INTRODUCTION

Aspect of the present application relates to process for the preparation of clopidogrel bisulfate and its intermediates.

Clopidogrel, having the chemical name (S)-(+)-α-(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 subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex. By inhibiting platelet aggregation, clopidogrel reduces the chance of arterial blockage, thus preventing strokes and heart-attacks.

Clopidogrel is marketed as bisulfate salt having the following chemical structure of 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 separation of enantiomers [dextrorotatory enantiomers and levorotatory enantiomers] from the racemic mixture is illustrated in the Scheme-1 of U.S. Pat. No. 4,847,265.

U.S. Pat. No. 5,204,469 describes the preparation of a Dextrorotatory methyl alpha-(2-thienylethylamino) (2-chlorophenyl)acetate and its salts. It also disclosed resolving the racemic methyl-α-amino (2-chlorophenyl) acetate using tartaric acid.

International Application Publication No. WO2006/003671A1 describes a process for resolution of methyl (+)-α-amino (2-chlorophenyI)acetate with tartaric acid in presence of solvent selected from acetone, methanol, ethanol, isopropyl alcohol, mixtures thereof and mixture of acetone and methanol.

U.S. Pat. No. 6,429,210 discloses crystalline Form I and Form II of clopidogrel hydrogen sulfate.

To reduce the manufacturing cost of the clopidogrel bisulfate at the commercial scale, it is essential to provide a simple and improved process for the preparation of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate and (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts, which is economical, ecofriendly and reproducible with high yield and purity.

BRIEF SUMMARY

In an aspect, the invention provides a process for the preparation (+)-methyl-2-amino-2-(2-chlorophenyl)acetate comprising:

a) reacting methyl-2-amino-2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) converting the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) to (+)-methyl-2-amino-2-(2-chlorophenyl)acetate using a base.

In an aspect, the invention provides a process for the preparation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts comprising:

a) reacting methyl-2-amino-2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) converting the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) to (+)-methyl-2-amino-2-(2-chlorophenyl)acetate using a base;

c) reacting (+)-methyl-2-amino-2-(2-chlorophenyl)acetate with 2-(thiophen-2-yl)ethyl p-toluenesulfonate or 2-(thiophen-2-yl)ethyl methylsulfonate to produce (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts.

In an aspect, the invention provides a process for the preparation of Clopidogrel or its pharmaceutically acceptable salts comprising:

a) reacting methyl-2-amino-2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) converting the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) to (+)-methyl-2-amino-2-(2-chlorophenyl)acetate using a base;

c) cyclizing (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts in presence of formaldehyde to produce Clopidogrel;

d) optionally converting the obtained clopidogrel in step d) into a clopidogrel bisulfate.

In an aspect, the present invention provides an improved process for the preparation of crystalline Form 1 of Clopidogrel bisulphate comprising:

a) providing a solution of clopidogrel freebase in an ketone solvent;

b) optionally, treating the solution obtained in step a) with charcoal;

c) adding butylated hydroxy toluene to the solution obtained in step b);

d) adding sulfuric acid to the solution obtained in step c);

e) optionally seeding the solution obtained in step (d) with crystalline Form 1 of clopidogrel bisulphate; and

f) isolating the crystalline Form 1 of Clopidogrel bisulphate.

DETAILED DESCRIPTION

In an aspect, the invention provides a process for the preparation (+)-methyl-2-amino-2-(2-chlorophenyl)acetate comprising:

a) reacting methyl-2-amino-2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) converting the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) to (+)-methyl-2-amino-2-(2-chlorophenyl)acetate using a base.

In embodiment of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out in a solvent mixture containing methanol and methyl-iso-butyl-ketone.

In specific embodiments of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out in presence 1 to 2 volume of methyl-iso-butyl-ketone and 3 to 6 volume of methanol to the weight of methyl-2-amino-2-(2-chlorophenyl)acetate.
In embodiment of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can also be carried out in a suitable alternative solvent. Suitable alternative solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved. Suitable alternative solvents that are useful in the reaction include, but are not limited to: C2-6 alcohols; C3-6 ketones; C2-6 ethers; C3-6 esters; C2-6 nitriles; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; any mixtures of two or more thereof; or their combinations with water in various proportions.

In embodiment of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out with suitable chiral acid. Chiral acid that are useful in the reaction include, but are not limited to: D-tartaric acid, L-tartaric acid, mandelic acid, lactic acid, camphoric acid, Di-p-toluoyl-L-tartaric acid(L-DTTA), Di-p-toluoyl-D-tararic acid(D-DTTA), Dibenzoyl-L-tartaric acid monohydrate(L-DBTA), Dibenzoyl-D-tartaric acid monohydrate(D-DBTA), D-malic acid, L-malic acid, D-2-chloromandelic acid, L-2-chloromandelic acid, camphorsulfonic acid, D-tyrosine, D-alanine, D-phenylalanine, naproxen, etc.

In specific embodiments of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out in the presence of 1 to 1.2 molar equivalent of L-tartaric acid per mole of methyl-2-amino-2-(2-chlorophenyl)acetate.

In embodiment of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature 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 about 1 hour to about 24 hours or longer.

In specific embodiment of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out at a temperature ranging from about 25°C to about 35°C.

In embodiment of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out optionally seeding with chiral salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate.

In specific embodiment of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out seeding with 0.25 to 1.5% of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate tartarate.

In embodiments of step a), chiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with any of the above listed suitable solvent.

In embodiment of step a), chiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be optionally purified by any method known in the art to improve its chemical and optical purities. Any of the suitable solvents listed above can be used for the purification. The purification can be done by using crystallization, recrystallization, slurry washing, column chromatography, or any methods known in the art by using the solvents which are described above for reaction.

In embodiment of step a), chiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be dried at suitable temperatures, such as from about 50°C to about 100°C and suitable pressures 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 temperatures and times will be sufficient to achieve desired product purity.

In embodiment of step a), the wet chiral salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate can be used directly into the next step.

In specific embodiment of step a), the resolution of methyl-2-amino-2-(2-chlorophenyl)acetate can be done using mixture of solvents methanol and methyl-iso-butyl-ketone. The yield and purity of the obtained chiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate is comparatively more with that of the processes known earlier.

In embodiment of step b), free base formation of chiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out in presence of suitable base. 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 metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, carboxylates, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, barium hydroxide, or the like; and organic bases such as, primary, secondary, or tertiary amines, such as ammonia, liquid ammonia, triethylamine, diisopropylamine, N-methylmorpholine.

In embodiment of step b), free base formation of chiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be carried out in water and water immiscible solvent added to the above obtained solid residue. Examples of such solvents include but are not limited toluene, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, acetaldehyde, n-butyraldehyde, toluene, dichloromethane, decalin, pentane, hexane, heptane, octane, nonane, cyclopentane, cyclohexane, or 1,4-dioxane.

In embodiment of step b), the reaction mass is brought to a temperature from about -25°C to about 30°C during the addition of base. The temperatures of the reaction mass may be maintained at the same temperature for about 15 minutes to about 10 hours or longer.

In embodiments of step b), the organic layer and aqueous layers may be separated.

In embodiments of step b), the obtained aqueous layer is further extracted with water immiscible organic solvent. The same process can be repeated until the aqueous layer is free from the desired compound.

In embodiments of step b), all the organic layers are combined and can be washed with water. The organic layer can be evaporated to produce the (+)-methyl-2-amino-2-(2-chlorophenyl)acetate as per the procedures known in the art.

