Process for the preparation of pure citalopram

Abstract

A process for the preparation of citalopram of formula (I) in which a compound of formula (II) wherein Z is iodo, bromo, chloro or CF 3 —(CF 2 ) n —SO 2 —O— n being 0, 1, 2, 3, 4, 5, 6, 7 or 8, is subjected to a cyanide exchange reaction in which the group Z is exchanged with cyanide by reaction with a cyanide source; the resultant crude citalopram product is optionally subjected to some initial purification and the crude citalopram base is subsequently subjected to a film distillation process; the resulting citalopram product is then optionally further purified and worked up and isolated as the base or a pharmaceutically acceptable salt thereof.

1 . A method for the preparation of a purified citalopram product, wherein a crude citalopram product is optionally subjected to purification; and the crude citalopram base is subsequently subjected to a film distillation process to remove high molecular reaction impurities; the resulting citalopram product is then optionally further purified and worked up and isolated as the base or a pharmaceutically acceptable salt thereof.  
     
     
         2 . The method according to  claim 1 , wherein the high molecular reaction impurities which are removed comprise dimeric forms of citalopram having the formulas:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 1  or  2  wherein the crude citalopram product is prepared by subjecting a compound of formula II  
       
         
           
           
               
               
           
         
       
       wherein Z is iodo, bromo, chloro or CF 3 —(CF 2 ) n —SO 2 —O— n being 0, 1, 2, 3, 4, 5, 6, 7 or 8, to a cyanide exchange reaction in which Z is exchanged with cyanide by reaction with a cyanide source.  
     
     
         4 . The process according to  claim 1  wherein the film distillation process is short path or thin film layer distillation.  
     
     
         5 . The process according to  claim 1 , wherein the crude citalopram base is dissolved in a solvent before it is subjected to film distillation.  
     
     
         6 . The process according to  claim 1 , wherein the distillation temperature is 200-300° C. and the pressure is 0.1-2.0 mmHg.  
     
     
         7 . The process according to  claim 6 , wherein the distillation temperature is 240-270° C. and the pressure is 0.6-0.8 mmHg.  
     
     
         8 . The process according to  claim 3 , wherein Z is Br and the cyanide exchange reaction is carried out by reaction with cuprous cyanide in a solvent.  
     
     
         9 . The process according to  claim 3 , wherein the cyanide exchange reaction is carried out by reaction with a cyanide source in the presence of a palladium catalyst and a catalytic amount of Cu +  or Zn 2+ .  
     
     
         10 . The process according to  claim 3  wherein the cyanide exchange reaction is carried out with Zn(CN) 2  in the presence of a palladium catalyst and a catalytic amount of Cu +  or Zn 2+ .  
     
     
         11 . The process according to  claim 10  wherein Z is Br.  
     
     
         12 . The process according to  claim 3  wherein Z is Cl or Br and the cyanide exchange reaction is carried out with a cyanide source in the presence of a nickel catalyst.  
     
     
         13 . The process according to  claim 12  wherein Z is Cl.  
     
     
         14 . The process according to  claim 12  which is carried out in the presence of a catalytic amount of Cu +  or Zn 2+ .  
     
     
         15 . The process according to  claim 4  wherein the film distillation process is thin film layer distillation.  
     
     
         16 . The process according to  claim 5  wherein the solvent is sulfolane.