Production methods of citalopram and intermediates therefor

Abstract

The present invention provides a production method of citalopram and intermediates therefor.

1 - 13 . (canceled)  
     
     
         14 . A method comprising converting a compound of the formula [IV] 
       
         
           
           
               
               
           
         
         to the corresponding compound of the formula [VI] 
         
           
             
             
                 
                 
             
           
         
       
     
     
         15 . A method of producing citalopram comprising converting a compound of the formula [IV]:  
       
         
           
           
               
               
           
         
         to the corresponding compound of the formula [VI]:  
         
           
             
             
                 
                 
             
           
         
         followed by alkylation of the compound of formula [VI] to form citalopram.  
       
     
     
         16 . The method of  claim 15 , wherein the alkylation of the compound of formula [VI] is carried out by reacting the compound of formula [VI] with 3-(dimethylamino)propyl halide.  
     
     
         17 . The method of  claim 15 , wherein the alkylation of the compound of formula [VI] is carried out by reacting the compound of formula [VI] with 3-(dimethylamino)propyl chloride.  
     
     
         18 . The method of  claim 15 , wherein the citalopram is isolated in the form of a base or an acid addition salt thereof.  
     
     
         19 . The method of  claim 18 , wherein the alkylation of the compound of formula [VI] is carried out by reacting the compound of formula [VI] with 3-(dimethylamino)propyl halide.  
     
     
         20 . A method for the preparation of citalopram, which method comprises the steps of (a) oxidizing the compound of formula [III] 
       
         
           
           
               
               
           
         
         to form an aldehyde compound of formula [IV] 
         
           
             
             
                 
                 
             
           
         
         (b) converting the aldehyde compound of formula [IV] to the corresponding 5-cyano compound of formula [VI] 
         
           
             
             
                 
                 
             
           
         
         (c) alkylating the 5-cyano compound of formula [VI] to form citalopram in the form of a base or an acid addition salt thereof.  
       
     
     
         21 . The method of  claim 20 , wherein the method further comprises the step of (d) isolating the citalopram in the form of a base or an acid addition salt thereof.  
     
     
         22 . The method of  claim 20 , wherein the compound of formula [III] is prepared by cyclizing the compound  
       
         
           
           
               
               
           
         
         to form a compound of formula [III].  
       
     
     
         23 . The method of  claim 22  wherein the method further comprises the step of (d) isolating the citalopram in the form of a base or an acid addition salt thereof.  
     
     
         24 . A method of  claim 20 , wherein the compound of formula [III] is oxidized by reacting the compound of formula [III] with hypochlorite.  
     
     
         25 . A method for the preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran of formula [VI] 
       
         
           
           
               
               
           
         
         comprising converting a 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran derivative of formula [IV] 
         
           
             
             
                 
                 
             
           
         
         or the formula [III] 
         
           
             
             
                 
                 
             
           
         
         to form the 5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzoftiran of formula [VI].  
       
     
     
         26 . The method of  claim 25 , wherein converting the compound of formula [IV] to the compound of formula [VI] comprises converting the aldehyde group of the compound of formula [IV] to an oxime followed by dehydration of the oxime group.  
     
     
         27 . The method of  claim 25 , further comprising the step of alkylating the compound of formula [VI] to form citalopram, and isolating citalopram or a pharmaceutically acceptable salt thereof.  
     
     
         28 . The method of  claim 27 , wherein converting the compound of formula [IV] to the compound of formula [VI] comprises converting the aldehyde group of the compound of formula [IV] to an oxime followed by dehydration of the oxime group.