Process for the preparation of valsartan

Abstract

Provided is a process for preparing valsartan and precursors thereof.

1 . Valsartan substantially free of its isoleucine analogue produced by a process comprising the steps of:
 a) obtaining one or more samples of at least a single valine or valine derivative batch;   b) measuring the level of isoleucine or corresponding isoleucine derivative in each of the samples of step (a);   c) selecting the batch of valine or its derivative that comprises a level of isoleucine or isoleucine derivative of less than about 0.1% as area percentage GC based on the measurement or measurements conducted in step (b); and   d) using the batch selected in step (c) to synthesize said valsartan.   
     
     
         2 . The process of  claim 1 , wherein the valsartan contains less than about 0.1% as area percentage HPLC its corresponding isoleucine derivative. 
     
     
         3 . The process of  claim 2 , wherein the level is 0.07%. 
     
     
         4 . The process of  claim 1 , wherein the level of the isoleucine or the corresponding isoleucine derivative in the batch of valine or its derivative of step (c) is less than about 0.07% as area percentage GC. 
     
     
         5 . The process of  claim 1 , wherein the analysis is carried out of the valine derivative in regard to its corresponding isoleucine derivative. 
     
     
         6 . Valsartan produced by a process comprising synthesizing valsartan from an initial sample of valine or a valine derivative, wherein the process analyzes the level of isoleucine or corresponding isoleucine derivative present in the initial sample at least at a single stage during the synthetic process to control amount of an impurity having the following structure: 
       
         
           
           
               
               
           
         
         being present in valsartan. 
       
     
     
         7 . The process of  claim 6  wherein the desirable level of the isoleucine analogue is NMT 0.1% as area percentage HPLC. 
     
     
         8 . The process of  claim 6 , wherein the analysis is carried out of the valine derivative in regard to its corresponding isoleucine derivative. 
     
     
         9 . The process of  claim 8 , wherein the derivative that is analyzed is a methyl ester. 
     
     
         10 . Valsartan produced by a process comprising the steps of:
 a) analyzing a C 1  to C 4  alkyl ester of L-valine for presence of its isoleucine analogue as an impurity;   b) selecting a sample that has NMT about 0.1% as area percentage GC of the isoleucine analogue of L-valine as determined by HPLC;   c) reacting compound G2:   
       
         
           
           
               
               
           
         
         with the L-valine ester in a first organic solvent to obtain a compound G3: 
       
       
         
           
           
               
               
           
         
         reacting compound G3 with an acylating agent in a second organic solvent to obtain a compound G4; 
       
       
         
           
           
               
               
           
         
         
           and 
         
         e) hydrolyzing compound G4 to obtain valsartan.
 wherein A is a C 1  to C 4  alkyl ester, X is a trityl group and L is a leaving group. 
 
       
     
     
         11 . The process of  claim 10 , wherein the first and second organic solvents are independently selected from the group consisting of acetonitrile, toluene, acetone, ethyl acetate, dimethyl acetamide, DMF, hexane and mixtures thereof. 
     
     
         12 . The process of  claim 10 , wherein step (c) is carried out in acetonitrile. 
     
     
         13 . The process of  claim 10 , wherein the valsartan contains less than 0.1% of its corresponding isoleucine derivative as area percentage HPLC. 
     
     
         14 . A pharmaceutical composition of valsartan comprising valsartan substantially free of its isoleucine analogue and a pharmaceutically acceptable excipient. 
     
     
         15 . A method of lowering systematic blood pressure in a human in need thereof comprising the step of administering the pharmaceutical composition of  claim 14  to the human.