Professional Documents
Culture Documents
The plan
1. Medical preparations from group of derivatives
of barbituric acid: barbital, barbital sodium,
phenobarbital,
phenobarbital
sodium,
benzonal, hexenal, thiopental sodium.
2. Primidone as structural analog of barbiturates.
Derivatives of pyrimidine
Completely
hydrogenated
cycle
3
hexahydropyrimidine:
of
4
HN
5
1
HN
N
2
pyrimidine
names
HN
O
HN
5
6
O
NH2
O
HO
NH2
HO
HN
H
C
-2H2O
H
5
HN
HO
HO
HN
R1
C
NH2
R2
O
-2H2O
O
4
HN
R1
5
R2
O
HN
OH
HN
H
O
O
HN
HN
O
HN
OH
HN
HN
O
N
O
R2
OH
N
O
HN
O
O
HN
HO
O
N
HN
O
OH
tautomerism).
R2
OH
R2
HN
HO
O
HN
R1
HN
R2
HN
R1
HN
R1
HN
R1
HN
O
N
H+ O
R1
N
NaOH
-H2O
R2
HN
pH ~10
Na+ O
ONa
R1
NaOH
pH~13
R2
HN
O
R1
R2
ONa
Barbituric acid and its salts do not have medical properties and
consequently are not drugs.
O
4
3N
R1
5
R2
N1
R
NaO
(NaS)
R1
5
N1
R
R2
Synthesis of barbiturates
OC2H5
OC2H5
C
R2
OC2H5
C
H
OC2H5
2C2H5Br
C2H5ONa
-2HBr
C2 H5
C2 H5
C
O
O
HN
C2 H5
HN
C2 H5
OC2H5
HCl
OC2H5
H2 N
H2 N
O
C
C2H5ONa
-C2H5OH
HN
C2 H5
C2 H5
NaO
HN
O
C2H5
5
N1
Barbitalum
C2H5
C8H12N2O3184.257-44-3
DEFINITION
Barbital contains not less than 99.0 per cent and not more than the equivalent of
101.0 per cent of 5,5-diethylpyrimidine-2,4,6(1H,3H,5H)-trione, calculated
with reference to the dried substance.
CHARACTERS
A white, crystalline powder or colourless crystals, slightly soluble in water, soluble in
boiling water and in alcohol. It forms water-soluble compounds with alkali hydroxides
Phenobarbital
Phenobarbitalum
HN
O
O
4
C 2H 5
5
HN1
C 6H 5
C12H12N2O3
DEFINITION
Phenobarbital contains not less than 99.0 per cent and not more
than the equivalent of 101.0 per cent of 5-ethyl-5phenylpyrimidine-2,4,6(1H,3H,5H)-trione, calculated with
reference to the dried substance.
CHARACTERS
A white, crystalline powder or colourless crystals, very slightly
soluble in water, freely soluble in alcohol. It forms water-soluble
compounds with alkali hydroxides and carbonates and with
Benzonal
Benzonalum
O
HN
C2H5
C6H5
O
C6H5
1-benzoyl-5-ethyl-5-phenyl-barbituric acid
CHARACTERS
A white, crystalline powder, melting point 134-137 ; very
slightly soluble in water, partly soluble in alcohol, freely soluble in
chloroform, soluble in ether.
Barbital sodium
Barbitalum-Natricum
HN
C 2H 5
C 2H 5
NaO
sodium 5,5-diethyl-barbiturate
CHARACTERS
A white, crystalline powder without smell, bitter taste. Water
solution has alkaline reaction;
freely soluble in water, slightly soluble in alcohol, practically
insoluble in ether.
Hexenal
Hexenalum
Hexobarbitalum
N
NaO
CH3
5
N
H 3C
sodium 1,5-dimethyl-5-(cyclohex-1-enyl)-1,3,5pyrimidine-2,4,6-trion
CHARACTERS
A white foamy consistence, at action CO2 (on the air) decomposes.
Hygroscopic.
very soluble in water and alcohol, practically insoluble in ether
Barbamyl
Barbamylum
3
HN
NaO
O
4
C 2H 5
5
N1
H2 H 2
C C CH
C5H11
CH3
CH3
sodium 5-ethyl-5-isoamyl-1,3,5-pyrimidine-2,4,6-trion
CHARACTERS
A white fine-crystalline powder without smell, hygroscopic;
Thiopental sodium
HN
C 2H 5
NaS
Ph Eur monograph 0212)
Thiopentalum-Natrium
C5H11
N
O
H
C
H2 H2
C C CH3
3
CH3
1
DEFINITION
CHARACTERS
A yellowish-white powder, hygroscopic, freely soluble in water,
partly soluble in ethanol.
