Title of Invention	PROCESS FOR PREPARATION OF (+)- METHYL (2-CHLOROPHENYL)-(6,7-DIHYDRO-4H -THIENO[3,2-C]PYRID-5-YL)ACETATE BISULPHATE (CLOPIDOGREL BISULPHATE)WITH ENHANCED CHIRAL PURITY
Abstract	The present invention discloses a process for preparation of (=)--methyl (2-chlorophenyl)- (6,7-dihydro-4H0thieno[3,2-c]pyrid-5-yl)acetate bisuphate (clopidogrel bisyphate) with enhanced chiral purity without using any resolving agent. More particfularly, the present invention discloses a process for converting the low chiral purity of (S)-isomer of clopidogrel bisuophate to high chiral purity compound by isolating the (R)-isomer of clopidogrel bisuphate by precipitating from the reacion mixture by maintaining the temperature and concentration of the sulphuric acid.

Title of Invention

PROCESS FOR PREPARATION OF (+)- METHYL (2-CHLOROPHENYL)-(6,7-DIHYDRO-4H -THIENO[3,2-C]PYRID-5-YL)ACETATE BISULPHATE (CLOPIDOGREL BISULPHATE)WITH ENHANCED CHIRAL PURITY

Abstract

The present invention discloses a process for preparation of (=)--methyl (2-chlorophenyl)- (6,7-dihydro-4H0thieno[3,2-c]pyrid-5-yl)acetate bisuphate (clopidogrel bisyphate) with enhanced chiral purity without using any resolving agent. More particfularly, the present invention discloses a process for converting the low chiral purity of (S)-isomer of clopidogrel bisuophate to high chiral purity compound by isolating the (R)-isomer of clopidogrel bisuphate by precipitating from the reacion mixture by maintaining the temperature and concentration of the sulphuric acid.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; Rule 13] "Process for preparation of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate (Clopidogrel bisulphate) with enhanced chiral purity" (a) ARCH PHARMALABS LIMITED (b) "H" Wing, 4th Floor, Tex Centre, Off Saki Vihar Road, Chandivali, Andheri (East), Mumbai - 400 072, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification describes the nature of this invention and the manner in which it is to be performed: Field of invention: The present invention relates to a process for preparation of clopidogrel bisulphate whose (S)-isomer is known for its advantage in therapeutics, especially for its platelet anti-aggregating and anti-thrombotic activities. More particularly, the present invention relates to a process for converting the low chiral purity of (S)-isomer of clopidogrel bisulphate to high chiral purity compound. Background and prior art: Clopidogrel is the international non-proprietary name of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate which is having the following structure. Clopidogrel"s platelet inhibiting activity makes it an effective drug for reducing the incidence ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis. By inhibiting platelet aggregation, clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks. 2 Recent studies have shown that clopidogrel is more effective in blocking platelet aggregation than asprin and is much gentler on the gastrointestinal tract. Clopidogrel is more effective than asprin event at much lower dosage. Clopidogrel is administered as its bisulphate salt. The enantiomer (S)-clopidogrel is particularly preferred since it is the pharmaceutically active compound. Process for preparation of thieno[3,2]pyridine derivatives having pharmacologically significant anti-aggregating and anti-thrombotic properties is disclosed in US6635763... and WO03093276. US Pat. Nos 4847265; 5132535; 6258961; 6215005 and 6180793, which are hereby incorporated by reference in their entirety, disclose methods that can be used to prepare clopidogrel hydrogen sulphate. Crystalline polymorphs of clopidogrel hydrogen chloride form I and form II and hydrates thereof and process for preparation thereof is disclosed in WO03066637. US2003225129 report crystalline forms III, IV, V, and VI of clopidogrel hydrogen sulphate and the amorphous form of clopidogrel hydrogen sulphate as well as their pharmaceutical compositions and methods of treatment. Orthorhombic polymorph of clopidogrel hydrogen sulphate or hydrogen sulphate of methyl(+)-(S)-alpha-(2-chlorophenyl)-4,5,6,7-tetrahydrotheino[3,2-c]pyridine-5-acetate and process for its preparation is disclosed in US6504030. Processes for separation of enantiomers of clopidogrel, and converting one enantiomer of clopidogrel to another enantiomer of clopidogrel are disclosed in US2004024012, in which the enantiomers are separated by crystallizing the (S)-enantiomer as camphor sulphonate salt from a hydrocarbon, or a mixture of a hydrocarbon and a co-solvent, preferably DMF: toluene and the (R)-isomer is racemized and recycled by reaction with a catalytic amount of a base, preferably with t-butoxide. 3 Methods for separating one enantiomer of clopidogrel from another by selective crystallization of the camphor sulfonate of the (S)-enantiomer by crystallizing in DMF, alcohols and ketones preferably from acetone is disclosed in US 4847265(EP291459 and JP63203684). Preparation of (S)-isomer by methods that control the chirality of the intermediates used in the synthesis of clopidogrel to reduce the formation of (R)-isomer was disclosed in US 6180875. US6635763 discloses chiral removal of (-) stereoisomer from a mixture containing excess of (+) isomer by treating with (IS) -(+) -camphor-10- sulphonic acid hydrate and process for preparation of clopidogrel is also disclosed. EP0281459 discloses the (S)-enantiomer of clopidogrel and its pharmaceutically acceptable salts and process for preparation of this compound starting from the racemate by using camphor 10-sulfonic acid. US6180793 discloses process for preparation of the racemic or optically active compounds of clopidogrel or their salts.US5204469 describes process for preparation of racemic clopidogrel and of its enantiomers. US6080875 and related publications W09851681, W09851682 and W051689, incorporated herein by reference, to prepare the (S)-enantiomer by methods that control the chirality of the intermediates used in the synthesis of clopidogrel to reduce the formation of (R)-enantiomer. A problem with the preparation of clopidogrel is the presence of therapeutically inactive enantiomer, the (R)-enantiomer. The presence of (R)-isomer leads to contamination of the main product reduces the yield of the (S)-enantiomer by being a waste product. So, there is a need in the art to develop the (S)-enantiomer of clopidogrel or its hydrogen 4 sulphate salt which is generally administered, substantially free of the (R)-enantiomer with high degree of chiral purity. Consequently, the present invention aims to provide an inexpensive, commercially viable process for preparation of (S)-enantiomer of clopidogrel bisulphate with high degree of chiral purity of above 99%. The present invention also discloses a novel process for converting the compound of clopidogrel bisulphate with low chiral purity (90-98%) to high chiral purity of 99% with out employing any resolving agent. Objectives of the invention: The main objective of the present invention is to prepare clopidogrel bisulphate with high chiral purity with 99.5%. Another objective of the present invention is to provide a novel process for converting the clopidogrel bisulphate with low chiral purity(90-98%) to compound of the formula with high chiral purity with 99.5%. The preferred object of the present invention is to provide a novel process to prepare (S)-isomer of clopidogrel bisulphate with high degree of chiral purity through a commercially viable process. Summary of the invention: The present invention discloses a process for preparation of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate (Clopidogrel bisulphate) with enhanced chiral purity without using any resolving agent, wherein the said process comprises dissolving (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate in acetone; and/or introducing the (+)-Methyl (2-chlorophenyl)-(6,7-dihydro^H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate salt in a mixture of demineral water and methylene chloride; treating the resultant solution with 10% sodium hydrogencarbonate for 30 minutes at room temperature; separating the organic phase and 5 concentrating under reduced pressure; dissolving the residue obtained in acetone; cooling to 0°C; adding concentrated Sulphuric acid with a molar range of 0.025mole to 0.1 mole by maintaining the temperature at 0°C to precipitate and to remove the salt of (R)-isomer of clopidogrel bisulphate; adding concentrated sulphuric acid to the filtrate dropwise by maintaining the temperature under 0°C, followed by aging for 30 minutes; warming the reaction mixture at 20-3 0°C and maintaining at the same temperature for further 6 hrs to obtain the white solid; filtering the solid and washing with acetone yields (S)-isomer of clopidogrel bisulphate. The preferred concentration of sulphuric acid to precipitate the (R)-isomer of clopidogrel bisulphate is 0.033mole. The preferred temperature range for the isolation of (R)-isomer is 0-10°C and preferred temperature is 5°C. Detailed description of the invention According to the present invention there is a process provided to prepare the (S)-isomer of clopidogrel bisulphate with high degree of chiral purity starting from the (S)-isomer of clopidogrel base having low chiral purity of 90% by precipitating the undesired (R)-isomer of clopidogrel bisulphate first by controlling the concentration of the sulphuric acid and the reaction temperature, followed by filtration of the (R)-isomer, then the isolation of the desired (S)-isomer of clopidogrel bisulphate with high chiral purity. The present invention provides a process to prepare the (S)-isomer of clopidogrel bisulphate with high chiral purity, in which the starting material is clopidogrel bisulphate of low chiral purity (90-98%), which is converted into free base first by treating with sodium hydrogencarbonate and converted into (S)-isomer of Clopidogrel bisulphate of high chiral purity. In a preferred embodiment of the invention, (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl) acetate is dissolved in acetone and cooled gradually to 0°C. 6 Concentrated sulphuric acid is added to this by maintaining the temperature at 0°C and stirred for 5 hrs. The salt formed is undesired (R)-isomer of clopidogrel bisulphate which is sucked off immediately. To the above mother liquor, concentrated Sulphuric acid is added dropwise by maintaining the temperature under 0°C followed by aging for 30 minutes. The reaction mixture is warmed to 20-3 0°C and maintained at same temperature for further 6 hrs. The white solid precipitate formed is filtered and washed with acetone to get high purity product of (S)-isomer of clopidogrel bisulphate. In another embodiment of the present invention, (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate bisulphate salt is taken into a mixture of demineral water and methylene chloride, and treated the resultant solution with 10% sodium hydrogen carbonate for 30 minutes at room temperature. The organic phase is separated and concentrated under reduced pressure. The residue obtained is dissolved in acetone, cooled gradually to 0°C, and Concentrated Sulphuric acid added by maintaining the temperature at 0°C. This is stirred for 5 hrs at the same temperature to precipitate the undesired isomer which is the (R)-isomer of clopidogrel bisulphate, which is removed and dried under reduced pressure. After the removal of the (R)-isomer, concentrated sulphuric acid is added drop wise to the mother liquor, by maintaining the temperature under 0°C followed by aging for 30 minutes. The reaction mixture is warmed to 20-30°C and maintained at the same temperature for further 6 hrs. The white solid precipitated is filtered and washed with acetone to get the (S)-isomer of clopidogrel bisulphate with high degree of chiral purity. The invention is further illustrated with the following examples which do not limit the scope of the invention described in the claims. Example: 1 100.0 gm (0.311mole) (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl) acetate is dissolved in 300.0 ml acetone and cooled gradually to 0°C. To the 7 reaction mixture is added 3.27 gm (0.033 mole) of concentrated sulphuric acid maintaining the temperature at 0°C. This is later stirred at 0°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 14.0 gm (11.0 %) salt is obtained. To the above mother liquor, 24.73 gm (0.25 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The reaction mixture is warmed to 20-3 0°C and maintained at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 100.0 gm (77.0%), chiral purity 99.5% and M.P: 176-182°C. Example: 2 100.0 gm (O.311mole) (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate is dissolved in 300.0 ml acetone and cooled gradually to 10°C. To this is added 3.27 gm (0.033 mole) of concentrated sulphuric acid maintaining the temperature at 10°C. This is later stirred at 10°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 19.0 gm (15.0 %) salt is obtained. To the above mother liquor, 24.73 gm (0.25 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The reaction mixture is warmed to 20-3 0°C and maintained at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 95.0 gm (73.0%), chiral purity 99.5% and M.P: 176-182°C. Example: 3 100.0 gm (0.311mole) (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate is dissolved in 300.0 ml acetone and cooled gradually to 5°C. To this is added 2.45 gm (0.025 mole) of concentrated sulphuric acid by maintaining the temperature at 10°C. This is later stirred at 10°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 14.0 gm (11.0 %) salt is obtained. To the above mother liquor, 24.73 gm (0.25 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The 8 reaction mixture is warmed to 20-3 0°C and maintain at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 95.0 gm (73.0%), chiral purity 99.5% and M.P: 176-182°C. Example: 4 100.0 gm (0.311mole) (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate is dissolved in 300.0 ml acetone and cooled gradually to 0°C. To this is added 9.8 gm (0.1 mole) of concentrated sulphuric acid maintaining the temperature at 0°C. This is later stirred at 0°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 47.0 gm (37.0 %) salt is obtained. To the above mother liquor, 24.73 gm (0.25 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The reaction mixture is warmed to 20-3 0°C and maintain at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 67.0 gm (51.0%), chiral purity 99.5% and M.P: 176-182°C. Example: 5 50.0 gm (0.119 mole) of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate bi sulphate salt is introduced in a mixture containing 150.0 ml of de-mineral water and 150.0 ml of methylene chloride. The resultant solution is treated with 200.0 ml (0.23 mole) 10% sodium bicarbonate 200.0 ml for 30 minutes at room temperature. The organic phase is separated and distilled under reduced pressure. The residue obtained is dissolved in 120.0 ml acetone and cooled gradually to 0°C. To this is added 1.01 gm (0.01 mole) of concentrated sulphuric acid maintaining the temperature at 0°C. This is later stirred at 0°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 4.0 gm (11.0 %) salt is obtained. To the above mother liquor, 10.2 gm (0.103 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The reaction 9 mixture is warmed to 20-30°C and maintain at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 40.0 gm (77.0%), chiral purity 99.5% and M.P: 176-182°C 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 scope, as defined by the appended claims. 10 We claim, 1. A process for preparation of enhanced chiral purity of (+)-Methyl (2- chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate (Clopidogrel bisulphate) without using any resolving agent; wherein the said process comprises, i) dissolving (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate in acetone; ii) cooling the solution to 0°C; adding concentrated sulphuric acid in molar range of 0.025 mole to 0.1 mole by maintaining the temperature between 0-10°C to precipitate and to remove the salt of (R)-isomer of clopidogrel bisulphate; adding concentrated sulphuric acid to the filtrate dropwise by maintaining the temperature under 0°C, followed by aging for 30 minutes ; wanning the reaction mixture at 20-30°C and maintain at the same temperature for further 6 hrs to obtain a white solid; filtering the solid and washing said solid with acetone to yield (S)-isomer of clopidogrel bisulphate; and optionally iii) introducing the (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate salt in a mixture of demineralized water and methylene chloride; treating the resultant solution with 10% sodium hydrogen carbonate for 30 minutes at room temperature to liberate the free base((+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate); separating the free base from organic phase; dissolving said free base in acetone; and treating the free base using the process as described in step (ii) to obtain (S) clopidogrel bisulphate with high chiral purity. 2. The process as claimed in claim 1, wherein the preferred concentration of sulphuric acid to precipitate the (R)- isomer of clopidogrel bisulphate is adjusted to 0.033mole. 3. The process as claimed in claim 1, wherein the preferred temperature range used for the isolation of (R)- isomer is 0-10°C. 4. The process as claimed in claim 3, wherein the preferred temperature is 5°C. 5. A process for preparation of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate (Clopidogrel bisulphate) with enhanced chiral purity as substantially described herein with reference to the foregoing examples 1 to 5. Dated this the 19th day of May 2004 DR. GOPAKUMAR G. NAIR Agent for the Applicant

