid, 729
Cassaidine, 728
Cassaine, 726, 727, 729
Cassanic acid, 728
Cassia absus, 723
Cassia Siamea, 780
Castor-oil seed, 5
" Cathine," 635
Caulophylline, 118
Caulophyllum thalictroides, 118, 146
Ceanothine, 772
Ceanothus spp., 772, 773
Celastrine, 780
Celastrus paniculata, 780
Cellianine, 774
Cephaeline, 394, 395, 396, 779
isocephseline, 398
worcephseline, 398
Cephcelis Ipecacuanha, 394
Cepharanthine, 350, 357, 358, 362
Cephalaria gigantea, 780
Ceratocapnos spp., 169
Cereus coryne, pharmacological action of
bases, 161
Cereus pecten aboriginum, 159
Cernuine, 755
Cevadilla seeds, 700
Cevadilline, 701, 705
Cevadine (crystallised veratrine), 701,
702, 775, 779
Cevanthridine, 703, 710, 712
Cevanthrol, 703, 710
Cevine, 701, 702, 710, 712
Chairamidine, 419, 467
Chairamine, 419, 467
Chaksine, isochaksine, 723
Chalchupines A and B , 761, 762
Chatinine, 778
Chavicine, 2
J-Cheilanthifoline, 170, 171, 339
Cheiranthin, 649
Cheiranthus spp., 649
Cheirinine, cheiroline, 649
Chelerythrine, 169, 173, 277, 278, 279
^-Chelerythrine, 277, 279, 280, 281
Chelidonine, 169, 173, 278, 279, 281, 282,
283
Chelidonium majtts, 119, 277, 283
Chin-Shien-Tiao-Hu-Lu, 351
Chlorocodides, a- and /S-, 217
Chlorocodon whiteii, 780
Chlorogenine. See Alstonine.
Chloromorphides, a- and /}-, 217, 254, 255
Chloroxylonine, 778
ChtoratyUm meietenia, 414, 778
787
788
INDEX
INDEX
Coroutine, 517
Coronarine, 501
Corybulbine, 170, 171, 172, 289
constitution, 290
tsoCorybulbine, 172, 290
Corycavamine, 172, 303
pharmacological action, 305
Corycavidine, 172, 303
Corycavine, 172, 303
pharmacological action, 305
Corydaldine, 285, 286, 290, 399
Corydaline, 170, 171, 172, 284, 290
Corydalis alkaloids, minor, 313
pharmacological action, 314
Corydalis and allied genera, alkaloids,
284
Corydalis spp., 160, 170, 171, 172, 313
Corydic acid, 285, 286
Corydilic acid, 285
Corydine, 172, 173, 308
t'soCorydine (luteanine), 171, 172, 173, 308
Corynanthe spp., 500
Corynantheidine, 504, 514
Corynantheine, 500, 503, 504
Corynanthic acid, 502, 503
Corynanthidic acid, 504
Corynanthidine, 500, 504
Corynanthine, 502, 503, 505
Corypalline, 160, 170, 171
Corypalmine, 170, 171, 172, 291, 342
t'soCorypalmine, 170, 212, 291, 294
Corytuberine, 172, 308
Cosciniumspp.,
329
Cotarnic acid, 200, 201, 202
Cotarnine, 187, 201, 202, 203, 206
pharmacological action, 211
neoCotamine, 205
Cotarnone, 202
Cotarnonitrile, 208
Coumingaine, 726
Coumingic acid, 729
Coumingidine, 726, 730
Coumingine, 726, 729
Courbonia virgata, 372
Crinamine, 411
Crinum s p p . , 406
Crossopteryx kotschyana, 756
Crossoptine, 756
Crotalaria s p p . , 601
Croton spp. ; crotonoside, 773
Cryptocaria spp., 319
Cryptocavine, 171, 172, 178, 299
Cryptolepine, 773
Cryptolepis sanguinolenta, 773
Cryptopalmatine, 293
Cryptopidene, 296
Cryptopine, 171, 172, 178, 292, 295
constitution, 296
synthesis, 298
Cryptopine and allied alkaloids, pharmacological action', 305
subgroup, alkaloids, 284, 294
a-aOoCryptopine (jS-homochelidonine), 169,
1 7 0 , 1 7 1 , 1 7 2 , 1 7 8 , 301
constitution and synthesis, 802
789
790
INDEX
Dihydrocinchonicine, 452
Dihydrocinchonidine, 429
Dihydrocinchonine, 428
Dihydrocinchotoxine, 452
Dihydrocodeine, 260
Dihydrocodeinone, 245, 260, 270
Dihydrocodeinone oxime, reactions, 244
Dihydrowetacodeinone, 249
Dihydrocryptopine and
isodihydrocryptopine, 296
Dihydroeupreicine, 452
Dihydrocupreidine, 431
Dihydrocupreine, 431
Dihydrodeoxymorphines, 254, 260-2
Dihydroecgonidine, 99
Dihydro-j8-erythroidines, 387
pharmacological action, 391, 392
Dihydronorharman, 498
Dihydrohemicytisylene, 144
<K-Dihydrolysergic acid, synthesis, 530
Dihydro-oc-matrinidine, 149
Dihydromorphine, 219, 260, 261
Dihydromorphinone, 246, 260
Dihydroniquidines, 453, 461
Dihydroniquine, 453
Dihydropapaverines, 185
Dihydroquinicine, 454
Dihydroquinidine, 430
e/nDihydroquinidine, 427
epi-C 3 -Dihydroquinidine, 454
Dihydroquinine, 429
e^iDihydroquinine, 426
epi-C 3 -Dihydroquinine, 444, 454
Dihydrosanguinarine, 281
Dihydroseopoline, 86
Dihydrosinomenine, 268, 269, 270
Dihydrospherophysines, 631
Dihydrostrychnidine, exhaustive
methylation, 577
Dihydrostrychnoline, 564
Dihydrothebacodeine, 269
Dihydrothebaine, 243
Dihydrothebainol, 243
Dihydrothebainol-6-methyl ether, 243
Dihydrothebainone-^j -5 : 6-methyl
enolate, 243
Dihydrometathebainone, 247, 248, 249
Dihydrothebainones, 247, 248, 250, .261,
270
Dihydrotoxiferine I and
isodihydrotoxiferine I, 382
norDihydrotropidine, 74
Dihydrotropilidene, 77, 78
Dihydrovomicidine, exhaustive
methylation, 593
Dihydroxydihydrosolanidine, 733
2 : 9-Dihydroxy-3 : 10-dimethoxytetrahydroproioberberine
See
Scoulerine.
a : /?-Dihydroxy-y-(2-methylphenoxy)propane, curarising action, 392
Dihydroxytropane, 9 1 , 100
Diketocassenic acid, 728
2 : 8-Diketonuoidine, 567, 568, 578, 574
Dilupine, 117,132
~
INDEX
a-
and
B-
(betaine
choline), 772
Ecboline, 517
Ecgonines, 93, 96
constitution, 97
pharmacological action, 110
Ecgoninic acid, 98
Echinops Ritro, 413
Echinopseine ; echinopsines, 413
Echitamidine, 716, 720
Echitamine, 716, 719, 758
Echitenine, 716, 720
Echium vulgare, 771
Eclipla alba, 35
Etasagnus s p p . ; eleagnine, 773
Mkeophora abutifolia, 872
Elissarrhena grandiflora, 372
791
792
INDEX
Fagaramide, 2
,/3-Fagarine. See Skimmianine.
Fagarines, 414
Fangchinine, 351
fangchinoline, 356
Febrifugines, 725
Feng-fan-chi, 351
Ferreira spectabilis, 631
Festuca arundinaceat, 750
Fibraurea chloroleuca, 329
Flindersia australis ; flindersine, 774
Floribundine ; floripavidine ; floripavine,
173, 276
Fluorocurine, 385
Fly agaric, 658
Foenugrec, 7
Formosanine, 756, 757
Fraxinus malacophylla, 780
FrUUlaria spp., alkaloids, 732
pharmacological action, 734
Fritillarine;
fritilline; fritimine, 732,
733, 734
Fuchsisenecionine, 601
Fumaria officinalis, 173
Fumarine. See Protopine.
