Processes for the Preparation of Veliparib and Intermediates Thereof

Abstract

The present invention provides processes for the preparation of Veliparib (1), as well as intermediates useful in the preparation thereof. In particular, processes are provided for the production of the compound of Formula (3), or a salt thereof, and cyclization to afford Veliparib (1).

What is claimed is: 
     
         1 . A process for preparing Veliparib (1): 
       
         
           
           
               
               
           
         
         or a salt thereof, from a compound of Formula (2): 
       
       
         
           
           
               
               
           
         
         or the salt thereof, wherein
 R is CO 2 R 1  or CN; and 
 R 1  is selected from a group consisting of H, an aliphatic group, a substituted aliphatic group, an aryl, a substituted aryl, an arylalkyl, and a substituted arylalkyl, 
 
         the process comprising:
 (i) when R is CO 2 R 1  and R 1  is H, treating the compound of Formula (2) with a chlorinating agent to activate the carboxylic acid followed by amidating the activated carboxylic acid with a source of ammonia; 
 (ii) when R is CO 2 R 1  and R 1  is selected from the group consisting of the aliphatic group, the substituted aliphatic group, the aryl, the substituted aryl, the arylalkyl, and the substituted arylalkyl, amidating the compound of Formula (2) with the source of ammonia; or 
 (iii) when R is CN, hydrolyzing the compound of Formula (2) in the presence of an acid (A2) or a base (B3). 
 
       
     
     
         2 . The process of  claim 1 , wherein R is CO 2 R 1 , R 1  is C1-C6 alkyl, and the process is conducted according to step (ii). 
     
     
         3 . The process of  claim 2 , wherein the ammonia source is selected from the group consisting of ammonia gas, ammonium hydroxide, and methanolic ammonia. 
     
     
         4 . The process of  claim 3 , wherein the ammonia source is methanolic ammonia. 
     
     
         5 . The process of  claim 1 , wherein R is CO 2 R 1  and R 1  is H, and the chlorinating agent in step (i) is selected from the group consisting of thionyl chloride and oxalyl chloride, and the source of ammonia is selected from the group consisting of ammonia gas, ammonium hydroxide, and methanolic ammonia. 
     
     
         6 . The process of  claim 1 , wherein R is CN and converting the compound of Formula (2) to Veliparib (1) according to step (iii) comprises hydrolyzing the compound of Formula (2) with the base (B3) which is potassium t-butoxide. 
     
     
         7 . A compound of Formula (2): 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein
 R is CO 2 R 1  or CN; and 
 R 1  is selected from a group consisting of H, a C2-C10 aliphatic group, a C1-C10 substituted aliphatic group, an aryl, a substituted aryl, an arylalkyl, and a substituted arylalkyl. 
 
       
     
     
         8 . The compound of  claim 7 , or the salt thereof, wherein R is CO 2 R 1  and R 1  is C2-C6 alkyl. 
     
     
         9 . The compound of  claim 7 , or the salt thereof, wherein R is CO 2 R 1  and R 1  is H.