FORM 2

THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"NEW PROCESS FOR PREPARATION OF CLOPIDOGREL"
2. APPLICANT (S):
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: B- Wing, 10th Floor, BSEL Tech Park, Sector 30 A,
Plot no. 39/5 & 39/5A, Opp. Vashi Railway Station, Navi Mumbai- 400 703, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed:

Technical Field of Invention
The present invention relates to an improved process for the preparation of (+)-(S)-methyl
2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate,commonly known as Clopidogrel or its addition salt in good yield and purity.
Background and Prior art
Clopidogrel, chemically known as (+)-(-S)-methyl2-(2-ch|orophenyl)-2-(6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl)acetate is an oral anti platelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It was disclosed in U.S. Pat. No. 4,529,596 in its racemic form for the first time and is represented by formula 1

Formula I
Clopidogrel is generally administered as the bisulphatt salt. Both the racemic and its enantiomeric form especially the S form is known in the prior art The S-enantiomer of Clopidogrel is preferred since it is pharmaceutically active compound.
Clopidogrel is disclosed in U.S. Pat. Nos. 4,529,596; 5,258,961; 5,036,156; 6,080,875; and 6,180,793 all of which are incorporated herein by reference for their disclosure and preparation of Clopidogrel.
Clopidogrel was initially prepared using alpha halogenophenyl acetic acid derivatives as disclosed in EP 099802, EP 0420706 and EP 0466569.

US patent 4,847,265 discloses a method of resolution of racemic mixture of clopidogrel by forming a salt of the racemic mixture of clopidogrel with an optically active acid, preferably levo-rotatory camphor- 10-sulfonic acid, crystallization from a solvent such as acetone and subsequent isolation of the (+) isomer using a base. The yield is about 50%.
U.S.4,529,596 discloses a racemic mixture of Clopidogrel and processes for preparing such mixture.
US 2005/0059696 discloses a process for the recovery of (S)(+)Clopidogrel bisulfate of formula (I) which comprises (a)preparing compound (-) or (+)-(2-chloro phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate methyl ester, hydrogen sulfate from its corresponding camphor sulfonic acid salt compound; transforming the obtained compound of step (a), into the compound of (2-chIorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetic acid; converting the compound of step (b) into racemic compound (±)-(2-chloro phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate methyl ester hydrogen sulfate and (d) resolving the obtained racemic compound of step (c), into the optically active (+)-(2-chloro phenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate methyl ester camphor sulfonic acid salt and further transforming the optically active (+)compound of step (d) into their pharmaceutically acceptable salts.
U.S 6,080,875, describes preparation of (S)-Clopidogrel by reaction of sodium 2-thienylglycidate with (S)- (2-chlorophenyl)glycine in the presence of cyanoborohydride.
US 5204469 discloses enantioselective preparation of (S)-Clopidogrel and its salt which comprises cyclization of methyl (+) alpha-(2-thienyl ethylamino) (2-chlorophenyl) acetate with aq. solution of formaldehyde (30%) in methylene chloride. In an embodiment of the said patent, the enantiomeric intermediate, methyl (+)alpha-(2-thienyl ethylamino) (2-chlorophenyl) acetate can be prepared by reacting methyl(+)-alpha-amino (2-chlorophenyI)acetate with (2-thienyl) ethyl para toluene sulphonate in methyl acetate and K2HP04 at a temperature of 80°C for 40 hrs. Further, in another embodiment of the said patent, methyl(+)-alpha-amino (2-chlorophenyl)acetate is obtained by esterification of alpha-amino(2-chlorophenyl)acetic acid with methanol in presence of thionyl chloride at a temperature below -10°C followed by resolution with (+)-tartaric acid in acetonitrile and

methyl ethyl ketone at about 60°C. The enantiomeric clopidogrel base so obtained is converted to its hemisulphate by reacting clopidogrel base with conc, sulphuric acid in acetone as a solvent.
The said patent also describes that the choice of solvent is critical since partial racemisation of compound IV may take place thus affecting the yield and purity of the final product.
US 2007/0225320 describes multi step process of preparation of S-Clopidogrel hydrogen sulphate starting from esterification of 2-chlorophenyl glycine in presence of methanol and sulphuric acid to give methyl a-amino(2-chlorophenyl) acetate (Formula V) which is subsequently resolved to obtain the desired dextro enantiomer of formula II. The resolution is carried out using L(+) tartaric acid in presence of methanol followed by separating so formed tartaric acid salt of S-(+) methyl α-amino (2-chlorophenyl) acetate from the reaction mixture and further heated the reaction mixture to about 30-100°C to form racemic methyl a-amino(2-chlorophenyl) acetate. This is further reacted with additional L(+) tartaric acid to obtain tartaric acid salt of S-(+) methyl α-amino(2-chlorophenyl) acetate. This is followed by reacting with a base such as sodium carbonate to yield the desired dextro enantiomer. The dextro enantiomer of formula II is then coupled with tosylate of thiophene-2-ethanol (Formula VII) in t-butyl acetate and dipotassium hydrogen phosphate to obtain compound of formula VII followed by cyclisation with aq. HCHO.
PCT publication WO 04/013147 teaches a process for obtaining S-clopidogrel by resolving racemic clopidogrel using (-)-camphor sulphonic acid and racemization of R clopidogrel isomer by reacting with a base. However, it does not teach resolution of intermediate compounds or racemization of unwanted isomer thereof.
WO 2006/003671 discloses resolution of racemic methyl amino (2-chlorophenyl) acetate of formula I with L (+) tartaric acid in presence of acetone and methanol at the temperature of about 30° C.
IN206667 describes a multistep process for the preparation of clopidogrel or its pharmaceutically acceptable salts following the routes described in Scheme 1 and/or

Scheme 2. In a preferred method the process involves conversion of epoxy alcohol (2) via azido ester to obtain clopidogrel base. The process also involves intramolecular cyclization of the intermediate (8) using dioxolane to obtain racemic clopidogrel base which is further resolved to obtain the desired isomer.
WO 2007/144729 relates to Clopidogrel preparation wherein methyl (2S)-amino-(2-chlorophenyl) acetate of formula II or its HC1 salt is reacted with 2-(2-thienyl) ethyl)-4 methylbenzene sulfonate of formula IV in presence, of triethylamine to give intermediate of formula III which is cyclized, in-situ with aq. formaldehyde to obtain (S) -Clopidogrel of formula I.
CN 101519401relates to preparation of intermediate (S)-2-(2-thiophene ethylamine)(2-chlorophennyl) methyl acetate of clopidogrel which involves reaction of (S)-(+) -chlorophenyl glycine methyl ester L-tartrate with p-substituted thiofuran benzene sulphonate- 2-ethyl esters.
WO 2008/034912 relates to a process for preparation of clopidogrel and to new polymorphic forms of clopidogrel salts. One of the process as disclosed in the said publication involves selective N-alkylation of racemic 2-chloro phenyl glycine (V) with alkylating agents such as halogen analogs; for eg;2-(2-thienyl)ethyl chloride (VI) or sulfonates, for eg; 2-(2-thienyl) ethyl benzene sulfonate in presence of propionitrile and a base such as sodium bicarbonate to obtain compound of formula (IV) which can be converted to its hydrochloride salt and then cyclised with paraformaldehyde in formic acid to give racemic clopidogrel free base of formula III. The racemic free base is then optically resolved to the desired S-clopidogrel (II) with (-) camphor- 10-sulphonic acid in acetone followed by esterification to yield clopidogrel. Clopidogrel of formula I so obtained is further converted to its sulphate salt in conventional manner.
In summary, the prior art processes suffer from the following drawbacks:
• Resolution of racemic Clopidogrel free base involves an additional resolution step which in turn reduces the yield of the desired end product.
• Use of costly resolving agent such as (±) camphor-10-sulphonic acid thus increasing the cost of production of Clopidogrel.

• The coupling reaction of racemic or enantiomeric methyl-amino-(2-chloro phenyl) ester with an alkylating agent in presence of organic solvents only may lead to partial racemization.
There still remains a need to prepare (S)-Clopidogrel and its acid addition salt having high chiral purity and which avoids the drawbacks of the prior arts.
Object of the invention
The main object of the present invention is to provide an improved process for the preparation of (S)-Clopidogrel and its addition salt having high chiral purity, industrially viable and environment friendly.
Summary of the invention
Accordingly, the present invention discloses an improved process for the preparation of S-Clopidogrel which comprises coupling S-(+)methyl-amino(2-chIorophenyl) ethanoate an intermediate (A) with 2-(2-chloroethyl) thiophene an intermediate (B) in presence of solvent to obtain methyl(2-chlorophenyl){[(2-thiophene-2-yl) ethyl]amino] ester of formula (IV) and optionally converting to its hydrochloride salt; followed by cyclization with aq. formaldehyde to obtain Clopidogrel base and further converting the base to its bisulphate salt.
Thus, the present invention provides an improved process for the preparation of (S) -Clopidogrel with high purity which comprises the preparation of intermediate A and intermediate B and coupling of A and B followed by cyclization to yield clopidogrel base.
Accordingly, intermediate A is prepared by esterifying amino(2-chlorophenyl)acetic acid to obtain racemic methyl amino(2-chlorophenyl)acetate, a compound of formula (II) followed by resolving compound of formula (II) with tartaric acid in presence of methanol and acetone to obtain tartrate salt of formula (III); and isolating S-(+)methyl-amino(2-chlorophenyl) ethanoate as freebase (intermediate A) from tartrate salt of formula (III) using a solvent mixture.

