Processes for the Preparation of Benzoimidazole Derivatives

Abstract

The present invention relates to a process for preparing a compound of the formula I or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof. wherein R 1 , R 2 , R 3 and R 4 are as defined herein. The compound of formula I is useful in the treatment of abnormal cell growth, such as cancer in mammals.

1 .- 40 . (canceled)  
   
   
       41 . A process for preparing a compound of formula VI  
     
       
         
         
             
             
         
       
       wherein Bn is benzyi;.  
       wherein each R 1 , R 2 , and R 3  is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, C 3 -C 6 )cycloalkyl, halo, cyano, CF 3 , difluoromethoxy, trituoromethoxy, —O(C 1 -C 6 )alkyl, —O(C 3 -C 6 )cycloalkyl, and —NR 12 R 13 ;  
       wherein R 4  is —(CR 5 R 6 ) m H or —(CR 7 R 8 ) n (4 to 10membered)-aromatic or non-aromatic heterocyclic, wherein m is an integer rangng from 1 to 5, wherein n is an integer ranging from 0 to 5 wherein said 4 to 10 membered heterocyclic when aromatic is optionally substituted by 1 to 3 R 11  substituents, and wherein said 4 to 10 membered heterocyclic wnen non-aromatic is opotionally substituted by 1 to 3 R 10  substituents at any position and optionally subtstituted by 1 to 3 R 11  substituents at any position not adacent to or directly attached to a heteroatom;  
       wherein each R 5 , R 6 , R 7  and R 8  is independently selected froml the group consisting of H and (C 1 -C 6 )alkyl;  
       wherein each R 9  is independently selected from H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo, cyano, CF 3 , difluoromethoxy, trifluoromethoxy, —O(C 1 -C 6 )alkyl, —O(C 1 -C 6 )cycloalkyl, and —NR 14 R 15 ;  
       wherein each R 10  is independently selected from H, (C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkyl;  
       wherein each R 11  is independently selected from halo, cyano, CF 3 , difluoromethoxy, trifluoromethoxy; —O(C 1 -C 6 )alkyl, —O(C 3 -C 6 )cycloalkyl, and —NR 16 R 17 ;  
       wherein R 12 , R 13 , R 14 , R 15 , R 16  and R 17  are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkyl;  
       wherein each of the aforesaid (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, —O(C 1 -C 6 )alkyl and —O(C 3 -C 6 )cycloalkyl substituents wherever they occur may optionally be independently substituted by one to three substituents independently selected from the group consisting of halo cyano, amino, (C 1 -C 6 )akylamino, [(C 1 -C 6 )alkyl] 2 -amino, perhalo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, and (C 1 -C 6 )alkoxy; comprising reacting a compound of formula VII  
       
         
           
           
               
               
           
         
       
       wherein R 3  and R 4  are as defined above for formula VI, with a compound of formula VIII  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are as defined above for formula VI, in the presence of 1, 2-Bis(diphenylphosphino)ethane, a palladiun catalyst and a base.  
     
   
   
       42 . A process according to  claim 41 , wherein the palladium catalyst is palladium acetate.  
   
   
       43 . A process according to  claim 41 , wherein the palladium catalyst is tris(dibenzylidene acetone) dipalladium (0).  
   
   
       44 . A process according to  claim 42 , wherein the base is cesiuim carbonate.  
   
   
       45 . A process according to  claim 42 , wherein each R 1 , R 2 , and R 3  is independently selected from H, (C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkyl, halo, and cyano.  
   
   
       46 . A process according to  claim 44 , wherein R 4  is —(CR 7 R 8 ) n (4 to 10 membered)-non-aromatic heterocyclic, wherein n is an integer from 0 to 1 and wherein said 4 to 10 membered nonaromatic heterocyclic group is optionally substituted by 1 to 3 R 10  substituents.  
   
   
       47 . A process according to  claim 46 , wherein said 4 to 10 membered non-aromatic heterocyclic is selected from the group consisting of tetrahydrofuranyl, morpholino and oxetanyl.  
   
   
       48 . A process according to  claim 47 , wherein said 4 to 10 membered non-aromatic heterocyclic is oxetanyl.  
   
   
       49 . A process according to  claim 41 , wherein R 1  and R 2  are both hydrogen, and the compound of formula VII is a compound of formula VIIA.  
     
       
         
         
             
             
         
       
     
   
   
       50 . A process according to  claim 41 , wherein the reaction is performed in the presence of an aromatic solvent, an ether or a mixture thereof.  
   
   
       51 . A process according to  claim 50 , wherein the reaction is performed in the presence of an aromatic solvent.  
   
   
       52 . A process according to claimn  51 , wherein the aromatic solvent is toluene.  
   
   
       53 . A process according to  claim 41 , wherein the reaction is performed at a temperature of ahout 90° C. to about 120° C.  
   
   
       54 . A process according to  claim 50 , wherein the ether is at least one member selected from the group consisting of tetrahydrofuran, dimethoxyethane, dimethylformamide and dioxane.