INTRODUCTION

Aspect of the présent application relate to process for the recovery of camphorsulfonic acid used in the resolution of racemic clopidogrel and re use of the recovered camphorsulfonic acid for resolution and an improved process for the racemization of R-isomer (or) enriched R-isomer of clopidogrel.

Clopidogrel, having the chemical name (S)-(+)-a-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetic acid methyl ester is an antithrombotic drug. It acts as an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subséquent ADP-mediated activation of glycoprotein GPIIb/llla complex.By inhibiting platelet aggregation, clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart-attacks.

Clopidogrel is marketed as bisulfate sait having the following chemical structure of formula I.

Formula I Clopidogrel bisulfate was first revealed in U.S. Pat. No. 4,847,265 assigned to
Sanofi and was claimed as dextrorotatory isomer. The séparation of enantiomers[dextrorotatory enantiomer and levorotatory enantiomer] from the racemic mixture is illustrated in the Scheme-1 of U.S. Pat. No. 4,847,265.

U.S. Pat. No. 4,847,265 discloses process for préparation of the dextrorotatory enantiomer of the clopidogrel bisulfate. Racemic clopidogrel is resolved using L-(-)-camphorsulfonic acid to obtain optically pure dextrorotatory isomer. The camphorsulfonate sait of clopidogrel is basified to produce clopidogrel freebase which is converted to a pharmaceutically acceptable sait. There are many other références which also disclose process for the resolution of racemic clopidogrel involving the use of camphorsulfonic acid.

Owing to the economy of the process, the expensive resolving agent camphor sulphonic acid should be recovered and recycled after resolution for reducing the cost. There are many publications disclosing différent processes for recovering camphor sulphonic acid after its use as resolving agent, still there remains a need for improved process for the recovery of camphorsulfonic acid. The présent application relates to the improved process for the recovery of camphorsulfonic acid used in the resolution of racemic clopidogrel.The présent invention also relates to the use of recovered camphorsulfonic acid again for the resolution purpose. None of the available reported processes involves the recovery of camphorsulfonic acid used in the synthesis of clopidogrel by using cation exchange resin.

To reduce the manufacturing cost of the clopidogrel bisulfate at the commercial scale, it is essential to racemize the R-isomer of clopidogrel (or) enriched R-isomer of clopidogrel produced during the resolution of racemic clopidogrel. The obtained racemic clopidogrel can be again resolved with the known process and can be converted into its pharmaceutically acceptable salts. US6635763, US6737411, US7985859B2, US2011190502A1, US 20050176960A1, WO2008130642A2, WO2006087729A1, WO2004074215A1 and IN193363 disclose the racemization of R-isomer of clopidogrel (or) enriched R-isomer of clopidogrel.

However, there remains a need to develop an improved process for the racemization of R-isomer of clopidogrel (or) enriched R-isomer of clopidogrel which is obtained during the resolution of racemic clopidogrel.

BREF SUMMARY

In an aspect, the application provides a process for the recovery of camphorsulfonic acid, which comprises:

1) treating the clopidogrel camphorsulfonic acid salt with a base to produce clopidogrel freebase in présence of water and organic solvent;

2) treating the aqueous layer containing sait of camphorsulfonic acid with cation exchangeresin; and

3) recovering the camphorsulfonic acid.

In another aspect, the application provides a process for the préparation of S (+) clopidogrel or salts thereof, the process comprising:

1) preparing a sait of racemic clopidogrel with a camphorsulfonic acid;

2) separating the S (+) clopidogrel camphorsulfonic acid and R (-) clopidogrel camphorsulfonic acid;

3) treating the above clopidogrel camphorsulfonic acid sait with a base to produce clopidogrel freebase in présence of water and organic solvent;

4) treating the aqueous layer containing sait of camphorsulfonic acid with cation exchange resin;

5) recovering the camphorsulfonic acid;

6) repeating steps (1) to step (3) with the recovered camphorsulfonic acid obtained in step (5); and

7) optionally, converting the S (+) clopidogrel obtained in step (3) to pharmaceutically acceptable salts thereof.

In another aspect, the application provides a process for the préparation of racemic clopidogrel comprising;

1) obtaining a solution of R(-) clopidogrel or enriched R(-) clopidogrel in one or more solvents;

2) contacting the solution obtained in step 1 with a base having moisture content more than 0.3%; and

3) recovering the racemic clopidogrel from the solution.

In another aspect, the application provides a process for the préparation of S (+) clopidogrel or salts thereof, the process comprising;

1) preparing a sait of racemic clopidogrel with a chiral auxiliary;

2) separating the S (+) clopidogrel and R (-) clopidogrel isomers;

3) racemizing the R (-) clopidogrel or enriched R (-) clopidogrel obtained in step 2) with a base having a moisture content of more than 0.3%, in a solvent to get racemic clopidogrel;

4) repeating steps 1) to step 2) with the racemic clopidogrel obtained in step 3); and

5) optionally, converting the S (+) clopidogrel obtained in step 2) to pharmaceutically acceptable salts thereof.

BREF DESCRIPTION OF THE DRAWING

Fig. 1 is a flow chart of the operator task in the preferred embodiment.

DETAILED DESCRIPTION

In an aspect, the application provides a process for the recovery of camphorsulfonic acid, which comprises;

1) treating the clopidogrel camphorsulfonic acid sait with a base to produce clopidogrel freebase in présence of water and organic solvent;

2) treating the aqueous layer containing sait of camphorsulfonic acid with cation exchange resin; and

3) recovering the camphorsulfonic acid.

In embodiments of step 1), the clopidogrel camphorsulfonic acid sait used herein can be obtained by any of the processes known in the art.

In embodiments of step 1), the clopidogrel camphorsulfonic acid can be S(+)-clopidogrel (-) camphorsulfonic acid or R(-)-clopidogrel (-) camphorsulfonic acid or S(+)-clopidogrel (+) camphorsulfonic acid or R(-)-clopidogrel (+) camphorsulfonic acid. In a preferred embodiment of step 1), the clopidogrel camphorsulfonic acid is S(+)-clopidogrel (-) camphorsulfonic acid or R(-)-clopidogrel (-) camphorsulfonic acid.

In embodiments of step 1), the treatment of clopidogrel camphorsulfonic acid sait to produce clopidogrel free base can be carried out in the présence of a base. Bases that are useful in the reaction include, but are not limited to: inorganic bases such as alkali métal or alkaline earth métal carbonates, hydrogen carbonates, hydroxides, carboxylates, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acétate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acétate, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acétate, barium hydroxide, or the like.

In another embodiment of step 1), the treatment of clopidogrel camphorsulfonic acid sait to produce clopidogrel free base can be carried out in the présence of inorganic base such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide. The sait of camphorsulfonic acid obtained from the above treatment dépends on the base/s used.

In embodiments of step 1), the reaction can be carried out in water.

In embodiments of step 1), the reaction can be carried out in présence of an organic solvent which has no adverse effect on the reaction or on the reagents involved in the reaction. Examples of such solvents include but are not limited to aliphatic hydrocarbons such as hexane, cyclohexane, heptane; aromatic hydrocarbons such as toluène or xylene; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; ester solvents such as ethyl acétate, propyl acétate or butyl acétate; alcohol solvents 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene giycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol; or their mixture thereof.

In embodiments of step 1), the treatment of clopidogrel camphorsulfonic acid sait to produce clopidogrel free base may be carried out at a température ranging from about -10°C to about the 50°C. In one embodiment, the reaction can be carried out from about -10°C to about 35°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction température and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of about 10 minutes to about 2 hours or longer.

In embodiments of step 1), the organic layer and aqueous layers may be separated. The organic layer may be washed with water. The organic layer may be distilled to produce the clopidogrel free base as per the procédures known in the art.

In embodiments of step 1), the aqueous layers can be separated and used for the step 2).

In embodiments of step 2), the aqueous layer containing sait of camphorsulfonic acid can be treated with cation exchange resin.

In embodiments of step 2), the aqueous layer containing sait of camphorsulfonic acid can be treated with cation exchange resin. Resins that are useful in the reaction include, but are not limited to: Thermax- Tulsion T-38, T-42, T-54, T-57, T-63, T-42 MP, T-62MP, T-63MP, CXO, CXO-9H and CH-90, Rohm & Haas-Amberlite IR-118, IR-120, IRA743, IRC-50S, IRP64 and CG-50, Relite CFA, CF, CFH, CFS, RPS or Relite CNS in H or Na form. If the resin is in Na form it must be converted to H form before use.

In embodiments of step 2), the resin can be reused many times for the recovery of camphorsulfonic acid by activating it again with the procédures known in the art.

In embodiments of step 2), cation exchange resin and sait of camphorsulfonic acid in aqueous solution are charged into column, wherein the ratio of L/D varies from 0.6 to 100, where L is length of column and D is diameter of column.

In embodiments of step 2), cation exchange resin and sait of camphorsulfonic acid in aqueous solution are charged into column, wherein the flow rate varies as column dimension changes and the range for small scale column opérations is 1-600 mL/min and for large scale opérations 1-600 L/min.

In embodiments of step 2), cation exchange resin and sait of camphorsulfonic acid in aqueous solution are charged into column, wherein the linear velocity or linear flow rate is related to volumetric flow rate through the column cross sectional area, the range of linear velocity is 1- 8 cm/min.

In embodiments of step 2), the camphorsulfonic acid can be eluted from the column by using solvents such as water or organic solvents or any mixture of organic solvents or any aqueous solutions.

In embodiments of step 3), the aqueous layers containing camphorsulfonic acid eluted from the column can be combined and concentrated to recover the camphorsulfonic acid. The concentration can be done through atmospheric distillation, vacuum distillation, thin film evaporator and spray dryer or any other methods known in the art. The distillation can be done at any suitable température.

In embodiments of step 3), the obtained camphorsulfonic acid after the concentration of water or any of the solvents used in step (2), optionally can be isolated by the procédures known in the art such as filtration, centrifugation, or any of the techniques known in the art.

In embodiments of step 3), the obtained camphorsulfonic acid after the concentration of water or any of the solvents used in step (2), optionally can be combined with a solvent.
The solvent can be added to the residue or solid obtained after the distillation of water and stirred for 15 minutes to 10 hours or longer. The solid obtained after the treatment with solvent can be isolated by the procédures known in the art such as filtration or centrifugation followed by optionally washing with the same solvent.

In embodiments of step 3), after the concentration of aqueous layer any solvent that can be added which has no adverse effect. Examples of such solvents include but are not limited to aliphatic hydrocarbons such as hexane, cyclohexane, heptane; aromatic hydrocarbons such as toluène or xylene; halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, or dichlorobenzene; ketone solvents such as acétone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone; ester solvents such as ethyl acétate, propyl acétate or butyl acétate; alcohol solvents such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phénol, glycerol, or d-C6 alcohols; carboxylic acid solvents such as acetic acid or propionic acid; nitrile solvents such as acetonitrile or propionitrile; or their mixture thereof. In a preferred embodiment of step 3), the solvent that can be used for the isolation of the camphorsulfonic acid are acetic acid and toluène.

In embodiments of step 3), the camphorsulfonic acid that is isolated can be dried at suitable températures, such as from about 40°C to about 100°C and suitable pressures from about 1 hour to about 24 hours or longer, using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying températures and times will be sufficient to achieve desired product purity. In embodiments of step 3), isolated camphorsulfonic acid can be in a crystalline, amorphous, hydrated, or solvated form.

The camphorsulfonic acid obtained according to the process of the présent application can be purified further by any of the methods known in the art such as recrystallization, crystallization, slurry washing, column chromatography etc.

The camphorsulfonic acid obtained according to the process of the présent application can be crystalline, amorphous, hydrate or solvate.

The camphorsulfonic acid obtained according to the process of the présent application can be monohydrate or anhydrous. Preferably the camphorsulfonic acid obtained according to the process of the présent application is monohydrate.

The camphorsulfonic acid obtained according to the process of the présent application can be (-) camphorsulfonic acid or (+) camphorsulfonic acid. The camphorsulfonic acid that can be recovered according to the process of the présent application will be substantially same as the camphorsulfonic acid. The recovered camphorsulfonic acid can be re used for the resolution of any racemic compounds. The recovered camphorsulfonic acid can be re used for the resolution of any racemic compounds such as racemic clopidogrel, racemic duloxetine, racemic atomoxetine etc.

In another aspect, the application provides a process for the préparation of S (+) clopidogrel or salts thereof, the process comprising;

1) preparing a salt of racemic clopidogrel with a camphorsulfonic acid;

2) separating the S (+) clopidogrel camphorsulfonic acid and R (-) clopidogrel camphorsulfonic acid;

3) treating the above clopidogrel camphorsulfonic acid salt with a base to produce clopidogrel freebase in présence of water and organic solvent;

4) treating the aqueous layer containing salt of camphorsulfonic acid with cation exchange resin;

5) recovering the camphorsulfonic acid;

6) repeating steps (1) to step (3) with the recovered camphorsulfonic acid obtained in step (5); and

7) optionally, converting the S (+) clopidogrel obtained in step 3) to pharmaceutically acceptable salts thereof.

In aspects of step 1 and step 6, the salt of racemic clopidogrel with a camphorsulfonic acid can be prepared with any of the procédures known in the art.

In aspects of steps 2 to 5, the camphorsulfonic acid can be recovered according to the process described in this application or according to the examples described in this patent application.

In an aspect of step 7, the conversion of S (+) clopidogrel into it's pharmaceutically can be carried out using any of the procédures known in the art.

In an embodiment, the présent application provides a process for the préparation of clopidogrel camphorsulfonic acid salt using the reduced quantifies of camphorsulfonic acid for the resolution of racemic clopidogrel. In an aspect, the quantity of camphorsulfonic acid used for the resolution of racemic clopidogrel varies from 0.5 to 1.05 moles, preferably 0.5 to 1.0 moles with respect to one mole of racemic clopidogrel.

In an aspect, the application provides a process for racemization of unwanted isomer of clopidogrel i.e.,R (-) clopidogrel or R (-) clopidogrel containing some amount of S (-) clopidogrel.

In another aspect, the application provides a process for the préparation of racemic clopidogrel comprising;

1) obtaining a solution of R(-) clopidogrel or enriched R(-) clopidogrel in one or more solvents;

2) contacting the solution obtained in step 1 with a base having moisture content more than 0.3%; and

3) recovering the racemic clopidogrel from the solution.

The US patent US 7,985,859 discloses the process for the racemization of R (-)- clopidogrel can be carried out by contacting the solution of R(-) clopidogrel with powdered anhydrous base having a particle size 400 micron or less. According to the file history of this patent, the applicant indicated that the anhydrous base used is having a moisture content of up to 0.2%. If the moisture content is more than 0.3%, then racemization reaction did not proceed effectively. Applicant also provided supporting examples to thèse statements.

It was surprisingly found that, the commercial bases such as powdered sodium carbonate or granular sodium carbonate having moisture content more than 0.3% also effectively racemized the solutions containing the R (-) clopidogrel or R (-) enriched clopidogrel. It was found that the particle size also not playing significant rôle in the racemization process.

In embodiments of step 1), the solution of R (-) clopidogrel or R (-) enriched clopidogrel can be obtained by any of the procédures known in the art or can be obtained by dissolving the R(-) clopidogrel or R(-) enriched clopidogrel in a suitable solvent or can be obtained from the mother liquor of the previous step or can be obtained according to the procédures described in this patent application. The solvents which can be used for making a solution of R (-) clopidogrel or R (-) enriched clopidogrel can be, but not limited to: Ci alcohols; C3-6 ketones; hydrocarbons such as aliphatic or aromatic or halogenated hydrocarbon; or any mixtures thereof; or their combinations with water in various proportions.

In embodiments of step 2), racemization of R (-) clopidogrel or R (-) enriched clopidogrel can be carried out by contacting the solution of R (-) clopidogrel or R (-) enriched clopidogrel obtained in step 1) with a suitable base having moisture content more than 0.3%. The base can be any organic or inorganic base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali métal or alkaline earth métal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, alkoxide e.g., sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acétate, sodium methoxide, potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acétate, potassium methoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acétate, lithium methoxide, barium hydroxide, calcium oxide, or the like; organic bases such as, primary, secondary, or tertiary aminés, such as ammonia, aqueous ammonia, triethylamine, diisopropylamine, N-methylmorpholine.

In embodiments of step 2), racemization of R (-) clopidogrel or R (-) enriched clopidogrel can be carried out at a température ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room température to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction température and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions out lined above, a period of from abouti 0 minutes to 24 hours or longer.

In embodiments of step 3), the racemic clopidogrel can be isolated using techniques such as décantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a solvent.

In embodiments of step 3), the racemic clopidogrel obtained upon the concentration of the solvent can be combined with water and water immiscible solvent. The organic layer and aqueous layer can be separated and the organic layer may be washed with water to remove the unwanted salts, if any. The organic layer may be further concentrated to produce racemic clopidogrel free base or the organic layer may be used for the next step without isolation Le., for the resolution step. The solvents that can be used for this step can be from any of the solvents described in the step 1) of this embodiment.

In another aspect, the application provides a process for the préparation of S (+) clopidogrel or salts thereof, the process comprising:

1) preparing a sait of racemic clopidogrel with a chiral auxiliary;

2) separating the S (+) clopidogrel and R (-) clopidogrel isomers;

3) racemizing the R (-) clopidogrel or enriched R (-) clopidogrel obtained in step 2) with a base having a moisture content of more than 0.3%, in a solvent to get racemic clopidogrel;

4) repeating steps 1) to step 2) with the racemic clopidogrel obtained in step 3); and

5) optionally, converting the S (+) clopidogrel obtained in step 2) to pharmaceutically acceptable salts thereof.

In an aspects of step 1) and step 2), the R (-) clopidogrel or enriched R (-) clopidogrel can be obtained by any of the procédures known in the art for example treating racemic clopidogrel with L(-) camphorsulfonic acid.

In an aspect of step 3), the racemization of R (-) clopidogrel or enriched R(-) clopidogrel can be carried out according to the process described in this application or according to the examples described in this patent application.

In an aspect of step 4), the préparation of S (+) clopidogrel can be carried out according to the procédures known in the art or according to the procédures in this patent application or according to the procédures described in the examples of this patent application.

In an aspect of step 5), the conversion of S (+) clopidogrel into its pharmaceutically can be carried out using any of the procédures known in the art.

In embodiments, the racemic clopidogrel and the camphorsulfonic acid recovered according to the présent application are sufficiently pure and can be used for proceeding to the next step.

The racemization reaction and/or recovery of camphorsulfonic acid described in this patent application can be repeated any number of times to enhance the yield and to reduce the cost of the clopidogrel or its sait production.

In embodiments, clopidogrel bisulfate prepared according to the process of the présent application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC).

Clopidogrel bisulfate produced by a method of présent application can be chemically pure of clopidogrel bisulfate having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC. Clopidogrel bisulfate produced by the methods of présent application can be chemically pure of clopidogrel bisulfate having purity greater than about 99.8% and containing no single impurity in amounts greater than about 0.1%, by HPLC.

Clopidogrel bisulfate obtained according to a process of the présent disclosure can be milled or micronized using any processes known in the art, such as bail milling, jet milling, wet milling, etc., to produce a desired particle size distribution. Clopidogrel bisulfate obtained according to certain processes of the présent disclosure has a particle size distribution wherein: d(0.1) is less than about 100 um or less than about 60 um; d(0.5) is less than about 125 um or less than about 95 um; and d(0.9) is less than about 200 um or less than about 160 um. Particle size distributions can be determined using any means, including laser light diffraction equipment, coulter counters, microscopic procédures, etc. The term d(x) in a distribution means that a particular fraction has particles with a maximum size being the value given, 0.5 representing 50% of the particles and 0.9 representing 90% of the particles.

In embodiments, the présent application provides pharmaceutical compositions containing a therapeutically effective amount of clopidogrel bisulfate, together with one or more pharmaceutically acceptable excipients. The pharmaceutical compositions comprising clopidogrel bisulfate of the application together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable préparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immédiate release, delayed release or modified release. Further, immédiate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt préparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or réservoir Systems, or combinations of matrix and réservoir Systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization.

Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, or modified release coated.

DEFINITIONS

The following définitions are used in connection with the disclosure of the présent application, unless the context indicates otherwise. In gênerai, the number of carbon atoms présent in a given group or compound is designated "Cx-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "Ci-C6" contains from 1 to 6 carbon atoms. The carbon number as used in the définitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.The term "reacting" is intended to represent bringing the chemical reactants together under conditionsthat cause the chemical reaction indicated to take place.

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "Ci-C6 alcohols" include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phénol, glycerol, or the like.

An "aliphatic hydrocarbon" is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or hâve as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called"aromatic." Examples of "C5-C8aliphatic or aromatic hydrocarbons" include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzène, toluène, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.

An "ester" is an organic compound containing a carboxyl group -(C=0)-0-bonded to two other carbon atoms. "C3-C6esters" include, but are not limited to, ethyl acétate, n-propyl acétate, n-butyl acétate, isobutyl acétate, t-butyl acétate, ethyl formate, methyl acétate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

A "halogenated hydrocarbon" is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A "ketone" is an organic compound containing a carbonyl group -(C=0)-bonded to two other carbon atoms. HC3-C6 ketones" include, but are not limited to, acétone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.

A "nitrile" is an organic compound containing a cyano -(CEN) bonded to another carbon atom. "C2-C6Nitriles" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

A "chiral auxiliary" is a compound, which is useful for resolution in organic synthesis. Examples of such chiral auxiliary include, but are not limited to camphorsulphonic acid, tartaric acid, mandelic acid, malic acid, lactic acid and camphoric acid.

Certain spécifie aspects and embodiments of the présent application will be explained in greater détail with référence to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procédures, as will be apparent to those skilled in the art, are intended to be within the scope of the présent application.

EXAMPLES

Example 1: Recovery of (-)-L-camphorsulfonic acid from aqueous layer containing sodium (-)-L-camphorsulfonate: T-57 resin (2.6 L) and water (2 L) were charged into a beaker at 25°C, the suspension was stirred for 5 minutes to obtain wet slurry of T-57 resin. The obtained wet slurry of T-57 resin was loaded into a column (8 cm X 100 cm) at 25°C, the wet T-57 resin was washed with water (2 L) for 1 hour, the flow rate of water maintained 250 mL/min, the sodium sait of (-)-L-camphorsulfonic acid in water (4 kg) obtained according to the prior art process described in example-4 of US7772398B2 was loaded into resin column. Water was continuously added in the resin column with a flow rate of 170 mL/min. The flow rate of the column was maintained 170 mL/min and the void volume (1200 mL) collected and discarded, the first fraction containing camphorsulfonic acid (3.3 L) was collected for 28 minutes, the second fraction containing camphorsulfonic acid (500 mL) was collected for 5 minutes and the third fraction containing camphorsulfonic acid (2 L) collected for 8 minutes. After completion of the fractions containing camphorsulfonic acid resin was washed with water (4 L). The fractions containing camphorsulfonic acid were evaporated under vacuum at 60°C to obtain a solid. The obtained solid compound was dried under vacuum at 60°C for 4 hours. Yield: 835 g; Spécifie Optical Rotation: -21.3°; Assay: 100.36%;

The resin used in the column was regenerated using 5 % hydrochloric acid followed by washing with water.

Example 2: Recovery of (-)-L-camphorsulfonic acid from aqueous layer containing sodium (-)-L-camphorsulfonate: T-57 resin (2.6 L) and water (2 L) were charged into a beaker at 25C, the suspension was stirred for 5 minutes to obtain wet slurry of T-57 resin. The obtained wet slurry of T-57 resin was loaded into a column (8 cm X 90 cm) at 25°C, the aqueous layer containing sodium (-)-L-camphorsulfonate (4 kg) obtained according to the prior art process described in example-4 in US7772398B2 was loaded into resin column. The flow rate of the column was maintained 160 mL/min, the void volume (1000 mL) was collected and discarded. The fractions containing camphorsulfonic acid were collected approximately 5 liters. This aqueous layer was used further for the isolation of camphor sulphonic acid.

Isolation of the (-)-L-camphorsulfonic acid was done the aqueous layer collected as above with différent methods.

Method a): The aqueous layer containing (-)-L-camphorsulfonic acid (500 mL) obtained above was charged into a round bottom flask at 27°C. The solvent was evaporated under vacuum at 90°C to obtain a solid compound. The obtained solid compound was dried at 90°C for 5 hours. Yield: 118 g; Spécific Optical Rotation: -20.38°; Assay: 99.82%;

Method b): The aqueous layer containing (-)-L-camphorsulfonic acid (500 mL) obtained above was charged into a round bottom flask at 27°C and stirred for 10 minutes. The aqueous layer was evaporated under vacuum at 756C to obtain a solid compound. Toluène (350 mL) was added to the obtained solid at 75°C, and raised the température of the reaction mass to 110°C. The obtained solution was distilled azeotropically for 30 minutes to remove the water and then cooled to 27°C. The solution was maintained for 1 hour at the same température. The solid compound was obtained by filtration, washed with toluène (200 mL) and suck dried at 27°C for 30 minutes. The solid compound was dried at 64°C for 4 hours. Yield: 94.5 g; Spécifie Optical Rotation: -20.923°; Assay: 101.08%;

Example 3: Isolation of (-)-L-camphorsulfonic acid in acetic acid: The aqueous layer containing sodium sait of (-)-L-camphorsulfonic acid (1000 mL) and dichloromethane (100 mL) were charged into a round bottom flask at 28°C and stirred for 15 minutes. The organic layer and aqueous layers were separated. The aqueous layer was passed through the column containing T-57 resin. The fractions containing camphorsulfonic acid were collected. The obtained aqueous layer from the resin column was concentrated under vacuum at 60°C to reduce the solvent. Further obtained solution was transferred into a 4-neck round bottom flask at 64°C and concentrated under vacuum. Acetic acid (280 mL) was added to the flask at 66°C under stirring and concentrated under vacuum. Further acetic acid (560 mL) was added to the flask under stirring at 70°C to get a clear solution.

The obtained solution was filtered through 0.45 micron filter under vacuum at 70°C. The filtrate was maintained at 60°C and charged into a 4-neck round bottom flask under stirring and cooled to 20°C and maintained for 2 hours 30. The precipitated solid was obtained by filtration and washed with acetic acid (70 mL) and dried under suction at 28°C for 1 hour. The compound was further dried on rotavapour under vacuum at 75°C for 7 hours. Yield: 104 g; Assay: 100.31 % and Spécifie Optical Rotation:-21.501°.
After collecting the fractions containing camphorsulfonic acid, the resin was washed with 5 % aqueous hydrochloric acid and followed by water to regenerate the resin.