Intermediate B is prepared by reacting 2-(2-chloroethy|) thiophene with thionyl chloride in presence of a base and in a solvent to obtain 2-(2-chloroethyl) thiophene (intermediate B).
The coupling of S- (+)methyl-amino(2-chlorophenyl) ethanoate intermediate A) with 2-(2-chloroethyl) thiophene (intermediate B) is conducted in presence of solvent to obtain methyl(2-chIorophenyl){[(2-thiophene-2-yl) ethyl]amino] ester of formula IV, which may optionally be converted to its hydrochloride salt; and the compound of formula IV is cyclized with aq. Formaldehyde to obtain clopidogrel base subsequently into its bisulphate salt.
In an aspect, amino (2-chlorophenyl) acetic acid (I) is reacted with thionyl chloride in presence of alcohols to obtain racemic methyl amino (2-chlorophenyl) acetate (II). The product is then isolated by solvent extraction technique. The solvent is selected from aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, toluene, xylene, halogenated hydrocarbons such as dichloromethane, ethylene dichloride etc. The pH of the reaction mass is maintained alkaline by adding a suitable base in order to lower the contamination of amino (2-chlorophenyl) acetic acid.
In a preferred aspect, racemic methyl amino (2-chlorophenyl) acetate, a compound of formula (II) is resolved using L-tartaric acid in a solvent mixture selected from but not limited to alcohols such as methanol, ethanol, propanol, butanol and the like; ketonic solvents such as acetone, methyl ethyl ketone, and the like; nitrile solvents such as acetonitrile and the like; to obtain the tartrate salt of S-(+)methyl-amino(2-chlorophenyl)ethanoate.
The tartrate salt of S-(+)methyl-amino(2-chlorophenyI)ethanoate is then isolated as intermediate (A); S-(+)methyl-amino (2-chlorophenyl) ethanoate from the solvent mixture consisting of water, hydrocarbon/halogenated hydrocarbons such as dichloromethane, ethylene dichloride, toluene etc.
In another aspect, the present invention involves preparation of 2-(2-chloroethyl) thiophene an intermediate B which comprises reacting 5-(thiophene-2-yl) ethanol with a chlorinating agent in presence of a base and in solvents selected from hydrocarbons such

as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like and the mixtures thereof. The chlorinating agent is selected from those known in the prior arts, preferably thionyl chloride. Suitable base include but not limited to methylamine, ethylamine, triethylamine, pyridine, alkali metal carbonates, alkali metal bicarbonates, and the like; preferably triethylamine.
In another preferred aspect, the reaction process comprises a coupling reaction wherein the intermediate (A) S- (+)-methyl-amino (2-chlorophenyl) ethanoate is coupled with 2-(2-chloroethyl) thiophene an intermediate (B) in presence or absence of KI and a phase transfer catalyst to obtain methyl (2-chloropheny){[(2-thiophene-2-yl) ethyl]amino] ester of formula (IV) and further converting to its hydrochloride salt. The process is carried out in presence of the solvent and a base. Suitable bases that can be used include but are not limited to inorganic bases selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; alkoxides such as sodium methoxide, potassium methoxide and the like; and organic bases such as methyl amine, ethylamine, triethylamine, pyridine etc. The solvent includes polar protic or aprotic solvents such as water, lower alcohols, halogenated hydrocarbons such as DCM, ethylene dichloride etc; acetone, DMF, DMSO, acetonitrile and the like. The presence of phase transfer catalyst makes the process easier, provides higher selectivity, and helps in retaining the chiral purity of the desired enantiomer.
This is followed by cyclization of methyl (2-chloropheny){[(2-thiophene-2-yl) ethyl]amino] ester of formula IV with aq. formaldehyde to obtain Clopidogrel base; and converting the base to its bisulphate salt.
Clopidogrel bisulphate obtained by the process of the present invention is free of impurities, has the desired chiral purity suitable for pharmaceutical preparations.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.
Detailed description of the invention
The present invention relates to an improved process for the preparation of S-C!opidogrel which comprises coupling S-(+)methyl-amino(2-chlorophenyI) ethanoate intermediate (A) with 2-(2-chloroethyl) thiophene an intermediate (B) in presence of solvent to obtain methyl(2-chlorophenyl){[(2-thiophene-2-yl) ethyl]amino] ester of formula (IV) and optionally converting to its hydrochloride salt; followed by cyclization with aq. formaldehyde to obtain Clopidogrel base and further converting the base to its bisulphate salt.
In an embodiment, the present invention provides an improved process for the preparation of S-Clopidogrel which comprises the following steps:
1. esterifying amino(2-chIorophenyl)acetic acid to obtain racemic methyl amino(2-chlorophenyl)acetate, a compound of formula (II) and resolving compound of formula (II) with tartaric acid in methanol and acetone to obtain tartrate salt of formula (III);
2. isolation from tartrate salt of formula (III) to obtain S-(+)methyl-amino(2-chlorophenyl) ethanoate as freebase (intermediate A) using a solvent mixture;
3. reacting 2-(thiophene-2-yl) ethanol with thionyl chloride in presence of a base and in a solvent to obtain 2-(2-chloroethyl) thiophene (intermediate B);
4. coupling of intermediate (A) with 2-(2-chloroethyl) thiophene an intermediate (B) in presence KI and PTC in presence of solvent to obtain methyl(2-chlorophenyl){[(2-thiophene-2-yl) ethyljamino] ester of formula (IV) and optionally converting to its hydrochloride salt;
5. cyclizing compound of formula (IV) with aq. formaldehyde to obtain Clopidogrel base and converting the base to its bisulphate salt

