Technical Field of Invention:
The present invention relates to an improved process for preparation of Methyl (+)-(S)-(2-chlorophenyl)-6, 7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulfate known as Clopidogrel bisulphate with high chiral purity. The invention more particularly relates to purification of 4,5,6,7-tetrahydro [3,2-c] thieno pyridine hydrochloride and clopidogrel bisulphate substantially free from known impurities namely Methyl (±) O chlorophenyl-6, 7-dihydrothieno [2, 3 c] pyridine 5 (4H) acetate and Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [3, 2 c] pyridine 5 (4H) acetic acid.
Background of the invention:
Clopidogrel's platelet inhibiting activity makes it an effective drug for reducing the incidence of ischaemic 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.
Clopidogrel known for its platelet aggregating and anti-thrombotic properties, which finds medicinal applications in this field, was disclosed in US Patent 4529596 in its racemic form for the first time.
The chemical name of clopidogrel is (+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate. It has the following structure

Clopidogrel is disclosed in U.S. Pat. Nos. 4,529,596 (EP 99802, JP 59027895), 6,258,961, 5,036,156 (EP 420706, JP 3120286), 6,080,875 (EP 971915, JP 2001513806),
9

6,180,793 (EP 981529, JP 2001525829), FR 2769313, all of which are incorporated herein by reference for their disclosure and preparation of clopidogrel.
Clopidogrel is administered as its bisulfate (hydrogensulfate) salt. Clopidogrel bisulfate is an ADP (Adenosine Di- Phosphate) receptor antagonist that is indicated for the reduction of atherosclerotic events including myocardial infarction, ischaemic stroke and vascular death in patients with atherosclerosis manifested by recent stroke, myocardial infarction or established peripheral vascular disease (Blair Jarvis and Kerryn Simpson, Drugs 2000, Aug; 60 (2): 347-377).
Clopidogrel bisulfate is designated chemically as methyl (-f)-(S)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate sulfate.Clopidogrel bisulfate has the following chemical structure:

Clopidogrel Synthesis reported in the literature starts with conversion of Thiophene 2 ethylamine to a Tetra hydro Thieno pyridine followed by condensation with a - Bromo Phenyl acetic acid derivatives.
JP62103088 describes the reaction of Thiophene-2-ethylamine with formaldehyde in an aqueous medium to produce imine which is further reacted with hydrogen chloride in a neutral polar solvent such as DMF to synthesize 4,5,6,7 tetrahydro [3, 2- c] thienopyridine hydrochloride (70% yield).. The imine compound produced by the above reaction is used preferably in a completely dehydrated state without purification for preparation of clopidogrel.

JP63101385 describes the reaction of thiophene-2-ethylamine with aqueous formaldehyde to produce 2-(2-thienyl)ethylamine formimine and reacting formimine with hydrochloric acid to yield 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride. Similar process for preparation of is disclosed in US 5132435; however, these patents do not mention the purification of thienopyridine hydrochloride.
US 5,036,156 discloses condensation of 4,5,6,7-tetrahydro thieno [3,2-c] pyridine with methyl .alpha.-bromo 2-chloro phenylacetate in presence of sodium bicarbonate at 80 ° C to yield clopidogrel. This patent does not disclose purification of the intermediate as well as clopidogrel bisulphate.
US 6800759 provides a process for preparation of clopidogrel starting with thieno pyridine hydrochloride followed by reaction of (R) and (S) clopidogrel in toluene with levorotatory camphor sulfonic acid in DMF to form (S) clopidogrel camphor sulfonate and converting the precipitated sulphonate salt to clopidogrel bisulfate. This patent also uses anhydrous DMF solvent for synthesis of thieno pyridine hydrochloride to avoid formimine hydrolysis and also does not disclose purification of thieno pyridine hydrochloride
WO2005104663 describes the process for preparation of Clopidogrel which comprises reaction of Thiophene-2-ethylamine and paraformaldehyde in presence of Dichloroethane and water is removed azeotropically. The reaction mass is then treated with 6.6 M HC1 in Dimethylformamide to obtain Thieno Pyridine Hydrochloride with 90% yield and further condensed with the Bromo Ester in presence of Triethyl Amine.
US 4529596 describe the condensation of tetra hydro thieno pyridine with chloro ester in dimethylformamide at a temperature of 60°C-90°C to produce clopidogrel with low yield (45%). However it does not suggest preparation and purification of the starting material tetrahydro thienopyridine. US 5189170 also discloses condensation of Thieno Pyridine base with the Bromo Ester in refluxing Methanol for 6 hours to obtain clopidogrel with an yield of 83%.These two patents necessitate the liberation of Thieno Pyridine base as a separate step though both patents are silent on this step.