Galanihus Woronom;
galantidine ;
galantine, 774
Galega officinalis ; galegine, 630
Galipea officinalis, 415, 416
Galipidine, 415
Galipine, 415, 416, 418
constitution, 417
Galipoidine, 416, 417
Galipoline, 416, 417, 418
Gambirine, 756
Ganiarine, 777
Garrya spp. ; garryine, 735
Gastrolobium calycinum, 780
Geissospermine, 735
Geissospermum spp., 735, 736
Gelsemicine, 737, 739, 740, 741
Gelsemidine, 737
Gelsemine, 49, 736, 737, 740
apo- and iso-gelsemines, 737
Gelseminine, 736, 737, 740
Gelsemium spp., alkaloids, 500, 736
pharmacological action, 740
Gelsemoidine, 737
Geneserine, 540, 547
Genista spp., 117
Genisteine, 117, 138,139
Gentiana Kirilowi ; gentianine, 742
Geqffrcea surnamensis ; geoflroyine, 631
Germerine, 701, 705, 710
Genuine, 701, 710, 712
degradation products, 711
tsogermine, 711
Girgensohnia spp., 1, 774
Girgensonine, 774
Glaucentrine, 172, 312
Glaucidine, 178, 311
Glaucine, 172,178, 311, 820
pharmacological action, 818
INDEX
793
Hemisparteilene, 135
Hemlock alkaloids, 13
pharmacological action, 21
Henbane, alkaloids, 66
pharmacological action, 106
Herapathite, 424
Hermidium alipes, 631
Hernandia s p p . , 319
Herpestine ; Herpestis monniera, 776
Heteratisine, 689
Hetisine, 689
Hexahydroanagyrine (d-sparteine), 130,
137
Hexahydroanagyryline, 141
Hexahydroyobyrine, 505
hexahydroyohimbol, 514
Hexalupine, 117,132
Hieracifoline, 601, 603
hieracinecio acid, 602
Hippophce rhamnoides, 773
H i s t a m i n e ; histidine, 518
Hodorine, 766
Holarrhena spp., alkaloids, 742
Halostachis caspica ; halostachine, 631
pharmacological action, 748
Hamadine, 67
Holarrhenine ; holarrhine, 743, 747
Hanadamine, 756, 757
holarrhimine, 742, 743, 747
Han-fang-ehi, 350, 351, 362
Homatropine, 74
hanfanchines, A, B , C, 350
pharmacological action, 109, 110
Hanssen's C 16 acid ex brucine or
^-homatropine, 101
strychnine, 567, 575
a-Homochelidonine, 169,277, 278,283, 295
Hanssen's C 19 acid ex brucine, 566, 575
/?-, y-Homochelidonines. See a-, fi-alloHarmaline, 488, 489, 490
cryptopines.
pharmacological action, 496
Homoapocinchenine, 440
syntheses, 494
" Homocinchonine," 427
Harmalol, 488, 489, 496
Homophleine, 729
H a r m a n , 486, 490, 507
Homoquinine, 430
pharmacological action of derivatives, Homotrilobine, 360
495, 514
Homotropine, 107
norHarman (3-carboIine), 486, 495, 508
Hordenine (Anhaline), 154, 155, 161, 633
Harmine, 488, 489, 490, 514, 748, 772
Hunnemannia fumaritefolia, 173
norHarmine, 490
hunnemannine, 173, 302
apoHarmine, 489, 492, 494, 497
Hydrangea umbcllata, 781
Harmol, 489
H y d r a s t a l ; hydrastic acid, 164, 165
parasiticidal action of ethers, 403
Hydrastine, 162, 209, 210, 328
pharmacological action, 496, 497
constitution, 163
Haslerine, 511
formula, 166-7
Hastacine, 601, 603
pharmacological action, 167, 212
hastanecine ; hastanecinic acid, 603
Hydrastinic acid, 164
Hedyotine ; Hedyotis auricularia, 774
Hydrastinine, 163, 187, 209
Heliopsis longipes, 774
pharmacological action, 161,167, 211
Heliotric acid, 603, 613
Hydrastis canadensis, alkaloids, 162, 200,
Heliotridane, 606, 608
328, 336
synthesis, 609
Hydrocinchonidine, 429
^-heliotridane, 606
Hydrocotarnine, 160,178, 200, 201, 203
Heliotridine, 602, 603, 604, 607
Hydrocotyle asiatica ; hydrocotyline, 775
constitution, 608
Hydrocupreidine and ethers of, 431
Heliotrine, 601, 603
Hydrocupreine and ethers of, 431
Heliotropium lasiocarpum, 601
Hydroergotinine. See Ergotoxine.
Hellebores, green and white, alkaloids, Hydrohydrastinine, 158,160,164,165,172
701, 705, 718
Hydroipecamine, 397
HeUeborus spp., 774, 775
Hydroquinidine, 419, 430
Helvetia escuknla, 775
Hydroquinone, 419, 429
Hemipinio acid, 201
Hydrorhombinine, 118,151
metaHemipinic acid, 188
9-Hydroxyeodeine, 284, 285
normetaHemipinic acid, 165
14-Hydroxycodeinone, 241, 246
tsoGlaucine, 320
Glaucium spp., alkaloids, 173
Gloriosa superba, 650
Glyoxaline group, 621
Gnoscopine (df-Narcotine), 178, 205
0-Gnoscopine, 205
Gonioma kamassi, 781
Gourd curare, 373
alkaloids, 380
Gramine, 484
Graminifoline, 601
Granatane, 62, 81
Granatolines, pharmacological action, 108
Grandiflorine, 671
Grantianine, 601, 603
Grantianinic acid, 603
Greenheart alkaloids, 363
Guvacine, 9
isoguvacine, 10
guvacoline, 10
Gymnocalycium gibbosum, 154
794
INDEX
7-Hydroxycodeinone, 271
Hydroxydihydrocinchonidine, 452
Hydroxydibydrocinehonines, 452
Hydroxydihydroquinidines, 454
Hydroxydihydroapoquinidines, 453
x-Hydroxydihydroquinine, 454
Hydroxydihydroapoquinines, 453
7-Hydroxydihydrothebainol, 271
Hydroxyheliotridane, 603, 604, 606, 607
4-Hydroxyhygric acid, 773
Hydroxylaudanosines, 188
Hydroxylupanine, 117, 131
Hydroxymagnoline, 355
a-Hydroxy-j8-phenylpropionyltropeine, 73
Hygric acid, 42, 101
Hygrines, 67, 93,101, 102, 103
Hygrinic acid (hygric acid), 42, 101
Hygroline, 102
Hygrophila spinosa, 772
Hyoscine, 64, 65, 66, 83, 84, 86, 89
pharmacological action, 106, 107, 111
apoHyoscine, 86
rf2-?iorHyoscine, 89
Hyoscyamine, 64, 65, 66, 69, 71, 79, 82,
83,84
constitution, 72
pharmacological action, 106, 110
worHyoscyamine, 64, 65, 66, 82, 83
^-Hyoscyamine, 66, 83
Hyoscyamus spp., 65, 66, 67, 68
Hypaconine, 681
Hypaconitine, 673, 674, 681
Hypaphorine, 386, 484
Hypecoum spp., 173
Hypoquebrachine, 511
Hypoxonitine, 681
IBOGA ; ibogaine, 768
Lappaconine, 686
Lappaconitine, 674, 686
Lasiocarpine, 601, 604
Lathreine, 47
Laudaline, 187
Laudanlne, 178, 191, 195, 220
pharmacological action, 197, 198
synthetic isomerides, 194
isoLaudanine ; i/r-laudanine, 194
Laudanidine (Maudanine), 178,193
Laudanosene, 187
Laudanosine, 178,187, 194,195
pharmacological action, 197,198
syntheses, 188
INDi EX
Laudanosoline, 189
(tt-Aoroolaudanosoline, 191
Laudanosolines, alkylated, 191
Lauracete, alkaloids, 317, 319
Laurales, alkaloids, 319
Laurelia spp., 319, 322
Laureline, 319, 322
constitution, 323
Laurepukine, 323, 324
Laur Jtetanine, 320, 323, 327
norLelobanidine, 23, 29
Lelobanidines, 23, 28, 29, 30, 31, 32
Lelobanines, 29, 30, 32
norLelobanines, 29, 30
Lelobine group, 23, 28, 29
Leontamine, 776
Leontice Eversmanii, 776
Leontidine, 776
Leonurus biennis, 781
Leptactina
senegambica;
leptactine,
776
Leptocladine, 772
Lettocine, 743, 748
Leuccena glauca, 2, 4
Leucaenine, 3
Leucenol (leucaenine), 2, 4
Litsea spp., 319, 320, 321, 326
Lobelan, 34
Lobelanidine, 23, 25, 27
rawLobelanidine, 23, 25, 28
Lobelanine, 23, 24, 25, 26, 27
norLobelanine, 23, 27
Lobelia alkaloids, 22
pharmacological action, 33
synthetic substitutes, 34
Lobelia spp., 22, 23, 33, 34
J-Lobeline, 23, 27, 49, 775
Lobeline group, 23, 24, 33
Lobinaline, 33, 34
Lobinanidines, 23, 31, 32, 33
Lobinanine, 31, 32
isoLobinanine, 31
Lobine, 781
Lobinine, 23, 30, 31, 32
isoLobinine, 23, 30, 31, 32, 34
Lobinine group, 23, 28, 30, 31
Lodal, 211
Lohitam, 47
Loiponic acid, 439
Lolium spp., 750
Lolium perenne, alkaloids, 749
Longilobine, 601, 604
Longinecic acid, 604
Lophantcera lactecens ; lophanterine, 776
Lophophorine, 154, 155,156, 160, 161
constitution, 158
" Loturine," 490
Loxopterygine, 782
Luciculine, 690
Lucidusculine, 673, 690
Lumicolchicine, 651
Lunacridine; lunacrine ; lunamaridine ;
lunamarine, 751, 752
Lwmtia cotttdata, alkaloids, 751
Lunasine, 751
795
See Protopine.