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; Rule 13]
"Process for preparation of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate (Clopidogrel bisulphate)
with enhanced chiral purity"
(a) ARCH PHARMALABS LIMITED
(b) "H" Wing, 4th Floor, Tex Centre, Off Saki Vihar Road, Chandivali, Andheri (East), Mumbai - 400 072, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in which it is to be performed:

Field of invention:
The present invention relates to a process for preparation of clopidogrel bisulphate whose (S)-isomer is known for its advantage in therapeutics, especially for its platelet anti-aggregating and anti-thrombotic activities. More particularly, the present invention relates to a process for converting the low chiral purity of (S)-isomer of clopidogrel bisulphate to high chiral purity compound.
Background and prior art:
Clopidogrel is the international non-proprietary name of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate which is having the following structure.

Clopidogrel"s platelet inhibiting activity makes it an effective drug for reducing the incidence ischemic strokes, heart attacks or claudication due to vascular diseases such as atherosclerosis. By inhibiting platelet aggregation, clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart attacks.
2

Recent studies have shown that clopidogrel is more effective in blocking platelet aggregation than asprin and is much gentler on the gastrointestinal tract. Clopidogrel is more effective than asprin event at much lower dosage. Clopidogrel is administered as its bisulphate salt. The enantiomer (S)-clopidogrel is particularly preferred since it is the pharmaceutically active compound.
Process for preparation of thieno[3,2]pyridine derivatives having pharmacologically significant anti-aggregating and anti-thrombotic properties is disclosed in US6635763... and WO03093276.
US Pat. Nos 4847265; 5132535; 6258961; 6215005 and 6180793, which are hereby incorporated by reference in their entirety, disclose methods that can be used to prepare clopidogrel hydrogen sulphate.
Crystalline polymorphs of clopidogrel hydrogen chloride form I and form II and hydrates thereof and process for preparation thereof is disclosed in WO03066637.
US2003225129 report crystalline forms III, IV, V, and VI of clopidogrel hydrogen sulphate and the amorphous form of clopidogrel hydrogen sulphate as well as their pharmaceutical compositions and methods of treatment.
Orthorhombic polymorph of clopidogrel hydrogen sulphate or hydrogen sulphate of methyl(+)-(S)-alpha-(2-chlorophenyl)-4,5,6,7-tetrahydrotheino[3,2-c]pyridine-5-acetate and process for its preparation is disclosed in US6504030.
Processes for separation of enantiomers of clopidogrel, and converting one enantiomer of clopidogrel to another enantiomer of clopidogrel are disclosed in US2004024012, in which the enantiomers are separated by crystallizing the (S)-enantiomer as camphor sulphonate salt from a hydrocarbon, or a mixture of a hydrocarbon and a co-solvent, preferably DMF: toluene and the (R)-isomer is racemized and recycled by reaction with a catalytic amount of a base, preferably with t-butoxide.
3

Methods for separating one enantiomer of clopidogrel from another by selective crystallization of the camphor sulfonate of the (S)-enantiomer by crystallizing in DMF, alcohols and ketones preferably from acetone is disclosed in US 4847265(EP291459 and JP63203684).
Preparation of (S)-isomer by methods that control the chirality of the intermediates used in the synthesis of clopidogrel to reduce the formation of (R)-isomer was disclosed in US 6180875.
US6635763 discloses chiral removal of (-) stereoisomer from a mixture containing excess of (+) isomer by treating with (IS) -(+) -camphor-10- sulphonic acid hydrate and process for preparation of clopidogrel is also disclosed.
EP0281459 discloses the (S)-enantiomer of clopidogrel and its pharmaceutically acceptable salts and process for preparation of this compound starting from the racemate by using camphor 10-sulfonic acid.
US6180793 discloses process for preparation of the racemic or optically active compounds of clopidogrel or their salts.US5204469 describes process for preparation of racemic clopidogrel and of its enantiomers.
US6080875 and related publications W09851681, W09851682 and W051689, incorporated herein by reference, to prepare the (S)-enantiomer by methods that control the chirality of the intermediates used in the synthesis of clopidogrel to reduce the formation of (R)-enantiomer.
A problem with the preparation of clopidogrel is the presence of therapeutically inactive enantiomer, the (R)-enantiomer. The presence of (R)-isomer leads to contamination of the main product reduces the yield of the (S)-enantiomer by being a waste product. So, there is a need in the art to develop the (S)-enantiomer of clopidogrel or its hydrogen
4

