PROCESSES AND INTERMEDIATES IN THE PREPARATION OF C5aR ANTAGONISTS

Abstract

Intermediates and methods are provided for the preparation of selected C5aR antagonist compounds.

1 .- 2 . (canceled) 
     
     
         3 . A method of preparing a compound having formula (I): 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein 
         R 1  is Cl or CF 3 ; 
         R 2  is F or Cl; and 
         R 3  is H or CH 3 ; 
       
       and wherein said compound of formula (I) is substantially free of enantiomeric or diastereomeric impurities, said method comprising: 
       (a) contacting a compound having the formula (i-3): 
       
         
           
           
               
               
           
         
       
       wherein R is selected from the group consisting of H, C 1-8  alkyl, aryl and aryl-C 1-4  alkyl, which is substantially free of enantiomeric or diastereomeric impurities, or a salt thereof, with a compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein LG is a leaving group; R 2  is F or Cl; and R 3  is H or CH 3 ; under conditions sufficient to form a compound of formula (i-4): 
       
         
           
           
               
               
           
         
       
       and 
       (b) contacting said compound of formula (i-4) with an aniline having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is Cl or CF 3 , in the presence of an organoaluminum reagent, an alkyllithium compound, a Grignard regent, an organozinc reagent, sodium hydride, and sodium, potassium or lithium HMDS salts to provide a compound of formula (I). 
     
     
         4 . (canceled) 
     
     
         5 . A method in accordance with  claim 3 , wherein step (b) includes hydrolysis of the ester present in said compound of formula (i-4), and contacting the intermediate carboxylic acid compound produced with an aniline having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is Cl or CF 3 ; under conditions sufficient to provide said compound of formula (I). 
     
     
         6 . A method of  claim 3 , wherein R 1  is CF 3 , R 2  is F, and R 3  is CH 3 . 
     
     
         7 . A method of  claim 3 , wherein R 1  is CF 3 , R 2  is Cl, and R 3  is H. 
     
     
         8 . A method of  claim 3 , wherein R 1  is Cl, R 2  is F, and R 3  is CH 3 . 
     
     
         9 .- 20 . (canceled)