In an embodiment, the process of the present invention includes the conversion of amino (2-chlorophenyl) acetic acid as the starting compound to S-(+)methyl-amino (2-chlorophenyl)ethanoate freebase (intermediate A) as shown in Scheme1:
Scheme 1: Preparation of Intermediate A

According to Scheme I, the first step includes esterification of amino (2-chlorophenyl) acetic acid (I), wherein, esterification is carried out by reacting amino (2-chlorophenyl) acetic acid (I) dissolved in lower alcohol (C1-C3) with thionyl chloride at 0-5°C under nitrogen atmosphere and then raising the temperature to 60-65°C and maintained till TLC indicated completion of reaction. The reaction mass is then cooled followed by distilling off the solvent under reduced pressure till thick residue. The residue is then dissolved in water and the pH of the aqueous layer is adjusted to pH above 8 with ammonia solution. This is followed by repetitive extraction with DCM, and distilling off DCM to obtain racemic methyl amino (2-chlorophenyl) acetate, a compound of formula (II).

The second step of Scheme 1 includes resolution of racemic methyl amino (2-chlorophenyl) acetate, a compound of formula (II) obtained in the step 1 with L-tartaric acid in a suitable solvent. Suitable solvents include but not limited to lower (C1-C3) alcohols and the like; ketonic solvents such as acetone, methyl ethyl ketone and the like; chlorinated hydrocarbons such as DCM, ethylene dichloride and mixtures thereof. The reaction is carried out at 20-35°C. Optionally, a small amount of pure (+)-tartrate salt of methyl amino (2-chlorophenyl)ethanoate may be added as seed crystals.
Accordingly, L-tartaric acid is dissolved in lower alcohol (C1-C3) until complete dissolution followed by addition of methyl amino (2-chlorophenyl) acetate in acetone at 40±2°C. The mass is further seeded with pure (+)-tartrate salt of methyl amino (2-chlorophenyl)acetate at 40±2°C. Cooled the reaction mass to 33±2°C and maintained the reaction mass for 30 hrs Filtered, washed with methanol, dried to obtain the tartrate salt of S-(+)-methyl amino (2-chlorophenyl) ethanoate(III).
Further, the crude tartrate salt of S-(+)-methyl amino (2-chlorophenyl) acetate(III) is purified from lower alcohol (C1-C3) at 33±2°C, filtered the solid and dried under vacuum. The filtrate is stored for the recovery and racemization of S-(+)-methyl amino (2-chlorophenyl) ethanoate.
The preferred embodiment of the present invention involves isolating Intermediate (A) from the pure and crude tartrate salt of S-(+)-methyi amino (2-chlorophenyl) ethanoate obtained in step 2 by solvent extraction method. The solvents used for extraction can be selected from water, aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, toluene, xylene, halogenated hydrocarbons such DCM, ethylene dichloride, and mixtures thereof. Distillation is done either under atmospheric pressure or under vacuum. The solvent extraction is preferably carried out in alkaline pH using a base. Suitable base include but not limited to organic or inorganic bases such as methylamine, ethylamine, triethylamine, alkali metal hydroxides, alkali metal carbonates or bicarbonates, methoxides, ammonia and the like.

Accordingly, the solution of tartrate salt obtained in step 2 is heated to 70-75°C to distill off the solvent. The residue is washed with water and DCM. The pH of the aqueous layer is adjusted to one using conc. HC1. This is followed by repetitive extraction with DCM and collecting the organic layer. The aqueous layer is adjusted to pH 8-9 using ammonia solution followed by repetitive extraction with DCM. DCM is then distilled off under atmospheric pressure or under vacuum to obtain S-(+) methyl amino (2-chlorophenyl) ethanoate, an intermediate A.
In another preferred embodiment, the process of the present invention comprises preparation of Intermediate B as shown in Scheme 2:
Scheme 2: Preparation of Intermediate B

2-flhiopher>-2-yl)ethanol 2-(2-chloroethy l)thiophene
According to Scheme II, 2-(2-chioroethyl) thiophene an intermediate (B) is prepared by treating 2-(thiophene-2-yl) ethanol with a chlorinating agent in presence or absence of a base and in solvents selected from hydrocarbons such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like and the mixtures thereof. The chlorinating agent is selected from those known in the prior arts, preferably thionyl chloride. Suitable base include but not limited to methylamine, ethylamine, triethylamine, pyridine etc, preferably triethylamine.
Thus a mixture of DCM, 2-(thiophene-2-yl) ethanol and triethyl amine are charged to R.B flask. This is followed by adding thionyl chloride under nitrogen atmosphere at 0-5°C. The reaction temperature is then raised to 25-35°C and maintained at 40±3°C till TLC indicated completion of reaction. The reaction mass is then cooled to 25-35°C followed by repetitive washings with DM water. The pH of the reaction mass is adjusted to 7-8 using sodium carbonate solution. The organic layer is separated and subjected to

distillation under atmospheric pressure or vacuum to obtain 2-(2-chloroethyI) thiophene an intermediate (B). The intermediate (B) is further purified under high vacuum distillation process.
In yet another preferred embodiment, Clopidogrel base and its acid addition salt is prepared by coupling tartrate salt of Intermediate A and Intermediate B obtained above, and as shown in Scheme 3:
Scheme 3: Preparation of Clopidogrel bisulphate

According to Scheme III, coupling of the intermediates (A) and (B) to obtain enantiomeric compound IV or its salt constitutes another preferred embodiment of the present invention. The reaction is carried out by dissolving the intermediate (A) in a solvent and a base in presence or absence of KI and a phase transfer catalyst. The reaction is carried out at reflux temperature. The phase transfer catalyst is selected from those

known in prior art, preferably tetrabutylammonium bromide (TBAB). The solvent includes polar protic or aprotic solvents such as water, lower alcohols, acetone, DMF, DMSO, acetonitrile and the like. Suitable bases that can be used include but are not limited to inorganic bases selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and the like; alkali rnetal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; methoxides such as sodium methoxide, potassium methoxide and the like; and organic bases such as methyl amine, ethylamine, triethylamine, pyridine etc. Use of phase transfer catalyst makes the process easier, provides higher selectivity, and helps in retaining the chiral purity of the desired enantiomer.
Accordingly, the tartrate salt (III) dissolved in water and DCM is treated with sodium carbonate to make the pH of the reaction mass alkaline (7.0-7.5) followed by repetitive washings with water to obtain methyl ester free base, an intermediate (A). The intermediate (A), acetonitrile, and sodium bicarbonate are charged to a R.B. flask followed by addition of intermediate (B). This is followed by addition of KI and TBAB, and heated the reaction mass to reflux and maintained till TLC indicated completion of reaction. After completion of the reaction, the reaction mass was filtered and washed with acetonitrile followed by distilling off the solvent under vacuum to obtain a residue. The residue is then dissolved in toluene followed by addition of HCl to precipitate the hydrochloride salt of compound (IV).
Further, compound IV or its HCI salt is subjected to cyclization to yield (S)-Clopidogrel base with formaldehyde as per process given in prior art.
S-Clopidogrel base obtained above may be converted to its bisulphate salt with cone. sulphuric acid and IPA.
In an aspect, Clopidogrel bisulphate obtained by the process of the present invention is free of impurities, has the desired chiral purity to be used as a pharmaceutically active ingredient.