Example 4: Resolution of racemic clopidogrel using recovered (-)-L-camphorsulfonic acid: Racemic clopidogrel bisulfate (300 g) and dichloromethane (750 mL) were charged into a round bottom flask at 27°C and stirred at the same température for 5 minutes. The reaction mass was cooled to 0°C. The aqueous solution of sodium carbonate was slowly added until the pH of the reaction mixture was from 7.8 (about 93.3 grams of sodium carbonate in 600 mL deionized water) at 0-5°C. The reaction mass was stirred for 15-20 minutes and the mass was allowed to settle. The layers were separated. The aqueous layer was extracted with dichloromethane (115 mL). The combined organic layer was washed twice with water (2 x 90 mL). Dichloromethane was distilled from the organic layer at a température below 58°C to obtain a residue. Acétone (150 mL) was charged to the residue and again distilled under vacuum at 58°C. Acétone (900 mL) was charged to the residue at 27°C and stirred the obtained solution. The recovered (-)-L-camphorsulfonic acid monohydrate (94.5 g) obtained from example- 2 was added to the solution under stirring at 33°C. clopidogrel camphorsulfonic acid (S)-isomer (0.3 g) was added to the reaction mass as a seed material at 30°C. The reaction mass was stirred at 28°C for 3 hours and further cooled to 15°C in 3 hours and stirred for 8 hours 30 minutes. The precipitated solid product was obtained by filtration and washed with chilled acétone (222 mL). The compound was dried under suction at 28°C for 1 hour. The compound was further dried under vacuum at 45°C for 2 hours. The dried product (130 g) and acétone (1040 mL) were charged into a round bottom flask at 28°C. Water (22.5 mL) was added to the reaction mass under stirring at 28°C. The reaction mass was heated to reflux to obtain clear solution and maintained for 20 minutes at reflux. The solution was cooled to 0°C and stirred for 1 hour at the same température. The precipitated solid compound was obtained by filtration and washed with acétone (130 mL). The compound was dried under suction at 28°C for 40 minutes. The compound was further dried under vacuum at 65°C for 4 hours. Yield: 95.4 g; Chiral purity: 99.97%, R-isomer: 0.03%; assay: 100.44% and SOR: +24.56° Purity by HPLC: 99.11%

Example 5: Préparation of racemic clopidogrel free base: Racemic clopidogrel bisulfate (800 g) and dichloromethane (2000 mL) were charged into a round bottom flask at 27°C, the reaction mass was stirred for 10 minutes. The aqueous solution of sodium carbonate was slowly added until the pH of the reaction mixture was 7.94 at 0-5°C. The reaction mass was stirred for 15-20 minutes and the mass was allowed to settle. The organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane (296 mL). The combined organic layer was washed with water (2x237 mL) and dried over sodium sulfate. The dried organic layer was evaporated under vacuum at 50°C to obtain a solid residue. Yield: 590 g;

Example 6: Resolution of racemic clopidogrel using recovered (-)-L-camphorsulfonic acid: Racemic clopidogrel free base (77 g) obtained from example-5 and acétone (300 mL) was charged into a round bottom flask at 27°C. The reaction mass was stirred at 27°C and (-)-L-camphorsulfonic acid monohydrate (30.2 g) obtained from example 3 was added and maintained the reaction mass for 2 hours and 30 minutes at 27°C. The reaction mass was cooled to 15°C in 3 hours and maintained at the same température for 8 hours. The obtained solid was filtered off and washed with chilled acétone (40 mL). The solid compound was dried under suction at 22°C for 30 minutes and then dried at 65°C under vacuum for 3 hours. Yield: 43.5 g.

The above obtained solid (43.5 g), acétone (348 ml_) and water (6.5 ml_) were charged into a round bottom flask at 27°C. The reaction mass was stirred and the température of the reaction mass was heated to 55°C and maintained the reaction mass for 20 minutes. The reaction mass was cooled to 5°C and maintained the reaction mass for 10 minutes, the obtained solid was filtered off and washed with acétone (39 ml_), the solid compound was dried with suction at 27°C for 25 minutes and further dried at 65°C under vacuum for 4 hours. Yield: 31.5 g. Chiral purity: 99.95% by HPLC; Purity: 99.10% by HPLC.

Example 7: Recovery of L-camphorsulfonic acid from mother liquor containing R-clopidogrel L-camphorsulfonate: Acétone mother liquor (500 ml_) obtained from example 6 was charged into a round bottom flask at 27°C, the mother liquor was evaporated under vacuum at 45°C to obtain a solid residue. Dichloromethane (300 ml_) was added to the solid residue and stirred the obtained solution and cooled to 3°C. The aqueous solution of sodium carbonate was slowly added until the pH of the reaction mixture was 8 at 0-5°C. The reaction mass was stirred for 15-20 minutes and the mass was allowed to settle. The organic and aqueous layers were separated. The aqueous layer was used for the isolation of (-)-L-camphorsulfonic acid.

T-57 resin (100 ml_) and water (100 ml_) were charged into a beaker at 28°C and stirred for 5 minutes to obtain wet slurry of T-57 resin. The obtained wet slurry of T-57 resin was loaded into a column with an internai diameter of 2.5 centimeter at 28°C. The aqueous layer from the above containing sodium (-)-L-camphorsulfonate (120 mL) was loaded into resin column, the flow rate was maintained 15 mL/min, the void volume (35mL) collected and discarded. The fractions containing camphorsulfonic acid were collected (140 mL) and distilled under vacuum at 90°C to obtain the solid compound. The obtained solid compound was dried under vacuum at 90°C for 5 hours. Yield: 22 g; Spécifie Optical Rotation: -19.82°; Assay: 98.54%;

Example 8: Préparation of clopidogrel camphorsulfonic acid sait using 0.65 moles of camphorsulfonic acid: Racemic clopidogrel bisulfate (400 g), dichloromethane (1600 mL) and water (400 mL) were charged into a round bottom flask at 28°C. The reaction mass was stirred for 10 minutes and cooled to 2°C. The aqueous solution of sodium carbonate (about 168 g sodium carbonate dissolved in 800 mL water) was slowly added until the pH of the reaction mixture was 7.8 at 8°C. The reaction mass was stirred for 15-20 minutes and the mass was allowed to settle. The layers were separated. The aqueous layer was extracted with dichloromethane (800 mL). The combined organic layer was washed with water (400 mL). The organic layer was evaporated under vacuum at 45°C to obtain a residue. Acétone (50 mL) was added to the residue and further distilled to remove dichloromethane to obtain residue. Acétone (1200 mL) was added to the residue and stirred to obtain a clear solution. L-camphorsulfonic acid monohydrate (143.6 g) was charged to the solution at 28°C. Clopidogrel camphorsulfonic acid (S)-isomer (0.2 g) was added to the reaction mass as a seeding material at 28° and stirred for 1 hour at 35°C. The reaction mass was refluxed for 1 hour 30 minutes cooled to 28°C and stirred for 2 hour 30 minutes. The reaction mass was further cooled to 8°C in 3 hours and maintained for 2 hour 30 minutes. The precipitated solid was obtained by filtration and washed with chilled acétone (150 mL) and dried under suction for 40 minutes at 25°C. The material was further dried under vacuum at 45°C for 4 hours. Yield: 194 g; Chiral purity: 99.55 %.

Example 9: Racemization of clopidogrel free base obtained from mother liquor of example-8 using sodium carbonate having moisture content of 13.2 %: Acétone mother liquor obtained from example-8 containing enriched (R)- clopidogrel camphorsulfonate was taken in a round bottom flask and distilled under vacuum at 57°C to obtain a residue. Dichloromethane (300 mL) was charged to the residue at 30°C and stirred to obtain solution. The reaction mass was further cooled to 15°C. The aqueous solution of sodium carbonate was slowly added until the pH of the reaction mixture was 7.95 at 15°C. The layers were separated and aqueous layer was extracted with dichloromethane (100 mL). The combined organic layer was dried over sodium sulfate.

The organic layer was distilled at 55°C to obtain residue. Methanol (50 mL) as added to the residue and further distilled at 55°C to obtain as a solid compound which was a free base of mixtures of R and S isomer of clopidogrel. Yield: 193 g; Chiral Purity: R-isomer 78% and S-isomer 21.97%.

Enriched (R)-clopidogrel free base (193 g) obtained above, methanol (965 mL) and sodium carbonate (76.2 g, moisture content 13.2%) were charged into a round bottom flask at 28°C. The reaction mass was heated to 64°C under stirring and maintained for 12 hours. The reaction mass was cooled to 30°C. The reaction mass was filtered to remove unwanted solid if any and washed with methanol (50 ml_). The filtrate was distilled completely at 64°C to obtain residue. Water (200 ml_) and dichloromethane (400 mL) were added to the residue at 30°C and stirred for 15 minutes at the same température. The layers were separated and the aqueous layer was extracted with dichloromethane (150 mL). The combined organic layer was dried over sodium sulfate. The organic layer was distilled completely and acétone (50 mL) was added to the residue which further distilled completely to obtain the residue which was racemic clopidogrel free base. Yield: 181 g; Chiral Purity: R-isomer 48.72% and S-isomer 51.28 %; HPLC Purity: 97.67%

Example-10: Préparation of clopidogrel camphorsulfonate sait using 0.55 mole of L-camphorsulfonic acid: Racemic clopidogrel free base (310 g) and acétone (1200 mL) were charged into a round bottom flask at 28°C. L-camphorsulfonic acid monohydrate (120.8 g) was charged to the flask at 28°C and stirred for 30 minutes at 30°C. The reaction mass was seeded with clopidogrel camphorsulfonic acid sait (S)-isomer (0.2 g) at 31°C and stirred for 3 hours at 31°C. The reaction mass was further cooled to 15°C in 3 hours and stirred for 9 hours. The solid compound was obtained by filtration and washed with chilled acétone (150 mL) and dried under suction for 30 minutes at 30°C. The compound was further dried under vacuum for 3 hours at 45°C. Yield: 180 g; Chiral purity: 99.12 % (S-isomer), R-isomer: 0.88%.

The filtrate obtained was distilled under vacuum at 57°C to obtain a residue. Dichloromethane (300 mL) was charged to the residue at 30°C and stirred to obtain solution. The reaction mass was further cooled to 15°C. The aqueous solution of sodium carbonate was slowly added until the pH of the reaction mixture was 7.95 at 15°C. The layers were separated and aqueous layer was extracted with dichloromethane (100 mL).

The combined organic layer was dried over sodium sulfate. The organic layer was distilled at 55°C to obtain residue. Methanol (50 mL) was added to the residue and further distilled at 55°C to obtain a residue which was a free base of mixtures of R and S isomer of clopidogrel. Yield: 199 g;

Example-11: Racemization of clopidogrel free base obtained from mother liquor of example-10 with sodium carbonate having moisture content of 13.2%: Enriched (R)-clopidogrel free base (199 g) obtained from the filtrate in example-10, methanol (995 mL) and sodium carbonate (78.5 g, moisture content of 13.2 %) were charged into a round bottom flask at 28°C. The reaction mass was heated to 64°C under stirring and maintained for 13 hours and 30 minutes. The reaction mass was cooled to 30°C. The reaction mass was filtered to remove unwanted if any and washed with methanol (50 mL). The filtrate was distilled completely at 64°C to obtain residue. Water (200 mL) and dichloromethane (250 mL) were added to the residue at 30°C and stirred for 15 minutes at the same température. The layers were separated and the aqueous layer was extracted with dichloromethane (100 mL).The combined organic layer was dried over sodium sulfate. The organic layer was distilled completely and acétone (50 mL) was added to the residue which was further distilled completely to obtain the residue which was racemic clopidogrel free base. Yield: 184 g; Chiral Purity: R-isomer 46.85% and S-isomer 53.15 %, HPLC Purity: 98.58%

