Note: Descriptions are shown in the official language in which they were submitted.
CA 02567806 2006-11-22
WO 2006/087729 PCT/IN2005/000048
Rapid Resolution Process of Clopidogrel Base and a Process for Preparation of
Clopidogrel Bisulfate Polymorph - Form I
Technical Field:
The present invention relates to a rapid resolution process of racemic
clopidogrel base
followed by conversion of the resolved (S) isomer to crystalline Clopidogrel
bisulfate
Form I. Clopidogrel bisulfate [Formula I] [Methyl (S)-(+)-a-(o-chlorophenyl)-
6,7-
dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate] is an
Antithrombotic
agent.
H3
0 O C1
N H2SO4,
S
Formula I
Background and Prior Art:
Clopidogrel is administrated as its hydrogen sulfate (syn. Bisulfate) salt.
Its antiplatelet
activity makes it an effective drug for reducing ischemic strokes, heart
attacks and in
atherosclerosis (a vascular disease causing claudication). Atherosclerosis is
a buildup
of plaque in the walls of arteries, which leads to thickening, and the
reduction in the
elasticity of the arteries. High Cholesterol, high blood pressure, smoking and
infection
also causes an injury to the inner walls of the arteries, which leads to the
atherosclerosis. The plaque formation leads to blood clotting which is due to
the
platelet aggregation at the site of the injury. This clotting becomes an
obstacle for the
flow of the blood to the vital organs causing heart attacks or other severe
problems.
Antiplatelet activity which fights against Atherosclerosis is exhibited by
Clopidogrel,
which binds adenosine diphosphate to its receptor and thereby induces platelet
reduction, which is desirable in fighting against atherosclerosis. Clopidogrel
has
found to be more effective in inhibiting platelet aggregation than aspirin and
is also
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CA 02567806 2006-11-22
WO 2006/087729 PCT/IN2005/000048
mild towards gastrointestinal tract. (S) enantiomer of clopidogrel is
pharmaceutically
active and is administrated as bisulfate salt.
U.S.Pat.No. 4, 529,596, discloses a racemic mixture of clopidogrel bisulfate
and
process for preparation of such mixture, which involves condensation reaction
between methyl-2-chloro-o-chlorophenylacetate and 4,5,6,7-tetrahydro
thieno[3,2-c]
pyridine. The reaction produces racemic clopidogrel.
U.S.Pat. No. 4,847,265 discloses process for preparation of the dextro-
rotatory
enantiomer of the clopidogrel bisulfate. Racemic clopidogrel is resolved using
camphor sulfonic acid to obtain optically pure dextro rotatory isomer. The
patent
describes the crystallization of the (S) enantiomer using dimethylformamide,
ketones
and alcohols. Amongst ketones, acetone is used for crystallization.
U.S.Pat. No. 5,036,156, discloses a method for preparation of an intermediate
in the
synthesis of clopidogrel, 2-chloro-a-bromophenyl acetic acid and a process for
condensing methyl ester with tetrahydrothienopyridine. The patent also
describes
process for preparation of pyridine derivative, which is one of the
intermediate for
preparation of clopidogrel.
U.S.Pat. No. 6,080,875 describes a process for preparation of methyl (+)-(S)-a-
(2-
thienyl-2-ethylamino)- a -(2-chlorophenyl)acetate hydrochloride by reaction of
sodium-2-thienylglycidate with (S) 2-chloro phenyl glycine in presence of
cyanoborohydride, This intermediate is further used to prepare (S)
clopidogrel. The
patent also describes the process for recemization of phenyl glycine esters.
U.S.Pat. No. 6,180,793 describes a process for preparation of (S) clopidogrel
by
reaction of 2-thiophene ethanol with (S)-2-chlorophenyl glycineamide, (S)-2-
chlorophenyl-a-amino acetonirile or (S)-2-chlorophenyl glycine methyl ester.
The
resulting compound is cyclised, hydrolysed and esterified.
U.S.Pat. No. 5, 204, 469 discloses enantioselective process for preparation of
clopidogrel through the reaction of (+) -2-chlorophenyl glycine and an
activated form
of 2-thiophene ethanol followed by cyclization with formaldehyde.
U.S.Pat. No. 6800759 describes a process for resolution of racemic
clopidogrel, along
with the conversion of (R) enantiomer of the clopidogrel to (S). The (S)
enatiomer is
separated by crystallizing it as camphor sulfonate salt from hydrocarbon, or a
mixture
of hydrocarbon and a co-solvent, preferably DMF:Toluene. The (R) enantiomer is
2
CA 02567806 2010-04-27
then racemized and recycled by reaction with catalytic amount of base. The
bases
used are metal alkoxide, preferably potassium-t-butoxide..
U.S.Pat. No. 4,847,265 describes the formation of the dextrorotatory isomer of
clopidogrel by salt formation using racemic compound and an optically active
acid
such as 10-L-camphorsulfonic acid in acetone, followed by successive
recrystallisation until a product with constant rotatory power was obtained,
followed
by the release of the dextro rotatory isomer from its salt by a base. The
hydrogen
sulfate salt is then obtained by dissolution of the base in acetone cooled in
ice and
addition of concentrated sulphuric acid to precipitation. The precipitate thus
obtained
is crystalline Form I.
WO 98/39286 discloses racemization process for phenyl glycine ester in which a
mixture of enantiomer of phenyl glycine ester is treated with a carbonyl
compound in
presence of carboxylic acid and single enantiomer of an N-protected-a-amino
acid as
a resolving agent. The formation of the imino intermediate causes the
racemisation of
the starting product and the precipitation of the single diastereomeric salt.
After
hydrolysis of the salt, an enantiomer of phenyl glycine ester is obtained.
WO/04/074215 discloses racemization process of (R) clopidogrel which involve
conversion of (R) isomer to its racemic salt such as Hydrochloride, which is
formed
by dissolution of (R) Clopidogrel in Isopropyl alcohol and concentrated HC1.
The salt
thus formed is further converted to Racemic Clopidogrel base by treatment with
base.
W02004013147 describes a process for racemization of (R) isomer of the
clopidogrel
by the reaction with catalytic amount of the base preferably with potassium t-
butoxide.
US 6,429,210 describe process for preparation of the dextrorotatory S
enantiomer of
Clopidogrel bisulfate in the crystalline Form I and Form II. This document
mentions
that (S)-Clopidogrel bisulfate of Form I has two crystallographically
independent
cations of clopidogrel and two independent bisulfate anions, wherein the two
independent cations are of similar conformation.
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US2003114479 describes the novel crystalline forms, Form III, IV and V of
clopidogrel hydrogen sulphate and amorphous form of clopidogrel hydrogen
sulphate
and processes for preparation of these forms and amorphous form as well as
their
pharmaceutical compositions. In this patent, polymorphic Form I is prepared by
suspending amorphous clopidogrel hydrogen sulphate in ether.
International Patent application W02004020443 describes process for
preparation of
Clopidogrel bisulfate Form I, which comprises separating out crystalline Form
I from
the solution of clopidogrel in the form of free base or salt in a solvent
selected from the
series of the primary, secondary or tertiary C 1-C5 alcohols or their Esters
with C 1-C4
carboxylic acids or optionally of mixtures thereof.
International application WO 2004048385 describes a process for the
preparation of
crystalline Form I of S-Clopidogrel hydrogen sulphate by reacting the
optically active
base, (S)-(+) clopidogrel with concentrated sulfuric acid, wherein the salt
formed by
the said reaction in the reaction medium is precipitated with the
precipitating solvent
such as aliphatic or cyclic ethers and/or their mixture or isobutyl methyl
ketone.
Form II of Clopidogrel Bisulfate is thermodynamically more stable and hence
small
change in condition during the preparation of Form I can result in Form II.
