FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2005
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
"A PROCESS FOR OBTAINING PURE (S)-(+)-CAMPHOR SULFONATE SALT OF CLOPIDOGREL"
2. APPLICANT (S)
NAME I NATIONALITY I ADDRESS
USV LIMITED INDIAN B.S.D. Marg , Govandi, Mumbai
400088, INDIA
3. PREAMBLE TO THE DESCRIPTION
COMPLETE SPECIFICATION The following specification particularly describes the invention and the manner in which
it is performed.

A process for obtaining pure (S)-(+)-camphor sulfonate salt of
clopidogrel Technical field of the invention
The present invention relates to a novel process for obtaining highly enantiomeric pure camphorsulfonate salt of (S)-(+)-methyl-a-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate of formula (I) (an intermediate for preparation of highly pure (S)-(+)-clopidogrel bisulfate).

Background and Prior Art
The dextrorotatory or (S)-enantiomer of methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate is pharmaceutically active and is administrated as bisulfate salt known as clopidogrel bisulfate.
Antiplatelet activity of (S)-(+)-clopidogrel bisulfate makes it an effective drug for reducing ischemic strokes, heart attacks and 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 cause 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 and other severe problems.
Antiplatelet activity, which fights atherosclerosis, is exhibited by clopidogrel. Clopidogrel binds adenosine diphosphate to its receptor and thereby induces platelet reduction, which is desirable in fighting against the atherosclerosis. Clopidogrel is found
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to be more effective in inhibiting platelet aggregation than aspirin and also mild towards
gastrointestinal tract.
The laevorotatory or (R)-enantiomer of this compound is described in United States
Patent No. 5, 225, 420 as being useful as an angiogenesis inhibitor.
U.S. Patent 4,529,596 discloses racemic mixture of clopidogrel bisulfate and process for
preparation of such mixture, which involves a condensation reaction between methyl-2-
chloro-o-chlorophenylacetate and 4,5,6,7-tetrahydrothieno [3,2-c] pyridine.
U.S. Patent 4,847,265 discloses a process for preparation of dextrorotatory enantiomer
of the clopidogrel bisulfate. Racemic clopidogrel is resolved using camphorsulfonic acid
to obtain optically pure dextrorotatory isomer. The patent describes the crystallization of
the (S)-enantiomer using diethylformamide, ketones and alcohols.
U.S. Patent 4, 847,265 describes the formation of the dextrorotatory isomer of
clopidogrel by salt formation using racemic clopidogrel and an optically active acid such
as 10-L-camphorsulfonic acid in acetone, followed by successive recrystallisation using
acetone until a product with constant rotatory power was obtained, followed by the
release of the dextrorotatory 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 sulfuric acid to precipitation. The precipitate thus obtained is crystalline
Form I.
U.S.Patent application 20040024012 describes a process for resolution of racemic
clopidogrel, along with the conversion of (R)-enantiomer of the clopidogrel to the (S)-
enantiomer. The (S)-enantiomer is separated by crystallizing it as camphor sulfonate salt
from hydrocarbon, or a mixture of hydrocarbon and a co-solvent, preferably dimethyl
formamide (DMF): toluene.
U.S. Patent application 20050059696 discloses purification of (S)-methyl-α-5-(4,5,6,7-
tetrahydrothieno[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l 0-camphorsulfonic
acid salt in acetone containing 1-2.5% of water.
WO2005077958 discloses purification of (S)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-
C]thienopyridyl) (2-chlorophenyl)acetate (S)-l 0-camphorsulfonic acid salt in polar
organic solvents like methyl ethyl ketone, methyl isobutyl ketone or non polar organic
solvent like toluene.
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WO2005104663 discloses a process to obtain substantially pure (S)-(+)-methyl-α-5-
(4,5,6,7-tetrahydro [3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphorsulfonic acid salt from a mixture of acetone: methylene dichloride (MDC),
acetone: toluene and acetone: cyclohexane from racemic methyl-α-5-(4,5,6,7-
tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate using anhydrous L-10-
camphorsulfonic acid.
