Industrial process for preparation of clopidogrel hydrogen sulphate

Abstract

An improved process for the manufacture of Clopidogrel starting from 2-(2-thienyl)ethylamine, which eliminates the isolation of an unstable intermediate like 2-(2-thienyl)ethyl formimine by subjecting it to a one pot cyclization to get 4,5,6,7-tetrahydrothieno (3,2-c) pyridine of Formula II and further reacting with halo-compound of formula III (where X is Cl or Br) at 20 to 90° C. temperature characterized in a solvent like water and/or dichloroethane in presence of organic or inorganic bases is disclosed herein. This inventions also discloses Crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate and its preparation thereof.

1 - 31 . (canceled) 
   
   
       32 . Crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate without detectable contamination of Form II crystals. 
   
   
       33 . Crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate according to  claim 32 , wherein the powder x-ray diffraction pattern contains no peaks of Form II in the region of 12.2-13.5±0.2 degrees 2θ angle. 
   
   
       34 . Crystalline Form I of (+)-(S)-clopidogrel hydrogen sulphate according to  claim 32 , wherein the powder x-ray diffraction pattern shows no peaks in the region of 12.2-13.5±0.2 degrees 2θ angle after storage for a period of at least one year. 
   
   
       35 . (+)-(S)-clopidogrel hydrogen sulphate according to  claim 32 , characterized by the x-ray diffraction pattern as shown in  FIG. 1 . 
   
   
       36 . A pharmaceutical composition comprising (+)-(S)-clopidogrel hydrogen sulphate according to  claim 32 . 
   
   
       37 . 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 
   
   
       38 . A process for making Form I crystals of (+)-(S)-clopidogrel hydrogen sulphate of Formula IB, 
     
       
         
         
             
             
         
       
     
     said process comprising:
 i) dissolving methyl (+)-(S)-[alpha]-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate ((+)-(S)-clopidogrel base) in ethyl acetate; 
 ii) cooling to a temperature of 18 to 20° C.; 
 iii) mixing said cooled solution with concentrated sulphuric acid in which the temperature not exceeding 30° C.; 
 iv) maintaining the salt mixture at 28 to 30° C. for 7 to 10 hours to effect precipitation of (+)-(S)-clopidogrel hydrogen sulphate in Form I; and 
 v) recovering said crystals of Form I. 
 
   
   
       39 . The process of  claim 38 , wherein step iii) is carried out while maintaining the temperature at 18 to 24° C. 
   
   
       40 . The process of  claim 38 , wherein the strength of said sulphuric acid is about 95 to 98%. 
   
   
       41 . The process of  claim 38 , wherein the molar ratio of sulphuric acid used is 1.02 to 1.1 relative to (+)-(S)-clopidogrel base. 
   
   
       42 . The process as claimed in any one of the  claim 38 , wherein the Form I crystals are recovered without detectable contamination by Form II crystals. 
   
   
       43 . Crystalline Form I of clopidogrel hydrogen sulphate prepared according to any one of the  claim 38 , characterized by a powder x-ray diffraction pattern containing no peaks in the region of 12.2-13.5±0.2 degrees 2θ angle. 
   
   
       44 . The process according to any one of the  claim 38 , wherein the recovered Form I crystals are characterized by a powder x-ray diffraction pattern as shown in  FIG. 1 . 
   
   
       45 . 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. 
     
   
   
       46 . The process of  claim 45 , wherein the step i) is performed in a solvent selected from aliphatic, aromatic hydrocarbons and chlorinated hydrocarbons. 
   
   
       47 . The process of  claim 46 , wherein the solvent is dichloroethane. 
   
   
       48 . The process of  claim 45 , wherein 2-(2-thienyl)ethyl formimine is formed in-situ by effective removal of water at reflux temperature and cyclized in presence of anhydrous hydrochloric acid. 
   
   
       49 . The process of  claim 45 , wherein said 4,5,6,7-tetrahydrothieno(3,2-c)pyridine is formed at a temperature ranging from about 60 to 90° C. 
   
   
       50 . The process of  claim 45 , wherein step ii) is carried out in dichloroethane. 
   
   
       51 . The process of  claim 45 , wherein the base is selected from trialkyl amines. 
   
   
       52 . The process of  claim 45 , wherein the base is triethyl amine. 
   
   
       53 . The process of in  claim 45 , wherein step ii) takes place at a temperature of 50 to 80° C. 
   
   
       54 . The process of  claim 45 , wherein the clopidogrel is prepared in a single-pot procedure without isolation of intermediates 4,5,6,7-tetrahydrothieno(3,2-c)pyridine or its salts. 
   
   
       55 . The process of  claim 45 , wherein step i) takes place in the presence of an acid catalyst. 
   
   
       56 . The process of  claim 55 , wherein the acid catalyst is hydrogenchloride. 
   
   
       57 . 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. 
   
   
       58 . The process of  claim 57 , wherein the solvent is a combination of dichloroethane and water. 
   
   
       59 . The process of  claim 57 , wherein the base is sodium carbonate or potassium carbonate. 
   
   
       60 . The process of  claim 57 , wherein reaction is performed at a temperature of 20 to 40° C. 
   
   
       61 . The process of  claim 57 , wherein the compound of Formula III is methyl-1-bromo-(2-chlorophenyl)acetate. 
   
   
       62 . The process of  claim 57 , further comprising the steps of treating said clopidogrel of Formula I with levo-rotatory camphor sulphonic acid in a solvent system of polar and apolar/weakly polar solvents; and obtaining substantially pure dextrorotatory clopidogrel of Formula IA 
     
       
         
         
             
             
         
       
     
   
   
       63 . The process of  claim 62 , wherein the solvent system is acetone and dichloromethane; acetone and toluene; or acetone and cyclohexane 
   
   
       64 . The process of  claim 63 , wherein the combination solvent is acetone and dichloromethane. 
   
   
       65 . The process of  claim 64 , wherein the ratio of acetone and dichloromethane is 10:1. 
   
   
       66 . 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. 
   
   
       67 . The process of  claim 66 , wherein the solvent system is acetone:dichloromethane, acetone:toluene, or acetone: cyclohexane. 
   
   
       68 . The process of  claim 67 , wherein the combination solvent is acetone:dichloromethane.