796
INDEX
iV-Methylgranatoline, 59
iV-Methylgranatonine, 58
Methylhannines, 492, 757
Methylhemisparteilene, 135
iV-Methyllaurotetanine, 821
Methyllycaconitine, 696
Methyl JV-methylmatrinate, 147
.W-Methylmezcaline, 154, 155
Methylmorphenol, 223
Methylmorphimethines, 218, 219, 223,
225, 237, 240
Methylmorphol, 223
2V-Methylmyosmine, 40
Methylnornarcotine, 200
JV-Methylnicotone, 42
iV-Methylnorpapaverinium phenolbetaine,
194, 195
Methylpelletierine, 55, 56
Methylisopelletierine, 55, 57
iV-Methylphenylethylamine, 772
JV-Methylpiperidine, 1, 774
Methylporphyroxine, 220
O-Methylpsychotrine, 394, 395, 397, 400
1-Methylpyrrolidine ; 1-methylpyrroline,
67
Methylstrychnine, 562
jS-Methyltetrahydrocoptisine, 345
a-Methyltetrahydropalmatine, 287
Methylthebaol, 225
1-Methyltropacocaine, 81
oc-Methyltropidine, 77, 78
1-Methyltropinone, 81
iV-Methyltyrosine, 631
Mezcaline (mescaline), 154, 156, 160, 161
Micranthine, 326, 327, 328
Mikanoidine, 601
Mimosa pudica, 4
Mimosine, 3, 4
Miotic action by physostigmine and its
substitutes, 549
" miotine," 550
Mitragyna spp., alkaloids, 756
Mitragynine, 756, 757
pharmacological action, 758
Mitraphylline; mitraspecine;
mitraversine, 756, 757
Mitrinermine, 756
Mo-fang-chi, 351
Momordica charantia; momordicine, 781
Monimiaceae, 317, 319
Monniera cuneifolia, 776
Monocrotalic acid, 604, 612
Monocrotaline, 601, 604
constitution, 610, 612
monocrotic acid, 604, 612
Monolupine, 117,132
Monspessulanine, 117,146
Moringa pterygosperma ; moringinine, 688
Morphenol, 224, 226
Morphine, 213, 219, 227
constitution, 222
estimation, 176
formulae', 284
isomerides, 217,219,224,886,28tMUW
manufacture, 179
INDEX
Morphine, pharmacological action, 196,
198,259
substitutes, 263
opoMorphine, 214, 217, 222, 224, 231, 232
constitution, 227
pharmacological action, 265
synthesis of dimethyl ether, 228
neoMorphine, 219
pharmacological action, 265
pseurfoMorphine, 215, 346
constitution, 255
^-Morphines, a-, /?-, y-, 215
constitution, 255
Morphine alkaloids, bimolecular types, 255
Morphine sub-group, alkaloids, 213
constitution, 222
ketones, 245
pharmacological action, 259
Morphol, 224, 226
Morphothebaine, 222, 227, 230, 232
pharmacological action, 266
Morphothebaine dimethyl ether, 231, 273
Moschatine, 779
Mucuna pruriens ; mucunadine ;
mucunine, 776
Mu-fang-chi; mufangchine, 351
Muricine ; muricinine, 317, 319
Muscarine, 658
pseuaomuscarines, 658, 660
Mydriatic alkaloids, 64
synthetic substitutes, 109
Myoctonine, 673, 686, 687
Myosmine, 47, 50
NANDAZURINE, 329
797
47
798
IN
protoPapaverine, 195
^-Papaverine (papaverine), 178,187
Papaverinic acid, 183
Papaverinol, 183, 188
Papilionaeeae, alkaloids, 116
Paraberine, 336
Paraisine t 781
Paramenispermine, 349
Paramorphine. iSee.Thebaine.
"Pareira b r a v a , " alkaloids, 363, 364,
377
Paricine, 419, 466
Paucine, 776
Pausinystalia spp., 500, 501
Payta bark ; paytamine ; paytine, 513
Pectenine, 159
Peganine. See Vasicine.
Peganum Harmala, alkaloids, 488, 617
Peimidine, 733
Peimine, 732, 734
Peiminine, 732, 733
Peimiphine, 733
Peimisine, 733
Peimitidine, 733
" Pei-mu," 732
Peimunine, 732, 734
Pelletierine, 55
constitution, 56
Pelletierine and associated bases,
pharmacological action, 62, 108
isoPelletierine, 55, 57, 58
pseudoPelletierine, 55, 58
constitution, 59
synthesis, 61
Pellitorine, 2
Pellote. See Mescal buttons.
