Processes for preparing different forms of (s)-(+)-clopidogrel bisulfate

Abstract

The invention provides improved processes for the preparation of hydrated form of (S)-(+)-Clopidogrel bisulfate as well as improved processes for the preparation of form-I and form-II of (S)-(+)-Clopidogrel bisulfate.

1 . A process for the preparation of hydrated form of amorphous(S)-(+)-Clopidogrel bisulfate comprising
 i. treating Clopidogrel base with dil. H 2 SO 4  in one or more suitable solvent(s);   ii. removing the solvent and isolating amorphous form by addition of one or more suitable antisolvent(s).   
   
   
       2 . A process for the preparation of hydrated form of amorphous(S)-(+)-Clopidogrel bisulfate comprising
 i. treating Clopidogrel base in one or more suitable solvent(s) and water with concentrated H 2 SO 4 ;   ii. removing the solvent and isolating the amorphous form by addition of one or more suitable antisolvent(s).   
   
   
       3 . A process for the preparation of hydrated form of amorphous(S)-(+)-Clopidogrel bisulfate comprising
 i. treating Clopidogrel bisulfate in dichloromethane-water with one or more suitable base(s), to obtain Clopidogrel base;   ii. treating the Clopidogrel base(s) with dil. H 2 SO 4  in one or more suitable solvent(s);   iii. removal of the solvent(s) and isolating the amorphous form by addition of suitable one or more antisolvent(s).   
   
   
       4 . A process for the preparation of hydrated form of amorphous(S)-(+)-Clopidogrel bisulfate comprising
 i. treating Clopidogrel bisulfate in dichloromethane-water with one or more suitable base(s), to obtain Clopidogrel base;   ii. treating Clopidogrel base with concentrated H 2 SO 4  in a mixture of suitable solvent(s) and water,   iii. removing the solvent and isolating the amorphous form by addition of one or more suitable antisolvent(s).   
   
   
       5 . A process for the preparation of hydrated form of amorphous (S)-(+)-Clopidogrel bisulfate comprising
 i. treating (S)-(+) Clopidogrel camphor-sulfonate in one or more suitable solvent(s) with a suitable base(s) to obtain Clopidogrel base wherein the suitable solvent is selected from ethyl acetate, dichloromethane, dichloroethane, chloroform or mixtures thereof   ii. treating the Clopidogrel base with concentrated H 2 SO 4  in a mixture of one or more suitable solvent(s) and water,   iii. removing the solvent(s) and isolating the amorphous form by addition of suitable one or more antisolvent(s).   
   
   
       6 . A process for the preparation of hydrated form of amorphous(S)-(+)-Clopidogrel bisulfate comprising
 i. treating (S)-(+) Clopidogrel camphor-sulfonate in one or more suitable a solvent(s) with one or more suitable base(s), to obtain Clopidogrel base wherein the suitable solvent is selected from ethyl acetate, dichloromethane, dichloroethane, chloroform, or mixture thereof;   ii. treating the Clopidogrel base with dilute H2SO4 in one or more suitable solvent(s);   iii. removing the solvent and isolating the amorphous form by addition of one or more suitable antisolvent(s).   
   
   
       7 . A process as claimed  claim 1 , wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, 1-butanol, 2-butanol, dichloromethane, dimethyl formamide, dimethyl acetamide, 1,4-dioxane, tetrahydrofuran, and mixtures thereof. 
   
   
       8 . A process as claimed in  claim 1 , wherein the antisolvent is selected from the group consisting of pentane, n-hexane, heptane, cyclohexane, pet ether, and mixtures thereof. 
   
   
       9 . A process as claimed in  claim 1 , wherein the base is selected from the group consisting of NaOH, KOH, LiOH, NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , and tertiary alkyl amines. 
   
   
       10 - 21 . (canceled) 
   
   
       22 . A process for the preparation of form II of (S)-(+)-Clopidogrel bisulfate comprising stirring the different amorphous forms in Methyl-tert-butyl ether and subsequent removal of the solvent. 
   
   
       23 . A method of treating cardiovascular and related diseases by providing a patient in need thereof, the various forms of (S)-(+)-Clopidogrel bisulfate prepared according to the present invention or pharmaceutical compositions containing the same. 
   
   
       24 . (canceled)