In an aspect, the invention provides a process for the preparation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts comprising:

a) reacting methyl-2-amino-2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) converting the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) to (+)-methyl-2-amino-2-(2-chlorophenyl)acetate using a base;

c) reacting (+)-methyl-2-amino-2-(2-chlorophenyl)acetate with 2-(thiophen-2-yl)ethyl p-toluenesulfonate or 2-(thiophen-2-yl)ethyl methylsulfonate to produce (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts

In aspects of steps a) and b), (+)-methyl-2-amino-2-(2-chlorophenyl)acetate can be prepared according to the process described in this patent application or according to the examples described in this patent application.

In embodiments of step c), the condensation reaction of (+)methyl-2-amino-2-(2-chlorophenyl)acetate with 2-(thiophen-2-yl)ethyl p-toluenesulfonate or 2-(thiophen-2-yl)ethyl methylsulfonate can be carried out in the presence of a base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, carboxylates, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, barium hydroxide, or the like; and organic bases such as, primary, secondary, or tertiary amines, such as ammonia, liquid ammonia, triethylamine, diisopropylamine, N-methylmorpholine, dipotassium hydrogen phosphate, disodium hydrogen phosphate, diammonium hydrogen phosphate etc.

In embodiments of step c), the condensation reaction can be carried out in the presence of 2 to 3 molar equivalent of base per molar equivalent of (+)methyl-2-amino-2-(2-chlorophenyl)acetate.

In specific embodiments of step c), the condensation reaction can be carried out in the presence of 2 to 3 molar equivalent of dipotassium hydrogen phosphate per molar equivalent of (+)methyl-2-amino-2-(2-chlorophenyl)acetate.

In embodiments of step c), the condensation reaction can be carried out in the presence of catalyst. Catalysts that are useful in the reaction include, but are not limited to: tetrabutyl ammonium bromide, potassium iodide, lithium bromide, sodium iodide, tetramethylammonium chloride, tetramethylammonium hydroxide, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetyl trimethylammonium bromide (CTAB), dimethyldioctadecylammonium chloride, phosphonium iodide, tetraphenylphosphonium chloride, tetramethylphosphonium iodide.

In embodiments of step c), the condensation reaction can be carried out in the presence of 0.05 to 0.1 molar equivalent of catalyst per molar equivalent of (+)methyl-2-amino-2-(2-chlorophenyl)acetate.

In specific embodiments of step c), the condensation reaction can be carried out in the presence of 0.05 to 0.1 molar equivalent of tetrabutyl ammonium bromide and potassium iodide per molar equivalent of (+)methyl-2-amino-2-(2-chlorophenyl)acetate.

In embodiments of step c), the condensation reaction can be carried out in presence 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 C1-6 alcohols; C3-6 ketones; C2-6 ethers; C3-6 esters; C2-6 nitriles; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; water; any mixtures of two or more thereof;

In embodiments of step c), the condensation reaction can be carried out in presence 0.7 to 1.3 volume of organic solvent to the weight of (+)methyl-2-amino-2-(2-chlorophenyl)acetate tartarate.

In specific embodiments of step c), the condensation reaction can be carried out in presence 0.7 to 1.3 volume of toluene to the weight of (+)methyl-2-amino-2-(2-chlorophenyl)acetate tartarate.

In embodiments of step c), the condensation reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature 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 about 15 minutes to about 35 hours or longer.

In specific embodiments of step c), the condensation reaction can be carried out at a temperature ranging from about 90°C to about 105°C.

In embodiments of step c), (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, to obtained solid residue.

In embodiment of step c), water and water immiscible organic solvent were added to above obtained solid residue and stirred for about 15 minutes, organic layer may be separated. The (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be isolated from organic layer using techniques such as evaporation, filtration by gravity or suction, decantation centrifugation, or the like to obtained solid residue.

In embodiment of step c), (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate can be converted to achiral acid salt. The salt formation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate with achiral acid can enhance the chemical and chiral purity.

In embodiment of step c), the salt formation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate with achiral acid can be carried out in a suitable solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved. Solvents that are useful in the reaction include, but are not limited to: C1-6 alcohols; C3-6 ketones; C2-6 ethers; C3-6 esters; C2-6 nitriles; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; any mixtures of two or more thereof; or their combinations with water in various proportions.

In embodiment of step c), the salt formation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate with achiral acid can be carried out in a suitable achiral acid. Achiral acid that are useful in the reaction include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid or sulfuric acid etc.

In embodiment of step c), the salt formation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate with achiral acid can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature 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 about 15 minutes to about 24 hours or longer.

In embodiments of step c), achiral acid salt of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a above listed suitable solvent.

In embodiment of step c), achiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be purified by any method known in the art to improve its chemical and optical purities. Any of the suitable solvents listed above can be used for the purification. The purification can be done by using crystallization, recrystallization, slurry washing, column chromatography, or any methods known in the art by using the suitable solvents which are described above for reaction.

In embodiment of step c), achiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be purified by slurrying in a solvent and achiral acid.

In specific embodiment of step c), achiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be purified by slurrying in acetone and concentrated HCl.

In embodiment of step c), achiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be purified in presence of 2 to 6 volume of solvent and 0.1 to 0.4 volume of achiral acid.

In specific embodiment of step c), achiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be purified in presence of 2 to 6 volume of acetone and 0.1 to 0.4 volume of concentrated HCl.

In specific embodiment of step c), achiral acid salt of (+)methyl-2-amino-2-(2-chlorophenyl)acetate can be purified by slurrying in acetone and concentrated HCl at the temperature from about -5oC to solvent boiling point.

In an aspect, the invention provides a process for the preparation of Clopidogrel bisulfate comprising:

a) reacting methyl-2-amino-2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) converting the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) to (+)-methyl-2-amino-2-(2-chlorophenyl)acetate using a base;

c) reacting (+)-methyl-2-amino-2-(2-chlorophenyl)acetate with 2-(thiophen-2-yl)ethyl p-toluenesulfonate or 2-(thiophen-2-yl)ethyl methylsulfonate to produce (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts;

d) cyclizing (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts in presence of formaldehyde to produce Clopidogrel;

e) optionally converting the obtained clopidogrel in step d) into a clopidogrel bisulfate.

In aspects of steps a) to c), (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts can be prepared according to the process described in this patent application or according to the examples described in this patent application.

In embodiment of step d) involves cyclizing (+)-α–(2-thien-2-yl)-ethyl amino) -α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts in presence of formaldehyde to produce clopidogrel.

In specific embodiment of step d) involves cyclizing (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts in presence of 4 to 6 volume of formaldehyde to produce clopidogrel.

In embodiment of step d), cyclisation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts can be carried out at a temperature ranging from about 0°C to 50°C. In one embodiment, the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature 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 about 1 hour to about 30 hours or longer.

In specific embodiment of step d), cyclisation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts can be carried out at a temperature ranging from about 20°C to about 30°C.

In embodiment of step d), the reaction mass is brought to a temperature from about -25°C to about 30°C during pH adjustment with aqueous base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, carboxylates, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, barium hydroxide, or the like; and organic bases such as, primary, secondary, or tertiary amines, such as ammonia, liquid ammonia, triethylamine, diisopropylamine, N-methylmorpholine.

In embodiments of step d), the organic layer and aqueous layers may be separated. The organic layer may be washed with water. The organic layer may be evaporated to produce clopidogrel as per the procedures known in the art.

