Crystalline pharmaceutical and methods of preparation and use thereof

Abstract

Novel crystalline polymorphic forms, Forms A, B, C, D, and E of a compound of Formula I, which has been found to be a potent inhibitor of LFA-1, are disclosed. Methods of preparation and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed in this invention.

1 . A method of synthesizing a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       comprising the steps:
 a) base hydrolysis of Formula AA with a base in an aprotic solvent: 
 
       
         
           
           
               
               
           
         
       
       wherein R is a carbon containing moiety; and
 b) isolating a compound of Formula I. 
 
     
     
         2 . The method of  claim 1 , wherein the aprotic solvent is dioxane. 
     
     
         3 . The method of  claim 1 , wherein the base is sodium hydroxide. 
     
     
         4 . The method of  claim 1 , wherein R is a substituted or unsubstituted group selected from lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, aryl, aralkyl, heterocyclyl, and heteroaryl groups. 
     
     
         5 . The method of  claim 1 , comprising the steps:
 a) base hydrolysis of Formula A:   
       
         
           
           
               
               
           
         
       
       with a base in an aprotic solvent; and
 b) isolating a compound of Formula I. 
 
     
     
         6 . The method of  claim 5 , wherein the aprotic solvent is dioxane. 
     
     
         7 . The method of  claim 5 , wherein the base is sodium hydroxide. 
     
     
         8 . A method of synthesizing a compound of Formula I: 
       
         
           
           
               
               
           
         
         comprising the steps: 
         a) acid hydrolysis of Formula AA with an acid in an aprotic solvent: 
       
       
         
           
           
               
               
           
         
       
       wherein R is a carbon containing moiety; and
 b) isolating a compound of Formula I. 
 
     
     
         9 . The method of  claim 8 , wherein the aprotic solvent is dioxane. 
     
     
         10 . The method of  claim 8 , wherein the acid is hydrogen chloride. 
     
     
         11 . The method of  claim 8 , wherein R is a substituted or unsubstituted group selected from lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, aryl, aralkyl, heterocyclyl, and heteroaryl groups. 
     
     
         12 . The method of  claim 8 , comprising the steps:
 a) acid hydrolysis of Formula A:   
       
         
           
           
               
               
           
         
       
       with an acid in an aprotic solvent; and
 b) isolating a compound of Formula I. 
 
     
     
         13 . The method of  claim 12 , wherein the aprotic solvent is dioxane. 
     
     
         14 . The method of  claim 12 , wherein the acid is hydrogen chloride. 
     
     
         15 . An isolated compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein said compound is synthesized according to the method of  claim 1 , and further wherein said compound has a lower level of residual palladium compared to a compound of Formula I prepared by palladium-catalyzed transfer hydrogenolysis.