Clopidogrel bisulfate is a chiral compound wherein the (S)-isomer is biologically active.
Hence the content of R- enantiomer must be carefully controlled in clopidogrel bulk
product as well as in the drug product. According to ICH guidance (ICH Q3B) entitled
"impurities in new drug products", the level of the impurities contained in the drug
product should also be carefully controlled and the upper level of the impurities should
be determined and supported by adequate data in the dossier file for registration of new
drug.
Thus, the prior art processes available for the purification of (S)-methyl-α-5-(4,5,6,7-
tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt
use either repetitive cycles or mixed solvents.
Therefore, an aspect of the present invention is to minimize unwanted (R)-enantiomer of
clopidogrel in the penultimate stage so as to have better control in the final stage of
preparation of clopidogrel bisulfate.
Another aspect of the present invention is to provide a novel purification procedure
wherein the desired pure (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt is separated having the
percentage of undesired (R)-(-)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt reduced to substantially below
0.1%.
The process for preparation of the clopidogrel is described in U. S. Pat. No. 4, 529,596,
which involves condensation of tetrahydrothienopyridine hydrochloride and ot-bromo-2-
chlorophenyl acetic acid methyl ester in acetone in presence of potassium carbonate,
which gives racemic clopidogrel.
The resolution process described in U.S. Patent 4,847,265 uses acetone as resolving
solvent and laevorotatory camphorsulfonic acid as a resolving agent. The process is time
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consuming and requires 72 hrs to obtain the (S)-isomer of clopidogrel camphor
sulphonate.
The purification process described in US Patent 4,847,265 for (S)-methyl-α-5-(4,5,6,7-
tetrahydro [3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid
salt is by repetitive recrystallisation in acetone to provide the product with enantiomeric
purity as high as 99.8%.
The process known in the art requires high volumes of acetone, typically 20 parts of
acetone for 1 part of salt giving poor yield, about 60-65% of pure product after every
crystallization step. On further conversion of purified (S)-(+)-methyl-α-5-(4,5,6,7-
tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt
to clopidogrel bisulfate, the (R)-isomer was found to increase to 0.4-0.6% due to
racemisation.
Thus there is a need for elimination or minimizing the unwanted (R)-enantiomer and
produce non-hygroscopic and fine crystalline product and yield a highly pure (S)-(+)-
methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphorsulfonic acid salt.
Accordingly, the present invention uses aliphatic nitriles, alcohols, esters and chlorinated
hydrocarbons as solvent and optionally aliphatic ethers as anti-solvent for the
purification or crystallization of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-
c]thienopyridyl) (2-chlorophenyl)acetate-(L)-10-camphorsulfonic acid salt.
Objects of the invention
A primary object of the present invention is to provide a simple and efficient process for
purification of (S)-enantiomer of the L-camphorsulfonate salt of (S)-(+)-methyl-α-5-
(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate.
Another object of the present invention is to provide a process for (S)-enantiomer of the
L-camphor sulfonate salt of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)
(2-chlorophenyl)acetate with high enantiomeric purity.
Still another object of the present invention is to provide a one-step purification process
in a single solvent.
It is also an object of the present invention to optionally use an anti-solvent in the
purification process.
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Yet another object of the present invention is to provide a process of purification of (S)-
(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate-(L)-10-
camphorsulfonic acid salt to obtain less than 0.1% of (R)-(-)-methyl-α-5-(4,5,6,7-
tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid
salt.
Summary of the invention
Accordingly, the present invention provides a process for purification of (S)-(+)-methyl-
α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphorsulfonic acid salt of formula (I), which comprises of dissolving crude (S)-(+)-
methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphorsulfonic acid salt in an aliphatic nitrile solvent at a temperature ranging between
70°C andl00°C, preferably at 90°C to obtain a solution, cooling the solution at a
temperature ranging between 0°C and 30°C, preferably at 5°C and filtering to obtain a
solid, and drying the solid at a temperature ranging between 50°C and 70°C, preferably
55°C to obtain purified (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt.