Pellotine, 154, 155, 156
constitution, 157
pharmacological action, 161
Pelosine. See Bebeerine.
Pentaclethra macrophylla, 776
Pentalupine, 118,132
Pepper. See Piper spp.
Pereirine ; pereiro bark, 735, 736
Perlolidine, 749, 750
Perloline, 749, 751
Persea gratissima, 320, 781
Pethidine, 265
Petrocapnos spp., alkaloids, 173
Petrosimonia monandra, 1
Pheanthus ebracteolatus, 350
Pheanthine, 350, 356
Phellodendron amurense, 329
Phenanthridine group, alkaloids, 406
Phenylalkylamines, 631
Phenyldehydrosparteine, pharmacological'
action, 152
Phenyldihydrothebaines, 238
Phenylglycollyltropeine, 74
Phoradendron spp., 631
Phtbalideisoquinoline alkaloids, 162, Vt9,
200, 209
pharmacological action, 211
Physalis mollis, 782
f
Physostigma venenosttm, alkaloids, 589
INDEX
Physostigmine, 262, 540
pharmacological action, 548
synthetic work, 641-7
isoPhysostigmine, 540, 547
Physostigmol; physostigmol ethyl ether,
541
Physovenine, 540, 548
Picraconitine, 675
Picralima klaineana, alkaloids, 759
Picrasma crenata, 782
Picrorocelline, 777
" Picrosclerotine," 517
Pillijanine, 753, 754, 755
Pilocarpidine, 621, 626
isopilocarpidine, 626, 627
syntheses, 625
Pilocarpine ; isopilocarpine, 621, 622
syntheses, 625
^Pilocarpine, 621
neoPilocarpine, 627
^-Pilocarpine, 621, 628
Pilocarpine and associates,
pharmacological action, 628
Pilocarpus spp., alkaloids, 621
Pilocereine ; Pilocereus sargentianus, 154
Pilopic acid, 622 ; isopilopic acid, 625
AomoPilopic a c i d ; Aomoisopilopic acid,
622, 624, 626
Pilosine, 621, 627
pilosinine, 627
synthesis, 628
Piper spp., 1, 2
piperidine, 1
piperine, 1
piperovatine, 2
Piptanthus nepalensis, 118
Piscidia erythrina, 782
Pithecolobine ; Pithecolobium Saman, 777
"Piule,"781
Platynecic acid (senecic acid lactone), 605,
613
Platynecine, 602, 605, 607
constitution, 609
Platyphylline, 602, 604, 613
pharmacological action, 614
Pneumus Boldus (Boldeafragrans), 319,325
Podalyria spp., 118
Polyporus frondosa, 782
Pomegranate root bark, alkaloids, 55
Pontaconitine, 674
Poroidine ; isoporoidine, 64, 66, 90
Porphyrine ; porphyrosine, 716
Porphyroxine, 178, 220
P o t curare, 373
alkaloids, 378
Premna integrifolia ; premnine, 777
Prostigmine, 262, 550
Protocurarine, 378, 391
Protocuridine ; neoprotocuridine, 378,392
Protocurine, 378
Protopine, 169, 170, 171, 172, 173, 178,
208,299
constitution and synthesis, 800
pharmacological action, 305
Protoveratridine, 701, 705, 710
799
QUEBKACHAMINE, 5 1 1 , 512
INDEX
800
Quinidinechloride, 439
apoQuinidines, 452
methyl ethers. See fcoQuinidines.
tsoQuinidines, 453,454
Quinidinone, 437
Quininal, 436
Quinine, 419, 421, 748, 776, 780, 781
configuration, 443
constitution, 435
detection, 424
isomerides, 453-4
pharmacological action, 478
salts, 422-3
synthesis, 461
synthetic replacements, 474, 476
transformation products, 448
Quinine and other cinchona bases; relative
anti-malarial efficiencies, 471
effect of structural change on antimalarial efficiency, 472
Quininechloride, 439
ethochloride, curariform action, 392
479
epiQuinine, 419, 426
A-Quinine, 419, 449,[454
apoQuinines, 452
isoQuinines, 444, 453
Quininic acid, 437, 438, 454
Quininone, 437, 438, 442
" Quinoidine," 426
Quinoline, alkylquinolines, occurrence in
Cusparia bark, 416
Quinoline group alkaloids, 413
isoQuinoline group alkaloids, 154
Quinolylphenetoledicarboxylic
acid ex
cinchonine, 441
Quinolylpiperidylcarbinols, syntheses, 460
Quinolylquinuelidine alkaloids, 418
Quinotoxine, 425. See also Quinicine.
