Method for the preparation of citalopram

Abstract

The invention provides a new and improved method for the preparation of 5-cyano-phtalid, which is a key intermediate in the preparation of the antidepressant compound citalopram.

1 . A method for the preparation of a compound of the formula  
       
         
           
           
               
               
           
         
         comprising reacting an isobenzofuran-1-one of the formula  
         
           
             
             
                 
                 
             
           
         
         wherein R′ is a halogen or CF 3 —(CF 2 ) n —SO 2 —, wherein n is 0-7, with a cyanide source optionally in the presence of a catalyst.  
       
     
     
         2 . The process of  claim 1  wherein R′ is Cl, Br or I.  
     
     
         3 . The process of  claim 1  wherein R′ is CF 3 —(CF 2 ) n —SO 2 —, wherein n is 0, 1,2,3 or 4.  
     
     
         4 . The process of  claim 1 , wherein the cyanide source is selected from (R″ 4 N)CN wherein each R″ is C 1-8 -alkyl, optionally two R″ together with the nitrogen form a ring structure; KCN, NaCN, Zn(CN) 2  or CuCN or combinations thereof.  
     
     
         5 . The process of  claim 1 , wherein Zn 2+  or Cu +  are added in substoichiometric amounts in combination with another cyanide source.  
     
     
         6 . The process of  claim 1 , wherein the catalyst is selected from Ni(PPh 3 ) 3 , Pd(PPh 3 ) 4 , Pd(dba) 3  or Pd(PPh) 2 Cl 2 .  
     
     
         7 . The process of  claim 1 , wherein a 5-chloro-isobenzofuran-1-one is subjected to NaCN in the presence of Ni-catalyst.  
     
     
         8 . The process of  claim 7  wherein the Ni-catalyst is Ni(PPh 3 ) 3  prepared in situ by subjecting NiCl 2  to a reducing agent, in the presence of PPh 3 .  
     
     
         9 . The process of  claim 8  wherein the reducing agent is Zn.  
     
     
         10 . The process of  claim 1 , wherein a 5-bromo- or 5-iodo-isobenzofuran-1-one is subjected to KCN, NaCN, Zn(CN) 2 , or CuCN or combinations thereof in the presence of Pd(PPh 3 ) 4 .  
     
     
         11 . The process according to  claim 1 ,  2  and  4  wherein a 5-bromo- or 5-iodo-isobenzofuran-1-one is subjected to KCN, NaCN, Zn(CN) 2 , or CuCN or combinations thereof and the process is performed without catalysts.  
     
     
         12 . The process of  claim 10  wherein the reaction is performed in an ionic liquid of the general formula R 4 N + X −  wherein each R represents C 1-8 -alkyl optionally two R″ together with the nitrogen form a ring.  
     
     
         13 . The process of  claim 10  wherein the reaction is performed under the influence of microwaves in an apolar solvent.  
     
     
         14 . The process according to  claim 10  or  claim 12  wherein the reaction is performed as a neat reaction.