US 4847265 (EP 291459, JP 63203684) discloses resolution of racemic clopidogrel using levo rotatory camphor sulfonic acid and purification of the salt with repeated recrystallization using acetone. This clopidogrel salt is treated with sodium bicarbonate in dichloromethane to liberate clopidogrel free base which is treated with concentrated sulfuric acid to precipitate (S) clopidogrel bisulphate with low yield.
As mentioned in the process of 265' patent S (+) Clopidogrel Bisulphate is pure but it is well known that Clopidogrel cannot be stored at ambient temperatures as it degrades into the corresponding Acid. Prior Art does not reveal any method to purify the product.
In above described processes the reactants per se are same but employ varying conditions to achieve better purity or yield. Although some of the problems are solved by modifying the reaction conditions or route of synthesis as taught by the prior art, there still exist problems like polymerization of intermediates and impure desired product which need to be investigated.
The method of manufacture of clopidogrel bisulphate involves the production of imine by reaction of Thiophene-2-ethylamine with aqueous formaldehyde. This imine is unstable and results in polymeric side products.
Furthermore, it is known that thiophene-2-ethylamine contains up to 0.5% of thiophene-3-ethylamine, which in turn reacts with aqueous formaldehyde solution to give 4,5,6,7 Tetrahydro [2, 3- c] Thienopyridine Hydrochloride. This is converted to Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [3, 2 c] pyridine 5 (4H) acetate designated as 'Impurity B' in the U.S. Pharmacopoeia monograph.
The above mentioned patents does not address the problem of contamination with 4,5,6,7 Tetrahydro [2, 3- c] thienopyridine and consequently the formation of Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [3, 2 c] pyridine 5 (4H) acetate, identified as 'Impurity B' in the monograph of U.S. Pharmacoepia.


Impurity B
Clopidogrel Bisulphate produced by the above processes is expected to contain traces of sulphuric acid and, in presence of moisture, the degradation of clopidogrel to the Acid impurity designated as 'Impurity A' in the US Pharmacopoeia is accelerated.

Impurity A
Carrying out reactions at temperatures as described in prior processes for longer periods leads to the formation of various impurities, which necessitates extra purification resulting into yield losses and increase in number of operations not desirable for a practical process. Moreover, the impurities and the amount at which these are formed in clopidogrel synthesis makes it very difficult to get satisfactory yields of product of pharmaceutical quality, yet a pure product can only be obtained at precisely defined conditions, which have been established by the present inventors when contemplating the present invention to overcome the above discussed disadvantages associated with the prior art.
Thus referring numerous processes of prior art publications/patents the present invention provides process for preparation of clopidogrel bisulphate stable at ambient temperature for long period of time typically for one year with improved yield and high purity thereby

limiting the formation of impurities in the reaction by developing a more efficient process.
Objectives of the present invention:
An object of the present invention is to provide a simple and improved process for the preparation of Clopidogrel bisulphate with yield of above 90%.
Another object of the present invention in its preferred form is to provide an improved industrial process for preparation of clopidogrel in high yield and pharmaceutical^ acceptable purity by reducing the formation of impurities normally associated in the prior processes namely Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [2, 3 c] pyridine 5 (4H) acetate (Impurity B) and Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [3, 2 c] pyridine 5 (4H) acetic acid (Impurity A).
Another objective of the invention is to provide a simple process for preparation of stable intermediate 4,5,6,7 Tetrahydro [3, 2 c] thienopyridine hydrochloride substantially free from [2, 3-c] thieno pyridine which is a precursor of 'Impurity B' and process for purification of clopidogrel bisulphate to obtain the product substantially free from impurity 'A', suitable for industrial scale up.
Summary of the invention
The present invention discloses an improved process for preparation of methyl (+)-(S)-alpha-(2-chlorphenyl) -6,7-dihydrothieno [3,2-C] pyridine-5 (4-H) -acetate hydrogen sulphate known as Clopidogrel bisulphate with high chiral purity. The invention further discloses a purification method for preparation of 4,5,6,7-tetrahydro thieno [3,2-c] pyridine hydrochloride substantially free from known impurity namely Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [2, 3 c] pyridine 5 (4H) acetate(Impurity B) and thereby producing clopidogrel bisulphate substantially in good yields. The invention further provides the purification of clopidogrel bisulphate free from Methyl (±) O chlorophenyl-6, 7-dihydrothieno [3, 2 c] pyridine 5 (4H) acetic acid (Impurity A).

In one embodiment, the invention discloses neat reaction of thiophene-2-ethylamine with aqueous formaldehyde to yield 4,5,6,7-tetrahydro thieno (3,2-c) pyridine, followed by treatment with dry HC1 gas dissolved in a mixture of Dimethylformamide and toluene to obtain 4,5,6,7-tetrahydro thieno (3,2-c) pyridine hydrochloride along with known impurity, ie. 4,5,6,7- tetrahydro thieno [2,3-c] pyridine hydrochloride (pre cursor of Impurity B) .
In another embodiment, 4,5,6,7-tetrahydro (3,2-c) thienopyridine hydrochloride is purified by refluxing with an alcoholic solvent to substantially eliminate precursor of Impurity B.
In a further embodiment, 4,5,6,7-tetrahydro (3,2-c) thieno pyridine hydrochloride is reacted with methyl-bromo-2-chloro phenyl acetate in presence of base; followed by treatment with sulfuric acid to obtain R,S clopidogrel bisulphate. The product thus obtained is treated with (L)-camphor sulphonic acid in methyl iso butyl ketone (MIBK) solvent to obtain (S)-clopidogrel camphor sulphonate salt. The salt thus obtained is converted into (S)-clopidogrel free base by treatment with sodium bicarbonate. (S)-clopidogrel free base is treated with sulphuric acid in acetone to obtain (S)-clopidogrel bisulphate salt in a conventional manner. The product (S)-clopidogrel bisulphate obtained is associated with known impurity Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [3, 2 c] pyridine 5 (4H) acetic acid. (Impurity A) resulting from the degradation of clopidogrel. This degraded impurity is formed due to the presence of traces of sulfuric acid.
Therefore, the invention further provides a novel purification process of (S) -clopidogrel bisulphate. Clopidogrel bisulphate is dissolved in alcoholic solvent to obtain clear solution. The solution is filtered, solvent is evaporated followed by addition of acetone. The solution is cooled to obtain pure clopidogrel bisulphate free from impurity A and washed the product with acetone.
Finally, (R)-clopidogrel free base is recovered from clopidogrel camphor sulphonate MIBK mother liquor and further converted to R, S clopidogrel bisulphate.

Thus the present improved process provides S (+) clopidogrel bisulphate substantially free from impurity.
Description of the invention:
The present invention describes an improved process for the preparation of S(+) clopidogrel bisulphate by using the stable and purified starting material 4,5,6,7 tetrahydro [3, 2- c] thienopyridine hydrochloride substantially free from 4,5,6,7 tetrahydro [2,3c] thieno pyridine (a pre-cursor of 'Impurity B') and further purifying S(+) clopidogrel bisulphate to obtain stable (S) (+) clopidogrel bisulphate substantially free of the Acid impurity designated as 'Impurity A' in the US Pharmacopoeia.
An improved process for the preparation of Clopidogrel bisulphate comprising the steps
of;
a) reacting thiophene-2-ethylamine with formaldehyde to yield 4,5,6,7-tetrahydrothieno (3,2-c) pyridine;
b) isolating and purifying the product of step a)to obtain thieno pyridine hydrochloride substantially free from the impurity 4,5,6,7 Tetra Hydro[2,3c] Thieno Pyridine;
c) condensing the product of step b) with methyl alpha -bromo,2-chloro phenyl acetate in methanol and in presence of suitable base to obtain RS clopidogrel bisulphate,
d) resolving the reacemate salt of step c) to obtain S(+) clopidogrel camphor sulphonate salt and basifying to yield S(+) clopidogrel base,
e) acidifying the base with sulphuric acid to obtain S(+) clopidogrel hydrogen sulphate and
f) purifying the product of step e) with alcoholic solvent to yield pure S (+) clopidogrel bisulphate substantially free from 'Impurity A' and to minimize the free sulphuric acid which is expected to accelerate the degradation to 'Impurity A'.
The present invention describes an efficient process for preparation and purification of 4,5,6,7 Tetrahydro [3, 2 c] thienopyridine hydrochloride substantially free of the [2,3c] isomer (Impurity B) as described in US pharmacopoeia monograph, suitable for use as an

intermediate for drugs like Ticlopidine and Clopidogrel. The process does not sacrifice the yield while producing a highly pure 4,5,6,7 Tetrahydro [3, 2 c] thienopyridine intermediate. Clopidogrel produced by using this intermediate is substantially free from Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [2, 3 c] pyridine 5 (4H) acetate, identified as 'Impurity B' in the monograph of U.S. Pharmacopoeia. This renders the product more stable and suitable for industrial scale-up.
In one aspect of the invention, thiophene-2-ethylamine is reacted with aqueous formaldehyde (37%) at 40°C-45°C without using solvent. After the completion of reaction toluene is added and the separated toluene layer is washed with water and to the obtained solution, dry hydrogen chloride gas dissolved in a mixture of Dimethylformamide and toluene is passed and the reaction mixture is stirred for 2 hours. The precipitated 4,5,6,7 Tetrahydro [3, 2- c] thienopyridine Hydrochloride along with known impurity Methyl (±) O chlorophenyl- 6, 7-dihydrothieno [2, 3 c] pyridine 5 (4H) acetate (impurity B) is filtered and dried.
In another aspect of the invention 4,5,6,7 Tetrahydro [3, 2- c] thienopyridine Hydrochloride is purified by refluxing with alcoholic solvent for 30 min to get pure 4,5,6,7 Tetrahydro [3, 2 c] thienopyridine hydrochloride ( purity - 99.9%) substantially free from 4,5,6,7 Tetra hydro [2,3c] thieno Pyridine.
The term 'alcoholic solvent' referred herein may be primary secondary or tertiary aliphatic alcohols.
Aliphatic alcohol used for purifying 4,5,6,7 Tetrahydro [3, 2 c] thienopyridine hydrochloride is selected form CI to C5 alcohol preferably 10% isopropyl alcohol.
Yet in another aspect of the present invention, 4,5,6,7 Tetrahydro [3, 2 c] thienopyridine hydrochloride is dissolved in methanol and charged with potassium carbonate and methyl, 2-bromo 2(0-chloro phenyl) acetate is added at 45°C over period of one hour. The reaction mixture is then refluxed for 5 to 10 hours, cooled and filtered to remove inorganic salts. The methanol is evaporated under reduced pressure and toluene is added to the obtained thick brown oily material. The toluene layer is then washed with water

and evaporated. To the obtained residue acetone is added, the solution is cooled and sulphuric acid is added to obtain purified R,S Clopidogrel bisulphate with high yield of 90%.
R, S Clopidogrel bisulphate thus obtained is charged water and methylene dichloride (MDC) and then basified with sodium carbonate at 10°c - 15°c and stirred for 1 hour at room temperature. The separated aqueous layer is extracted with MDC and washed the combined organic layer with water. The solvent is evaporated completely to obtain residue. To this residue L- Camphor sulfonic acid in MIBK is added and the reaction mixture is heated at 65°c- 75°c for 1 hour, cooled to room temperature and allowed to settled for a period 37 hours (The reaction mixture is stirred for 2 minutes for every 3 hours during settling period). Then the reaction mass is heated to 60°c and cooled to 10°c - 15°c, stirred at 10°c - 15°c for 2 hours. The mass obtained is filtered (spare the MIBK mis for R, S - Clopidogrel bi sulphate recovery), washed with ethyl acetate and dried to get S (+)-Clopidogrel Camphor Sulphonate salt. Specific Optical Rotation (SOR): +24.905°(C -1.68% in MeOH)
S(+)-Clopidogrel camphor sulphonate salt dissolved in water and MDC is treated with sodium bicarbonate at 10°c - 15°c. Separated aqueous layer is extracted with MDC, the combined organic layer is washed with water and solvent is evaporated completely to get S(+)- Clopidogrel free base.
In another aspect of the present invention, S(+)- Clopidogrel free base is dissolved in acetone and treated with carbon at reflux temperature. To this free base sulphuric acid (98%) is added at 20°c and stirred for 2 hours at the same temperature. The mass obtained is filtered to get S (+) - Clopidogrel bisulphate and Specific Optical Rotation (SOR) is measured as +55.915°(C =2% in MeOH).
S (+) -Clopidogrel Bisulphate prepared by the above process is expected to contain traces of Sulphuric Acid which in the presence of moisture accelerates the degradation of clopidogrel to the Acid impurity designated as 'Impurity A' in the US Pharmacopoeia. Prior art does not teach any method of process for purification of the product.

The present invention describes a method of purification of S (+) Clopidogrel Bisulphate which is able to remove any traces of the sulphuric acid present in the final product. As a result the crystallized product is stable at ambient temperatures for longer period typically for one year.
Thus, S (+) Clopidogrel Bisulphate obtained by above described process is dissolved in alcoholic solvent and heated to 45°C to obtain a clear solution. The solution is filtered, evaporated the solvent followed by addition of acetone. The solution is then cooled tol5°C - 20°C, the obtained precipitated is filtered and washed with acetone to get pure S(+) Clopidogrel bisulphate free of'Impurity A'.
The alcoholic solvent used for purification of S (+) clopidogrel bisulphate is selected from CI to C5 alcohol preferably methanol.
Finally, (R)-clopidogrel free base is recovered from clopidogrel camphor sulphonate MIBK mother liquor during resolution of RS clopidogrel. Evaporating MIBK from the mother liquor completely and adding water and MDC to the obtained residue followed by treatment with sodium carbonate at 10°c - 15°c. The separated organic layer is washed with water and solvent is evaporated completely followed by addition of acetone to get a clear solution. Sulphuric acid (98%) is added to this clear solution and the reaction temperature is maintained at 0°c - 5°c for 1 hour. The precipitated product is filtered and washed with chilled acetone to get R- Clopidogrel bisulphate.
The above recovered R- Clopidogrel bisulphate in a mixture water and MDC is treated with sodium carbonate at 10°c - 15°c.The Separated aqueous layer is extracted with MDC and washed with water. Solvent is evaporated completely to get R- Clopidogrel. The obtained R-Clopidogrel is charged with toluene, potassium carbonate and KOH and the reaction mixture is maintained at reflux temperature till the Specific Optical Rotation (SOR) of the reaction mass becomes 0° (approximately 8 hours). The reaction mixture is then cooled to RT and washed with water. The separated toluene layer is first washed with sodium bicarbonate solution and evaporated completely to get the residue. This residue is dissolved in acetone and sulphuric acid (98%) is added at 0°c - 5°c and the reaction temperature is maintained at 0°c - 5°c for 1 hour. The precipitated RS-

Clopidogrel bisulphate is filtered and dried. Specific Optical Rotation (SOR): -0.001° (C =2% inMeOH)and MR: 218°c-220°c.
The process of the present invention is described herein below with reference to the following examples, which are illustrative and should not be construed as limiting the scope of the present invention in any manner.
Examples: Example 1
Preparation of 4,5,6,7 Tetrahydro [3, 2- c] thienopyridine Hydrochloride [THTP HC1]. To a clean and dry reactor, 50 Kg Thiophene-2-ethylamine and 37 Kg of 37% formaldehyde was added and stirred for two hours at 40°C-45°C. After the completion of reaction, 200 lit. of toluene was added. The organic layer was washed with water and dried over sodium sulphate [solution A].
Simultaneously, to mixture of 50 Kg toluene and 50 Kg Dimethylformamide 20 Kg of dry HC1 was passed. To this solution A was added and stirred for 2 hours. The precipitated 4,5,6,7 Tetrahydro [3, 2- c] thienopyridine Hydrochloride was filtered and dried to get 67 Kg of product. [THTP HC1].
Purification of 4,5,6,7 Tetrahydro [3, 2- c] thienopyridine Hydrochloride:-67 Kg THTP HC1 and 200 lit.of 10% aq isopropyl alcohol were refluxed for 30 min., cooled to 5°C and filtered to get 60-61 Kg of pure [99.9%] 4,5,6,7 Tetrahydro [3, 2 c] thienopyridine hydrochloride.
Example 2
Preparation of RS-Clopidogrel Bisulphate
To a clean and dry Reactor, 300 Lts of methanol, 50 Kg of 4,5,6,7, Tetrahydrothieno [3, 2 c] pyridine HC1, 60 Lts of potassium carbonate were charged and 90 Kg of Methyl -alpha-Bromo, 2-chloro phenyl acetate was added at 45°C over period of one hour. The mixture was refluxed for 5 - 8 hours, cooled and filtered to remove inorganic salts. The methanol was evaporated under reduced pressure. To the thick brown oily material 300 Lts of toluene was added the toluene layer washed with water, dried over sodium sulphate and evaporated. 250 Lts of Acetone was added, cooled and 15 Lts of sulphuric acid was