Further details of the process of the present invention will be apparent from the examples presented below. Examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
Examples
Example 1: Preparation of racemic methyl amino C2-chlorophenyl) acetate (II)
To a neat, clean dry four neck 1lit R.B flask with reflux condenser and thermometer pocket, was charged 400ml methanol 100g of amino (2-chlorophenyl) acetic acid, stirred the mass for l0min followed by purging of nitrogen gas. The reaction mass was cooled to 0-5°C followed by addition of 59 ml thionyl chloride maintaining the temperature of the reaction mass at 0-5°C under nitrogen atmosphere. The reaction mass was stirred for 30min at 0-5°C and the temperature was then raised to 25-35°C. The reaction mass was then heated to 60-65°C and maintained at this temperature for 5 hours until TLC indicated completion of reaction. Cooled the reaction mass to 25 - 35°C and distilled off the mass at 50-55°C under vacuum till thick residue. The reaction mass was cooled to 25-35°C. Released the vacuum and charged 450 ml DM water and stirred. This was followed by addition of 100ml of dichloromethane (DCM), stirred and settled the reaction mass for 30 min. The organic layer was separated and the aqueous layer was repeatedly washed with DCM (2 x50ml), stirred and separated the organic layers The aqueous layer was charged into RB flask and the pH of the reaction mass was adjusted to 8.0-9.0 using 250ml ammonia solution. Charged 200ml DCM to the aqueous layer and stirred, settled for 30 min. Separated lower organic layer and collected separately. The DCM layer was then separated and the combined organic layers were washed with 2x 100 ml DM water, stirred and settled and separated. To the organic layer was charged sodium chloride solution stirred, settled and separated. The organic layer was then distilled off atmospherically upto 45°C. Cooled the mass to 25-35°C. Further distilled off DCM under vacuum upto 45°C. Released the vacuum to obtain racemic methyl amino (2-chlorophenyl) acetate. Syrup wt: 83-89 gm. Theoretical yield: 107.5gm

Example 2: Preparation of tartrate salt of S-(+) Methyl-amino -("2-chlorophenyl) ethanoate
To a neat, clean, dry four neck Hit R.B flask with reflux condenser and thermometer pocket, was charged 400 ml methanol and 68gm L(+)tartaric acid. Stirred for 30min at 30±2°C till complete dissolution of tartaric acid. The reaction mass was filtered and the filtrate was collected. The reaction mass was heated to 40±2°C.This was followed by addition of filtrate of methyl-amino-(2-Chlorophenyl) acetate solution (Example 1) (prepared by dissolving l00gm of methyl-amino-(2-Chlorophenyl) acetate (0.501 mole) in 100 ml acetone) drop wise maintaining temperature of reaction mass at 40±2°C. Stirred the mass for l0min. Seeded with pure tartrate salt of methyl amino (2-chlorophenyl) acetate(5gm) at 40±2°C, slowly cooled the reaction mass to 33±2°C and maintained at this temperature for 30hours. Filtered the obtained solid and the filtrate (A) was collected. Washed the wet cake with chilled methanol and collected the filtrate (B). Suck dried the solid under vacuum. Unloaded the wet cake and the combined filtrates (A) and (B) were stored for the recovery and racemization. The wet cake was weighed. The solid S-(+) Methyl-amino-(2-chIorophenyl) acetate tartrate salt was dried at 55-60°C for 4 hours.
Dry wt: 90-105 grams. Theoretical yield: 87.59gm
Example 3: Purification of crude tartrate salt of S-(+) Methyl -amino-(2-chlorophenyi) acetate
To a neat, clean, dry four neck Hit R.B flask with reflux condenser and thermometer pocket was charged 300ml methanol and lOOgm of crude tartrate salt of S-(+)-Methyl-amino-(2-chlorophenyl) acetate (Example 2), stirred the reaction mass for 15 min and heated the mass at 33±2°C and maintained for 6 hours at the same temperature. The solid obtained was filtered and collected the filtrate (A). The wet cake was washed with chilled methanol and collected the filtrate (B). Suck dried the solid under vacuum. Unloaded the wet cake and weighed. The combined filtrates (A) and (B) were stored for the recovery and racemization. Dried the solid at 55-60°C for 4 hours. Dry wt: 75-80gm

Theoretical yield: l00gm
Example 4: Preparation of 2-(2-chloroethvl) thiophene (Intermediate —B)
To a neat, clean, and dry four neck 2L RB flask with reflux condenser and thermometer pocket was charged 500 ml of dichloromethane (DCM) Then charged 2-thiophene ethanol (100 gm, 0.781 mole). Stirred the mass for 10 minutes, followed by addition of triethyl amine (120 gm, 1.188 mole). This was followed by addition thionyl chloride (120 gm, 1.008 mole) at 0 -5°C over a period of 15 min. The reaction mass was stirred for 15min at 0-5°C and the temperature of the reaction mass was raised to 25 - 35°C. The reaction mass was further heated to 40±3°C and maintained at this temperature for 3 hours until TLC indicated completion of reaction. The reaction mass was then cooled to 25 - 35 °C followed by addition of DM water (500 ml). Stirred the mass for 25 minutes and the pH of the reaction mass was adjusted between 7.0-8.0 using sodium carbonate solution.Stirred, settled for 30min and separated the layers; discarded aq. layer; further charged the collected organic layer into RB flask and repetitively washed with 2x 500 ml DM water, stirred, settled and separated the layers. DCM was then distilled off atmospherically upto 55°C. Cooled the mass to 25-35°C and applied vacuum followed by distillation of DCM under vacuum upto 45°C till thick residue of 2-(2-chloroethyl) thiophene was obtained. Syrup wt: 100-1 l0gm Theoretical yield: 114gm
Example 5: Purification by high vacuum distillation of 2-(2-chloroethyl) thiophene (Intermediate -B)
To a neat, clean, and dry two neck 1L RB flask with high vacuum distillation set up was charged crude chloro compound (490gm) (Example 4). High vacuum was applied followed by slow heating and distilling off the compound under vacuum as indicated in the table below:

S.No Bath Temp.°C Vapour Temp. °C Vacuum Torr Remark
1 68-87 38-42 28-32 Low boiler

impurities
2 94-97 77-93 20-21 First cut
3 97-128 93-94 19-20 Main cut
Released the vacuum and discarded the residue.
Example 6: Preparation of Coupled amine hydrochloride
To a neat, clean, and dry four neck 2L RB flask with reflux condenser and thermometer pocket was charged 400ml of DM water and 200gm purified Tartrate salt of S-(+)Mettvyl -amino-(2-chlorophenyl) acetate (0.572 mole) (Example 3), stirred for 5 min followed by addition of 400ml DCM and adjusted the reaction mass to pH 7.0-7.5 using sodium bicarbonate solution using online pH meter. Stirred and settled the reaction mass for 30min at the same temperature, maintaining the pH of the aqueous layer alkaline (7.0-7.5) using sodium bicarbonate solution. Separated the layers and collected the organic layer. The aqueous layer was charged to RB flask and washed with DCM (200ml), stirred, settled, and separated to obtain the organic layer. The aqueous layer was further extracted with DCM. The combined organic layers were washed with DM water (3*200ml), stirred and separated. To the separated organic layer in the R.B. flask was charged sodium chloride solution, stirred, settled and separated the organic layer. The organic layer was charged into R.B. flask and DCM was then distilled off under vacuum at 25-30°C till thick syrup was obtained. The vacuum was then released and the syrup was checked for the methyl ester content.
To the neat, clean, and dry four neckl L RB flask with reflux condenser and thermometer pocket was charged 500ml acetonitrile and stirred the mass for 10. This is followed by addition of lOOgm methyl ester freebase and reaction mass was stirred until complete dissolution of syrup. Then charged sodium carbonate (106gm), stirred for lOmin followed by subsequent charging of chloro compound (92gm), potassium iodide (41.5gm) and TBAB (5.0gm) and stirred for 10 min. The reaction mass was refluxed and maintained at reflux temperature for 48 hours until the TLC indicated completion of reaction. Cooled the reaction mass to 25-30°C and filtered to collect the filtrate. The wet cake was then washed with 100ml of acetonitrile, filtered to collect the filtrate. The combined filtrates were charged into R.B. flask and applied vacuum and distilled off acetonitrile under

vacuum upto 45°C. The syrup was then charged into a neat, clean, and dry four necklL R.B. flask with reflux condenser and thermometer pocket followed by addition of 700ml of toluene, stirred until complete dissolution of the syrup. To the clear solution was added 300ml acetic acid solution. The organic layer was then charged into R.B. flask followed by addition of sodium chloride solution, stirred, settled and separated the layers. The separated organic layer was charged into R.B. flask, cooled the reaction mass to 10-15°C and added 63ml hydrochloric acid at the same temperature. Stirred the mass for 15 min at 10-15°C and further stirred for 2 hours. Filtered the reaction mass. Washed the wet cake with 10ml toluene, suck dried the solid under vacuum for 15 min, washed the wet cake with 300ml hexane, suck dried the solid under vacuum for 15 min. The product was dried at 55-60°C for 6-8 hours. Actual yield: 130-140 gm Theoretical yield: 198gm
Example 7: Preparation of Clpidogrel bisulphate
To a neat, clean, and dry four neck 2L RB flask with reflux condenser and thermometer pocket was charged 600ml of-40% formaldehyde solution and l00gm of coupled amine hydrochloride (0.2890 moles)(example 6). The reaction mass was stirred for 10 min and maintained for 20 hours and the sample was checked for coupled amine hydrochloride content by TLC. The reaction mass was filtered and the filtrate collected was charged into another neat, clean, and dry four neck 2L R.B. flask with reflux condenser and thermometer pocket and 400ml DCM; cooled the mass to 5-10°C. The pH of the reaction mass was adjusted to 7.0-7.5 by adding ~25%ammonia solution (600ml) using online pH meter. Stirred the mass for 30min at 5-10°C, settled for 30min and maintained pH of the aqueous layer within the limit. The organic layer was separated and the aqueous layer was extracted with (2 x 100ml) DCM, stirred, settled and separated organic layer. The aqueous layer was again extracted with 100ml DCM, stirred, settled and separated to obtain organic layer.
To a neat, clean, and dry four neck 1L R.B. flask with reflux condenser and thermometer pocket was charged combined organic layers and 400ml acetic acid solution, stirred, settled and separated the layers. The organic layer was washed with (2 x 100 ml) DM water, stirred, settled and separated the layers. To the organic layer was added sodium

