Chemical process

Abstract

Processes for preparing compounds of Formula I and IV are described.

1 . A process for the preparation of a compound of the Formula I 
     
       
         
         
             
             
         
       
     
     wherein,
 X 1  is selected from O, NR 1  or S; and 
 X 2  is selected from CH or N; 
 wherein R 1  is a nitrogen-protecting group, 
 which comprises:— 
 the sequential reaction of a compound of the Formula II 
 
     
       
         
         
             
             
         
       
     
     with,
   (i) methyl- or an optionally substituted aryl-lithium; and then   (ii) n-butyl-, s-butyl-, t-butyl- or n-hexyl-lithium; and then   (iii) a borate ester.   
 
   
   
       2 . The process according to  claim 1  wherein X 1  is O. 
   
   
       3 . The process according to  claim 1  wherein X 2  is N. 
   
   
       4 . The process according to  claim 1  wherein said methyl- or an optionally substituted aryl-lithium is 4-methylphenyllithium or methyllithium. 
   
   
       5 . The process according to of  claim 1  wherein said n-butyl-, s-butyl-, t-butyl- or n-hexyl-lithium is n-hexyllithium or n-butyllithium. 
   
   
       6 . The process according to  claim 1  wherein said borate ester is triisopropylborate. 
   
   
       7 . [4-(1,3,4-Oxadiazol-2-yl)phenyl]boronic acid prepared by the process as claimed in  claim 1 . 
   
   
       8 . A process for preparing compounds of Formula IV: 
     
       
         
         
             
             
         
       
     
     which comprises coupling [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a compound of Formula III: 
     
       
         
         
             
             
         
       
     
     wherein P is a nitrogen-protecting group. 
   
   
       9 . The process according to  claim 8  which takes place in the presence of
 (i) a source of palladium (0) selected from PdCl 2 , Pd(Ph 3 P) 4  or Pd(OAc) 2 ;   (ii) a suitable ligand selected from triphenylphosphine or 3,3′,3″-phosphinidyne tris(benzenesulphonic acid) trisodium salt;   (iii) a base selected from triethylamine, benzyldimethylamine, N-methylmorpholine, N-methylpiperidine, triethanolamine, ethyldiethanolamine, diisopropylethylamine, potassium acetate, cesium fluoride or potassium fluoride.   
   
   
       10 . The process according to  claim 8  wherein said [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid is prepared according to the process as claimed in of  claim 1 . 
   
   
       11 . The process according to  claim 8  wherein P is isobutoxycarbonyl. 
   
   
       12 . A compound of Formula IV: 
     
       
         
         
             
             
         
       
     
     wherein P is a nitrogen-protecting group. 
   
   
       13 . A compound of Formula IV as claimed in  claim 11  which is  N -(isobutoxycarbonyl)  N -(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulphonamide.