Method for preparation of optionally 2-substituted 1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acids

Abstract

A new method for the preparation of optionally 2-substituted 1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acid compounds of Formula 1 is disclosed wherein R 1 is H or an optionally substituted carbon moiety. Also disclosed is the method comprising additional steps to prepare optionally substituted 4-pyrimidinecarboxylic acids and esters using the compound of Formula 1 as an intermediate.

1 - 25 . (canceled) 
     
     
         26 . A method for preparing a compound of Formula 1 or 1a 
       
         
           
           
               
               
           
         
       
       wherein R 1  is optionally substituted cyclopropyl or an optionally substituted phenyl; comprising the steps of:
 (1) contacting a mixture comprising (a) a compound of Formula 2a 
 
       
         
           
           
               
               
           
         
       
       wherein M is alkali metal and R 2  and R 3  are independently C 1 -C 4  alkyl, (b) a C 1 -C 4  alkanol, and (c) a first portion of water, with a solution comprising a first base and a second portion of water, said base being in an amount sufficient to create a first resultant solution having a pH ranging from about 10 to about 14, said first resultant solution comprising a compound of Formula 2b, 
       
         
           
           
               
               
           
         
       
       wherein M and R 3  are defined as above for Formula 2a;
 (2) contacting the first resultant solution comprising the compound of Formula 2b with a compound of Formula 3 or an acid salt thereof or with a solution comprising a compound of Formula 3 or an acid salt thereof, 
 
       
         
           
           
               
               
           
         
         wherein R 1  is defined as above for Formula 1, and a second base in an amount sufficient to create a second resultant solution having a pH ranging from about 9 to about 12, said second resultant solution comprising a salt of the compound of Formula 1; and 
         (3) adding an acid to the second resultant solution comprising the salt of the compound of Formula 1 to form the compound of Formula 1. 
       
     
     
         27 . The method of  claim 26  wherein R 1  is optionally substituted cyclopropyl. 
     
     
         28 . The method of  claim 26  wherein the first base added in step (1) is an alkali metal hydroxide. 
     
     
         29 . The method of  claim 26  wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 
     
     
         29 . The method of  claim 26  wherein the pH of the first resultant solution in step (1) is in a range of about 11 to about 13. 
     
     
         30 . The method of  claim 26  wherein the molar ratio of the compound of Formula 3 or an acid salt thereof to the compound of Formula 2a is in a range of 0.7 to about 0.9. 
     
     
         31 . The method of  claim 26  wherein the second base added in step (2) is an alkali metal hydroxide. 
     
     
         32 . The method of  claim 31  wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 
     
     
         33 . The method of  claim 26  wherein the pH of the second resultant solution in step (2) is in a range of about 10.5 to about 11.5. 
     
     
         34 . The method of  claim 26  wherein the acid added in step (3) is a mineral acid. 
     
     
         35 . The method of  claim 34  wherein the acid is sulfuric acid or hydrochloric acid. 
     
     
         36 . A method for preparing a compound of Formula 4 or 4a 
       
         
           
           
               
               
           
         
       
       wherein R 1  is optionally substituted cyclopropyl or an optionally substituted phenyl, comprising the method of claim  1  and a further step comprising contacting the compound of Formula 1 with a chlorinating agent. 
     
     
         37 . A method for preparing a compound of Formula 6 
       
         
           
           
               
               
           
         
       
       wherein R 1  is optionally substituted cyclopropyl or an optionally substituted phenyl, comprising the method of claim  14  and a further step comprising contacting the compound of Formula 4 or 4a with a chloride displacement agent 
     
     
         38 . A method for preparing a compound of Formula 7 
       
         
           
           
               
               
           
         
       
       wherein R 1  is optionally substituted cyclopropyl or an optionally substituted phenyl, comprising the method of claim  15  and a further step comprising contacting the compound of Formula 6 with ammonia. 
     
     
         39 . A method of preparing a compound of Formula 8 
       
         
           
           
               
               
           
         
       
       wherein R 1  is optionally substituted cyclopropyl or an optionally substituted phenyl; and R 4  is C 1 -C 14  alkyl, C 2 -C 14  alkoxyalkyl, C 2 -C 14  hydroxyalkyl or benzyl; comprising the method of claim  16  and an additional step of contacting the compound of Formula 7 with an R 4  transfer agent. 
     
     
         40 . The method of claim  7  wherein R 4  is C 1 -C 8  alkyl or C 2 -C 8  alkoxyalkyl. 
     
     
         42 . The method of  claim 28  wherein R 4  is C 1 -C 4  alkyl. 
     
     
         43 . A compound of Formula 5a