Process for preparing 2-amino-5-cyanobenzoic acid derivatives

1. A method for preparing a compound of Formula 1

wherein

R 1 is NHR 3 or OR 4 ;

R 2 is Cl or CH 3 ;

R 3 is H, C 1 -C 4 alkyl, cyclopropyl, cyclopropylmethyl or methylcyclopropyl; and

R 4 is H or C 1 -C 4 alkyl;

comprising contacting (1) a compound of Formula 2

wherein X is Br or Cl;

with (2) at least one compound of Formula 3

M 1 CN  3

wherein M 1 is an alkali metal

in the presence of (3) a solvent comprising one or more organic solvents selected from ethers and nitriles; and (4) a catalytically effective amount of a palladium complex comprising at least one tertiary phosphine ligand selected from the group consisting of benzyl-di-1-adamantylphosphine, di-tert-butylneopentylphosphine or tri-tert-butylphosphine;

provided that when R 2 is Cl, then X is Br; and when X is Cl, then the tertiary phosphine ligand is tri-tert-butylphosphine.

2. The method of claim 1 wherein the palladium complex is generated in situ.

3. The method of claim 1 wherein the palladium is complexed with tri-tert-butylphosphine.

4. The method of claim 1 wherein the solvent comprises one or more organic solvents selected from the group consisting of tetrahydrofuran, dioxane and acetonitrile.

5. The method of claim 1 wherein the solvent comprises a crown ether.

6. The method of claim 1 wherein the compound of Formula 2, the at least one compound of Formula 3, the palladium complex and the solvent are contacted at a temperature between about 0 and about 140° C.

7. The method of claim 6 wherein the compound of Formula 2, the at least one compound of Formula 3, the palladium catalyst and the solvent are contacted at a temperature between about 20 and about 100° C.

8. The method of claim 1 wherein the compound of Formula 2, the at least one compound of Formula 3, the palladium catalyst and the solvent are contacted in the presence of a catalyst promoter.

9. The method of claim 1 wherein the compound of Formula 2, the at least one compound of Formula 3, the palladium catalyst and the solvent are contacted in the presence of zinc metal.

10. The method of claim 1 wherein R 1 is NHR 3 .

11. The method of claim 1 wherein R 3 is C 1 -C 4 alkyl or cyclopropylmethyl.

12. The method of claim 11 wherein R 3 is methyl.

13. The method of claim 1 wherein R 2 is methyl.

14. The method of claim 1 wherein M 1 is Na or K.

15. The method of claim 1 wherein R 1 is NHR 3 , R 2 is methyl, R 3 is methyl, X is Br, M 1 is Na, the palladium complex comprises tri-tert-butylphosphine, and the solvent is tetrahydrofuran.

16. The method of claim 15 wherein the compound of Formula 2, the at least one compound of Formula 3, the palladium catalyst and the solvent are contacted in the presence of zinc metal.

17. The method of claim 1 wherein a solution of the palladium complex in a solvent comprising an ether is contacted with a mixture comprising the compound of Formula 2, at least one compound of Formula 3 and a nitrile solvent.

18. A method for preparing a compound of Formula 5

wherein

R 2 is Cl or CH 3 ;

R 3 is H, C 1 -C 4 alkyl, cyclopropyl, cyclopropylmethyl, or methylcyclopropyl;

Z is CR 17 or N;

R 14 is Cl, Br, CF 3 , OCF 2 H or OCH 2 CF 3 ;

R 15 is F, Cl or Br;

R 16 is H, F or Cl; and

R 17 is H, F, Cl or Br;

using a compound of Formula 1

wherein

R 1 is NHR 3 or OR 4 ; and

R 4 is H or C 1 -C 4 alkyl;

characterized by preparing said compound of Formula 1 by the method of claim 1 .

19. The method of claim 18 wherein R 1 is NHR 3 , R 2 is methyl, R 3 is methyl, R 14 is Br, R 15 is Cl, R 16 is H, and Z is N.