The present invention relates to the novel process for resolution of racemic
clopidogrel
base followed by conversion of the resolved (S) isomer to crystalline
Clopidogrel
bisulfate Form I. The present invention also relates to the racemization of
unwanted
(R) isomer. The present invention also relates to a process for resolution of
clopidogrel
base which is simple and less time consuming. The present invention also
relates to the
process for preparation of crystalline Form I of Clopidogrel Bisulfate from
(S)
clopidogrel base, which is reproducible. The present invention also relates to
the
process for preparation of crystalline Form I of Clopidogrel Bisulfate, which
is cost
effective and economical. The present invention also relates to the process
for
preparation of crystalline Form I of Clopidogrel Bisulfate, which is
commercially
viable.
4
CA 02567806 2009-06-05
SUMMARY OF THE INVENTION
The present invention discloses novel process for resolution of racemic
clopidogrel
base followed by conversion of the resolved (S) isomer to crystalline
Clopidogrel
bisulfate Form I. The present invention also discloses the racemization of
unwanted
(R) isomer and further resolution to pure (S) isomer. The present invention
further
discloses the preparation of crystalline Form of Clopidogrel Bisulfate Form I,
by
dissolving (S) Clopidogrel base in a solvent such as acetic acid and adding
antisolvent
such as di-isopropyl ether containing sulfuric acid.
In order to lower the time period and initiate the fast crystallization of the
(S)
clopidogrel camphorsulfonate salt, the resolution is carried out in a mixture
of solvent
which comprises aliphatic ketones preferably Acetone and acyclic simple ethers
like
Diisopropyl ether, methyl-tert-butyl ether, diethyl ether, preferably methyl-
tert-butyl
ether (MTBE). The resolution takes place within 4 Hrs to 10 Hrs.
The unwanted (R) isomer separated during the resolution is further converted
to (S)
isomer by dissolving the (R)-isomer in C5-C7aliphatic hydrocarbon/ C1-C5
alcohols/or
aliphatic ethers like di ethyl ether, methyl-t-butyl ether, di isopropyl
ether,
Tetrahydrofuran (THF), 1,4-Dioxane, as solvents containing base such as metal
alkoxide.
The resolved (S) Clopidogrel base is dissolved in a solvent such as acetic
acid and
adding antisolvent such as di-isopropyl ether containing sulfuric acid to get
the
crystalline Form I of Clopidogrel bisulfate.
According to one aspect of the present invention there is provided a process
for rapid
resolution of methyl (+) a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-
5(4H)-
acetate comprising;
a) treating methyl (+) a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-
c]pyridine-5(4H)-acetate using levo rotatory camphor-10- sulfonic acid
CA 02567806 2010-04-27
in a mixture of organic solvents under stirring for 2-12 hrs within a
temperature range of 0-70 C;
b) purifying the (S)-clopidogrel camphor sulphonate salt in a ketonic
solvent.
c) converting the obtained methyl (S)-(+)-a-(o-chlorophenyl)-6,7-
dihydrothieno[3,2-c]pyridine-5(4H)-acetate camphor sulphonate salt
into (S) clopidogrel base by treating with aqueous base in suitable
organic solvent.
According to another aspect of the present invention there is provided a
process for
rapid resolution of methyl ( ) a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-
c]pyridine-
5(4H)-acetate as substantially described herein particularly with reference to
the
examples.
According to another aspect of the present invention there is provided an
improved
process for the preparation of methyl (S)-(+)-a-(o-chlorophenyl)-6,7-
dihydrothieno[3,2-c]pyridine-5(4H)-acetate bisulfate Form I [(S)-Clopidogrel
bisulfate
Form I]
which comprises;
a) condensing 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride with
a-bromo-2-chlorophenyl acetic acid methyl ester in an organic solvent at
an ambient temperature in presence of an inorganic base; extracting the
racemic clopidogrel base with a lower chlorinated hydrocarbon;
b) resolving the racemic clopidogrel base using levo rotatory camphor-10-
sulphonic acid in a mixture of organic solvents under stirring for few hrs
within a temperature of range of 0-70C;
c) purifying the obtained (S)-Clopidogrel camphor sulfonate salt in a
ketonic solvent;
d) converting the (S)-Clopidogrel camphor sulfonate salt to (S)-
Clopidogrel free base; and
e) converting the clopidogrel base into clopidogrel bisulfate Form I by
dissolving (S)-Clopidogrel free base in a solubilizing solvent to form a
6
CA 02567806 2010-04-27
clear solution; adding the solution of sulfuric acid in antisolvent within
temperature range 0-25 C and stirring for several hours; filtering the
separated solid to get the crystalline polymorphic Form I.