In embodiment of step e), the salt formation of clopidogrel free base with hydrogen sulfate can be carried out in a suitable solvent. Suitable solvent can be any solvent which has no adverse effect on the reaction or on the reagents involved. Solvents that are useful in the reaction include, but are not limited to: C1-6 alcohols; C3-6 ketones; C2-6 ethers; C3-6 esters; C2-6 nitriles; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; any mixtures of two or more thereof; or their combinations with water in various proportions.

In embodiment of step e), the salt formation of clopidogrel free base with hydrogen sulfate can be carried out in an aqueous acetone, where in the water content in aqueous acetone vary from 0.1 to 0.3 volumes with respect to the weight of clopidogrel free base.

In embodiment of step e), the salt formation of clopidogrel free base with hydrogen sulfate can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent.

In one embodiment, the salt formation can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature 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 about 1 hour to about 30 hours or longer.

In specific embodiment of step e), the salt formation of clopidogrel free base with hydrogen sulfate can be carried out at a temperature ranging from about 20°C to about 30°C.

In embodiments of step e), clopidogrel hydrogen sulfate can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation or the like, and optionally washing the resulting solid with a above listed suitable solvent.

In an aspect, the present invention provides an improved process for the preparation of crystalline Form 1 of Clopidogrel bisulphate comprising:

a) providing a solution of clopidogrel freebase in an ketone solvent;

b) optionally, treating the solution obtained in step a) with charcoal;

c) adding butylated hydroxy toluene to the solution obtained in step b);

d) adding sulfuric acid to the solution obtained in step c);

e) optionally seeding the solution obtained in step (d) with crystalline Form 1 of clopidogrel bisulphate; and

f) isolating the crystalline Form 1 of Clopidogrel bisulphate.

In embodiments, the clopidogrel freebase solution can be prepared by dissolving clopidogrel freebase in a ketone solvent. The suitable ketone solvents that may be used for the preparation of clopidogrel freebase solution include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; or mixtures thereof.

In embodiments, the clopidogrel freebase solution can be prepared at any suitable temperatures, such as from about 0°C to about the reflux temperature of the solvent used.

In embodiments, clopidogrel freebase solution can be optionally treated with charcoal, or any other suitable material to remove water, impurities and to improve the colour. In specific embodiment the clopidogrel freebase solution can be treated with charcoal.

The solution obtained above may be filtered to remove insoluble particles if any. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

In embodiments, clopidogrel freebase solution can be treated with butylated hydroxy toluene to remove impurities.

In embodiments, any source of sulfuric acid may be used for the preparation of clopidogrel bisulfate from clopidogrel free base. The source may be concentrated sulfuric acid, aqueous sulfuric acid or sulfuric acid in a solvent etc.

In embodiments, the sulfuric acid in a solvent can be prepared by adding ketone solvent to the sulfuric acid, ketone solvents that may be used for the preparation of sulfuric acid solution include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; or mixtures thereof.

In embodiments, the sulfuric acid in a solvent can be prepared at any suitable temperatures, such as from about 0°C to about the room temperature of the solvent used. In specific embodiments, the sulfuric acid solution can be prepared at the temperature below 5°C.

In embodiments, clopidogrel bisulfate can be prepared by adding sulfuric acid to the clopidogrel freebase solution.

In embodiments, the sulfuric acid added to the clopidogrel free base solution at any suitable temperatures, such as from about -10°C to about 50°C for about 5 minutes to 2 hours or longer.

In embodiments, optionally the reaction mass can be seeded with clopidogrel bisulfate Form 1.

In embodiments, the clopidogrel bisulfate suspension can be maintained at a temperature from about -10°C to about 30°C. The maintenance time may vary from about 30 minutes to about 14 hours, or longer. In general, yields of the crystalline product will be improved by maintaining the lowest temperatures that are above the freezing point of the solution, and by increasing the solute content of the solution.

In embodiments, crystalline clopidogrel bisulfate can be isolated using any techniques, such as decantation, filtration by gravity or suction, centrifugation, or the solvent can be evaporated from the mass to obtain the desired product, and optionally the solid can be washed with a solvent, to reduce the amount of entrained impurities.

In embodiments, crystalline clopidogrel bisulfate can be dried at about 25oC to about 110oC under atmospheric or reduced pressures for about 10 minutes to about 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. Drying temperatures and times will be sufficient to achieve desired product purity.

In specific embodiments, the crystalline clopidogrel bisulfate dried under vacuum for 6-8 hours at 55-70°C.

The starting materials i.e., 2-(thiophen-2-yl)ethyl p-toluenesulfonate or 2-(thiophen-2-yl) ethyl methylsulfonate; and methyl-2-amino-2-(2-chlorophenyl)acetate can be produced according to the process known in the art or according to the process described herein.

The tosylation or mesylation of thiophene-2-ethanol can be carried out in the presence of a base. Bases that are useful in the reaction include, but are not limited to; inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, carboxylates, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, barium hydroxide, or the like; and organic bases such as, primary, secondary, or tertiary amines, such as ammonia, liquid ammonia, triethylamine, diisopropylamine, N-methylmorpholine.

The tosylation or mesylation of thiophene-2-ethanol can be optionally carried out in the presence of phase transfer catalyst. Phase transfer catalysts that are useful in the reaction include, but are not limited to: tetrabutyl ammonium bromide, tetramethylammonium chloride, tetramethylammonium hydroxide, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetyl trimethylammonium bromide (CTAB) or dimethyldioctadecylammonium chloride, phosphonium iodide, tetraphenylphosphonium chloride, tetramethylphosphonium iodide.

The tosylation or mesylation of thiophene-2-ethanol can be carried out in presence 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 C1-6 alcohols; C3-6 ketones; C2-6 ethers; C3-6 esters; C2-6 nitriles; halogenated hydrocarbons; aliphatic or aromatic hydrocarbons; aprotic polar solvents; any mixtures of two or more thereof; or their combinations with water in various proportions.

The reaction mass is brought to a temperature from about -25°C to about 30°C during the addition of base. The temperatures of the reaction mass may be maintained at the same temperature for about 15 minutes to about 10 hours or longer.

The reaction mass can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about room temperature to about boiling point of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature 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 about 1 hour to about 24 hours or longer.

2-(thiophen-2-yl)ethyl p-toluenesulfonate or 2-(thiophen-2-yl) ethyl methylsulfonate can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation to obtained solid residue.

The methylation of 2-chlorophenylglycine can be carried out in presence of thionyl chloride, methanol and DMF to produce methyl-2-amino-2-(2-chlorophenyl)acetate.

The methylation of 2-chlorophenylglycine can be carried out at a temperature ranging from about 0°C to about 70oC. In one embodiment, the reaction can be carried out from about 26°C to about 66oC. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature 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 about 1 hour to about 24 hours or longer.

Methyl-2-amino-2-(2-chlorophenyl)acetate can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, or removal of solvent by evaporation to obtained solid residue. Water and water immiscible solvent added to the obtained solid residue. Examples of such solvents include but are not limited toluene, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, acetaldehyde, n-butyraldehyde, toluene, dichloromethane, decalin, pentane, hexane, heptane, octane, nonane, cyclopentane, cyclohexane, or 1,4-dioxane.

The organic layer and aqueous layers may be separated. The obtained aqueous layer is further extracted with water immiscible organic solvent. The same process can be repeated until the aqueous layer is free from the desired compound. The organic layer may be washed with water. The organic layer may be evaporated to produce the methyl-2-amino-2-(2-chlorophenyl)acetate as per the procedures known in the art.

In embodiments, clopidogrel bisulfate obtained and purified by a method of the present disclosure has less than about 0.1% by HPLC of any of the impurities mentioned below, and total impurities content less than about 0.5% by HPLC. In embodiments, clopidogrel bisulfate obtained has less than about 0.05% by HPLC of any of the impurities mentioned below, and total impurities content less than about 0.25% by HPLC.

As used herein, “amide impurity” refers to (2-(2-amino-2-(2-chlorophenyl)acetamido)-2-(2-chlorophenyl)acetic acid represented by Formula Ia; “Dimer impurity” refers to methyl-2-(bis(2-(thiopheny-2-yl)ethyl)amino)-2-(2-chlorophenyl)acetate represented by Formula Ib; =J “Dimer acid impurity” refers to 2-(bis(2-(thiopheny-2-yl)ethyl)amino)-2-(2-chlorophenyl)acetic acid represented by Formula Ic.

“Iodo impurity” refers to 2-(2-iodoethyl)thiophene represented by Formula Id.

“Bromo impurity” refers to 2-(2-bromoethyl)thiophene represented by Formula

“N-methyl impurity” refers to methyl-2-(2-chlorophenyl)-2-(methyl (2-(thiophene-2-yl) ethyl) amino) acetate represented by Formula If.

“Monohydroxymethyl impurity” refers to methyl 2-(2-chlorophenyl)-2-(2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate represented by Formula Ig.

“Dihydroxy methyl impurity” refers to methyl 2-(2,3-bis(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-2-(2-chlorophenyl)acetate represented by Formula Ih.

“Clopidogrel Sulfonic acid impurity” refers to (S)-5-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-sulfonic acid represented by Formula Ii.

“Clopidogrel R-Isomer impurity” refers to (R)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate represented by Formula Ij.

“Methyl 2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate R-Isomer impurity” refers to (R)-methyl 2-(2-chlorophenyl)-2-((2-(thiophen-2-yl)ethyl)amino)acetate represented by Formula Ik.

“Methyl 2-amino-2-(2-chlorophenyl)acetate impurity” refers to (R)-methyl 2-amino-2-(2-chlorophenyl)acetate represented by Formula Il.

Determination of residual solvents in Clopidogrel bisulfate.

During the residual solvents analysis of Clopidogrel Bisulfate in regular diluents like N,N-DMA, N-Methyl pyrrolidone, 1,3-Dimethyl-2-Imidazolidinone, some unknown impurities were observed, due to the interference from the sample matrix, which increases on subsequent injections of sample solution. The Clopidogrel bisulphate has significant amount of sulphuric acid, which is non volatile. The origin of degradation may be the diluent. A common GC diluent, Benzyl alcohol was tried and found that, no unknown impurities were observed even after third injection, but, increase in content of Toluene. Even though the results with benzyl alcohol were not satisfactory, the fact that the alcohols as diluent are arresting the degradation caused due to sulphuric acid, gave an idea of exploring a different high boiling, aprotic, aromatic alcohol. p-Cresol as a diluent was used and no degradents were found in subsequent injections.

Further problem of using p-cresol, as it got solidified at room temperature since the melting point of p-cresol is 35 ° C was eliminated by using 9:1 mixture of p-Cresol and Benzyl alcohol, which reduced the freezing point of p-Cresol and remained as liquid at room temperature.

The analytical method controls the degradation of sample matrix, there by facilitating the hassle free estimation of residual solvents in Clopidogrel bisulfate.

TABLE 1
GC conditions for determining residual solvents in Clopidogrel bisulfate
Column __ DB-624 (105 mts, 0.53 _ mm ID, 3µm film thickness)
Injector Temperature 120°C
Detector Temperature (FID) 280°C
Oven temperature Initially held at 35°C for 10 minutes, then raised to
110°C at a rate of 5°C per minute, held at 110°C for 28 minutes. Again increased the temperature to
280°C at a rate of 45°C and held at 280°C for 40 minutes.
Hydrogen flow : 40 mL/min
Air flow : 400 mL/min
Make up flow( Nitrogen) : 20 mL/min
Carrier Gas : Helium
Ramped pressure : Initially kept at 10 Psi for 55minutes, then increase
to 30 Psi, at a rate of 20 Psi and hold at 30Psi for
10 minutes.
Injection volume : 3.0µL
Split : 1:10
Diluent : p-Cresol and Benzyl alcohol in the ratio of 9:1
Viscosity delay : 5 or 7 (Based on instrument)
Concentration : 50mg/mL

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference 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 present application have 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.

Clopidogrel bisulfate obtained according to a process of the present disclosure can be milled or micronized using any processes known in the art, such as ball milling, jet milling, wet milling, etc., to produce a desired particle size distribution. Clopidogrel bisulfate obtained according to certain processes of the present disclosure has a particle size distribution wherein: d(0.5) is less than about 150 µm, or less than about 100 µm, or less than about 25 µm; and d(0.9) is less than about 200 µm, or less than about 100 µm, or less than about 50 µm. Particle size distributions can be determined using any means, including laser light diffraction equipment (such as those sold by Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom), Coulter counters, microscopic procedures, 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.

DEFINITIONS

The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise. In general, the number of carbon atoms present 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 “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions 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. “C1-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, phenol, glycerol, or the like.

An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have 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-C8 aliphatic 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, benzene, toluene, 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=O)-O-bonded to two other carbon atoms. “C3-C6 esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

An “ether” is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, 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=O)-bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.

A “nitrile” is an organic compound containing a cyano -(C≡N) bonded to another carbon atom. “C2-C6 Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference 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 procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES

Example 1A: Preparation of 2-(thiophen-2-yl)ethyl p-toluenesulfonate.

Water (100 ml), toluene (50 ml) and thiophene-2-ethanol (25 g) were charged into a round bottom flask at 27oC and stirred at the same temperature for 10 minutes. The reaction mass was cooled to 10°C. The aqueous solution of sodium hydroxide (15.6 g of sodium hydroxide in 25 ml water) was slowly added to the reaction mass at 10-13°C for 1 hour. Tetra-n-butylammonium bromide (0.75 g) was added to the reaction mass at the same temperature. p-toluene sulfonyl chloride solution (41 g of p-toluene sulfonyl in 50 ml toluene) was added to the reaction mass at 12°C for 2 hours. The reaction mass was stirred for 1 hour 20 minutes, then the reaction mass was heated to 27oC and stirred for 1 hour 45 minutes. The organic layer was separated and washed with water (100 ml). The organic layer was evaporated under vacuum at 50oC to obtain a residue. Yield: 54.9 g; Purity by HPLC: 97.09%.

Example 1B: Preparation of 2-(thiophen-2-yl)ethyl p-toluenesulfonate.

Water (80 ml), toluene (40 ml) and thiophene-2-ethanol (20 g) were charged into a round bottom flask at 27oC and stirred at the same temperature for 10 minutes. The reaction mass was cooled to 10°C. The aqueous solution of sodium hydroxide (12.5 g of sodium hydroxide in 20 ml water) was slowly added to the reaction mass at 10-14°C for 1 hour. Tetra-n-butylammonium bromide (0.6 g) was added to the reaction mass at the same temperature. p-toluene sulfonyl chloride solution (32 g of p-toluene sulfonyl in 60 ml toluene) was added to the reaction mass at 12°C for 2 hours. The reaction mass was stirred for 1 hour 20 minutes, then the reaction mass was heated to 29oC and stirred for 5 hours. The organic and aqueous layers were separated. Water (60 ml) was added to the separated organic layer and heated to 44oC and stirred for 10 minutes. The organic and aqueous layers were separated. Water (20 ml) was added to the separated organic layer and heated to 44oC and stirred for 10 minutes. The organic and aqueous layers were separated; the organic layer was evaporated under vacuum at 54oC to obtain a residue. Yield: 43.8 g; Purity by HPLC: 98.19%.