Identification
1. Formation of the painted complexes (various colours for
different barbiturates) with salts of heavy metals (Co (NO3)
2 in the presence of CaCl2, CuSO4 in the presence of
3 and 23, CuSO4 in neutral medium (that not are
formed precipitates Me(OH)n ).
O
N
C2H5
O
C6H5
NH
O
Cu
C2H5
HN
C6H5
O
N
R1
O
R2
N
O
Cu
From steam-dimethylaminobenzaldehyde
and concentrated H2SO4:
O
HN
R1
NaO
+ HCl
R2
HN
R1
O
R2
HN
H
C
O
C
OCH3
+ Na+
H
C
O
C
OCH3
ONa
+ NaCl
O
HN
O
C 2H 5
O
HN
O
HN
NaNO3
H2SO4(conc)
-H2O
C 2H 5
O
HN
O
NO2
O
6
+ 2FeCl3 + 10 H2O
C
O
ONa
Fe Fe(OH)3 7H2O
3
+ 3C6H5COOH + 6NaCl
CH3
NaO
+ Br2
NaO
N
H3C
N
O
CH3
H3 C
Br
O
Br
C2H5
NaS
HN
CH
6NaOH
H2 H2
C C CH3
C2H5
H
HC C
COONa
H2 H2
C C CH3
CH3
O CH3
Na2S + Pb(CH3COO)2
PbS + 2CH3COONa
black precipitate
At interaction with ions Ag + are formed onesubstituted (soluble in water) and two- substituted
(insoluble in water) silver salts. In the presence of Na2CO3
at first Na-salt, and then Ag-salt in positions 4 and 6 are
formed
N
R1
N
Na2CO3
R1
R2
R2
OAg
R1
O
R2
N
OH
AgNO3
-NaNO3
R1
R2
OH
OH
OH
OAg
ONa
OH
OAg
N
Na2CO3
R1
O
N
R2
ONa
OAg
AgNO3
R1
R2
OAg
Tests
Assay of barbiturates
For quantitative definition of barbiturates
various methods are used:
1. Titrimetric:
a) acid- base titration in water,
aqueous-alcoholic and non-aqueous
mediums;
b) argentometry;
c) bromatometry;
d) iodo-chlorometry (for barbiturates
with nonsaturated bonds, for example,
hexenal).
2. Gravimetry.
3. Photocolorimetry.
benzonal.
R1
O
+
R2
N
R
C
N
CH3
CH3
R1
O
+
R2
N
R
CH3
CH3
O
N
R1
CH3ONa
NaO
O
H
C
H
CH3O
R2
_
+
R2
R1
O
O
CH3
_
+
CH3OH
CH3O
CH3
CH3
CH3
O
CH3
+ NaOH
CH3
O
N
O
R1
+ Na
R1
R2
NaO
R2
N
R
Em = . m.
O
HN
O
N
R1
+ NaOH
HO
R2
N
R
R1
R1
+ H2O
NaO
R2
N
R
C2H5OH
R2
N
R
Em = . m.
O
HN
O
N
R1
+ NaOH
HO
R2
N
R
R1
R1
+ H2O
NaO
R2
N
R
C2H5OH
R2
N
R
HN
R1
+ HCl
NaO
R2
N
R
R1
R2
+ NaCl
The free alkaly (NaOH), which is formed at hydrolysis of sodium salts of barbiturates,
titrate with acid too:
O
O
N
R1
+ HOH
NaO
HO
R2
N
O
R1
R2
N
R
+ NaOH
Where:
% NaOH the maintenance of free alkali in substance, in %;
K coefficient (factor), which calculate as a parity between molar
weights of salt and sodium hydroxide NaOH.
At quantitative definition of thiopental sodium by means of acidimetry
define the total maintenance of Sodium (titrate with sulphatic acid H2SO4 in the
presence of methyl red as indicator).
5. Argentometry
1. Method of Fialkov and employees (benzonal)
Shot of test substance (the acid or salt form) dissolve in 5 %
anhydrous solution of sodium carbonate Na2CO3 and titrate with
nitrate AgNO3 without the indicator to occurrences of not
disappearing dregs (the two-substituted Ag-salt).
insoluble two- substituted Ag-salt is formed, that specifies in the titration end.
