Kinetic resolution of a intermediate useful in the production of benazepril and analogues thereof

Abstract

The present invention provides an efficient synthetic process for making benazepril and analogues thereof by having an intermediate compound undergo epimerization and kinetic resolution.

We claim:  
     
         1 . A process for the preparation of a compound of the formula (III)  
       
         
           
           
               
               
           
         
       
       comprising the steps of reacting a compound of the formula (I)  
       
         
           
           
               
               
           
         
       
       wherein Z1 is a halogen, with a compound of the formula (II)  
       
         
           
           
               
               
           
         
       
       where R 1  hydrogen, lower alkyl or a combination of hydrogen and alkyl group; 
 R 2  is a lower alkyl group having 1 to 4 carbon atoms; and  
 Z 2  is a halogen;  
 in an aprotic polar solvent catalyzed by a phase transfer catalyst.  
 
     
     
         2 . The process of  claim 1 , wherein the phase transfer catalyst is selected from the group consisting of tetra-alkylammonium halides, N-dodecyl-N-methyl-ephedrinium halides, phenyltrimethylammonium halides, phenyltrimethylammonium methosulfate, benzyltrimethylammonium halides, N-benzylcinchoninium halides, benzyldimethyldodecylammonium halides and benzethonium halides.  
     
     
         3 . The process of  claim 1 , wherein the reaction is further catalyzed by an alkali earth metal halide salt.  
     
     
         4 . The process of  claim 3  wherein the salt is sodium iodide or lithium iodide.  
     
     
         5 . The process of the  claim 1 , wherein the reaction is carried out under basic condition.  
     
     
         6 . The process of  claim 5  where the basic condition is provided by adding a base selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and lithium carbonate, and barium carbonate.  
     
     
         7 . The process of the  claim 1  wherein the reaction temperature is between 60° C. and 140° C.  
     
     
         8 . A compound of the formula (IV)  
       
         
           
           
               
               
           
         
       
     
     
         9 . A process for making a carboxylic acid of the formula (V) comprising epimerizing IV(R,S) in a solution comprising a polar or non-polar solvent to a compound V where R 1  and R 2  are independently H, benzyl, alkylsilyl or carbamate  
       
         
           
           
               
               
           
         
       
     
     
         10 . The process of  claim 9  wherein the epimerization is done by heating the solution.  
     
     
         11 . A process of  claim 9  in which R 1 =H, R 2 =H, and epimerization occurs by heating the solution.  
     
     
         12 . A process of  claim 11  in which the solvent is an alcohol, organic acid or aromatic hydrocarbon.  
     
     
         13 . A process of  claim 9  in which R 1 =H, R 2 =H and a base is used to epimerize IV(R,S).  
     
     
         14 . The process of  claim 13  wherein the base is selected from the group consisting of alkoxide, hydroxide, carbonate and amine.  
     
     
         15 . A process of  claim 14  in which R 1 =H, R 2 =H, the base is sodium methoxide, and the solvent is methanol.  
     
     
         16 . The process of  claim 9 , further comprising selectively precipitating the compound of formula V during epimerzation.  
     
     
         17 . The process of  claim 16  in which the epimerization occurs by heating the solution.  
     
     
         18 . The process of  claim 17  in which the solvent is an aromatic hydrocarbon or an organic acid.  
     
     
         19 . The process of  claim 18  wherein the organic acid is acetic acid or propionic acid.  
     
     
         20 . The process of  claim 18  in which the organic solvent is xylene and the temperature for epimerization is greater than 120° C.  
     
     
         21 . The process of  claim 9  wherein the carboxylic acid of formula V is converted to an alkyl ester by esterification.  
     
     
         22 . The process of  claim 21  in which the esterification is effected with an alkyl halide and potassium or sodium carbonate in a organic solvent.  
     
     
         23 . A process of  claim 22  in which the organic solvent is dimethylacetamide.