In one aspect the invention relates to a process for purification of (S)-(+)-methyl-α-5-
(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic
acid salt, said process comprising:
a) dissolving crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-
c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt
in an aliphatic nitrile solvent at a temperature ranging between 70°C
andl00°C, preferably 90°C,
b) cooling the solution at a temperature ranging between 0°C and 30°C,
preferably 5°C and filtering to obtain a solid , and
c) drying the solid at a temperature ranging between 50°C and 70°C,
preferably 55°C to obtain purified (S)-(+)-methyl-α-5-(4,5,6,7-
tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphorsulfonic acid salt.
In another aspect the invention relates to the use of acetonitrile as the aliphatic nitrile solvent.
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In yet another aspect the invention relates to the process of purification, wherein the
purified (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt as obtained contains less than
0.1% of (R)-(-)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt.
The organic solvent is selected from a group consisting of aliphatic nitriles, ketones,
alcohols, esters and chlorinated hydrocarbons, preferably acetonitrile, propionitrlie,
acrylonitrile, acetone, methanol, ethanol, ethyl acetate, iso-propyl alcohol and
methylenedichloride. The anti-solvent is selected from aliphatic ethers, preferably diethyl
ether, diisopropyl ether or methyl tertiary butyl ether and the anti-solvent is used when
alcohol or ester or chlorinated hydrocarbon is used as the solvent.
The pure (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)-10-camphorsulfonic acid salt as obtained contains less than
0.1% (R)-(-)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)-10-camphorsulfonic acid salt. Detailed description of the invention
The present invention relates to a process for purification of (S)-enantiomer achieved by crystallization of the crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt from aliphatic nitrile solvents preferably acetonitrile, propionitrile or acrylonitrile or ketones preferably acetone. The invention also relates to a purification process for (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt, wherein alcoholic solvents preferably methanol, ethanol or isopropanol, esters preferably ethyl acetate and chlorinated hydrocarbons preferably methylene dichloride or chloroform are used as dissolving agents and regeneration is achieved by adding aliphatic ethers preferably methyl tertiary butyl ether, diisopropyl ether or diethyl ether as an antisolvent.
Further, the invention relates to a purification process to obtain optically active (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt containing minimum (R)-(-)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10- camphorsulfonic acid salt.
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In one embodiment the invention provides a process for purification of (S)-(+)-methyl-a-
5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-IO-
camphorsulfonic acid salt, said process comprising:
a) dissolving crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-
c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt
in an aliphatic nitrile solvent at a temperature ranging between 70°C and
100°C, preferably 90°C, to obtain a solution,
b) cooling the solution at a temperature ranging between 0°C and 30°C,
preferably 5°C and filtering to obtain a solid , and
c) drying the solid at a temperature ranging between 50°C from 70°C,
preferably 55°C to obtain purified (S)-(+)-methyl-α-5-(4,5,6,7-
tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphorsulfonic acid salt. In another embodiment the invention relates to the use of acetonitrile as the aliphatic nitrile solvent.
In yet another embodiment the invention relates to the process of purification, wherein
the purified (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)-l O-camphorsulfonic acid salt as obtained contains less than
0.1% of (R)-(-)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)- 1 O-camphorsulfonic acid salt.
The crystallization process involves dissolution of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)-(2-chlorophenyl)acetate (L)-1O-camphorsulfonic acid salt in 1-4 parts of acetonitrile. The dissolution may be carried out under reflux condition. The clear solution was filtered and cooled to 0-30°C. The separated solid was isolated by filtration and dried at 50-70°C to obtain a pure (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphor sulfonic acid salt with the undesired (R)-(-)-isomer less than 0.1%.
The crystallization process can also be carried out by dissolving the crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl)-(2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt in acetone. The dissolution may be carried out at reflux temperature. The solvent is then distilled out and cool the solution to room temperature and further cool to 15-20°C to obtain a pure (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-
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c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphor sulfonic acid salt with the
undesired (R)-(-)-isomer less than 0.1%.