added and the purified materials filtered, dried to get lOlKgs. of R,S Clopidogrel bisulphate as white solid.
Example 3
Preparation of S+ Clopidogrel Camphor Sulphonate salt (Resolution of RS Clopidogrel Bisulphate
To clean reactor 1500 Its water, 750 Its of Methylene Di Chloride (MDC) and 150 kgs of RS-Clopidogrel bisulphate were charged. Then basified with sodium carbonate at 10°c -15°c and stirred for 1 hour at room temperature and separated layers. Extracted aqueous layer with 375 Its of MDC and washed the combined organic layer with water. Distilled off MDC completely, 106 kgs of residue obtained. To this 390 Its of Methyl Iso butyl Ketone (MIBK) and 37.5 kgs of L- Camphor Sulfonic acid were charged. Then the reaction mass was maintained at 65°c- 75°c for 1 hour to get clear solution and cooled to room temperature(RT). Settled the reaction mass for a period 37 hours (The reaction mixture was stirred for 2 minutes for every 3 hours during settling period ). Then the reaction mass heated to 60°c and cooled to 10°c - 15°c, stirred at 10°c - 15°c for 2 hours. Filtered the mass (spare the MIBK mis for RS - Clopidogrel bi sulphate recovery), washed the cake with ethyl acetate and dried to get 64.5 kgs of S(+)-Clopidogrel Camphor Sulphonate. Specific Optical Rotation (SOR): +24.905°(C =1.68% in MeoH)
Example 4
Preparation of S(+)ClopidogreI Base
To a clean reactor 193 Its of water, 273 Its of MDC and 64.5 kgs of S(+)- Camphor sulphonate were charged and treated with sodium bicarbonate at 10°c - 15°c. The organic layer is separated at 30°c and aqueous layer is extracted with MDC, washed the combined organic layer with water. The solvent (MDC) is distilled off completely to get 37.3 kgs of S (+)- Clopidogrel Base.
Example 5
Preparation of S+Clopidogrel bisulphate
To above obtained 37.3 kgs S(+)- Clopidogrel Base, charged 175 Its of acetone and

treated with 4.1 kgs carbon at reflux temperature. To this 7.7 Its of sulphuric acid(98%) was charged at 20°c and stirred for 2 hours at 20°c.Filtered the mass and dried to get 38.6 kgs S(+) - Clopidogrel bi sulphate. Specific Optical Rotation (SOR): +55.915°(C =2% in MeoH).
Purification of S+ Clopidogrel Bisulphate:
50 Kg of Clopidogrel Bisulphate was dissolved in 200 Lts of Methanol and heated to 45°C to obtain clear solution. The solution was filtered, methanol was evaporated and 150 Lts acetone was added. The mixture was cooled 15°C - 20°C, filtered, and washed with 25 Lts of acetone. The compound was dried 45°C - 50°C to obtain 45 Kg of pure Clopidogrel bisulphate free of impurity - A.
Example 6
Recovering R Clopidogrel during Step IV and producing R,S Clopidogrel Bisulphate from the Recovered product.
To a clean reactor 400 Its of Clopidogrel Camphor sulphonate MIBK mother liquor of example 3 was charged and distilled off MIBK completely. To the residue obtained 120 Its of water and 225 Its of Methylene Di Chloride was added and basified with sodium carbonate at 10°c - 15°c. The separated organic layer was washed with water. The solvent was distilled off completely and approximately 72 kgs residue was obtained. 165 Its of acetone was charged to the residue obtained and stirred to get a clear solution. 13 Its of Sulphuric acid (98%) was added to this solution and the reaction temperature was maintained at 0°c - 5°c for 1 hour. The mass thus obtained was filtered and washed with chilled acetone and dried to get 26.25 kgs of R- Clopidogrel bi sulphate.
To the above compound(R- Clopidogrel bi sulphate), 100 Its of water and 245 Its of MDC were charged and basified with sodium carbonate at 10°c - 15°c.The Separated aqueous layer was extracted with MDC and the combined organic layer was washed with water. MDC was distilled off completely to get R- Clopidogrel. 200 Its of toluene, 14.9 kgs of potassium carbonate and 2 kgs of KOH were charged with R-Clopidogrel. The reaction mass was maintained at reflux temperature till the SOR of the reaction mass becomes 0°