According to another aspect of the present invention there is provided a
process for
racemization of the unwanted (R) isomer of clopidogrel base comprises;
a) dissolving (R) Clopidogrel Base in organic solvent;
b) treating the (R) Clopidogrel Base with metal alkoxide;
c) stirring the suspension for few hours;
d) neutralizing the base by aqueous acid;
e) isolating the racemic base from an organic layer; and recycled for
further resolution into its (R) and (S) stereo isomers.
According to another aspect of the present invention, there is provided a
process for
making Clopidogrel Bisulfate Form I as substantially described in the present
document and more particularly with reference to the examples presented in the
present document.
According to another aspect of the present invention, there is provided a
process for
racemization of the unwanted (R) isomer of clopidogrel base as substantially
described
in the present document and more particularly with reference to the examples
presented in the present document.
According to another aspect of the present invention, there is provided a
process of
preparation of methyl (S)-(+)-a-(o-chlorophenyl)- 6,7 -dihydrothieno [3,2-c]
pyridine-
(4H)-acetate bisulfate [(S)-Clopidogrel bisulfate] which comprises;
a) condensing 4,5,6,7-Tetrahydrothieno [3,2-c] pyridine hydrochloride with a-
bromo-
2-chlorophenyl acetic acid methyl ester in an organic solvent at temperature
of 80-85
C in presence of an inorganic base to obtain racemic Clopidogrel base;
b) resolving the racemic clopidogrel base using levo rotatory camphor- 10-
sulphonic
acid in a mixture of organic solvents under stirring for 2-12 hrs within a
temperature of
range of 0-70 C;
c) purifying the obtained (S)-Clopidogrel camphor sulfonate salt in a ketonic
solvent;
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CA 02567806 2010-04-27
d) converting the (S)-Clopidogrel camphor sulfonate salt to (S)-Clopidogrel
free base
by separating the camphor sulfonic acid moiety from the (S)-Clopidogrel
camphor
sulfonate salt;
e) dissolving (S)-Clopidogrel free base in a solubilizing solvent to form a
clear
solution;
f) mixing together, at a temperature of 0-25 C, the solution of step e) and
an
antisolvent comprising sulfuric acid, and stirring the obtained solution;
g) filtering the separated solid to get crystalline (S)-Clopidogrel bisulfate
having two
crystallographically independent cations of clopidogrel and two independent
bisulfate
anions, wherein said two independent cations are of similar conformation.
DETAILED DESCRIPTION OF THE INVENTION
According to another aspect, the present invention relates to the novel
process for
resolution of racemic clopidogrel base followed by conversion of the resolved
(S)
isomer to crystalline Clopidogrel bisulfate Form I. The present invention also
relates to
the racemization of unwanted (R) isomer of Clopidogrel base. The process is
shown as
below,
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OCH3
H
N C1
+ CI
OCH3 N
S Br i) DMF
S O
ii) K2C03
A O iii) MDC IRIS
B
CH2SO1H
Acetone + DIPS
OCH3
OC H3 H
C1
N +
Cl i) MDC,
ii)aHC0
= S JJ S CHZSO;
(Is) sla
i) Acetic acid,
ii) H2SO4
iii) DIPE
O OCH3
CI
O N HzSO4
S
Clopidogrel Bisulfate (Form I)
The manufacturing process described in this invention involves preparation of
racemic
Clopidogrel by the process similar to described in U.S.Pat. No.4,529,596. The
said
process comprises, condensation of the 4,5,6,7-tetrahydrothieno[3,2-c]pyridine
hydrochloride (A) and a-bromo-2-chlorophenyl acetic acid methyl ester (B) in
DMF
in presence of potassium carbonate, which gives racemic clopidogrel free base
(IRIS).
The process is shown below.
