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

1. 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.

2. The method of claim 1 wherein R 1 is optionally substituted cyclopropyl.

3. The method of claim 1 wherein the first base added in step (1) is an alkali metal hydroxide.

4. The method of claim 3 wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.

5. The method of claim 1 wherein the pH of the first resultant solution in step (1) is in a range of about 11 to about 13.

6. The method of claim 1 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.

7. The method of claim 1 wherein the second base added in step (2) is an alkali metal hydroxide.

8. The method of claim 7 wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide.

9. The method of claim 1 wherein the pH of the second resultant solution in step (2) is in a range of about 10.5 to about 11.5.

10. The method of claim 1 wherein the acid added in step (3) is a mineral acid.

11. The method of claim 10 wherein the acid is sulfuric acid or hydrochloric acid.

12. 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.

13. 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 12 and a further step comprising contacting the compound of Formula 4 or 4a with a chloride displacement agent.

14. 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 13 and a further step comprising contacting the compound of Formula 6 with ammonia.

15. 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 14 and an additional step of contacting the compound of Formula 7 with an R 4 transfer agent.

16. The method of claim 15 wherein R 4 is C 1 -C 8 alkyl or C 2 -C 8 alkoxyalkyl.

17. The method of claim 16 wherein R 4 is C 1 -C 4 alkyl.

18. The method of any one of claims 1 - 15 or 16 - 17 wherein R 1 is cyclopropyl.