(approximately 8 hours). It was then cooled to RT and charged with 100 Its of water. The organic layer was separated and washed with sodium bi carbonate solution. Toluene was distilled off completely to get 27.5 kgs of residue. This residue was dissolved in 151 Its of acetone and 6 Its Sulphuric acid (98%) at 0°c - 5°c was added. The reaction temperature was maintained at 0°c - 5°c for 1 hour.it was then filtered and the filtered mass was dried at 50°c to get 35 kgs of RS- Clopidogrel bi sulphate. Specific Optical Rotation (SOR): -0.001° (C =2% in MeOH) and MR: 218°c-220°c.

We claim,
1. An improved process for preparation of (+) (S)-Clopidogrel bisulphate comprising
the steps of;
a) reacting thiophene-2-ethylamine with formaldehyde to yield 4,5,6,7-tetrahydrothieno (3,2-c) pyridine followed by treatment with hydrochloric acid to isolate 4,5,6,7 tetrahydro [3, 2- c] thienopyridine hydrochloride;
b) purifying the compound of step (a) to obtain pure product substantially free from 4,5,6,7 Tetrahydro [2, 3 c] thienopyridine hydrochloride;
c) condensing the product of step b) with methyl alpha-bromo,2-chloro phenyl acetate in presence of potassium carbonate in methanol followed by treatment with sulphuric acid to obtain R S clopidogrel bisulphate;
d) resolving the clopidgrel bisulphate of step c) followed by treatment with sodium bicarbonate to isolate S(+) clopidogrel free base;
e) treating S (+) clopidogrel free base of step (d) with sulphuric acid to obtain S(+) clopidogrel bisulphate and
f) purifying the product of step e) to yield pure S (+) clopidogrel bisulphate substantially free from 'Impurity A'.

Impurity A
2. The process as claimed in claim 1 wherein the said purification in step (b) comprises refluxing 4,5,6,7 tetrahydro [3, 2 c] thienopyridine in alcoholic solvent to get pure 4,5,6,7 tetrahydro [3, 2 c] thienopyridine hydrochloride free from 4,5,6,7 Tetrahydro [2, 3 c] thienopyridine hydrochloride.
3. The process as claimed in claim 1 and 2 wherein the purity of 4,5,6,7 tetrahydro [3, 2 c] thienopyridine hydrochloride is greater than 99.5% HPLC.

4. The process as claimed in claim 1 and 2 wherein the said alcoholic solvent is
selected from primary, secondary or tertiary aliphatic alcohols preferably aqueous
isopropyl alcohol.
5. The process as claimed in claim 1, wherein said purification in step (f) comprising
the steps of:
a) dissolving clopidogrel bisulphate in alcoholic solvent by heating at 45°Cto
obtain clear solution;
b) filtering the solution of step (a) and evaporating the solvent to obtain
residue and
c) adding acetone to the residue obtained in step (b) followed by cooling to
get pure S (+)Clopidogrel bisulphate free of Impurity - A.
6. The process as claimed in claim 5 wherein the said alcoholic solvent in step (a) is
selected from the group comprising primary, secondary or tertiary aliphatic
alcohols preferably methanol.
7. An improved process for preparation of (+) (S)-clopidogrel bisulphate as
substantially described herein with reference to the examples 1 to 6 and
claims 1 to 4.