Example-12: Préparation of Clopidogrel bisulfate: (S)-Clopidogrel camphorsulfonate (80 g) obtained by using recovered L-camphorsulfonic acid and dichloromethane (350 ml) were charged into a round bottom flask at 27°C. The reaction mass was cooled to 0-5°C and stirred 15 minutes. The aqueous solution of sodium carbonate (about 11 g sodium carbonate dissolved in 90 mL water) was slowly added until the pH of the reaction mixture was 7.7 at 1°C. The reaction mass was stirred for 15-20 minutes and the mass was ailowed to settle. The layers were separated. The aqueous layer was extracted with dichloromethane (2 x 120 mL). The combined organic layer was washed with water (2 x 120 mL). The organic layer was evaporated under vacuum at 56°C to obtain a residue. 2-butanol (90 mL) was added to the residue at 56°C and stirred for 3 minutes. The obtained solution was again distilled at 60°C to obtain residue. 2-butanol (720 mL) was charged to the residue at 40°C and stirred for 5 minutes to obtain a solution. Activated carbon (4.0 g) was charged to the solution and stirred for 25 minutes at 30°C. The reaction mass was filtered through hyflo bed and washed with 2-butanol (100 mL). The filtrate was charged into a round bottom flask at 26°C. Sulfuric acid (7.1 ml) was slowly in 20 minutes at 26°C. (S)-clopidogrel bisulfate sait (0.4 g) was added under stirring to the reaction mass as a seed material at 25°C and stirred for 6 hours at 25°C.The reaction mass is further cooled to 23°C and stirred for 1 hour. The precipitated solid was filtered and washed with 2-butanol (80 mL) and cyclohexane (40 mL). The product was dried under suction for 30 minutes at 27°C and further dried at 100°C for 6 hours. The product obtained as Form I of clopidogrel bisulfate.

Yield: 29 g; HPLC purity: 99.90%.

Throughout this application, various publications are referenced. The disciosures of thèse publications in their entireties are hereby incorporated by référence into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.

While particular embodiments of the présent application hâve been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the application. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.

We Claim:

1. A process for recovery of camphorsulphonic acid, comprising the steps of:

1) treating the clopidogrel camphorsulfonic acid salt with a base to produce clopidogrel freebase in présence of water and organic solvent;

2) treating the aqueous layer containing salt of camphorsulfonic acid with cation exchange resin; and

3) recovering the camphorsulfonic acid.

2. A process for the préparation of S (+) clopidogrel or salts thereof, comprising the
steps of:

1) preparing a sait of racemic clopidogrel with a camphorsulfonic acid;

2) separating the S (+) clopidogrel camphorsulfonic acid and R (-) clopidogrel camphorsulfonic acid;

3) treating the above clopidogrel camphorsulfonic acid salt with a base to produce clopidogrel freebase in présence of water and organic solvent;

4) treating the aqueous layer containing sait of camphorsulfonic acid with cation exchange resin;

5) recovering the camphorsulfonic acid;

6) repeating steps (1) to step (3) with the recovered camphorsulfonic acid obtained in step (5); and

7) optionally, converting the S (+) clopidogrel obtained in step (3) to pharmaceutically acceptable salts thereof.

3. The process according to claims 1 and 2, wherein the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.

4. The process according to claims 1 and 2, wherein the organic solvent is selected from dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, hexane, cyclohexane, heptane, toluène, xylene, dioxane, dimethoxyethane, ethyl acétate, propyl acétate, butyl acétate, butanol, pentanol, 2-ethoxyethanol, diethylene glycol or their mixture thereof.

5. The process according to daims 1 and 2, wherein the cation exchange resin is selected from Thermax- Tulsion T-38, T-42, T-54, T-57, T-63, T-42 MP, T-62MP, T-63MP, CXO, CXO-9H and CH-90, Rohm & Haas-Amberlite IR-118, IR-120, IRA743, IRC-50S, IRP64 and CG-50, Relite CFA, CF, CFH, CFS, RPS or Relite CNS in H.

6. The process according to claim 5, wherein the cation exchange resin is T-57.

7. A process for the préparation of racemic Clopidogrel, comprising the steps of:

1) obtaining a solution of R(-) clopidogrel or enriched R(-) clopidogrel in one or
more solvents;

2) contacting the solution obtained in step (1) with a base having moisture content more than 0.3%; and

3) recovering the racemic clopidogrel from the solution.

8. A process for the préparation of S (+) clopidogrel or salts thereof, comprising the
steps of:

1) preparing a salt of racemic clopidogrel with a chiral auxiliary;

2) separating the S (+) clopidogrel and R (-) clopidogrel isomers;

3) racemizing the R (-) clopidogrel or enriched R (-) clopidogrel obtained in step (2) with a base having a moisture content of more than 0.3%, in a solvent to get racemic clopidogrel;

4) repeating steps (1) to step (2) with the racemic clopidogrel obtained in step (3); and

5) optionally, converting the S (+) clopidogrel obtained in step (2) to pharmaceutically acceptable salts thereof.

9. The process according to daims 7 and 8, wherein the solvent is selected from,
methanol, ethanol, propanol, butanol, acétone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, toluène, dichloromethane or their mixture thereof.

10. The process according to claims 7 and 8, wherein the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.