Regioselective preparation of 2-amino-5-trifluoromethylpyrimidine derivatives

Abstract

The present invention relates to a method of making 2,4-differentiated 5-trifluoromethylpyrimidines, which are useful as intermediates in the manufacture of active pharmaceutical substances.

1 . A process for making a compound of formula III 
       
         
           
           
               
               
           
         
         wherein 
         T is an oxygen, sulphur or nitrogen functionality; and 
         R1 and R2 are substituents independently selected from the group consisting of hydrogen, an aromatic group and an aliphatic group, or taken together —N(R1)R2 can form a 4-11 membered aromatic or aliphatic ring; 
         said method comprising reacting a compound of formula I 
       
       
         
           
           
               
               
           
         
         in which 
         X1 is a leaving group selected from the group consisting of: 
         phenyloxy optionally substituted by 1-5 suitable substituents, 
         heterocyclyl N-oxy optionally substituted by 1-5 suitable substituents, and 
         heteroaryl N-oxy optionally substituted by 1-5 suitable substituents, and 
         X2 is a leaving group, 
         with an oxygen, sulfur or nitrogen nucleophile of formula T-H; 
         and 
         reacting the compound obtained with an amine of formula II
   HN(R1)R2  (II)
 
 
         to form a compound of formula III. 
       
     
     
         2 . The process of  claim 1  wherein X1 and X2 are different leaving groups. 
     
     
         3 . The process of  claim 1  wherein X2 is chlorine. 
     
     
         4 . The process of  claim 1  wherein one of R1 and R2 is hydrogen and the other is an aromatic group. 
     
     
         5 . The process of  claim 1  wherein X2 is chlorine and X1 is 4-chlorophenyloxy. 
     
     
         6 . The process of  claim 1  wherein X2 is chlorine and X1 is 4-nitrophenyloxy. 
     
     
         7 . The process of  claim 1  further comprising the step of preparing the compound of formula I by reacting a compound of formula I′ 
       
         
           
           
               
               
           
         
         in which 
         X and X′ are the same or different, and 
         X′ is X2, and 
         X is a leaving group, 
         with a hydroxy compound of formula XI-H, preferably in the presence of a suitable inorganic or organic auxiliary base, to form said compound of formula I. 
       
     
     
         8 . The process of  claim 7  wherein X and X′ are the same and are chlorine and/or wherein, as said auxiliary base, N-methyl-morpholine is present. 
     
     
         9 . The process of  claim 8  wherein the preparation reaction of said compound of formula I is conducted in ethanol, 2-propanol or a mixture thereof.