Industrial process for preparation of clopidogrel hydrogen sulphate

Crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate without detectable contamination of Form II crystals.

A pharmaceutical composition comprising crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate characterized by powder x-ray diffraction pattern containing no peaks of Form II in the region of 12.2-13.5±0.2 degrees 2θ angle

A process for making clopidogrel of Formula I comprising

• i) reacting 2-(2-thieno)ethylamine of Formula IV with paraformaldehyde to form 4,5,6,7-tetrahydrothieno(3,2-c)pyridine of Formula II, wherein the step takes place in a single vessel without isolation of 2-(2-thienyl)ethyl formimine;
• and
• ii) reacting the compound of Formula II with a halobenzene derivative of Formula III, wherein X═Cl or Br, in presence of a base in a solvent selected from dichloroethane or water or a mixture of water and hydrocarbon/chlorinated hydrocarbon solvents to obtain clopidogrel and isolating said clopidogrel as free base or its salt.

A process for preparation of clopidogrel of Formula I

• comprising the step of reacting 4,5,6,7-tetrahydrothieno(3,2-c)pyridine of formula II
• or its salt with a halobenzene derivative of Formula III
• in presence of a base in a solvent, wherein the solvent is chlorinated hydrocarbon, water or a mixture of water and hydrocarbon solvents selected from aliphatic, aromatic and chlorinated hydrocarbons.

A process for preparation of dextrorotatory clopidogrel or its salt comprising the step of resolving racemic clopidogrel with levo-rotatory camphor sulphonic acid in a solvent system of polar and apolar/weakly polar solvents to obtain substantially pure dextrorotatory clopidogrel of Formula IA.