Regioselective preparation of substituted pyrimidines

Abstract

The present invention relates to a method of making pyrimidines of formula (III) wherein X1, X2, R1 and R2 have the meanings as defined herein.

What is claimed is: 
     
         1 . A method for making a compound of formula III 
       
         
           
           
               
               
           
         
       
       wherein
 X2 is a leaving group, and 
 R1 and R2 are substituents independently selected from hydrogen, an aromatic group and an aliphatic group, or taken together —N(R1)R2 can form a 4-11 membered aromatic or aliphatic ring, 
 comprising reacting a compound of formula I 
 
       
         
           
           
               
               
           
         
         with an amine of formula II [HN(R1)R2] 
         in the presence of a non-nucleophilic auxiliary base 
         in a solvent or mixture of solvents selected from non-nucleophilic alcohols 
         to form a compound of formula III, 
       
       wherein
 X1 is a leaving group. 
 
     
     
         2 . The method of  claim 1  wherein X1 and X2 are the same or different leaving groups independently selected from halide, arylsulfonate, alkylsulfonate, perfluoroalkylsulfonate, arylsulfinate and alkylsulfinate. 
     
     
         3 . The method of  claim 1  wherein X1 and X2 are the same or different leaving groups and are each independently halides. 
     
     
         4 . The method of  claim 1  wherein X1 and X2 are chloride. 
     
     
         5 . The method of  claim 1  wherein one of R1 and R2 is hydrogen and the other is an aromatic group, such as e.g. optionally substituted phenyl. 
     
     
         6 . The method of  claim 1  wherein said non-nucleophilic auxiliary base is N,N-diisopropyl-ethylamine. 
     
     
         7 . The method of  claim 1  wherein said non-nucleophilic alcohols are tert-butanol, tert-pentanol, neo-pentanol, sec-pentanol and sec-isoamylalcohol. 
     
     
         8 . The method of  claim 1  wherein said reaction is conducted in tert-butanol as reaction solvent. 
     
     
         9 . The method of  claim 1  wherein said reaction is conducted at a reaction temperature from about room temperature to about boiling temperature of the solvent(s) used. 
     
     
         10 . The method of  claim 1  wherein said reaction is conducted at a reaction temperature from about 40° C. to about 80° C. 
     
     
         11 . The method of  claim 1  wherein said reaction is conducted at about 80° C. 
     
     
         12 . The method of  claim 1  characterized in that said reaction is conducted without any Lewis acidic metal cation. 
     
     
         13 . The method of  claim 1  further comprising the steps of precipitating the compound of formula III from the reaction mixture, collecting the precipitate, washing the precipitate and drying the precipitate. 
     
     
         14 . The method of  claim 1  further comprising the step of reacting said compound of formula III with an oxygen, sulphur or nitrogen nucleophile. 
     
     
         15 . The method of  claim 13  further comprising suspending the precipitate in water after it is precipitated from the reaction mixture. 
     
     
         16 . The method of  claim 13  characterized in that the precipitate is a substantially regioisomerically pure compound of formula III. 
     
     
         17 . The method of  claim 1  characterized in that a substantially regioisomerically pure compound of formula III is produced.