/MsoQuinotoxine, 444, 454
Quinovatine, 466. See also Aricine.
Quinuclidine, 436, 443
and derivatives, syntheses, 455
Quirandine, 511
Quisqualis indica, 782
Quitenidine, 437
Quitenine, 436
RADDEANENE, 732,
734
alkaloids, 702
Sabadilline (cevadilline); sabadine ;
sabadinine (cevine), 701, 705. See also
Cevine, 702
Salsamine, 160
Salsola Richteri, alkaloids, 159
Salsolidine, 159,160
Salsoline, 158,159, 161
Sanguinaria
canadensis, alkaloids, 173
277 283
Sanguinarine, 169, 173, 277, 278, 279,
280
Sankhpuspine, 773
Sansevieria zeylanica, 782
Sarcocapnos spp., 173
Sarcocephalus Didderichii, 782
Sarothamnine, 117,138
Sarracema purpurea, 777
Sarsapogenin, conversion t o a
dihydrosolanidine, 666
Sassy bark, 725
EX
Sauroxine ; saururine, 753, 754
Saussurea Cappa ; saussurine, 782
Sceleranecic acid, 605
Sceleratine, 602, 605
Schaenocaulon officinale, 700
Scopine, 64, 66, 88, 107
^-scopine, 89
nor- ^-scopine, 89
Scopolamine, see Hyoseine;
norscopolamine, see norHyoscine.
Scopolia spp., 66, 68, 82, 85
Scopolic acid, 86
Scopoligenine, 86
Scopoline, see Oscine ; norScopoline, see
norOscine.
Scopolinic acid, 33
Scoulerine, 170, 171, 172, 173, 290, 291
Secaleaminosulphonic acid, 518
Secaline, 517
Sedamine, 777
Sedum acre, 35, 777
Sekisanine ; sekisanoline, 406, 411
Sempervirine, 500, 737, 738, 740
Senecic acid, 605, 606, 613
Senecic acid lactone, 605, 613
Senecifolic acid, 606
Senecifolidine, 602, 606
Senecifoline, 602, 606
Senecifolinine, 603, 606
Senecio alkaloids, 601
toxicology, 614
Seneciocic acid, 613
Senecionine, 602, 606
Seneciphyllic acid, 605, 606
Seneciphylline, 602, 606
Sensibamine, 518, 519
Sepeerine, 363
Septentrionaline, 674, 686
Serpentine ; serpentinine, 762, 763
Sesbania tripeti, 118
Setaria lutescens, 750
Shobakunine, 329, 340
Sida rhombifolia, 635
Silvasenecine, 602
Sinactine (Z-tetrahydroepiberberine), 173,
268, 272, 329, 338, 339
Sinalbine ; sinapic acid ; sinapine, 648
Sinomenine, 268, 273, 351
hydrate, 270
Sinomenol, 270
Sinomenium acutum, alkaloids, 268, 329,
349, 350, 351
pharmacological action, 273
Skatole, 738
Skimmia spp., 413, 414
Skimmianal, 414
Skimmianic acid, 414
Skinimianine, 414, 752, 773
tsoSkimmi&nine, 414
Sigmine, 782
Sinine, 780
Sinostemonine, 767
SmOax pteude Mna, 782
Socratines, a-,
faw.1?
Solaoeiae,4n
801
Solanaceous alkaloids, 64
analytical methods, 69
distribution in plants, 65-7
pharmacological action, 105
Solandra spp., 66, 82
Solandrine, 82
Solaneine, 662
Solangustidine; solangustine, 671
Solanidine, 661, 662, 671, 708, 712, 713
dehydrogenation products, 663
heterocyclic residue, 665
proximate derivatives, 664
structure, 665, 667
Solanine, 661
Solanine-s. See Solasonine.
" Solanines," pharmacological action, 671
Solanocapsidine, 671
Solanocapsine, 670
Solanum nigrum, 48
Solarium spp., 661, 666, 669, 670, 671
Solasodine, 666, 713
Solasonine, 666, 669
Solauricidine, 669
Solauricine, 668
Sophocarpidine. See Matrine.