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Tr O1 OCHz
H CI CI
N '- N
+ Br OCH3 i) DMF
S ii) K2C03
O iii) MDC S
A B IRIS )
The present invention relates to rapid and simple process for resolution of
(S)
clopidogrel base (Is) which, comprises the steps of reacting a mixture of (R)
and (S)
clopidogrel base (IRIS) with laevo rotatory camphor sulfonic acid (II) in a
mixture of
solvents to precipitate (S) clopidogrel camphor sulfonate.
The Chiral, laevo rotatory camphor- l0-sulfonic acid of formula (II) is
allowed to react
with the racemic clopidogrel base of Formula (IRIS) in the mixture of solvent
comprises a ketone and/or an aliphatic ether according to following scheme.
OCH3 OCH3
H
CI I CI
N Acetone + DIPS I N +
CHZS03H
S S
CH2S03-
IRIS )
(II)
(IS II)
The ketones are selected from group consisting of acetone, 2-butanone, methyl
iso-
butyl ketone and 3-pentanone, preferably acetone. The ethers are selected from
the
group comprising of di ethyl ether, methyl-t-butyl ether, di isopropyl ether,
THE and
1,4-Dioxane, preferably methyl-tert-butyl ether. The mixture of solvent is
about 10%
v/v to about 50% v/v of ether in acetone preferably 50% v/v.
CA 02567806 2009-06-05
The (S) Clopidogrel camphor sulfonate salt (IsII) is further purified with
ketonic
solvents like acetone, 2-butanone, 3-pentanone, methyl-tert-butyl ketone.
Converting the (S) Clopidogrel camphor sulfonate salt (IsII) to (S)
Clopidogrel free
base of formula (Is) by the conventional technique. Dissolving the resolved
(S)
Clopidogrel base (Is) in glacial acetic acid at room temperature; followed by
adding an
antisolvent containing sulfuric acid to the solution at room temperature.
Stirring the
reaction mixture for 24 hours at room temperature, filtering and drying the
crystals to
obtain Form I of Clopidogrel Bisulfate.
The unwanted (R) isomer Clopidogrel base (IR) enriched in the mother liquor of
resolution is diluted with ether, washed with sodium bicarbonate solution to
remove
camphor sulfonate. The ether layer containing the enriched unwanted (R)
Clopidogrel
base (IR) isomer is treated with a base such as metal alkoxide preferably
potassium-t-
butoxide to get back racemic clopidogrel base (IRIS) which is then resolved
again as
earlier described. This process is shown in the following scheme.
O OCH3 O OCH3
cl CI
N N
0i) I O
S ii) Metal alkoxid~
(IR) IRIS )
11
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The entire sequence of the process is shown below,
4,5,6,7-Tetrahydrothieno[3,2-c] pyridine hydrochloride (A) +
a-bromo-2-chlorophenyl acetic acid methyl ester (B)
DMF, MDC
Racemic Clopidogrel Base (IRIS)
Laevo-camphor sulfonic acid (II)
Acetone + MTBE
Sat. NaHCO3 and MDC
salt (IsII) + Filtrate (IRj1) R enriched
Recrystallised in acetone Clopidogrel
Base (IRIS)
Salt (IsII)
DIPE +
ase
Sat. NaHCO3 and MDC Acetic acid
S-Clopidogrel base (Is) (Dextro rotatory enetiomer) Racemic
Clopidogrel
Base (IRIS)
Acetic acid, Conc. H2SO4 and DIPE
S-Clopidogrel Bisulfate (Form I)
As used herein, a solvent is any liquid substance, which has capacity to
dissolve the
organic compound, Clopidogrel Bisulfate, either at room temperature or higher
temperature. Antisolvent is an organic solvent in which organic compound such
as
Clopidogrel Bisulfate has poor solubility.
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As used herein, room temperature means a temperature from about 10 C to 45 C,
preferably 25 C to 30 C
The quality of clopidogrel bisulfate of Form I without detectable
contamination by
Form II, obtained in accordance with this invention, is characterized by X-Ray
crystallographic data, Differential Scanning Calorimeter and Fourier-transform
infrared (FT-IR) spectrum.
