Methods of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate
First Claim
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.
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Abstract
Methods of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. One method comprises adding methyl isobutyl ketone to an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenyl-boronic acid to form an organic phase comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and an aqueous phase. The organic phase and the aqueous phase are separated. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid is reacted 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, which is deacetylated to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.
7 Citations
19 Claims
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1. A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, comprising:
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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. - View Dependent Claims (2, 3, 4, 5, 6, 7)
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8. A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, comprising:
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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. - View Dependent Claims (9, 10, 11, 12, 13)
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14. A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, comprising:
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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. - View Dependent Claims (15, 16)
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17. A method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, comprising:
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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. - View Dependent Claims (18, 19)
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Specification