Process for manufacture of fosinopril sodium

Abstract

The present invention discloses a process for the synthesis of fosinopril as a single desired isomer of high purity in two steps comprising of (a) preparation of fosinopril as a mixture of four diastereomers and (b) separation of the desired isomer from the mixture through formation of alkali metal salts followed by crystallisation.

1 - 47 . (canceled)  
   
   
       48 . A process for preparation of fosinopril sodium of formula (I)  
     
       
         
         
             
             
         
       
     
     predominantly in polymorphic Form-A which comprises (a) reacting a mixture containing four diastereomers of the formulae (IIA), (IIB), (IIC) and (IID)  
     
       
         
         
             
             
         
       
     
     with an alkali metal carrier in the presence of a solvent to obtain a mixture containing alkali metal salts of said four diastereomers of the formulae (IIA), (IIB), (IIC) and (IID); 
 (b) recrystallising from said solvent, a mixture containing predominantly alkali metal salts of the diastereomers of the formulae (IIA), and (IIC);  
 (c) treating said mixture with an acid;  
 (d) reacting the free acid so obtained with a cesium salt in the presence of a solvent;  
 (e) crystallizing from said solvent in the presence of water, a compound of formula (IIIA)  
                     
 (f) reacting said compound of formula (IIIA) with an acid in the presence of a solvent and water to give the fosinopril diastereomer (IIA)  
                     
 (g) converting compound (IIA) to fosinopril sodium polymorphic Form-A comprising mixing together said compound (IIA) with a sodium metal carrier in presence of a solvent or a mixture of solvents to fosinopril sodium of formula (I); and  
 (h) crystallizing the fosinopril sodium of formula (I) thus formed in the same solvent or mixture of solvents containing water content <0.20% to give fosinopril sodium polymorphic Form-A.  
 
   
   
       49 - 53 . (canceled)