sulphate (l0gm) and stirred the mass for 20min. Filtered the reaction mass through hyflo bed and collected the filtrate. Washed the hyflobed with DCM (50ml) and collected the filtrate followed by addition of neutral alumina (l00gm).Stirred the reaction mass for 60 min. Filtered the reaction mass and collected the filtrate. Washed the solid with 50 ml DCM and collected the filtrate. The combined filtrates were charged into RB flask, applied vacuum and distilled off DCM under vacuum till thick residue. To the residue was added 300ml of IPA, stirred until complete dissolution of syrup. Activated carbon (3gm) was added and stirred the reaction mass for 30min. Filtered the reaction mass through hyflo bed made in IPA and collected the filtrate. The hyflo bed was further washed with 50ml of IPA and collected the filtrate.
To a neat, clean, and dry four neck 500ml R.B flask with reflux condenser and thermometer pocket was charged IPA(90ml); followed by adding sulphuric acid (32gm) at the same temperature, The said colorless sulphuric acid solution was then added to the above reaction mass over a period of 60-90 min at 25-30°C, stirred for 60min and added pure clopidogrel bisulphate (Igm), maintained the reaction mass for 12 hours. Cooled the reaction mass to 0-5°C and maintained at the same temperature for 2 hours. Filtered the reaction mass and was washed with prechilled isopropyl alcohol(l00ml). Suck dried the solid for 15min and further dried the solid at 55-60°C for 8hours. Actual yield: 90-100gm Theoretical yield: I21.38gm
Example 8: Recovery and Racemization for S- (+) Methyl -amino-(2-chlorophenyl) acetate
To a neat, clean, and dry four neck 500ml R.B flask with reflux condenser and thermometer pocket was charged 773 ml of crude and pure tartrate salt filtrate and distilled off the solvent at 70-75°C till thick residue. Cooled the mass to 25-35°C. Weighed the residue and recorded the weight (~85gm). To the residue was charged DM water (225ml) and DCM (225ml), stirred and adjusted the pH of the aqueous layer to pH less than one using cone. HC1 (~100ml). Separated the layers and collected the organic layer. The aqueous layer was extracted with DCM (2 x 50ml) and separated the organic layers. The combined organic layers were sent for DCM recovery and to the aqueous layer in RB flask was added ammonia solution (~100ml) till pH of the aqueous layer is

between 8-9. The aqueous layer was further extracted with (2 x 150ml) of DCM until the methyl ester content in the aqueous layer was within the limit, and collected the organic layers (D) and (E). The organic layers were further washed with (2 x 50ml) DM water followed by addition of sodium chloride solution. Stirred and settled; the separated organic layer was heated upto 45°C atmospherically to distill off DCM. Cooled the reaction mass to 25-35°C. Applied vacuum and distilled off DCM under vacuum upto 45°C to obtain thick residue. Released the vacuum, unloaded the syrup and weighed. Syrup wt: 28-32gm Theoretical Yield: 43.32gm

We claim,
1. A process for preparation of (S) clopidogrel or its pharmaceutical salt comprising a step of coupling S- (+) Methyl -amino-(2-chlorophenyl) acetate an intermediate (A) with 2-(2-chloroethyl) thiophene an intermediate (B) in presence of solvent to obtain methyl(2-chlorophenyl){[(2-thiophene-2-yl) ethyljamino] ester of formula (IV).
2. The process according to claim 1, wherein said process comprises the following steps:

a) coupling (+) Methyl -amino-(2-chlorophenyl) acetate an intermediate (A) with 2-(2-chloroethyl) thiophene an intermediate (B) in presence of solvent to obtain methyl(2-chlorophenyl){[(2-thiophene-2-yl) ethyljamino] ester of formula (IV);
b) optionally converting to its hydrochloride salt;
c) cyclizing the formula IV in presence of aq. formaldehyde to obtain Clopidogrel base; and
d) converting the base to its bisulphate salt.

3. The process according to claim 1, wherein said coupling reaction is carried out in a solvent and a base in presence of KI and a phase transfer catalyst.
4. The process according to claim I, wherein said solvent is selected from polar protic or aprotic solvents such as water, lower alcohols, acetone, DCM, DMF, DMSO and acetonitrile.
5. The process according to claim 1, wherein said base is an inorganic base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; methoxides such as sodium methoxide, potassium methoxide; ammonia and organic bases such as methyl amine, ethylamine, triethylamine and pyridine.

6. The process according to claim 1, wherein the phase transfer catalyst is TBAB.