Processes and Intermediates for Preparing a Macrocyclic Protease Inhibitor of HCV

Abstract

A process for preparing [(1R,2R)-4-oxo-1,2-cyclopentanedicarboxylic acid II, by the resolution of racemic 4-oxo-1,2-cyclopentanedicarboxylic acid (V), said process comprising: (a) reacting 4-oxo-1,2-cyclopentanedicarboxylic acid (V) with brucine or (1R,2S)-(−)-ephedrine, thus preparing the bis-brucine or bis-(1R,2S)-(−)-ephedrine salt of (V), and (b) precipitating selectively the bis-brucine or bis-(1R,2S)-(−)-ephedrine salt of (1R,2R)-4-oxo-1,2-cyclopentanedicarboxylic acid II, while the bis-brucine or bis-(1R,2S)-(−)-ephedrine salt of [(1S,2S)-4-oxo-1,2-cyclopentanedicarboxylic acid stays in solution; (c) liberating the acid II by removal of brucine or (1R,2S)-(−)-ephedrine from the precipitated salt obtained in step (b).

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The [(1R,2R)-4-oxo-1,2-cyclopentanedicarboxylic acid salt with brucine (1:2), having the structure III. 
     
     
         5 . The [(1R,2R)-4-oxo-1,2-cyclopentanedicarboxylic acid salt with (1R,2S)-(−)-ephedrine (1:2), having the structure IV. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . A compound of formula X: 
       
         
           
           
               
               
           
         
         wherein Bn is benzyl. 
       
     
     
         11 . A compound of formula XI: 
       
         
           
           
               
               
           
         
         wherein Bn is benzyl and Quin is as defined in  claim 8 . 
       
     
     
         12 . A compound of formula XII: 
       
         
           
           
               
               
           
         
         wherein Quin is as defined in  claim 8 . 
       
     
     
         13 . A compound of formula XIII: 
       
         
           
           
               
               
           
         
         wherein Quin is as defined in  claim 8 . 
       
     
     
         14 . A compound of formula XIV: 
       
         
           
           
               
               
           
         
         wherein Quin is as defined in  claim 8 . 
       
     
     
         15 . A compound of formula XIX: 
       
         
           
           
               
               
           
         
         wherein R 2  is hydrogen, C 1-4 alkyl, aryl, halogen, —SO 2 —C 1-4 alkyl, CN, or NO 2 . 
       
     
     
         16 . A compound of formula XX: 
       
         
           
           
               
               
           
         
         wherein R 2  is hydrogen, C 1-4 alkyl, aryl, halogen, —SO 2 —C 1-4 alkyl, CN, or NO 2 . 
       
     
     
         17 . A compound of formula XXI: 
       
         
           
           
               
               
           
         
         wherein R 2  is hydrogen, C 1-4 alkyl, aryl, halogen, —SO 2 —C 1-4 alkyl, CN, or NO 2 . 
       
     
     
         18 . The compound of  claim 15 ,  16  or  17 , wherein in the compound of formula XIX, respectively XX or XXI, R 2  is 4-NO 2 .