Sophocarpine, 116, 118, 148, 150, 152
Sophochrysine, 118, 150
Sophora spp., alkaloids, 118, 138, 150
pharmacological action, 152
Sophoramine, 118, 150
Sophoridine, 118, 150, 152
Sophorine (cytisine), 142
Sparteilene, 135
Sparteine, 49, 54, 116, 117, 118, 130, 133,
138, 142, 148, 169, 674
pharmacological action, 152
rf-Sparteine (pachycarpine), 138,142
^t-Sparteine, 138
tsoSparteines, 134, 136, 152
Spartioidine, 602
Spartium junceum, 118
Spartyrine, 136
Spathulatine, 118,132
Sphasranthine ; Splueranthus indieus, 777
Sphoerophysa sahula;
sphaerophysine
(spherophysine), 630
Spigelia marylandica ; spigeline, 782
Spilanthol, 2
Sprintillamine, 774
Sprintilline, 775
Squalidine, 602, 606
Squalinecic acid, 606
i-Stachydrine, 42, 773
Slachys spp., 7
Stapmsagroine, 700
Staphisine, 699
Stemonacew spp., alkaloids, 765
Stemonidine, 765, 766
isoStemonidine, 765
Stemonine ex Stemona ovata, 765
ex S. tuberosa, 766
Stephania cepharantha, 346, 850
Stephania spp., alkaloids, 350, 851, 861,
862
Stephanine, 861
802
INDEX
mmEX
Sbunbergin, 351
f k l o i d i n e (tiglyl-^-tropeine), 64, 66, 89
nOacora racemosa ; tiliacorine, 350
Tmospora spp., 329
Tobacco alkaloids, 35
smoke, alkaloids, 46
Toddalia aculeata; toddaline ;
toddalinine, 329
Tomato grafts on alkaloid-bearing
solanacese, 48
d-Tomentocurine, 377
" Totaquina," 419, 420
Toxiferine, 380
Toxiferines I and I I , 382, 384
Toxiferines, H a and lift chlorides, 383,
384
C-Toxiferine I, 383, 385
C-Toxiferine I I , 382, 384
Trachelantamidine, 606
Trachelantamine, 602, 606, 607
pharmacological action, 614
Trachelanthus korolkovi, 602
Trachelantic acid, 606, 607
Trachelantidine, 607
Trachelantine, 602, 607
Trianthema monogyna, 778
Trichocereus spp. ; trichocereine, 161
Trichodesma spp., 601, 602
Trichodesmine, 602, 607
Triclisia Gillelii ; tricliseine ; triclisine,
778
Trigonella Fcenumgrcecum, 7
Trigonelline, 7, 413, 671, 772
Trilobamine, 350, 357
Trilobine, 350, 358, 359, 360, 362
tsoTrilobine, 350, 359, 360
Trilupine, 117, 132
Trimethylcoclaurine, 353
Trimethylcolchicinic acid, 651
Trimethylpapaveroline, 194, 195 .
Tritopine. See Laudanidine.
Tropacocaine, 62j 64, 79,100
pharmacological action, 106
Tropane, 87, 108
Tropane group alkaloids, 64, 776
pharmacological action, 105
Tropeines, 73, 79, 81
Tropenbne, 80
Tropic acid, 72
Tropidine, 59, 74, 75, 77, 78, 98
Tropigenine (nortropine), 64, 75, 86, 90,
91,98
^-Tropigenine (nor-0-tropine), 76
Tropilene, 74, 75, 77
Tropilidene, 75, 77, 98
Tropine, 59, 64, 67, 73, 76, 77, 84, 86, 89,
97, 98, 99, 101, 107, 110, 441
constitution, 74
syntheses, 77
Tropine and allied amino-alcohols, alkaloids derived from, 64
flOfTropine, 64, 75, 86, 90, 9 1 , 98
Mor-^-Troplne, 76
^flSpopine, 4 , 7 5 , 77, 80, 9 9 , 1 0 0 , 1 1 0
f l & i n f e a d d , 59, 75, 76, 77, 98
803
INDSM
80*
"YAOsrNK,"48s.
Yatanine, 778
Yobyrine, 600,504,505,507,509,514,739
synthesis, 510
Yobyrone, 505, 607, 739
Yohimbe, alkaloids, 500
" Yohimbenine," 500
Yohimbenone, 505
Yohimbic acid, 501, 505
isomerides, 502, 503, 505
Yohimbine, 161, 500, 501, 503, 505, 511,
735
constitution, 504
formulas, 508
reaction products, 507
apoYohimbine, 503, 504, 506, 509
a-isoYohimbine, 503, 506
norYohimbine. See Yohimbic acid.
Yohimbine and isomerides, 500, 502, 503,
505, 506
constitution, 504
pharmacological action, 513
Yohimbol; aHoyohimbol; epiyohimbol,
505
Yohimbone, 504, 505
aMoYohimbone, 505
Yulocrotine, 781
See Papaveraldine.