X-ray powder diffraction pattern has been obtained on D 8 -Advance, Bruker
AXE,
Germany, diffractometer equipped with Scintillation detector using Copper Ka
(X = 1.5406 A) radiation with scanning range between 2-50 0 at scanning speed
of
2 /min.
Differential Scanning Calorimeter was performed on Mettler DSC 20 instrument.
Samples of 2 mg to 3 mg weighed in aluminium crucibles with holes were scanned
at a
heating rate of 10 C per minute under nitrogen atmosphere at rate of 35
ml/min.
The Fourier-transform infrared (FT-IR) spectrum of Form I was obtained on a FT-
IR
8300, Shimadzu instrument, in the range of 400-4000 cm -1 with a resolution of
4 m-1.
The spectrum is entirely different from the spectrum of Form II disclosed in
patent US
6429210.
The mixture of organic solvents can comprise an ether and a ketonic solvent.
The
ketonic solvent can be selected from alphatic ketones (for example acetone, 2-
butanone, 3-pentanone, methyl iso-butyl ketone, preferably acetone). The ether
can be
selected from various ethers (for example di ethyl ether, di isopropyl ether,
methyl-
tert- butyl ether, preferably methyl-tent- butyl ether). For example, the
mixture of
solvents used can be a proportion ranging from 1:9 to 1:1 v/v of ether in
ketonic
solvent. For example, the proportion can be 1:1.
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When treating methyl (+) u-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-
5(4H)-
acetate using levo rotatory camphor-10- sulfonic acid in the mixture of
organic
solvents, stirring can be done carried out preferably for 8 Hrs.
For example, resolution can be preferably carried out at 25-55 C.
For example, the ketonic solvent can be selected from acetone, 2-butanone, 3-
pentanone, and methyl iso-butyl ketone, and can be preferably acetone.
For example, the organic solvent can be a dipolar aprotic solvent, preferably
dimethyl
formamide. The lower halogenated hydrocarbon is preferably methylene
dichloride.
The solubilizing solvent can be a C1-C5 carboxylic acid preferably glacial
acetic acid.
For example, the inorganic base can be selected from sodium bicarbonate and
potassium carbonate.
For example, the racemic clopidogrel base can be extracted with lower
halogenated
hydrocarbon.
For example, when adding the solution of sulfuric acid in antisolvent, such a
step can
be done within temperature range 0 to 25 C or 0 C to 5 C and stirring can be
carried
out for several hours. For example, the antisolvent can be selected from
aliphatic
ethers (such as diethyl ether, di isopropyl ether, methyl-tert-butyl ether
preferably di
isopropyl ether). The reaction mixture can be stirred preferably up to 16 hrs.
For example, the organic solvent used for racemization can be selected from
the group
of aliphatic ethers (such as diethyl ether, di isopropyl ether, methyl-tert-
butyl ether or
mixtures thereof, preferably di isopropyl ether).
For example, the bases used for racemization can be selected from
sodium/potassium
methoxide, ethoxide and butoxide, preferably potassium tert-butoxide.
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For example, stirring of the suspension can be carried out for 2-24 hours,
preferably 12
Hrs.
For example, the aqueous acids can be selected from HCI, H2SO4, and acetic
acid, and
it can be preferably acetic acid.
BRIEF DESCRIPTION OF THE FIGURES
Fig. 1 Shows the X-ray Diffraction Diagram of Clopidogrel Bisulfate Form I
Fig. 2 Shows the DSC Thermogram of Clopidogrel Bisulfate Form I
Fig. 3 Shows the FT-IR Spectrum of Clopidogrel Bisulfate Form I
Fig I of the polymorphic form obtained by this method, Form I shows an X-ray
powder diffraction pattern which is characterized by having peaks at about
9.21, 9.56,
14.85, 15.53, 15.23, 20.62, 21.59, 23.19, 23.85, 25.52, + 0.2 degrees. Fig 2
shows the
DSC thermogram of Form I which is characterized by having sharp endotherm at
187 C followed by another sharp endotherm at 212 C. The FT-IR spectrum of Form
I
shows absorption at 2987, 2952, 1751, 1477, 1436, 1220, 1191, 867, 841, 766,
592 cm
' which is shown in Fig 3.
