AU2005327776A1 - Rapid resolution process for clopidogrel base and a process for preparation of Clopidogrel bisulfate polymorph - Form I - Google Patents

Description

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)-(+)-ct-(o-chlorophenyl)-6,7 dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulfate] is an Antithrombotic agent.

CH

3 Cl N / H 2 SO4, S Formula I Background and Prior Art: Clopidogrel is administrated as its hydrogensulfate (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 1 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 WO 2006/087729 PCT/IN2005/000048 then racemrnized 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 HCI. The salt thus formed is further converted to Racemic Clopidogrel base by treatment with base. WO2004013147 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, Form II. 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. 3 WO 2006/087729 PCT/IN2005/000048 International Patent application WO2004020443 describes process for preparation of Clopidogrel bisulfate Form 1, 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 C1-C5 alcohols or their Esters with CI-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. 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 4 WO 2006/087729 PCT/IN2005/000048 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 Cs-C 7 aliphatic hydrocarbon/ C 1

-C

5 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. DETAILED DESCRIPTION OF THE INVENTION 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 1. The present invention also relates to the racemization of unwanted (R) isomer of Clopidogrel base. The process is shown as below, 5 WO 2006/087729 PCT/IN2005/000048 H O O CHz + C I B OCH3 OICI SBr- IDMF A ii) K 2

CO

3 03 A O id) MDC S IRIS B CH2S03H Acetone + DIPE (II) 0 OCH3 OC HO C C! - t)MDC,+ N i) NaHC0 3 0 S0

CH

2 S0 3 ' (Is) ( ) i) Acetic acid, 11) HI1S0 4 111) DOWE 0- OCt)J ill DIPE O O0C H 3 CI S H 2 S 0 4 Clopidogrel Bisulfate(Form 1) The manufacturing process described in this invention involves preparation of racemrnic 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 (-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. 6 WO 2006/087729 PCT/IN2005/000048 OCH, H CI O + OCH 3 N S i) MDC 0 AB 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-10-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. 0 OCH 3 OCH 3 H 1 ci ON Acetone+ DIPE N O 00 CH1OI Q SCH2SHCH 2

SO

3 0 ((slI (1R1() 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, THF 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. The (S) Clopidogrel camphor sulfonate salt (IsIl) is further purified with ketonic solvents like acetone, 2-butanone, 3-pentanone, methyl-tert-butyl ketone. 7 WO 2006/087729 PCT/IN2005/000048 Converting the (S) Clopidogrel camphor sulfonate salt (IslI) 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 ,OCH, OCH3 CI ci N N i) DIPE . C ii) Metal alkoxide C (lR) 1 IRIS) 8 WO 2006/087729 PCT/IN2005/000048 The entire sequence of the process is shown below, 4,5,6,7-Tetrahydrothieno[3,2-c] pyridine hydrochloride (A) + c-bromo-2-chlorophenyl acetic acid methyl ester (B) I DMF, MDC Racemnic Clopidogrel Base (IRIs) Laevo-camphor sulfonic acid (II) Acetone + MTBE Sat, NaHCO, and MDC salt (Isl) + Filtrate (IR,II) R enriched Recrystallised in acetone Clopidogrel Base (IRIs) Salt (Isll) DIPE + ase Sat. NaHCO 3 and MDC Acetic acid S-Clopidogrel base (Is) (Dextro rotatory enetiomer) Racemic Clopidogrel Base (IRIs) Acetic acid, Cone. H 2 S0 4 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. As used herein, room temperature means a temperature from about 10 0 C to 45 0 C, preferably 25 0 C to 30'C 9 WO 2006/087729 PCT/IN2005/000048 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 KoX (X= 1.5406 A) radiation with scanning range between 2-50 0 at scanning speed of 2o/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 0 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' . The spectrum is entirely different from the spectrum of Form II disclosed in patent US 6429210. 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 0 C followed by another sharp endotherm at 212 0 C. The FT-IR spectrum of Form I shows absorption at 2987, 2952, 1751, 1477, 1436, 1220, 1191, 867, 841, 766, 592 crn -I which is shown in Fig 3. 10 WO 2006/087729 PCT/IN2005/000048 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 c-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 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 (Isl). 10g (0.03 mole) of Racemic clopidogrel obtained from Example 1 was dissolved in 20 nil 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 0 C for 8 Hrs. Filter the solid separated and washed with acetone and dried under vacuum at 50 'C. m.p 163-165, [c)D 20 = 24.7, yield =58% b) Conversion of (S) Clopidogrel camphor sulfonate salt (IsIL) to (S) Clopidogrel Base (s). 5 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% 11 WO 2006/087729 PCT/IN2005/000048 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. H 2

SO

4 was added drop wise at the 10 0 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. = 184-186oC, [ct]D 2 0 55.6, Yield = 85%. 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 10g (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. 12

Claims (21)

1. 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 in a mixture of aliphatic ketone and aliphatic ether under stirring for a duration ranging from 2-12 hours within a temperature range of 0-70 0 C to obtain (S)-(+) clopidogrel camphor sulphonate salt; b) purifying the (S)-(+)-clopidogrel camphor sulphonate salt using an aliphatic ketone solvent to obtain purified (S)-(+)- clopidogrel camphor sulphonate salt; and c) converting the obtained methyl (S)-(+)-clopidogrel camphor sulphonate salt into (S)-(+)-clopidogrel base by treating with lower chlorinated hydrocarbon and aqueous base.

2. The process as claimed in claim 1, wherein the aliphatic ketone is selected from a group consisting of acetone, 2-butanone, 3-pentanone, methyl iso-butyl ketone.

3. The process as claimed in claim 1, wherein the aliphatic ether is selected from the group consisting of di-ethyl ether, di-isopropyl ether and methyl-tert- butyl ether.

4. The process as claimed in 1, wherein said aliphatic ketone and aliphatic ether is in a proportion of 1:1 to 1:9.

5. The process as claimed in 1, wherein said aliphatic ketone and aliphatic ether is in a proportion of 1:1.

6. The process as claimed in claim 1, wherein the stirring is carried out for a duration ranging from 6 to 12 hours.

7. The process claimed in claim 1, wherein said temperature ranges from 25"C-55°C. WO 2006/087729 PCT/IN2005/000048 17

8. The process as claimed in claim 1, wherein said lower chlorinated hydrocarbon is methylene dichloride.

9. The process as claimed in claim 1, wherein said aqueous base is sodium bicarbonate.

10. An improved process for the preparation of (S)-(+)-Clopidogrel bisulfate Form I, said process comprising: a. condensing 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride with ca bromo-2-chlorophenyl acetic acid methyl ester in dimethyl formamide (DMF) at a temperature ranging from 80'C-85°C in presence of an inorganic base, extracting with lower chlorinated hydrocarbon to obtain methyl (+) a-(o chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate; b. treating methyl (+) a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H) acetate with levo rotatory camphor-10-sulphonic acid in a mixture of aliphatic ketone and aliphatic ether under stirring for a duration ranging from 2-12 hours within a temperature of range of 0OC-70'C to obtain (S)-(+)-Clopidogrel camphor sulphonate salt; c. purifying the (S)-(+)-Clopidogrel camphor sulfonate salt using an aliphatic ketone solvent to obtain purified (S)-(+)-clopidogrel camphor sulphonate salt; d. converting said purified (S)-(+) Clopidogrel camphor sulfonate salt into (S)-(+) Clopidogrel base by treating with a lower chlorinated hydrocarbon and an aqueous base; and e. converting said (S)-(+)-Clopidogrel free base into (S)-(+)-Clopidogrel bisulfate Form I by dissolving said (S)-(+)-Clopidogrel free base in a CI-C5 carboxylic acid followed by adding sulfuric acid and an antisolvent selected from a group of aliphatic ether within a temperature range 0-25 0 C with stirring for a suitable time duration of 12-48 hours followed by filtering to obtain (S)-(+)-Clopidogrel WO 2006/087729 PCT/IN2005/000048 18 bisulphate Form I.

11. The process as claimed in Claim 10, wherein said inorganic base is potassium carbonate.

S12. The process as claimed in Claim 10, wherein said lower chlorinated hydrocarbon is methylene dichloride.

13. The process as claimed in claiml0, wherein said aliphatic ketone is selected from a group consisting of acetone, 2-butanone, 3-pentanone, methyl-iso-butyl ketone.

14. The process as claimed in claim 10, wherein the aliphatic ether is selected from the group consisting of di-ethyl ether, di-isopropyl ether and methyl tert-butyl ether.

15. The process as claimed in 10, wherein said aliphatic ketone and aliphatic ether is in a proportion of 1:1 to1:9..

16. The process as claimed in 10, wherein said aliphatic ketone and aliphatic ether is in a proportion of 1:1.

17. The process as claimed in claim 10(b), wherein said stirring is carried out for a duration ranging from 6 to 12 hours.

18. The process as claimed in claim 10, wherein said aqueous base is sodium bicarbonate.

19. The process as claimed in claim 10, wherein said CI-Cs carboxylic acid is glacial acetic acid.

20. The process as claimed in claim 10(e), wherein said suitable time duration is WO 2006/087729 PCT/IN2005/000048 19 16 hours.

21. The process as claimed in claim 10, wherein said (S)-(+)-Clopidogrel bisulphate Form I is in crystalline form. WO 2006/087729 PCT/IN2005/000048 20 Statement under Article 19(1) 1.1 The present invention relatesto an improved process for the preparation of methyl (S)-a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5( 4 H) acetate hydrogen sulphate (Clopidogrel bisulphate) Form I. Applicant has gone through the written opinion of International Search Report and observe that: 1. Novelty of claims 1-24 acknowledged. 2. Inventive step of claims 1-24 lacking. 3. Industrial Applicability of claims 1-24 acknowledged. 1.2 ISR refers. to four prior art documents D 1 , D 2 , D 3 and D 4 . International Search Report (ISR) reveals that the subject matter of the present invention could be arrived at from the cited prior arts D, and D 2 . 2.1 Applicant believe that their process is different from the processes described in documents D 1 and D 2 referred to in ISR for the following: 2.2 Claim 1 2.2.1 Step (a): Present invention uses mixture of aliphatic ketone and aliphatic ether, stirring for 2-12 hours ranging from 0-70'C; yield of 58% is obtained. Dl uses DMF and toluene as disclosed in example 4, total time required and yield is not mentioned; D2 uses isopropyl alcohol (disclosed in Example 8) or diglyme (disclosed in Example 9); stirring time is (96+102 hours) in Example 8 and 49 hours in Example 9; yield is not provided. There is difference in reaction solvents of present invention vis-a-vis D1 and WO 2006/087729 PCT/IN2005/000048 21 D2 and faster reaction as compared to Dl and D2 is obtained which serves as the unexpected result. 2.2.2 Step b: Present invention uses aliphatic ketone; in Dl and D2 no purification is suggested. 2.2.3 Step c: Present invention yield of 97% is achieved; in Dl yield is not mentioned; in D2 yield of 56% and 54.81% is disclosed in example 8 & 9 respectively. Therefore unexpected yield of 97%/o of (S)-(+)-clopidogrel is obtained as against DI and D2 by optimizing the previous step of obtaining (S)-(+) clopidogrel camphor sulphonate which in turn results in the higher yield of (S)-(+)-clopidogrel base. 2.3 Claim 11 (presently claim 10) 2.3.1 Step a: Present invention suggests use of dimethyl formamide and methylene chloride as disclosed in example 1. Yield obtained is 92% racemic clopidogrel; Dl uses only acetone and yield is not mentioned; in D2 no equivalent step is mentioned. 2.3.2 Step b-d: The steps b, c and d of present claim 10 correspond to differences mentioned in paragraph 2.2.1, 2.2.2 and 2.2.3 respectively. 2.3.3 Step e: The present invention uses, acetone, glacial acetic acid and di-isopropyl ether and yield of 85% (S)-(+) clopidogrel bisulfate form I. D1 uses ethyl acetate, water and acetone, and yield is not mentioned; in D2 no such equivalent step is taught. 2.4 Therefore an unexpected result of higher resolution of the racemic Clopidogrel and higher yield of (S)-(+) clopidogrel bisulfate form I is WO 2006/087729 PCT/IN2005/000048 22 obtained in present invention vis-a-vis Dl and D2 by use of different reaction solvents and conditions at each step. 2.5 Therefore, for a person skilled in the art it is non-obvious to arrive at the solution of Invention 1 (as referred in the ISR) after reading the documents Dl and D2 and hence the present invention involves an inventive step.