R1
N
Na2CO3
R1
R2
R2
OAg
N
Na2CO3
O
R2
OH
-NaNO3
R1
R2
OH
OAg
R1
AgNO3
OH
OH
OAg
ONa
OH
R1
O
N
R2
ONa
OAg
AgNO3
R1
R2
OAg
CH3
NaO
+ Br2
NaO
N
H3C
N
O
CH3
H3C
Br
O
Br
O
N
CH3
NaO
+ ICl
NaO
N
H3C
CH3
I
N
O
H3C
O
Cl
ICl + KI = I2 + KCl
I2 + Na2S2O3 = 2NaI + Na2S4O6
Carry out the control test.
m(hexenal) = . m./2
8. Gravimetry
Gravimetric method usually is used for quantitative definitions of
Na-salts of barbiturates (for example, thiopental sodium), and also at
the analysis of medicinal mixtures.
To water solution of preparation add diluted chloride acid HCl.
O
HN
O
HN
R1
+ HCl
NaO
R2
HN
O
R1
+ NaCl
R2
HN
O
Storage
Group of strong preparations.
In the dense corked container.
Hygroscopic preparations in the dry, cool place, protected
from light.
Phenobarbital and benzonal in the banks of dark glass, in the
place protected from light.
Hexenal and thiopental sodium in glass bottles on 0,51,0 g,
which are hermetically closed by rubber stoppers, are fitted by
aluminium caps; in the dry, cool place protected from light. As the
stabilizer to hexenal add 0,050,25 % sodium hydroxide NaOH, to
thiopental sodium
56 % of sodium carbonate Na2CO3.
Water solutions of barbiturates Na-salts easily hydrolyze,
therefore them prepare on a physiological solution in aseptic
conditions directly ahead of the use (ex tempore).
Primidone
Hexamidinum
Primidonum
O
HN
C2H5
5
1
HN
C6H6
C12H14N2O2 218.3
DEFINITION
5-Ethyl-5-phenyldihydropyrimidine-4,6(1H,5H)-dione.
The chemical structure of primidine is analogue of barbiturates, but unlike
phenobarbital, primidone do not have hydroxy-group == on the 2-position in
the ring.
Synthesys
Primidone is synthezed from phenylethylmalonic ester:
CO OC2H5
C2H5
C
C2H5
CO OC2H5
KOH
-HCl
-C2H5OK
CONH2
C2H5
C
C2H5
CONH2
COOH
C2H5
PCl5
C
C2H5
HC
NH2
COOH
C2H5
COCl
C
C2H5
COCl
2NH4OH
-2HCl
HN3
C 2H 5
HN
C6H6
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Very slightly soluble in water, slightly soluble in ethanol (96 per
IDENTIFICATION
A. (BrPh). Measure of ratio of the absorbance.
B. (BrPh). Infrared absorption spectrophotometry.
D. (BrPh, SP X). Melting with anhydrous sodium
carbonate (BrPh) or
alkalis (SP X). Mix 0.2 g and 0.2 g of anhydrous sodium carbonate R. Heat until the mixture
melts. Ammonia is evolved which is detectable by its alkaline reaction
HN3
C2 H 5
HN
+NaOH
tC
C6H6
2NH3
C2H5
+ Na2CO3 + HC
+
H
CHCOONa
C2H5
C2H5
CHCOONa
+H2SO4
CHCOOH +NaHSO
C2H5
C2H5
SO3Na
HO
2
HO
SO3Na
HO
HC
H2SO4
HO
C
H2
HO
OH
SO3H HO3S
SO3H HO3S
C
H
HO
O
OH
SO3H HO3S
OH
[O]
H2O
TESTS
IMPURITIES
Specified impuritiesA, B, C, D, E, F.
F. 5-ethyl-5-phenyl-2-[(1RS)-1-phenylpropyl]dihydropyrimidine-4,6(1H,5H)dione.
Ph Eur
ASSAY
(BpPh). Dissolve 60.0 mg with heating in 70 ml of ethanol (96 per cent) R,
cool and dilute to 100.0 ml with the same solvent. Prepare a reference solution in
the same manner using 60.0 mg of primidone CRS. Measure the absorbance
(2.2.25) of the 2 solutions at the absorption maximum at 257 nm.
Calculate the content of C12H14N2O2 from the absorbances measured and
the concentrations of the solutions.
Storage
List of strong preparations.
In the dense corked container.