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] to form a compound of formula III, 
         wherein 
         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. 
       
     
     
         2 . The method of  claim 1  wherein X1 and X2 are the same or different leaving groups independently selected from
 phenyloxy optionally substituted by 1-5 suitable substituents on the phenyl ring, such as e.g. nitrophenyloxy like 2- or 4-nitrophenyloxy, or pentafluorophenyloxy, 
 heterocyclyl N-oxy optionally substituted by 1-5 suitable substituents on the heterocyclyl ring, such as e.g. N-succinimidoxy or N-phthalimidoxy, and 
 heteroaryl N-oxy optionally substituted by 1-5 suitable substituents on the heteroaryl ring, such as e.g. benzotriazol-1-oxy, 7-aza-benzotriazol-1-oxy or 1,2,3-benzotriazin-4(3H)-one-3-oxy. 
 
     
     
         3 . The method of  claim 1  wherein X2 is the same as X1. 
     
     
         4 . The method of  claim 1  wherein one of R1 and R2 is hydrogen and the other is an aromatic group. 
     
     
         5 . The method of  claim 1  wherein X1 and X2 are the same and are 4-nitrophenyloxy. 
     
     
         6 . The method of  claim 1  wherein X1 and X2 are the same and are benzotriazol-1-Oxy. 
     
     
         7 . The method of  claim 5  wherein said reaction is conducted at a reaction temperature from about 70° C. to about 120° C. 
     
     
         8 . The method of  claim 6  wherein said reaction is conducted at a reaction temperature from about 0° C. to about 50° C. 
     
     
         9 . The method of  claim 1  characterized in that said reaction is conducted without any Lewis acidic metal cation. 
     
     
         10 . The method of  claim 3  further comprising as a first step reacting a compound of formula I′ 
       
         
           
           
               
               
           
         
         in which 
         both X are the same or different leaving groups including those independently selected from the group consisting of halide, arylsulfonate, alkylsulfonate, perfluoroalkylsulfonate, arylsulfinate and alkylsulfinate, 
         with a hydroxy compound of formula H-X1 preferably in the presence of a suitable non-nucleophilic inorganic or organic auxiliary base, to form a compound of formula I. 
       
     
     
         11 . The method of  claim 10  wherein both X are the same and are chloride and/or wherein, as said auxiliary base, N,N-diisopropyl-ethylamine is present. 
     
     
         12 . The method of  claim 10  wherein the preparation reaction of said compound of formula I is conducted at a reaction temperature from about 0° C. to about 70° C. 
     
     
         13 . The method of  claim 10  wherein one or more of the following is used:
 relative to the amount of said compound of formula I′,
 1.0-2.4 equivalents of said hydroxy compound of formula H-X1, 
 1.5-2.3 equivalents of said auxiliary base, and 
 1.0-1.2 equivalents of said amine of formula II. 
 
 
     
     
         14 . The method of  claim 1  wherein said reaction is conducted in a suitable organic solvent or mixture of solvents, such as e.g. comprising tetrahydrofurane, 2-methyl-tetrahydrofurane, N-methyl-2-pyrrolidinone, or one or more non-nucleophilic alcohols like tert-butanol, tert-pentanol, neo-pentanol, sec-pentanol and/or sec-isoamylalcohol, or mixtures thereof. 
     
     
         15 . The method of  claim 1  further comprising the step of reacting the compound of formula III with an oxygen, sulphur or nitrogen nucleophile. 
     
     
         16 . The method of  claim 1  wherein one or more of the intermediates obtained are isolated. 
     
     
         17 . The method of  claim 1  wherein one or more of the intermediates obtained are not isolated. 
     
     
         18 . 2,4-bis(p-nitrophenyloxy)-5-trifluoromethylpyrimidine. 
     
     
         19 . 2,4-bis(benzotriazol-1-oxy)-5-trifluoromethylpyrimidine.