Optionally, the crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in alcoholic solvents
or esters or chlorinated hydrocarbons under reflux condition at 70-100°C. The solution is
maintained at reflux temperature for 30 minutes and an anti-solvent, preferably
diisopropyl ether (DIPE) is added. The resultant solution is allowed to cool to 0-30°C.
The separated solid was isolated by filtration and dried at 50-70°C to obtain a pure (S)-
(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphor sulfonic acid salt with the undesired (R)-(-)-isomer less than 0.1%.
The advantage of having less (R)-enantiomer is to have better control on the formation of
(R)- enantiomer during the preparation of clopidogrel bisulfate.
The use of only 1-4 parts of acetonitrile increases the batch size. Increase in batch size
leads to increase in production capacity. Lower quantity of solvent used for purification
also reduces the effluent load considerably.
An embodiment of the present invention is to provide a process for purification of (S)-
(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphorsulfonic acid salt of formula (I), which comprises of dissolving crude (S)-
methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-
camphorsulfonic acid salt in an organic solvent, optionally adding an anti-solvent
followed by obtaining the product by conventional methods.
Another embodiment of the present invention is the organic solvent used is selected from
a group consisting of aliphatic nitriles, alcohols, esters and chlorinated hydrocarbons,
preferably from acetonitrile, propionitrile, acrylonitrile, acetone, methanol, ethanol,
isopropanol, ethyl acetate, methylenedichloride or chloroform.
It is an embodiment of the present invention that the anti-solvent is selected from
aliphatic ethers, preferably methyl tertiary butyl ether, diisopropyl ether or diethyl ether.
It is also an embodiment of the present invention, wherein the anti-solvent is used when
alcohol or ester or chlorinated hydrocarbon is used as the solvent.
The preferred embodiment of the present invention is that the crude (S)-(+)-methyl-α-5-
(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic
acid salt is dissolved at a temperature of about 70-100°C, preferably at 90°C.
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Yet another embodiment of the present invention is the purified (S)-(+)-methyl-α-5-
(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic
acid salt as obtained contains less than 0.1% of (R)-(-)-methyl-α-5-(4,5,6,7-
tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid
salt.
A further embodiment of the present invention is that the process provides better
recovery of the (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-
chlorophenyl)acetate (L)-10-camphorsulfonic acid salt, about 80% as compared to -60%
in prior art.
Still another embodiment of the present invention is to use single solvent thus allowing
its recovery and recycle thereby reducing the load on effluent treatment plant (ETP) and
environment.
The 'single solvent' refers to the preferred solvent acetonitrile and ketone.
The purity of the product was determined by USP method using HPLC.
The following examples are illustrative of the present invention and should not be
construed as limiting the scope of the invention in any manner. It is understood that the
variations of the process described below are possible without departing from the scope
and spirit of the invention.
Example 1 Purification of (S)-(+)-methyl-a-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in 100 ml of acetonitrile under reflux condition at 90°C. The solution is maintained at reflux temperature for 30 minutes. The resultant clear solution is allowed to cool to 30°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55°C for 3-4 hrs (Yield = 63%); Purity = 99.82%; It-content = 0.074%.
Example 2 Purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
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25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in 75 ml of acetonitrile under reflux condition at 90°C. The solution is maintained at reflux temperature for 30 minutes. The resultant clear solution is allowed to cool to 30°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55° C for 3-4 hrs. (Yield = 64%); Purity = 99.71%; R-content = 0.074%.
Example 3 Purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyI) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in 50 ml of acetonitrile under reflux condition at 90°C. The solution is maintained at reflux temperature for 30 minutes. The resultant clear solution is allowed to cool to 30°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55°for 3-4 hrs (Yield = 77%); Purity = 99.72%; R-content = 0.076%.
Example 4 Purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in 25 ml of acetonitrile under reflux condition at 90°C. The solution is maintained at reflux temperature for 30 minutes. The resultant clear solution is allowed to cool to 30°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55°C for 3-4 hrs (Yield = 78%); Purity = 99.80%; R-content = 0.049%.
