United States Patent 11»
Mudryk et al.
[5] PREPARATION OF OPLAT
INTERMEDIATES AND USES OF SALTS
{75} Inventors: Bogdan Mudryk, East Windsor
ster Sapino, Sewell, bath of N.ls
Semen Dung Boston Pas Al
Sebastian, Deptford, Nh
[73] Assigace: Johnson Matthey Public Limited
Company, London, United Kingdom
[21] Appl. No.: 09/107,509
[22], Filed: Jun. 30, 1998
[30] Foreign Application Priority Data
Jue, 30, 1997 [GB] United Kingdom oman
[51] Int. C1? Co7p 471/08
[52] US. Cl S648; 546/45,
[58] Field of Search 54644, 45
[56] References Cited
USS. PATENT DOCUMENTS
3,894,026 7/1975 ‘Sohar etal. 250/285
54085,480 81977. Rapoport. 250/285
Grass Silom Schwarz 304158 R
4795313 1/1989 Schwartz Stoi4s
512975 5/1992 Wallace 546/45
FOREIGN PATENT DOCUMENTS
902 257
Wigs
Germany
US006090943A_
uy) Patent Number: 6,090,943
[45] Date of Patent: Jul. 18, 2000
1.260699 1/1972 United Kingdom
OTHER PUBLICATIONS
Schwartz et al, J. Med. Chem., vol. 2
1525-1528 (1981) (XPO02078240),
Noble, Synthesis, pp. 1-6, 1970 (XP002078241).
Seki, Chem. Pharm. Bull., vol. 18, No. 4, pp. 671-676
(4970) (XPO02078242),
Thara_ et al, Synlett, No. 6, pp. 435-436 (1993)
(XP002078243).
“Houben Weyl: Methoden der Organischen Chemie, Bd
Vila” (1978), George Thieme Verlag, Stuttgart, p. 161
(XP002078244).
“Houben Weyl: Methoden der Organischen Chemie, Bd
E15”, (1993), George Thieme Verlag, Stuttgart, pp. 201-205
(XP002078245).
No. 12, pp.
Primary Examiner—Alan L. Rotman
Attorney, Agent, or Firm—Pillsbury, Madison & Sutro LLP
(57) ABSTRACT
‘A process forthe preparation of thebaine, its salts such as the
bitartrate, and analogues thereof, together with a novel
intermediate useful in said process are disclosed. Thebaine
bitartrate is itself useful in the preparation of oxycodone;
analogues are useful in the preparation of anslogous
|4-hydroxymorphinones.
4 Claims, No Drawings6,090,943
1
PREPARATION OF OPIATES,
INTERMEDIATES AND USES OF SALTS.
‘This invention relates to a process for the preparation of |
thebaine and analogues thereof, and fo a novel intermediate
useful in such a process. In particular, the invention relates
to the preparation of thebaine from N-methyl morphinans,
its isolation asa salt and the use of the salt in the preparation
‘of Nemethyl-14-hydroxymorphinones,
‘Thebaine is an N-methylmorphinan having the structure
a:
“
cH.
CH
cme
‘Thebaine and analogous compounds containing a dienol
ether or a dienol ester are useful intermediates in. the
preparation of L4-hydroxymorphinans, such as oxycodone,
naltrexone, nalbuphine and naloxone. Oxycodone is the
ccortesponding 14-hydroxy-N-methylmorphinone baving the
structure (B):
®
cu
Unfortunately, thebaine is expensive and is not always
readily available in industrially required quantities. Sobat et
al, US. Pat. No, 3,894,026, disclose a method for producing
thebaine, but the Starting material is salutaridinol, which is
itself not readily available. Therefore, it is desirable 10
prepare thcbaine or its analogues, directly or though known
intermediates, from more readily available morphinans such
as codeine and morphine.
Codeine isthe coreesponding 6-OH monoenolether ana-
logue of thebaine.
Rapoport etal, US. Pat. No. 4,045,440, provide a method
for producing thebaine fom codeine via the intermediate
cexdeine methyl ether. This method requires a 90-second
reaction time in preparation ofthe intermediate, and is thus
not suitable for use on an indusrial scale. The method also
requires. a 24-hour reaction period for conversion of the
intermediate to thebaine, and employs « heterogeneous
catalyst, manganese dioxide, or the transformation, leading
to further dificulties on seale-up.
Schwartz, US. Pat, Nos. 4,872,253 and 4,795,813 and J
Med. Chem. 24, 1525 (1981) provides a methed for pro-
ducing certain dienol ester analogues of thebaine having the
structural formula (C):
0
as
os
ss
4s
ss
6s
o
RHO,
watt
T
RHO’
wherein R" is lower alkyl, R'is eyano or acyl, and R'is
acyl. These thebaine analogues, in whieh the N-methyl
group has been replaced by R', are useful as intermediates
for naloxone, naltrexone and nalbuphine, but are not useful
as intermediates to L4-hydroxy-morphinan compounds hav-
ing an N-methyl group, such as oxyceslone or oxymorphone
For these compounds, thebaine is the desired intermediate,
since it has the required N-methyl substituent,
Further, the method of Schwartz, which employs a reae-
tioa temperature of 80-100° C. to introduce the R’? acyl
group, may not readily be extended to preparation of an
Nemethyl dienol ester, since at such a temperature, the
N-methyl group would also be acylated, leading to
by-products and reduced yield, Extension of this method to
the preparation of N-methyl dienol etber compounds, such
asthebaine, is also not feasible. At the esetion temperatures
employed to introduce R™, not only would the N-methyl
group be alkylated, leading to by-products and reduced
yield, but the alkylating agent would be destroyed by
reaction with the base employed inthe proces.
Wallace, U.S. Pat. No. 5,112,975, employs. a process
similar to that of Schwartz to prepare compounds of struc-
tural formula (C), but wherein the R'? is an alkoxyearbonyl
substituent, This process differs from that disclosed. by
‘Schwartz in that the ultimate starting material is morphine,
rather than codeine, but has limited use as a method for
preparing thebaine or thebaine analogues with N-alkyl sub-
stitution for the same reasons given in the preceding para-
graph,
British patent number 1,260,699 discloses a method for
preparation from codeine of dienol ethers analogous to
thebaine. However, the method used for isolation of these
dienol ethers is lengthy, requiring a chromatographic
separation, and gives a low yield of the produet. For these
reasons, this method is not useful for large-scale preparation
of thebaine.
It has now been found possible to provide an efficient,
high-yielding process for the preparation of thebaine ot
thebaine analogues (ie. having N-CH, substitution) con-
twining a dienol ester of a dienol ether, from moxphinone,
codeinone or analogues thereof which contain an a,f-
unsaturated ketone via a novel alkoxylated intermediate
‘Accordingly, the present invention provides a process for
the preparation of a compound of formula (I) oF salt thereat6,090,943
®
Ro”
wherein R? and R® are the same or different and each is a
protecting group; and
RE is lower alkyl, allyl or lower alkyl substituted by”
cycloalkyl; said process comprising the reaction of the
‘compouad of formula (I):
aw
RM
SNe
|
mo"
wherein R! and R? are as hereinbefore defined; and M is an
alkali metal or a quaternary ammonium cation; with a
‘compound of formula R°X, wherein R’ is as hereinbefore
defined and X is a leaving group; and, optionally, but
preferably, the reaction of the compound of formula (I) so
prepared with an acid, such as L-tatari acid, to give a salt
such as the bitartrate, of the compound of formula (),
Preferred protecting groups inthe definition of Rand R
are selected from alkyl or acyl groups. Preferred alkyl
groups are selected from lower alkyl, trilkylsiyl,alkyldiar-
Ybsilyl and acyl, although they may also be selected from
aryl and alkylaryl, any of which alkyl and aryl groups may
be substituted by halo, Preferred aryl groups are phenyl.
Preferred acyl groups are selected from those of formula
R°CO-, wherein R'is selected from lower alkyl, lower alkyl
substituted by halo or phenyl, and aryl, such as phenyl and
substituted phenyl. R" is preferably selected from lower
alkyl, phenyl or substituted phenyl. Preferably, alkyl groups
herein have from 1-6, more preferably 14, carbon atoms;
and aryl groups herein are phenyl, optionally substituted by
alkyl andor halo, such as chloro.
Tnan especially preferred aspect of the present invention,
the compounds prepared by the above process are com:
ppounds of formula (I) wherein RY, R and R® may be the
same or different and each is lower alkyl, for example Cy.
alkyl, such as C,_, alkyl and preferably methyl or ethyl. Ta
a particularly preferred aspect, the compound prepared is
thebaine or a salt thereof, preferably the bitartrate salt,
Suitable agents R°X used in the preparation of the com-
pounds of formula (I) include those alkylating or acylatin
agents where R° is preferred as defined hereinbefore. Suit
able leaving groups X are hal, alkanoate, benzoate, substi
tuted benzoate, alkyl sulphate, alkyl ‘sulphonate, aryl
sulphate, arylsulphonate, halosulphonate,
haloalkylsulphonate, tetra-alkylimmonium halide and
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