sulphate salt which is generally administered, substantially free of the (R)-enantiomer with high degree of chiral purity.
Consequently, the present invention aims to provide an inexpensive, commercially viable process for preparation of (S)-enantiomer of clopidogrel bisulphate with high degree of chiral purity of above 99%. The present invention also discloses a novel process for converting the compound of clopidogrel bisulphate with low chiral purity (90-98%) to high chiral purity of 99% with out employing any resolving agent.
Objectives of the invention:
The main objective of the present invention is to prepare clopidogrel bisulphate with high chiral purity with 99.5%.
Another objective of the present invention is to provide a novel process for converting the clopidogrel bisulphate with low chiral purity(90-98%) to compound of the formula with high chiral purity with 99.5%.
The preferred object of the present invention is to provide a novel process to prepare (S)-isomer of clopidogrel bisulphate with high degree of chiral purity through a commercially viable process.
Summary of the invention:
The present invention discloses a process for preparation of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate (Clopidogrel bisulphate) with enhanced chiral purity without using any resolving agent, wherein the said process comprises dissolving (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate in acetone; and/or introducing the (+)-Methyl (2-chlorophenyl)-(6,7-dihydro^H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate salt in a mixture of demineral water and methylene chloride; treating the resultant solution with 10% sodium hydrogencarbonate for 30 minutes at room temperature; separating the organic phase and
5

concentrating under reduced pressure; dissolving the residue obtained in acetone; cooling to 0°C; adding concentrated Sulphuric acid with a molar range of 0.025mole to 0.1 mole by maintaining the temperature at 0°C to precipitate and to remove the salt of (R)-isomer of clopidogrel bisulphate; adding concentrated sulphuric acid to the filtrate dropwise by maintaining the temperature under 0°C, followed by aging for 30 minutes; warming the reaction mixture at 20-3 0°C and maintaining at the same temperature for further 6 hrs to obtain the white solid; filtering the solid and washing with acetone yields (S)-isomer of clopidogrel bisulphate.
The preferred concentration of sulphuric acid to precipitate the (R)-isomer of clopidogrel bisulphate is 0.033mole.
The preferred temperature range for the isolation of (R)-isomer is 0-10°C and preferred temperature is 5°C.
Detailed description of the invention
According to the present invention there is a process provided to prepare the (S)-isomer of clopidogrel bisulphate with high degree of chiral purity starting from the (S)-isomer of clopidogrel base having low chiral purity of 90% by precipitating the undesired (R)-isomer of clopidogrel bisulphate first by controlling the concentration of the sulphuric acid and the reaction temperature, followed by filtration of the (R)-isomer, then the isolation of the desired (S)-isomer of clopidogrel bisulphate with high chiral purity.
The present invention provides a process to prepare the (S)-isomer of clopidogrel bisulphate with high chiral purity, in which the starting material is clopidogrel bisulphate of low chiral purity (90-98%), which is converted into free base first by treating with sodium hydrogencarbonate and converted into (S)-isomer of Clopidogrel bisulphate of high chiral purity.
In a preferred embodiment of the invention, (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl) acetate is dissolved in acetone and cooled gradually to 0°C.
6

Concentrated sulphuric acid is added to this by maintaining the temperature at 0°C and stirred for 5 hrs. The salt formed is undesired (R)-isomer of clopidogrel bisulphate which is sucked off immediately. To the above mother liquor, concentrated Sulphuric acid is added dropwise by maintaining the temperature under 0°C followed by aging for 30 minutes. The reaction mixture is warmed to 20-3 0°C and maintained at same temperature for further 6 hrs. The white solid precipitate formed is filtered and washed with acetone to get high purity product of (S)-isomer of clopidogrel bisulphate.
In another embodiment of the present invention, (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate bisulphate salt is taken into a mixture of demineral water and methylene chloride, and treated the resultant solution with 10% sodium hydrogen carbonate for 30 minutes at room temperature. The organic phase is separated and concentrated under reduced pressure. The residue obtained is dissolved in acetone, cooled gradually to 0°C, and Concentrated Sulphuric acid added by maintaining the temperature at 0°C. This is stirred for 5 hrs at the same temperature to precipitate the undesired isomer which is the (R)-isomer of clopidogrel bisulphate, which is removed and dried under reduced pressure. After the removal of the (R)-isomer, concentrated sulphuric acid is added drop wise to the mother liquor, by maintaining the temperature under 0°C followed by aging for 30 minutes. The reaction mixture is warmed to 20-30°C and maintained at the same temperature for further 6 hrs. The white solid precipitated is filtered and washed with acetone to get the (S)-isomer of clopidogrel bisulphate with high degree of chiral purity.
The invention is further illustrated with the following examples which do not limit the scope of the invention described in the claims.
Example: 1
100.0 gm (0.311mole) (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl) acetate is dissolved in 300.0 ml acetone and cooled gradually to 0°C. To the
7