Example 1C: Preparation of 2-(thiophen-2-yl) ethyl methylsulfonate.

Methane sulfonyl chloride (49.14 g) and toluene (200 ml) were charged into round bottom flask at 27oC and stirred at the same temperature for 5 minutes. The reaction mass was cooled to 2°C. The triethyl amine (65.12 g) was slowly added to the reaction mass at 2-7°C for 40 minutes. The reaction mass was heated to 27oC and stirred for 2 hours 40 minutes. The reaction mass was filtered under vacuum and washed with toluene (2X50 ml). The organic layer was washed with water (5X100 ml). 10% NaCl solution (100 ml) was added to the organic layer and stirred for 10 minutes. The organic layer was separated and evaporated under vacuum at 54oC to obtain a residue. Yield: 74.6 g.

Example 2: Preparation of methyl-2-amino-2-(2-chlorophenyl)acetate.
2-chlorophenylglycine (20 g) and methanol (80 ml) were charged into a round bottom flask at 26oC. The reaction mass was stirred at the same temperature for 5 minutes. DMF (0.12 ml) was added to the reaction mass at the same temperature. Thionyl chloride (12.5 ml) was added to the reaction mass at 26oC for 30 minutes. The reaction mass was heated to 66oC and stirred for 5 hour 45 minutes. The reaction mass was evaporated under vacuum at 57oC to obtain a solid. Toluene (20 ml) and water were added to the obtained solid at 26oC and stirred for 15 minutes, The organic and aqueous layers were separated and the aqueous layer, toluene (80 ml), the aqueous solution of sodium carbonate (13.7 g of sodium carbonate in 100 ml water) were charged into a round bottom flask at 26oC. The reaction mass was stirred for 30 minutes, the layers were separated, the aqueous layer was extracted with toluene (80 ml). The combined organic layers were washed with water (40 ml). The organic layer was evaporated under vacuum at 55oC to obtain a residue. Yield: 18.5 g; Purity by HPLC: 98.75%.

Example 3A: Preparation of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate tartarate.

Methyl-2-amino-2-(2-chlorophenyl)acetate (20 g) and methyl ethyl ketone (MEK) (30 ml) were charged into a round bottom flask at 26oC. The reaction mass was stirred at the same temperature for 1 hour 48 minutes. The reaction mass was cooled to 10oC, tartarate salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate (0.2 g) was added to the reaction mass as a seeding material followed by stirred for about 10 minutes. L(+)-Tartaric acid solution (16.5 g L(+)-Tartaric acid in 120 ml methanol) was added to the reaction mass at 9°C for 1 hour. The reaction mass was heated to 25°C and stirred for 16 hours. The reaction mass was cooled to 12°C and stirred for 1 hour and 45 minutes. The precipitated solid product was obtained by filtration and washed with methyl ethyl ketone (10 ml) and methanol (10 ml). The compound was dried under vacuum at 54°C for 3 hours. Yield: 26 g; Chiral purity: 98.13% by HPLC; Purity by HPLC: 97.60%.

Example 3B: Preparation of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate tartarate.

Methyl-2-amino-2-(2-chlorophenyl)acetate (20 g) and methyl isobutyl ketone (32 ml) were charged into a round bottom flask at 26oC. The reaction mass was stirred for 3 hours at the same temperature. Tartarate salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate (0.2 g) was added to the reaction mass as a seeding material material followed by stirred for about 10 minutes. L(+)-Tartaric acid solution (16.5 gram L(+)-Tartaric acid in 80 ml methanol) was added to the reaction mass for 1 hour 30 minutes and stirred for 41 hours. The reaction mass was cooled to 12°C and stirred for 1 hour 30 minutes. The precipitated solid product was obtained by filtration and washed with methyl isobutyl ketone (30 ml). The compound was dried under vacuum at 55°C for 5 hours 30 minutes. Yield: 31.5 g; Chiral purity: 99.09% by HPLC; Purity by
HPLC: 97.42%.

Example 3C: Preparation of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate tartarate.

Methyl-2-amino-2-(2-chlorophenyl)acetate (20 g) and acetone (30 ml) were charged into a round bottom flask at 27oC. The reaction mass was stirred for 3 hours at the same temperature. Tartarate salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate (0.2 g) was added to the reaction mass as a seeding material followed by stirred for about 10 minutes. L(+)-Tartaric acid solution (16.5 gram L(+)-Tartaric acid in 80 ml methanol) was added to the reaction mass for 1 hour and stirred for 26 hours. The reaction mass was cooled to 12°C and stirred for 1 hour. The precipitated solid product was obtained by filtration and washed with acetone (30 ml). The compound was dried under vacuum at 53°C for 5 hours. Yield: 28.7 g; Chiral purity: 98.75% by HPLC; Purity by HPLC: 97.56%.

Example 3D: Preparation of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate tartarate.

Methyl-2-amino-2-(2-chlorophenyl)acetate (20 g) and methyl isobutyl ketone (30 ml) were charged into a round bottom flask at 26oC. The reaction mass was stirred for 5 minutes at the same temperature. (+)-methyl-2-amino-2-(2-chlorophenyl)acetate tartarate (0.175 g) was added to the reaction mass as a seeding material followed by stirred for about 10 minutes. L(+)-Tartaric acid solution (16.5 gram L(+)-Tartaric acid in 90 ml methanol) was added to the reaction mass for 2 hour and stirred for 24 hours. The reaction mass was cooled to 12°C and stirred for 2 hour. The precipitated solid product was obtained by filtration and washed with methyl isobutyl ketone (20 ml). The compound was dried under suction for 15 minutes. The compound was further dried under vacuum at 57°C for 9 hours. Yield: 29.4 g; Chiral purity: 98.65% by HPLC;

Example 4: Preparation of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate.

Tartarate salt of methyl-2-amino-2-(2-chlorophenyl)acetate (600 g), water (1800 ml) and dichloromethane (1200 ml) were charged into a round bottom flask followed by stirred for about 5 minutes. The reaction mass was cooled to 0oC. Liquid NH3 (225 ml) was slowly added until the pH of the reaction mixture was from 7.5 at 0-2°C. The layers were separated. The aqueous layer was extracted with dichloromethane (2X300 ml). The combined dichloromethane was washed with water (300 ml). Dichloromethane was distilled from the organic layer under vacuum at a temperature at 45°C to obtain a residue. Yield: 336.5 g; Chiral Purity: 98.80%. by HPLC

Example 5A: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate. (+)-methyl-2-amino-2-(2-chlorophenyl)acetate (8.4 g), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (14.4 g), sodium bicarbonate (10.8 g), lithium bromide (0.4 g), tetra-n-butylammonium bromide (1.35 g) and acetonitrile (45 ml) were charged into a round bottom flask at 26oC. The reaction mass was heated to 79oC and stirred for 30 hours. The reaction mass was cooled to 26oC. Toluene (45 ml) and water (45 ml) were added to the reaction mass at 26oC and stirred for 10 minutes, the layers were separated, the aqueous layer was extracted with toluene (15 ml). The combined toluene layer was washed with water (45 ml). The toluene layer was evaporated under vacuum at 53oC to obtain a residue. Yield: 13.1 g; Purity by HPLC: 73.92%; Chiral purity: 97.10% by HPLC.

Example 5B: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate.

(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (8.4 g), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (14.4 g), sodium bicarbonate (10.8 g), lithium bromide (0.4 g) and acetonitrile (45 ml) were charged into a round bottom flask at 26oC. The reaction mass was heated to 79oC and stirred for 30 hours. The reaction mass was cooled to 26oC. Toluene (45 ml) and water (45 ml) were added to the reaction mass at 26oC and stirred for 10 minutes, the layers were separated, the aqueous layer was extracted with toluene (15 ml). The combined toluene layer was washed with water (45 ml). The toluene layer was evaporated under vacuum at 53oC to obtain a residue (13.3 g). Yield: 13.3 g; Purity by HPLC: 68.32 %; Chiral purity: 98.14% by HPLC.

Example 5C: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate.

(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (111 g), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (204 g), sodium bicarbonate (144 g), acetonitrile (600 ml), tetra-n-butylammonium bromide (18.4 g) and potassium iodide (9.6 g) were charged into a round bottom flask at 26oC. The reaction mass was heated to 81oC and stirred for 33 hours. The reaction mass was cooled to 30oC. The reaction mass was filtered and washed with acetonitrile (200 ml). The reaction mass was evaporated under vacuum at 55oC to obtain a solid residue. Toluene (600 ml) and water (200 ml) were added to the obtained residue at 26oC and stirred for 20 minutes, the layers were separated, the aqueous layer extracted with toluene (400 ml). The combined toluene layer was evaporated under vacuum at 55oC to obtain a residue. Yield: 196 g; Purity by HPLC: 79.74 %; Chiral purity: 97.15% by HPLC.

Example 5D: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate.

(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (8.4 g), 2-(thiophen-2-yl)ethyl methanesulfonate (10.6 g), dipotassium hydrogen phosphate (22.4 g), water (4.5 ml), tetra-n-butylammonium bromide (1.38 g) and potassium iodide (0.71 g) were charged into a round bottom flask at 26oC. The reaction mass was heated to 80oC and stirred for 30 hours. The reaction mass was cooled to 26oC. Toluene (75 ml) and water (75 ml) were added to the reaction mass at 26oC followed by stirred for 20 minutes, the layers were separated, the organic layer washed with water (50 ml). The combined toluene layer was evaporated under vacuum at 56oC to obtain a residue. Yield: 13.8 g.

Example 5E: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate.

(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (8.4 g), 2-(thiophen-2-yl)ethyl methanesulfonate (10.6 g), dipotassium hydrogen phosphate (22.4 g), acetonitrile (22.5 ml) and potassium iodide (0.71 g) were charged into a round bottom flask at 26oC. The reaction mass was heated to 80oC and stirred for 30 hours. The reaction mass was cooled to 26oC. Toluene (75 ml) and water (75 ml) were added to the reaction mass at 26oC fallowed by stirred for 20 minutes, the layers were separated, the organic layer washed with water (50 ml). The combined toluene layer was evaporated under vacuum at 56oC to obtain a residue Yield: (14.0 g).

Example 6A: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate hydrochloride.

(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (28 g), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (48.4 g), dipotassium hydrogen phosphate (74.65 g), lithium bromide (1.24 g), tetra-n-butylammonium bromide (4.6 g) and acetonitrile (150 ml) were charged into a round bottom flask at 26oC. The reaction mass was heated to 81oC and stirred for 30 hours. The reaction mass was cooled to 28oC and stirred for 1 hour. The reaction mass was filtered and washed with acetonitrile (50 ml). The reaction mass was evaporated under vacuum at 54oC to obtain a residue. Toluene (150 ml) and water (150 ml) were added to the obtained residue at 28oC and stirred for 15 minutes, the layers were separated, the aqueous layer was washed with toluene (50 ml). The combined toluene layer was evaporated under vacuum at 55oC to obtain a residue (51.4 g). The obtained solid residue and toluene (170 ml) were charged into a round bottom flask and stirred for 5 minutes. The reaction mass was cooled to 13oC and added concentrated HCl (14.4 ml). The reaction mass was heated to 58oC and stirred for 1 hour. The precipitated solid product was obtained by filtration and washed with toluene (50 ml). The compound was dried under vacuum at 58°C for 5 hours. Yield: 41.4 g.

Example 6B: Purification of (+)-α–[(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate hydrochloride.

(+)-α–[(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate hydrochloride (40 g) obtained according to the example 6A, acetone (200 ml) and concentrated HCl (10 ml) were charged into a round bottom flask at 26oC followed by stirred for 5 minutes. The reaction mass was heated to 56oC and stirred for 30 minutes. The reaction mass was cooled to 11oC and stirred for1 hour. The precipitated solid product was obtained by filtration and washed with acetone (25 ml). The compound was dried under vacuum at 55°C for 5 hours. Yield: 30.6 g; Purity by HPLC: 99.49%; Chiral purity: 99.58 % by HPLC.

Example 6C: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate hydrochloride.

(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (50 g), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (48.4 g), dipotassium hydrogen phosphate (74.65 g), potassium iodide (2.37 g) and acetonitrile (150 ml) were charged into a round bottom flask at 26oC. The reaction mass was heated to 81oC and stirred for 31 hours. The reaction mass was cooled to 29oC and stirred for 1 hour. The reaction mass was filtered and washed with acetonitrile (50 ml). The reaction mass was evaporated under vacuum

at 54oC to obtain a residue. Toluene (150 ml) and water (150 ml) were added to the obtained residue at 28oC and stirred for 15 minutes, the layers were separated, the aqueous layer was washed with toluene (50 ml). The combined toluene layer was evaporated under vacuum at 55oC to obtain a solid residue (52.4 g). The obtained residue and toluene (170 ml) were charged into a round bottom flask and stirred for 5 minutes. The reaction mass was cooled to 10oC and added concentrated HCl (14.4 ml). The reaction mass was heated to 58oC and stirred for 1 hour. The precipitated solid product was obtained by filtration and washed with toluene (50 ml). The compound was dried under vacuum at 58°C for 4 hours. Yield: 41.6 g.

Example 6D: Purification of (+)-α–[(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate hydrochloride.
(+)-α–[(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate hydrochloride (40 g) obtained according to the example 6C, acetone (200 ml) and concentrated HCl (10 ml) were charged into a round bottom flask at 26oC followed by stirred for 5 minutes. The reaction mass was heated to 56oC and stirred for 30 minutes. The reaction mass was cooled to 12oC and stirred for1 hour. The precipitated solid product was obtained by filtration and washed with acetone (25 ml). The compound was dried under vacuum at 55°C for 5 hours. Yield: 32.3 g; Purity by HPLC: 99.66 %; Chiral purity: 99.71 % by HPLC.

Example 6E: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate hydrochloride.
(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (28 g), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (45.5 g), dipotassium hydrogen phosphate (74.6 g), potassium iodide (1.3 g), tetra-n-butylammonium bromide (2.2 g) and toluene (50 ml) were charged into a round bottom flask at 26oC. The reaction mass was heated to 92oC and stirred for 31 hours. The reaction mass was cooled to 29oC. Toluene (100 ml) and water (200 ml) were added to the reaction mass. The layers were separated, the aqueous layer was extracted with toluene (100 ml). The combined toluene layer was evaporated under vacuum at 55oC to obtain a residue (52.0 g). The obtained residue and toluene (170 ml) were charged into a round bottom flask and stirred for 5 minutes. Concentrated HCl (15 ml) was added to the reaction mass at 22oC. The reaction mass was heated to 55oC and stirred for 1 hour. The precipitated solid product was obtained by filtration and washed with toluene (50 ml). The compound was dried under vacuum at 55°C for 6 hours. Yield: 43.2 g; Purity by HPLC: 95.78%; Chiral purity: 98.52% by HPLC.