The following examples are provided to illustrate the invention and are not
limiting the
scope of the complete disclosure.
Example 1
Synthesis of Racemic Clopidogrel Base (IR, s)
50 g (0.284 mole) of Tetrahydrothienopyridine hydrochloride (A) was reacted
with 83
g (0.315 mole) of a-bromo-2-chlorophenyl acetic acid methyl ester (B) in 2.5
Lt. DMF
in presence of 83 g. (0.6 mole) potassium carbonate. The reaction mixture was
heated
at 80-85 C under nitrogen atmosphere for 4 Hrs. The reaction mixture was
filtered at
RT and washed the residue with DMF. The DMF was concentrated under vacuum to
CA 02567806 2009-06-05
obtain a viscous liquid. To this viscous liquid, water was added and the base
was
extracted from the aqueous layer using methylene dichloride. The methylene
dichloride was concentrated under vacuum to get pure Clopidogrel base. Yield =
92%
Example 2
Resolution of Racemic clopidogrel base(IRIs)
a) Conversion of Racemic clopidogrel base (IRIS) to (S) Clopidogrel camphor
sulfonate
salt (IsI1).
I Og (0.03 mole) of Racemic clopidogrel obtained from Example 1 was dissolved
in 20
ml Methyl-tert-butyl-ether and to this 3.82 (0.016 mole) g. of L-(-)-Camphor
sulfonic
acid was added. To this solution 20 ml acetone was added to get the clear
solution. The
solution was stirred at 50 C for 8 Hrs. Filter the solid separated and washed
with
acetone and dried under vacuum at 50 C. m.p 163-165, [aID = 24.7, yield =58%
b) Conversion of (S) Clopidogrel camphor sulfonate salt (IsII) to (S)
Clopidogrel Base
(Is).
g (0.009 mole) of the (S) Clopidogrel camphor sulfonate salt obtained from
example
2 was suspended in 20 ml MDC. To this add 20 ml aqueous solution of saturated
sodium bicarbonate. After vigorous stirring, the organic phase was separated
and dried
over sodium sulfate. The solvent was removed under reduced pressure. The
residue
obtained was (S) Clopidogrel Base. Yield = 97%
Example 3
Preparation of Clopidogrel bisulfate form I from (S) Clopidogrel base (Is).
5 g (0.015 mole) of (S) Clopidogrel was dissolved in 25 ml of Glacial acetic
acid at
room temperature. The solution was filtered to remove any suspended particles.
This
clear solution was added to 200 ml of Di isopropyl ether containing 1.5g
(0.015 mole)
conc. H2SO4 was added drop wise at the 10 C. The solution was stirred for 6
hrs. at
the same temperature and further 10 Hrs at room temperaturte. The solid was
filtered,
washed with Di isopropyl ether and dried to get Form I, m.p. = 184-186 C,
[a]D20 =
55.6, Yield = 85%.
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CA 02567806 2009-06-05
Example 4
Racemization of (R) Clopidogrel (IR)
The mother liquor obtained from Example 2(a) was washed with the saturated
sodium
bicarbonate solution. The organic layer was separated and dried over anhydrous
sodium sulfate. The organic layer was concentrated under vacuum to obtain the
oily
liquid. The I Og (0.031 mole) of oily liquid was then dissolved in 50 mL Di
isopropyl
ether and to this 2 g (0.017 mole) of potassium-tert-butoxide was added at
room
temperature. After 12 Hrs, potassium tert-butoxide was neutralized with acetic
acid.
The organic phase was extracted with 50 mL water thrice. The organic phase was
dried
over anhydrous sodium sulfate and concentrated to obtain the oily liquid,
yield 75%.
The racemic clopidogrel thus obtained was resolved with the process described
in
example 3.
While the present invention is described above in connection with preferred or
illustrative embodiments, these embodiments are not intended to be exhaustive
or
limiting of the invention. Rather, the invention is intended to cover all
alternatives,
modifications and equivalents included within its spirit and scope, as defined
by the
appended claims.
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