Process for the production of quinazolines

Abstract

The present invention relates to a novel process for producing quinazoline compounds which are useful in therapy. More specifically, the compounds are useful in the treatment of benign prostatic hyperplasia.

1 . A process wherein the compound of formula (C):  
       
         
           
           
               
               
           
         
       
       wherein; 
 R 5  and R 6  taken together represent a 4-, 5-, 6-, or 7-membered N-containing heterocyclic ring optionally containing at least one further heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C 1-4  alkyl, C 1-4  alkoxy, halogen, CONR 7 R 8 , SO 2 NR 7 R 8 , (CH 2 ) b NR 8 R 9  and NHSO 2 (C 1-4  alkyl), and when S is a member of the ring system, it may be substituted by 1 or 2 oxygen atoms;  
 R 7  and R 8  independently represent H or C 1-4 alkyl, or together with the N atom to which they are attached they may represent a 5- or 6-membered heterocyclic ring containing at one heteroatom selected from N, O and S; and  
 b represents 0, 1, 2 or 3  
 is formed by reaction of a compound of formula (E) with a compound of formula (F):  
                     
 
     
     
         2 . A process as claimed in  claim 1 , wherein R 5  and R 6  together with the N atom to which they are attached represent a saturated 6-membered N-containing ring which is fused to an optionally substituted benzene or pyridine ring.  
     
     
         3 . A process as claimed in  claim 2 , wherein R 5  and R 6  together with the N atom to which they are attached represent a tetrahydroisoquinoline ring system.  
     
     
         4 . A process as claimed in  claim 3 , wherein R 5  and R 6  together with the N atom to which they are attached represent 5-methylsulfonylamino tetrahydroisoquinoline.  
     
     
         5 . A process as claimed in  claim 1 , wherein the reaction is carried out in the presence of an aqueous base.  
     
     
         6 . A process as claimed in  claim 5 , wherein the aqueous base is sodium hydroxide.  
     
     
         7 . A process as claimed in  claim 1 , wherein the compound of formula (C) is N-(2-amidino-1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide.  
     
     
         8 . A process wherein the compound of formula (B):  
       
         
           
           
               
               
           
         
       
       wherein; 
 R 1  represents C 1-4  alkoxy optionally substituted by one or more fluorine atoms;  
 R 2  represents H or C 1-6  alkoxy optionally substituted by one or more fluorine atoms; are as defined above; and  
 R 3  represents a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally substituted by one or more groups selected from halogen, C 1-4  alkoxy, C 1-4  alkyl and CF 3 ;  
 is formed by reaction of the compound of formula (D):  
                     
 wherein;  
 R 1  to R 3  are as defined above; and  
 R 9  is a leaving group; with a pyridine derivative.  
 
     
     
         9 . A process as claimed in  claim 8 , wherein R 9  is iodine.  
     
     
         10 . A process as claimed in  claim 8 , wherein the pyridine derivative is a pyridyl boronate.  
     
     
         11 . A process as claimed in  claim 8 , wherein the reaction is carried out in a polar aprotic solvent.  
     
     
         12 . A process as claimed in  claim 11 , wherein the polar aprotic solvent is dioxane.  
     
     
         13 . A process as claimed in  claim 8 , wherein the reaction is carried out in the presence of a catalyst.  
     
     
         14 . A process as claimed in  claim 13 , wherein the catalyst is a palladium (0) catalyst.  
     
     
         15 . A process as claimed in  claim 8 , wherein the product is 6-fluoro-3,4-dimethoxy-2-(2-pyridyl)benzonitrile.