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

A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)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 4-chloro-2-fluoro-3-methoxyphenylboronic acid;
• separating the methyl isobutyl ketone and 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the water;
• reacting the 4-chloro-2-fluoro-3-methoxyphenylboronic acid with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate in methyl isobutyl ketone 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.

A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)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 ester of 2,6-CFA;
• contacting the boronic acid ester of 2,6-CFA with aqueous sodium hydroxide to produce a sodium salt of the boronic acid ester of 2,6-CFA;
• contacting the sodium salt of the boronic acid ester of 2,6-CFA with aqueous hydrochloric acid;
• adding methyl isobutyl ketone to the aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid;
• separating the methyl isobutyl ketone and 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the water;
• adding methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate, a palladium catalyst, a phosphine ligand, and an aqueous base to produce a reaction product of the 4-chloro-2-fluoro-3-methoxy-phenylboronic acid and methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate, resulting in 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;
• 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.

A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxy-phenyl)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 ester of 2,6-CFA;
• contacting the boronic acid ester of 2,6-CFA with aqueous potassium hydroxide to produce a potassium salt of the boronic acid ester of 2,6-CFA;
• contacting the potassium salt of the boronic acid ester of 2,6-CFA with aqueous hydrochloric acid;
• adding methyl isobutyl ketone to the aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid;
• separating the methyl isobutyl ketone and 4-chloro-2-fluoro-3-methoxyphenylboronic acid from the water;
• adding methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate, a palladium catalyst, a phosphine ligand, and an aqueous base to produce a reaction product of the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate, resulting in a first aqueous phase and a first organic phase;
• separating the first aqueous phase and the first organic phase;
• adding an aqueous sodium bisulfate 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;
• 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.