The above obtained compound (40 g), toluene (25 ml), acetone (180 ml) and concentrated HCl (9.5 ml) were charged into a round bottom flask at 28°C. The reaction mass was heated to 56°C and stirred for 45 minutes. The reaction mass cooled to 11°C and stirred for 30 minutes. The precipitated solid product was obtained by filtration and washed chilled acetone (25 ml). The compound was dried under vacuum at 55°C for 5 hours. Yield: 34.6 g; Purity by HPLC: 99.59%; Chiral purity: 99.61% by HPLC.

Example 6F: Preparation of (+)-α–[(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate hydrochloride.
(+)-α–[(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate (13.4 g) obtained according to the example 5D and toluene (50 ml) were charged into a round bottom flask at 26oC fallowed by stirred for 5 minutes. Concentrated HCl (5 ml) was added to the reaction mass. The reaction mass was heated to 58oC and stirred for1 hour. The precipitated solid product was obtained by filtration and washed with toluene (15 ml). Obtained wet compound, acetone (60 ml) and concentrated HCl (5 ml) were charged into a round bottom flask at 26oC followed by stirred for 5 minutes. The reaction mass was heated to 56oC and stirred for1 hour. The reaction mass was cooled to 1oC and stirred for1 hour. The precipitated solid product was obtained by filtration and washed with acetone (15 ml). The compound was dried under vacuum at 55°C for 5 hours. Yield: 10.5 g; Purity by HPLC: 99.46%; Chiral purity: 99.62% by HPLC.

Example 6G: Preparation of (+)-α–[(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate hydrochloride.
(+)-α–[(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate (13.4 g) obtained according to the example 5E and toluene (50 ml) were charged into a round bottom flask at 26oC followed by stirred for 5 minutes. Concentrated HCl (5 ml) was added to the reaction mass. The reaction mass was heated to 58oC and stirred for1 hour. The precipitated solid product was obtained by filtration and washed with toluene (15 ml). Obtained wet compound, acetone (60 ml) and concentrated HCl (5 ml) were charged into a round bottom flask at 26oC followed by stirred for 5 minutes. The reaction mass was heated to 56oC and stirred for1 hour. The reaction mass was cooled to 10oC and stirred for1 hour. The precipitated solid product was obtained by filtration and washed with acetone (15 ml). The compound was dried under vacuum at 57°C for 5 hours. Yield: 10.6 g; Purity by HPLC: 99.64%; Chiral purity: 99.72% by HPLC.

Example 6H: Preparation of (+)-α–[(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate hydrochloride.
(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (28 g), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (48.4 g), sodium bicarbonate (36 g), potassium iodide (2.4 g) and acetonitrile (150 ml) were charged into a round bottom flask at 28oC. The reaction mass was heated to 81oC and stirred for 38 hours. The reaction mass was cooled to 26oC. The reaction mass was filtered and washed with acetonitrile (50 ml). The reaction mass was evaporated under vacuum at 55oC to obtain a residue (47.3 g). The reaction mass was cooled to 26oC. Toluene (150 ml) and water (100 ml) were added to the reaction mass at 26oC and stirred for 15 minutes, the layers were separated, the aqueous layer washed with toluene (50 ml). The combined toluene layer was evaporated under vacuum at 55oC to obtain a residue (47 g). Toluene (170 ml) was added to the obtained solid residue at 26oC and stirred for 5 minutes. The reaction mass was cooled to 10oC and added concentrated HCl (14.4 ml). The reaction mass was heated to 55oC and stirred for 1 hour. The precipitated solid product was obtained by filtration and washed with toluene (50 ml). The compound was dried under vacuum at 55°C for 7 hours. Yield: 42.1 g; Purity by HPLC: 93.15%; Chiral purity: 97.90% by HPLC.

Example 6I: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate hydrochloride.
(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (11.2 g), 2-(thiophen-2-yl)ethyl p-toluenesulfonate (19.4 g), dipotassium phosphate (29.8 g), water (6 ml), tetra-n-butylammonium bromide (1.8 g) and potassium iodide (1 g) were charged into a round bottom flask at 26oC. The reaction mass was heated to 80oC and stirred for 27 hours. The reaction mass was cooled to 30oC. Toluene (80 ml) and water (80 ml) were added to the reaction mass at 26oC and stirred for 20 minutes, the layers were separated, the aqueous layer washed with toluene (80 ml). The combined toluene layer was evaporated under vacuum at 55oC to obtain a residue (19.4 g). Toluene (70 ml) was added to the obtained residue at 26oC and stirred for 5 minutes. The reaction mass was cooled to 14oC and added Aq.HCl (5.8 ml). The reaction mass was heated to 55oC and stirred for 1 hour. The precipitated solid product was obtained by filtration and washed with toluene (40 ml). The compound was dried under vacuum at 56°C for 4 hours. Yield: 17.1 g; Purity by HPLC: 96.13%; Chiral purity: 98.34% by HPLC.

Example 6J: Preparation of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate hydrochloride.
(+)-methyl-2-amino-2-(2-chlorophenyl)acetate (28 g), sodium bicarbonate (36 g) and acetonitrile (150 ml) were charged into a round bottom flask at 28oC. 2-(thiophen-2-yl)ethyl p-toluenesulfonate (48.4 g), tetra-n-butylammonium bromide (4.6 g) and potassium iodide (2.4 g) were added to the reaction mass. The reaction mass was heated to 81oC and stirred for 31 hours. The reaction mass was cooled to 30oC. The reaction mass was filtered and washed with acetonitrile (50 ml). The reaction mass was evaporated under vacuum at 55oC to obtain a residue (51.3 g). The reaction mass was cooled to 26oC. Toluene (150 ml) and water (100 ml) were added to the obtained solid residue at 28oC and stirred for 15 minutes, the layers were separated, the aqueous layer extracted with toluene (50 ml). The combined toluene layer was evaporated under vacuum at 55oC to obtain a residue (45.7 g). The obtained residue and toluene (170 ml) were charged into a round bottom flask and stirred for 5 minutes. The reaction mass was cooled to 10oC and added Aq.HCl (14.4 ml). The reaction mass was heated to 55oC and stirred for 1 hour. The precipitated solid product was obtained by filtration and washed with toluene (50 ml). The compound was dried under vacuum at 55°C for 4 hours. Yield: 41.5 g; Purity by HPLC: 93.57%. Above obtained solid compound (40 g), toluene (25 ml), acetone (190 ml) and concentrated HCl (9.5 ml) were charged into a round bottom flask at 26oC. The reaction mass was heated to 56oC and stirred for 0.5 hours. The reaction mass was cooled to 11oC. The precipitated solid product was obtained by filtration and washed with acetone (25 ml). The compound was dried under vacuum at 55°C for 2 hours. Yield: 33.6 g; Purity by HPLC: 99.68%; Chiral purity: 99.44% by HPLC.

Example 7A: Preparation of Clopidogrel free base.
(+)-α–[(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate hydrochloride (100 g) and formaldehyde solution (500 ml) were charged into a round bottom flask at 26oC. The reaction mass was stirred at the same temperature for 24 hours. The reaction mass was filtered. The reaction mass was charged into a round bottom flask at 26oC. The reaction mass was cooled to 10oC. The dichloromethane (500 ml) was added to the reaction mass. The aqueous solution of sodium carbonate (about 15 grams of sodium carbonate in 500 ml water) was slowly added until the pH of the reaction mixture was from 7.5 at 10-12°C. The layers were separated. The aqueous layer was extracted with dichloromethane (500 ml). The combined organic layer was washed with water (300 ml). Dichloromethane was distilled from the organic layer at a temperature at 45°C to obtain a residue. Yield: 98.7 g; Purity by HPLC: 96.55%.

Example 7B: Preparation of Clopidogrel free base.
(+)-α–[(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl) methyl acetate hydrochloride (100 g) and formaldehyde solution (500 ml) were charged into a round bottom flask. The reaction mass was stirred at 28oC for 24 hours. The reaction mass was washed with ethyl acetate. The reaction mass was cooled to 10oC. The aqueous solution of sodium carbonate was slowly added until the pH of the reaction mixture was from 7.5 (about 15 grams of sodium carbonate in 500 ml water) at 10°C. The layers were separated. The aqueous layer was extracted with dichloromethane (500 ml). The combined organic layer was washed with water (300 ml). Dichloromethane was distilled from the organic layer at a temperature at 45°C to obtain a residue. Yield: 84.0 g; Purity by HPLC: 97.64%.

Example 8: Preparation of Clopidogrel bisulfate Form II.
37-40% of Formoldehyde solution (7.5 liters) and (+)-α–[(2-thien-2-yl)-ethyl amino) -α-(2-chlorophenyl) methyl acetate hydrochloride (1.5 kg) were charged into a reactor under nitrogen atmosphere. The reaction mass was stirred at 28oC for 26 hours. The reaction mass was filtered and washed with water (1.5 liters). The reaction mass was cooled to 3oC and charged dichloromethane (6 liters). The aqueous solution of sodium carbonate was slowly added until the pH of the reaction mixture was from 7.25 (about 0.55 kg of sodium carbonate in 4.5 liters of water) at 8°C. The layers were separated. The aqueous layer was extracted with dichloromethane (3 liters). The combined organic layer was washed with water (3 liters). Dichloromethane was distilled from the organic layer at 44°C to obtain a residue. Acetone (1.5 liter) was added to the reaction mass and distilled at 44°C. Acetone (7.5 liters) was charged in to the reaction mass. The reaction mass was stirred at 36oC until the clear solution observe. Water (0.225 liters) was added to the reaction mass. The reaction mass was cooled to 3oC and slowly added sulfuric acid (0.43 kg) for 60 minutes. Form II of clopidogrel bisulfate (0.015 kg) was added to the reaction mass as a seeding material followed by stirred for about 1.5 hours at 3oC. The reaction mass was stirred at 28oC for 17 hours. The reaction mass was cooled to 3oC and stirred for 60 minutes. The precipitated solid product was obtained by filtration and washed with acetone (1.5 liters). The compound was dried under vacuum at 48°C for 3 hours. Yield: 83.3%; Purity by HPLC: 99.68%; Chiral purity: 99.54% by HPLC.

Example 9: Preparation of a clopidogrel bisulfate Form I Clopidogrel freebase (40 g), methylisobutyl ketone (150 ml) and carbon (2 gm) were charged into a round bottom flask at 27°C. The reaction mass was stirred for 4 minutes at 27°C and filtered. Butylated hydroxy toluene (80 mg) was added to the filtrate. The reaction mass was charged into reactor and cool to -10°C. The solution of sulfuric acid (11.6 gm) in methylisobutyl ketone (120 ml) was added slowly to the reaction mass at -10°C for 60 minutes. The reaction mass was stirred for 10 minutes at -10°C. Methylisobutyl ketone (100 ml) was added to the reaction mass at -10°C. The reaction mass was stirred for 60 minutes at 8°C. Methylisobutyl ketone (100 ml) was added to the reaction mass at 8°C. The reaction mass was stirred for 60 minutes at 13°C. Methylisobutyl ketone (100 ml) was added to the reaction mass at 13°C. The reaction mass was stirred for 60 minutes at 18°C. Methylisobutyl ketone (100 ml) was added to the reaction mass at 18°C. The reaction mass was stirred for 13 hrs at 24°C. The precipitated solid product was obtained by filtration. The compound was dried under vacuum for 8 hours at 65°C. Yield: 37.2 g.

We Claim:

1. A process for the preparation (+)-methyl-2-amino-2-(2-chlorophenyl)acetate comprising:

a) reacting methyl-2-amino-2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) treating the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) with a base to produce (+)-methyl-2-amino-2-(2-chlorophenyl)acetate.

2. The process according to claim 1, wherein the chiral acid is selected from L-tartaric acid, mandelic acid, lactic acid, camphoric acid, Di-p-toluoyl-L-tartaric acid(L-DTTA), Dibenzoyl-L-tartaric acid monohydrate(L-DBTA), L-malic acid, L-2-chloromandelic acid, camphorsulfonic acid.

3. The process according to claims 1 and 2, wherein the chiral acid is L-tartaric acid.

4. The process according to claim 1, wherein the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonia, aqueous ammonia, triethylamine, diisopropylamine, N-methylmorpholine.

5. The process according to claims 1 and 4, wherein the base is aqueous ammonia.

6. A process for the preparation of (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-
chlorophenyl)methyl acetate or its pharmaceutically acceptable salts comprising:

a) reacting methyl-2-amino-2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) treating the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) with base to produce (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

c) reacting (+)-methyl-2-amino-2-(2-chlorophenyl)acetate with 2-(thiophen-2-yl)ethyl p-toluenesulfonate or 2-(thiophen-2-yl)ethyl methylsulfonate to produce (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate.

d) optionally converting the obtained (+)-α–(2-thien-2-yl)-ethyl amino)-α-(2-chlorophenyl)methyl acetate in step c) into a pharmaceutically acceptable salts of (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate.

7. A process for the preparation of clopidogrel or its pharmaceutically acceptable salts comprising:

a) reacting methyl-2-aminon -2-(2-chlorophenyl)acetate with chiral acid in presence of methanol and methyl-iso-butyl-ketone to produce chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

b) treating the chiral acid salt of (+)-methyl-2-amino-2-(2-chlorophenyl)acetate obtained in step a) with base to produce (+)-methyl-2-amino-2-(2-chlorophenyl)acetate;

c) reacting (+)-methyl-2-amino-2-(2-chlorophenyl)acetate with 2-(thiophen-2-yl)ethyl p-toluenesulfonate or 2-(thiophen-2-yl)ethyl methylsulfonate to produce (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts;

d) cyclizing (+)-α–(2-thien-2-yl)-ethyl amino) - α-(2-chlorophenyl)methyl acetate or its pharmaceutically acceptable salts in presence of formaldehyde to produce Clopidogrel;

e) optionally converting the obtained clopidogrel in step d) into a clopidogrel bisulfate.

8. A process for the preparation of crystalline Form 1 of Clopidogrel bisulphate comprising:

a) providing a solution of clopidogrel freebase in an ketone solvent;

b) optionally, treating the solution obtained in step a) with charcoal;

c) adding butylated hydroxy toluene the solution obtained in step b);

d) adding sulfuric acid to the solution obtained in step c);

e) optionally, seeding the solution obtained in step (d) with crystalline Form 1 of clopidogrel bisulphate; and

i) isolating the crystalline Form 1 of Clopidogrel bisulphate.

9. The process according to claim 8, wherein the ketone solvent is selected from acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; or mixtures thereof.

10. The process according to claims 8 and 9, wherein the ketone solvent is methyl isobutyl ketone.