reaction mixture is added 3.27 gm (0.033 mole) of concentrated sulphuric acid maintaining the temperature at 0°C. This is later stirred at 0°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 14.0 gm (11.0 %) salt is obtained. To the above mother liquor, 24.73 gm (0.25 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The reaction mixture is warmed to 20-3 0°C and maintained at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 100.0 gm (77.0%), chiral purity 99.5% and M.P: 176-182°C.
Example: 2
100.0 gm (O.311mole) (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate is dissolved in 300.0 ml acetone and cooled gradually to 10°C. To this is added 3.27 gm (0.033 mole) of concentrated sulphuric acid maintaining the temperature at 10°C. This is later stirred at 10°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 19.0 gm (15.0 %) salt is obtained. To the above mother liquor, 24.73 gm (0.25 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The reaction mixture is warmed to 20-3 0°C and maintained at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 95.0 gm (73.0%), chiral purity 99.5% and M.P: 176-182°C.
Example: 3
100.0 gm (0.311mole) (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate is dissolved in 300.0 ml acetone and cooled gradually to 5°C. To this is added 2.45 gm (0.025 mole) of concentrated sulphuric acid by maintaining the temperature at 10°C. This is later stirred at 10°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 14.0 gm (11.0 %) salt is obtained. To the above mother liquor, 24.73 gm (0.25 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The
8

reaction mixture is warmed to 20-3 0°C and maintain at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 95.0 gm (73.0%), chiral purity 99.5% and M.P: 176-182°C.
Example: 4
100.0 gm (0.311mole) (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate is dissolved in 300.0 ml acetone and cooled gradually to 0°C. To this is added 9.8 gm (0.1 mole) of concentrated sulphuric acid maintaining the temperature at 0°C. This is later stirred at 0°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 47.0 gm (37.0 %) salt is obtained. To the above mother liquor, 24.73 gm (0.25 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The reaction mixture is warmed to 20-3 0°C and maintain at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 67.0 gm (51.0%), chiral purity 99.5% and M.P: 176-182°C.
Example: 5
50.0 gm (0.119 mole) of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno [3,2-c]pyrid-5-yl)acetate bi sulphate salt is introduced in a mixture containing 150.0 ml of de-mineral water and 150.0 ml of methylene chloride. The resultant solution is treated with 200.0 ml (0.23 mole) 10% sodium bicarbonate 200.0 ml for 30 minutes at room temperature. The organic phase is separated and distilled under reduced pressure. The residue obtained is dissolved in 120.0 ml acetone and cooled gradually to 0°C. To this is added 1.01 gm (0.01 mole) of concentrated sulphuric acid maintaining the temperature at 0°C. This is later stirred at 0°C for further 5 hrs. The salt is immediately sucked off. After drying under reduced pressure, 4.0 gm (11.0 %) salt is obtained. To the above mother liquor, 10.2 gm (0.103 mole) of concentrated sulphuric acid is added drop wise by maintaining the temperature under 0°C followed by aging 30 minutes. The reaction
9

mixture is warmed to 20-30°C and maintain at same temperature for further 6 hrs. The white solid precipitate is filtered and washed with 50.0 ml acetone. The yield of the product is 40.0 gm (77.0%), chiral purity 99.5% and M.P: 176-182°C
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 scope, as defined by the appended claims.
10

We claim,
1. A process for preparation of enhanced chiral purity of (+)-Methyl (2-
chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate
(Clopidogrel bisulphate) without using any resolving agent; wherein the said
process comprises,
i) dissolving (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate in acetone;
ii) cooling the solution to 0°C; adding concentrated sulphuric acid in molar range of 0.025 mole to 0.1 mole by maintaining the temperature between 0-10°C to precipitate and to remove the salt of (R)-isomer of clopidogrel bisulphate; adding concentrated sulphuric acid to the filtrate dropwise by maintaining the temperature under 0°C, followed by aging for 30 minutes ; wanning the reaction mixture at 20-30°C and maintain at the same temperature for further 6 hrs to obtain a white solid; filtering the solid and washing said solid with acetone to yield (S)-isomer of clopidogrel bisulphate; and optionally
iii) introducing the (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate salt in a mixture of demineralized water and methylene chloride; treating the resultant solution with 10% sodium hydrogen carbonate for 30 minutes at room temperature to liberate the free base((+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate); separating the free base from organic phase; dissolving said free base in acetone; and treating the free base using the process as described in step (ii) to obtain (S) clopidogrel bisulphate with high chiral purity.
2. The process as claimed in claim 1, wherein the preferred concentration of
sulphuric acid to precipitate the (R)- isomer of clopidogrel bisulphate is adjusted
to 0.033mole.
3. The process as claimed in claim 1, wherein the preferred temperature range used
for the isolation of (R)- isomer is 0-10°C.

4. The process as claimed in claim 3, wherein the preferred temperature is 5°C.
5. A process for preparation of (+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate bisulphate (Clopidogrel bisulphate) with enhanced chiral purity as substantially described herein with reference to the foregoing examples 1 to 5.
Dated this the 19th day of May 2004
DR. GOPAKUMAR G. NAIR
Agent for the Applicant

Documents:

573-mum-2004-cancelled pages(16-01-2005).pdf

573-mum-2004-claims(granted)-(16-06-2005).doc

573-mum-2004-claims(granted)-(16-06-2005).pdf

573-mum-2004-correspondence(16-06-2005).pdf

573-mum-2004-correspondence-(ipo)-(31-03-2008).pdf

573-mum-2004-form 1(16-06-2005).pdf

573-mum-2004-form 19(05-07-2004).pdf

573-mum-2004-form 2(granted)-(16-06-2005).doc

573-mum-2004-form 2(granted)-(16-06-2005).pdf

573-mum-2004-form 26(02-06-2004).pdf

573-mum-2004-form 26(16-06-2005).pdf

573-mum-2004-form 3(19-05-2004).pdf

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Patent Number

213619

Indian Patent Application Number

573/MUM/2004

PG Journal Number

12/2008

Publication Date

21-Mar-2008

Grant Date

09-Jan-2008

Date of Filing

19-May-2004

Name of Patentee

M/S. ARCH PHARMALABS LIMITED

Applicant Address

H WING 4TH FLOOR, TEX CENTRE, OFF SAKI VIHAR ROAD, CHANDIVALI, ANDHERI (EAST), MUMBAI 400 072,

Inventors:

#	Inventor's Name	Inventor's Address
1	KAMATH AJIT	ARCH PHARMALABS LIMITED H WING 4TH FLOOR, TEX CENTRE, OFF SAKI VIHAR ROAD, CHANDIVALI, ANDHERI (EAST), MUMBAI 400 053
2	MALI SUBHASH	ARCH PHARMALABS LIMITED H WING 4TH FLOOR, TEX CENTRE, ORRSAKI VIHAR ROAD, CHANDIVALI, ANDHERI (EAST), MUMBAI 400 053
3	RANBHAN KAMLSEH	ARCH PHARMALABS LIMITED H WING 4TH FLOOR, TEX CENTRE, ORRSAKI VIHAR ROAD, CHANDIVALI, ANDHERI (EAST), MUMBAI 400 053
4	CHOUDHARY CHANDRAKANT	ARCH PHARMALABS LIMITED H WING 4TH FLOOR, TEX CENTRE, ORRSAKI VIHAR ROAD, CHANDIVALI, ANDHERI (EAST), MUMBAI 400 053
5	PATIL JYOTIBA	ARCH PHARMALABS LIMITED H WING 4TH FLOOR, TEX CENTRE, ORRSAKI VIHAR ROAD, CHANDIVALI, ANDHERI (EAST), MUMBAI 400 053
6	ZUNJARRAO YUVRAJ	ARCH PHARMALABS LIMITED H WING 4TH FLOOR, TEX CENTRE, ORRSAKI VIHAR ROAD, CHANDIVALI, ANDHERI (EAST), MUMBAI 400 053

PCT International Classification Number

A61K 9/20

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA