Methods of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate

1. A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, comprising:

adding methyl isobutyl ketone to an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid to form a methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and an aqueous phase;

separating the methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the aqueous phase;

reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the methyl isobutyl ketone solution with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate, without concentrating or isolating the 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the methyl isobutyl ketone solution, to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate; and

deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

2. The method of claim 1 , wherein adding methyl isobutyl ketone to an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid comprises partitioning the 4-chloro-2-fluoro-3-methoxyphenylboronic acid into the methyl isobutyl ketone.

3. The method of claim 1 , wherein reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the methyl isobutyl ketone solution with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate comprises reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid, the methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate, triphenylphosphine, and a palladium catalyst in the methyl isobutyl ketone solution.

4. The method of claim 1 , wherein deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate in methyl isobutyl ketone.

5. The method of claim 1 , wherein deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises reacting the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate with anhydrous hydrochloric acid.

6. The method of claim 1 , further comprising adding a salt to a mixture of the methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and the aqueous phase.

7. The method of claim 6 , wherein adding a salt to a mixture of the methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and the aqueous phase comprises adding a saturated solution of sodium chloride to the mixture.

8. A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, comprising:

producing an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid;

adding methyl isobutyl ketone to the aqueous solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid to form a methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and an aqueous phase;

separating the methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the aqueous phase;

reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the methyl isobutyl ketone solution with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate, without concentrating or isolating the 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the methyl isobutyl ketone solution, to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate; and

deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

9. The method of claim 8 , wherein producing an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid comprises:

contacting 2-chloro-6-fluoroanisole (2,6-CFA) with n-butyl lithium to produce a lithiated derivative of 2,6-CFA;

contacting the lithiated derivative of 2,6-CFA with trimethyl borate to produce a boronic acid derivative of 2,6-CFA;

contacting the boronic acid derivative of 2,6-CFA with aqueous sodium hydroxide to produce a sodium salt of the boronic acid derivative of 2,6-CFA; and

contacting the sodium salt of the boronic acid derivative of 2,6-CFA with aqueous hydrochloric acid.

10. The method of claim 8 , wherein reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in methyl isobutyl ketone solution with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises:

adding an aqueous base to a reaction product of the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate to produce a first aqueous phase and a first organic phase;

separating the first aqueous phase and the first organic phase;

adding an aqueous sodium bisulfite solution to the first organic phase to produce a second aqueous phase and a second organic phase;

separating the second aqueous phase and the second organic phase; and

concentrating the second organic phase in vacuo.

11. The method of claim 8 , wherein producing an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid comprises:

contacting 2-chloro-6-fluoroanisole (2,6-CFA) with n-butyl lithium to produce a lithiated derivative of 2,6-CFA;

contacting the lithiated derivative of 2,6-CFA with trimethyl borate to produce a boronic acid derivative of 2,6-CFA;

contacting the boronic acid derivative of 2,6-CFA with aqueous potassium hydroxide to produce a potassium salt of the boronic acid derivative of 2,6-CFA; and

contacting the potassium salt of the boronic acid derivative of 2,6-CFA with aqueous hydrochloric acid.

12. The method of claim 8 , wherein deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises adding methanol and anhydrous hydrochloric acid to the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

13. The method of claim 8 , wherein deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises forming the methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate at a yield of from about 87% to about 90% based on methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate.

14. A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, comprising:

contacting 2-chloro-6-fluoroanisole (2,6-CFA) with n-butyl lithium to produce a lithiated derivative of 2,6-CFA;

contacting the lithiated derivative of 2,6-CFA with trimethyl borate to produce a boronic acid derivative of 2,6-CFA;

contacting the boronic acid derivative of 2,6-CFA with aqueous sodium hydroxide to produce an aqueous phase comprising a sodium salt of the boronic acid derivative of 2,6-CFA;

contacting the aqueous phase comprising the sodium salt of the boronic acid derivative of 2,6-CFA with aqueous hydrochloric acid to produce an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid;

adding methyl isobutyl ketone to the aqueous solution to form a methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid;

separating the methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxy phenylboronic acid from the water;

reacting methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate with the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the methyl isobutyl ketone solution, without concentrating or isolating the 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the methyl isobutyl ketone solution, in the presence of a palladium catalyst, a phosphine ligand, and an aqueous base to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate; and

deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate in the methyl isobutyl ketone to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

15. The method of claim 14 , wherein deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises adding methyl isobutyl ketone, methanol, and anhydrous hydrochloric acid to the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

16. The method of claim 14 , wherein deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises forming the methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate at a yield of from about 87% to about 90% based on methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate.

17. A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, comprising:

contacting 2-chloro-6-fluoroanisole (2,6-CFA) with n-butyl lithium to produce a lithiated derivative of 2,6-CFA;

contacting the lithiated derivative of 2,6-CFA with trimethyl borate to produce a boronic acid derivative of 2,6-CFA;

contacting the boronic acid derivative of 2,6-CFA with aqueous potassium hydroxide to produce an aqueous phase comprising a potassium salt of the boronic acid derivative of 2,6-CFA;

contacting the aqueous phase comprising the potassium salt of the boronic acid derivative of 2,6-CFA with aqueous hydrochloric acid to produce an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid;

adding methyl isobutyl ketone to the aqueous solution to form a methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid;

separating the methyl isobutyl ketone solution comprising the 4-chloro-2-fluoro-3-methoxy phenylboronic acid from the water;

reacting methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate with the 4-chloro-2-fluoro-3-methoxyphenylboronic acid in the methyl isobutyl ketone solution, without concentrating or isolating the 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the methyl isobutyl ketone solution, in the presence of a palladium catalyst, a phosphine ligand, and an aqueous base to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate; and

deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate in the methyl isobutyl ketone to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

18. The method of claim 17 , wherein deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises adding methyl isobutyl ketone, methanol, and anhydrous hydrochloric acid to the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.

19. The method of claim 17 , wherein deacetylating the methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate comprises forming the methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate at a yield of from about 87% to about 90% based on methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate.