Synthesis of 6,7-Dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonic acid amides

Abstract

Disclosed is a multi-step process for preparing a compound of Formula I: wherein R 1 to R 3 are as defined herein. The compounds of formula I inhibit the binding of human intercellular adhesion molecules to the Leukointegrins. As a result, these compounds are useful in the treatment of inflammatory and immune cell-mediated diseases.

1 . A compound of the formula XIX: 
     
       
         
         
             
             
         
       
       wherein R 1  is selected from bromo, trifluoromethoxy, cyano and pyrimidin-5-yl optionally mono- or di-subsituted by NH 2 ; and R b  is C 1-4  alkyl. 
     
   
   
       2 . A process for preparing a compound of formula XIX according to  claim 1 , said process comprising reacting the compound of formula XVII, wherein R 1  is as defined in  claim 1 , with a compound of formula XVIII, where R a  is aryl and R b  is C 1-4  alkyl, and an organic base in a polar organic solvent to form a compound of the formula XIX: 
     
       
         
         
             
             
         
       
     
   
   
       3 . A process for preparing a compound of formula XX, wherein R 1  is selected from bromo, trifluoromethoxy, cyano and pyrimidin-5-yl optionally mono- or di-subsituted by NH 2 , said process comprising:
 reacting the compound of formula XIX according to  claim 1  with a compound of formula (R c ) 3 P, where R c  is C 1-4 alkyl, C 3-6 cycloalkyl or aryl, a carbon tetrahalide and a tri-C 1 I 6 alkylamine in an aprotic organic solvent, followed by adding an acid to form a compound of the formula XX, or   alternatively, reacting a compound of the formula XIX with a compound of the formula (R c ) 3 PX 2 , wherein R c  is C 1-4 alkyl, C 3-6 cycloalkyl or aryl, and X is a halide, and a tri-C 1-6 alkylamine, in an aprotic organic solvent, followed by adding an acid to form a compound of the formula XX, or   alternatively, reacting a compound of formula XIX with a boronic acid compound ArB(OH) 2 , wherein Ar is an aromatic carbocyclic group substituted with one or more electron withdrawing groups, in an aprotic organic solvent to form a compound of the formula XX: