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 CH 3 or Cl;

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

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

comprising contacting (1) a compound of Formula 2

wherein each X is independently Br, Cl or I;

with (2) at least one compound of Formula 3

M 1 CN  3

wherein M 1 is sodium, potassium, cesium or rubidium;

and (3) a compound of Formula 4

wherein

R 5 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R 11 ;

R 6 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R 12 ;

R 7 is a phenyl ring optionally substituted with up to 5 substituents independently selected from R 13 ;

R 8 is a phenyl ring or a naphthalenyl ring system, each ring or ring system optionally substituted with up to 5 substituents independently selected from R 14 ;

each R 9 and R 10 is independently a displaceable ligand; or

R 9 and R 10 together are a bidentate, displaceable ligand; and

each R 11 , R 12 , R 13 and R 14 is independently fluorine, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkoxy, C 1 -C 6 alkylamino or C 2 -C 6 dialkylamino;

provided that when X is Cl, then R 2 is methyl.

2. The method of claim 1 wherein the reagents (1), (2) and (3) are contacted in the presence of a reducing agent comprising one or more compounds selected from the group consisting of metal reducing agents and silane reducing agents.

3. The method of claim 2 wherein the reducing agent comprises one or more compounds selected from the group consisting zinc and polymethylhydrosiloxane.

4. The method of claim 1 wherein R 1 is NHR 3 , R 3 is CH 3 , R 2 is CH 3 and X is Br or Cl.

5. The method of claim 1 wherein M 1 is selected from the group consisting of sodium and potassium.

6. The method of claim 1 wherein the compound of Formula 4 comprises [1,1′-bis-(diphenylphosphino)ferrocene][(1,2,5,6)-1,5-cyclooctadiene]nickel.

7. The method of claim 1 wherein the reagents (1), (2) and (3) are contacted in the presence of a suitable solvent comprising one or more nitrile solvents.

8. The method of claim 7 wherein the suitable solvent comprises one or more solvents selected from the group consisting of acetonitrile, propionitrile and butyronitrile.

9. The method of claim 8 wherein the suitable solvent comprises acetonitrile.

10. The method of claim 1 further comprising preparing the compound of Formula 4 wherein R 9 and R 10 together are a cycloalkadiene bidentate ligand; by contacting (i) a compound of Formula 5

wherein each Y is independently Cl, Br or I;

with (ii) a cycloalkadiene bidentate ligand, (iii) at least one metal reducing agent and (iv) a nitrile solvent.

11. The method of claim 10 wherein each R 5 , R 6 , R 7 and R 8 is a phenyl ring, and R 9 and R 10 together are 1,5-cyclooctadiene.

12. The method of claim 1 further comprising contacting (a) a compound of Formula 5

wherein each Y is independently Cl, Br or I;

with (b) a cycloalkadiene bidentate ligand and (c) at least one metal reducing agent to form a mixture comprising a compound of Formula 4 wherein R 9 and R 10 together are a cycloalkadiene bidentate ligand; wherein the mixture comprising the compound of Formula 4 is contacted with (1) the compound of Formula 2 and (2) the at least one compound of Formula 3.

13. The method of claim 12 wherein each R 5 , R 6 , R 7 and R 8 is a phenyl ring, and R 9 and R 10 together are 1,5-cyclooctadiene.