Method of preparing benzyl 4-amino-3-chloro-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate

1. A method for preparing the compound of Formula I:

comprising the steps of:

a) combining a compound of Formula II, anhydrous ammonia, and a solvent selected from acetonitrile, propionitrile, benzonitrile, toluene, xylene, THF, dioxane, mono- and diethyleneglycol ethers, mono- and dipropyleneglycol ethers, tert-amyl methyl ether (TAME), methyl tert-butyl ether (MTBE1), or a mixture thereof; and maintaining a pressure of from about 40 to about 150 pounds per square inch gauge (psig) with anhydrous ammonia;

b) isolating a compound of Formula III from the combination of step a);

c) combining the isolated compound of Formula III from step b) with anhydrous HCl to form an HCl salt of Formula IV;

d) isolating the compound of Formula IV from step c) and combining the isolated compound of Formula IV with a base to reform the compound of Formula III;

e) adding a chlorinating agent to the combination of step d); and

f) isolating the compound of Formula I.

2. The method of claim 1 , further comprising reisolating the compound of Formula III after step d) prior to adding the chlorinating agent in step e).

3. The method of claim 1 , wherein the solvent is acetonitrile.

4. The method of any of claim 1 , wherein the combination of step a) is maintained at a pressure of from about 70 to about 100 pounds per square inch gauge (psig) with anhydrous ammonia.

5. The method of claim 1 , wherein the combination of step a) is maintained at a temperature of from about 60 to about 130° C.

6. The method of any of claim 1 , wherein the combination of step a) is maintained at a temperature of from about 80 to about 120° C.

7. The method of claim 1 , wherein step b) comprises removing ammonium fluoride and substantially all of the residual ammonia from the combination of step a).

8. The method of claim 7 , wherein the ammonium fluoride is removed by filtration or centrifugation.

9. The method of claim 7 , wherein the residual ammonia is removed by distillation or by sparging with an inert gas.

10. The method of claim 1 , wherein isolating the compound of Formula IV in step d) comprises isolating the compound of Formula IV by filtration or centrifugation.

11. The method of claim 2 , wherein reisolating the compound of Formula III further comprises an aromatic hydrocarbon solvent, toluene, xylene, or benzonitrile.

12. The method of claim 1 , wherein the base in step d) comprises triethylamine.

13. The method of claim 2 , wherein reisolating the compound of Formula III comprises washing with water.

14. The method of claim 1 , wherein the chlorinating agent in step e) is 1,3-dichloro-5,5-dimethylhydantoin.

15. The method of claim 1 , wherein the combination in step d) comprises a one-phase solvent system comprising a solvent selected from toluene, xylene, acetonitrile, benzonitrile, ethyl acetate, THF, dioxane, tert-amyl methyl ether (TAME), methyl tert-butyl ether (MTBE) and/or a chlorinated hydrocarbon selected from dichloromethane and 1,2-dichloroethane.

16. The method of claim 1 , wherein after isolation in step f) the compound of Formula I is purified by crystallization from a solvent comprising 2 ethyl-1-hexanol.

17. The method of claim 1 , wherein after isolation in step f) the compound of Formula I is purified by crystallization from a solvent mixture comprising an aliphatic hydrocarbon that is a hexane or a mixture of hexanes, and an aromatic hydrocarbon that is toluene.

18. The method of claim 1 , wherein after isolation in step f) the compound of Formula I is purified by crystallization from a solvent mixture comprising 2-ethyl-1-hexanol, heptanes, and toluene.