Hepatitis C Virus Inhibitors

Abstract

The present disclosure relates to methods for making compounds useful in the treatment of Hepatitis C virus (HCV) infection.

1 . A process for preparing a compound of formula (X) 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from hydrogen and a nitrogen protecting group; 
         the process comprising:
 (a) reacting a compound of formula (II) 
 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from hydrogen and a nitrogen protecting group; and 
 R 2  is selected from amino, alkoxy, and arylalkoxy; and 
 with a base, and 
 (b) treating the product of step (a) with water. 
 
       
     
     
         2 . The process of  claim 1  wherein R 1  is hydrogen. 
     
     
         3 . The process of  claim 1  wherein R 1  is a nitrogen protecting group. 
     
     
         4 . The process of  claim 3  wherein the nitrogen protecting group is a tert-butoxycarbonyl group. 
     
     
         5 . The process of  claim 1  wherein the base is selected from a metal alkoxide and a metal hydroxide. 
     
     
         6 . The process of  claim 5  wherein the base is selected from sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium isopropoxide, potassium tert-butoxide, lithium tert-butoxide, and lithium isopropoxide. 
     
     
         7 . The process of  claim 1  further comprising treating a product of formula (I) 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen; 
         with a nitrogen protecting reagent to provide a compound of formula (I) 
       
       
         
           
           
               
               
           
         
         wherein R 1  is a nitrogen protecting group. 
       
     
     
         8 . The process of  claim 7  wherein the nitrogen protecting group is tert-butoxy carbonyl. 
     
     
         9 . A process for preparing a compound of formula (Z) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 4  and R 5  are independently selected from hydrogen, alkyl, aryl, arylalkyl, heterocyclyl, and heterocyclylalkyl; 
 the process comprising: 
 treating a compound of formula (Q) 
 
       
       
         
           
           
               
               
           
         
         with a base in the presence of ammonium acetate. 
       
     
     
         10 . The process of  claim 9  wherein the base is selected from a tertiary amine, an aromatic amine, an aniline, and a substituted imidazole. 
     
     
         11 . The process of  claim 9  wherein the base is selected from 1,4-dimethylpiperazine, 3-quinuclidinol, 3-methylpyridine, 1-methylimidazole, dimethylbutylamine, N,N-dimethylaniline, dimerpranol, quinoxazoline, creatinine, 2-methylimidazole, 4-methylimidazole, imidazole, morpholine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, collidine, 4-chloroimidazole, 2-chloroimidazole, 4-cyanoimidazole, benzimidazole, diisopropylethylamine and 2,6-lutidine. 
     
     
         12 . The process of  claim 9  wherein the base is imidazole. 
     
     
         13 . A process for the preparation of Example 145 
       
         
           
           
               
               
           
         
         Example 145, 
       
       the process comprising:
 (a) treating Example 143 
 
       
         
           
           
               
               
           
         
         Example 143, 
       
       with Example 144 
       
         
           
           
               
               
           
         
         Example 144, 
       
       in the presence of a base to produce a compound of formula (V) 
       
         
           
           
               
               
           
         
         (b) treating the compound of formula (V) with ammonium acetate in the presence of a base; and 
         (c) treating the product of step (b) with methanol. 
       
     
     
         14 . The process of  claim 13  which is a continuous process.