Example 5 Purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in 75 ml of
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acetonitrile under reflux condition at 90°C. The solution is maintained at reflux temperature for 30 minutes. The resultant clear solution is allowed to cool to 0-5°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55°C for 3-4 hrs (Yield = 80%); Purity = 99.78%; R-content = 0.059%.
Example 6 Purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt is suspended in 750 ml of ethyl acetate under reflux condition at 77°C. The solution is maintained at reflux temperature for 30 minutes. The resultant suspension is allowed to cool to 25-30°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55°C for 3-4 hrs. Yield = 87%; Purity = 99.46%; R-content = 0.231%.
Example 7 Purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt is dissolved in 250ml of isopropyl alcohol (IPA) under reflux condition at 82°C. The solution is maintained at reflux temperature for 30 minutes. The resultant clear solution is allowed to cool to 0-5°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55°C for 3-4 hrs. Yield = 60%; Purity = 99.72%; R-content = 0.065%.
Example 8 Purification of (S)-(+)-methyI-a-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chIorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in 250 ml of methanol under reflux condition at 65°C. The solution is maintained at reflux temperature for 30 minutes. To this clear solution 1750 ml diisopropyl ether (DIPE) is
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added at reflux temperature. The resultant solution is allowed to cool to 25-30°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55°C for 3- 4 hrs. Yield = 89%; Purity = 99.75%; R-content = 0.048%.
Example 9 Purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in 250ml of methylenedichloride (MDC) under reflux condition at 40°C. The solution is maintained at reflux temperature for 30 minutes. To this clear solution 1750 ml diisopropyl ether (DIPE) is added at reflux temperature. The resultant solution is allowed to cool to 25-30°C and maintained for 2 hrs at the same temperature under stirring. The solid separated is isolated by filtration and dried at 55°C for 3-4 hrs. Yield = 64%; Purity = 99.72%; R-content = 0.020%).
Example 10 Purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyI) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
25g of crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt is dissolved in 575ml of acetone under reflux condition at 56°C. The solution is maintained at reflux temperature for 30 minutes. 450ml of acetone is distilled out. The resultant solution is allowed to cool to 25-30°C and further cooled to 20-25°C. The solid separated is isolated by filtration and dried at 55°C for 3-4 hrs. Yield = 85%; Purity = 99.86%; R-content = 0.041%.
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I/We claim:
1. A process for purification of (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-
c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt,
said process comprising:
a) dissolving crude (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-
c]thienopyridyl) (2-chlorophenyl)acetate (L)-10-camphorsulfonic acid salt
in an aliphatic nitrile solvent at a temperature ranging between 70°C and
100°C to obtain a solution,
b) cooling the solution at a temperature ranging between 0°C and 30°C and
filtering to obtain a solid, and
c) drying the solid at a temperature ranging between 50°C and 70°C to obtain
purified (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l0-camphorsulfonic acid salt.
2. The process as claimed in claim 1, wherein the aliphatic nitrile solvent is acetonitrile.
3. The process as claimed in claim 1, wherein the dissolving temperature is 90°C.
4. The process as claimed in claim 1, wherein the cooling temperature is 5°C.
5. The process as claimed in claim 1, wherein the drying temperature is 55°C
6. The process as claimed in claim 1, wherein the purified (S)-(+)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)-l 0-camphorsulfonic acid salt as obtained contains less than 0.1% of (R)-(-)-methyl-α-5-(4,5,6,7-tetrahydro[3,2-c]thienopyridyl) (2-chlorophenyl)acetate (L)- 10-camphorsulfonic acid salt.


Dated this 1st day of August 2006.

To
The Controller of Patents
The Patent Office, at Mumbai

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T. SRINIVASAN Agent for the Applicant

Abstract
The present invention relates to a purification process using acetonitrile as a solvent to yield pure camphor sulfonate salt of (S)-(+)-methyl-α-5-[4,5,6,7-tetrahydro[3,2-c]thienopyridyl]-(2-chlorophenyl)acetate, an intermediate for the preparation of highly pure (S)-(+)-clopidogrel bisulfate.
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