Concise process for preparing 3-pyrrolidine carboxylic acid derivatives

Abstract

The present invention relates to a process for preparing 3-pyrrolidine carboxylic acid derivatives, and particularly a simple process for preparing 5-substituted 3-pyrrolidine carboxylic acid derivatives. In addition, the present invention relates to a novel pyrrolidine carboxylic acid derivative, its manufacture, pharmaceutical compositions containing it and its use as a catalyst.

1 . A process for preparing compound of formula IV: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are each independently hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, halo-C 1-7 -alkyl, C 1-7 -alkoxy-C 1-7 -alkyl, aryl-C 1-7 -alkyl, or heteroaryl-C 1-7 -alkyl; or 
 R 1  and R 2  together form —(CH 2 ) n —, and n is 2 to 6; 
 R 3  is hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, halo-C 1-7 -alkyl, C 1-7 -alkoxy-C 1-7 -alkyl, aryl-C 1-7 -alkyl, or heteroaryl-C 1-7 -alkyl; 
 R 4  is hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, halo-C 1-7 -alkyl, C 1-7 -alkoxy-C 1-7 -alkyl, aryl-C 1-7 -alkyl, or heteroaryl-C 1-7 -alkyl; and 
 R 5  is hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, halo-C 1-7 -alkyl, C 1-7 -alkoxy-C 1-7 -alkyl, aryl-C 1-7 -alkyl, or heteroaryl-C 1-7 -alkyl; 
 or a pharmaceutically acceptable salt thereof, which process comprises 
 step A: reacting compound of formula II: 
 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined above, with compound of formula III: 
       
       
         
           
           
               
               
           
         
         wherein R 3 , R 4  and R 5  are as defined above, in the presence of at least one of compound X which is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       to obtain compound of formula IV. 
     
     
         2 . The process according to  claim 1  for preparing compound of formula IV: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are each independently hydrogen, C 1-7 -alkyl, or halo-C 1-7 -alkyl-; or 
 R 1  and R 2  together form —(CH 2 ) n —, and n is 2 to 5; 
 R 3  is hydrogen, C 1-7 -alkyl, or halo-C 1-7 -alkyl; 
 R 4  is hydrogen, C 1-7 -alkyl, halo-C 1-7 -alkyl, or aryl-C 1-7 -alkyl; and 
 R 5  is hydrogen, C 1-7 -alkyl, or halo-C 1-7 -alkyl; 
 or a pharmaceutically acceptable salt thereof, which process comprises 
 step A: reacting compound of formula II: 
 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined above, with compound of formula III: 
       
       
         
           
           
               
               
           
         
         wherein R 3 , R 4  and R 5  are as defined above, in the presence of at least one of compound X which is selected from the group of B, D, E, F, and F′ 
         to obtain compound of formula IV. 
       
     
     
         3 . The process according to  claim 1  for preparing compound of formula IV: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are each independently hydrogen or C 1-7 -alkyl; or 
 R 1  and R 2  together form —(CH 2 ) n —, and n is 4 or 5; 
 R 3  is hydrogen or C 1-7 -alkyl; 
 R 4  is hydrogen, C 1-7 -alkyl, or benzyl; and 
 R 5  is hydrogen or C 1-7 -alkyl; 
 or a pharmaceutically acceptable salt thereof, which process comprises 
 step A: reacting compound of formula II: 
 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are as defined above, with compound of formula III: 
       
       
         
           
           
               
               
           
         
         wherein R 3 , R 4  and R 5  are as defined above, in the presence of at least one of compound X which is selected from the group of F and F′ 
         to obtain compound of formula IV. 
       
     
     
         4 . The process according to  claim 1 , which process further comprises
 reacting the compound of formula II with the compound of formula III, in the presence of an additive.   
     
     
         5 . The process according to  claim 4 , wherein
 the additive is at least one selected from the group consisting of acetic acid, benzoic acid, and imidazole.   
     
     
         6 - 12 . (canceled)