Process for the preparation of 4-(4-amino-3-fluorophenoxy)-N-methylpyyridine-2-carboxamide

Patent metadata

Field	Value
Publication number	US-10822305-B2
Application number	US-201916243284-A
Country	US
Kind code	B2
Filing date	Jan 9, 2019
Priority date	Apr 15, 2010
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

The present invention relates to a process for preparing 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, its salts and monohydrate.

First claim

What is claimed is:

1. A process for the preparation of a compound of formula IV

comprising
i) reacting 4-amino-3-fluorophenol with a compound of Formula (VI)

to form a compound of formula III

ii) reacting a compound of formula II

with a compound of formula Ill to form a compound of formula IV,
wherein said compound of formula III is in a solution with an organic solvent and
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl,
or
R 1 and R 2 are joined and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered cycloalkyl ring.

2. A process for the preparation of a compound of formula IV

comprising reacting a purified compound of formula II, wherein said compound of formula II is >98% pure, with a compound of formula Ill

wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl,
or
R 1 and R 2 are joined and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered cycloalkyl ring

wherein the compound II and compound III are reacted in a solution of an organic solvent in the presence of a base.

3. A process according to claim 2 , wherein said organic solvent is 1-methyl-2-pyrrolidinone, dimethylformamide, N,N-dimethylacetamid, dimethyl sulfoxide, sulfolane or mixtures thereof.

4. A process according to claim 3 , wherein said organic solvent is 1-methyl-2-pyrrolidinone and/or dimethylformamide.

5. A process according to claim 2 , wherein said base is an alkali metal hydroxide or an alkali metal alkoxide.

6. A process according to claim 2 , wherein said base is potassium tert-butoxide.

7. A process according to claim 2 , wherein said base is potassium tert-butoxide in a tetrahydrofuran solution.

8. A process according to claim 2 , wherein the reaction mixture of the compound of formula II and a compound of formula III is heated to a temperature of from 50° C. to 150° C. and acetic acid in water is added.

9. A process according to claim 2 , wherein the reaction mixture is heated to a temperature of from 80° C. to 120° C. and after 2-4 hours the temperature is adjusted to between 50° C. to 90° C.

10. A process according to claim 2 , wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl, 2-hexyl and 3-hexyl.

11. A process according to claim 2 , wherein R 1 and R 2 are joined and, taken together with the carbon atom to which they are attached, form a 4- to 7-membered cycloalkyl ring.

12. A method of purifying a compound of Formula II

comprising
a) solving 4-chloro-N-methyl-2-pyridinecarboxamide in an organic solvent,
b) adding an alcohol to the solution of step a
c) treating the solution of step b with an acid precursor within 5-60 minutes of the addition of alcohol in step b to generate an acid in situ
d) isolating the salt of 4-chloro-N-methyl-2-pyridinecarboxamide by precipitation wherein said compound is >98% pure.

13. The method of claim 12 , wherein the precipitated purified salt of 4-chloro-N-methyl-2-pyridinecarboxamide is further solved in an organic solvent, and is neutralized by adding an aqueous solution of sodium hydroxide.

14. The method of claim 12 , wherein the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol, glycerol or a mixture thereof.

15. The method of claim 13 , wherein the organic solvent is tetrahydrofuran, toluene, ethyl acetate, dioxane, methyl tert-butyl ether, dimethoxyethane, dimethylsulfoxid, dimethylformamid, 1-methyl-2-pyrrolidinone or mixtures.

16. The method of claim 13 , wherein the organic solvent is tetrahydrofuran, toluene or mixtures thereof.

17. The method of claim 13 , wherein the alcohol is methanol, ethanol or isopropanol.

18. The method of claim 12 , wherein in step c the acid precursor is acylchloride, acylbromide, acetylchloride, acteylbromide, propionylchloride or propionylbromide.

19. The method of claim 12 , wherein in the situ preparation of the acid occurs without water.

20. The method of claim 12 , comprising adding the acid precursor within 10-30 minutes of the addition of alcohol in step b.

21. A composition comprising the compound of the formula (I)

wherein the composition comprises one or more anilinic substances each in an amount equal to or less than 0.05% by weight based on the weight of the compound of the formula (I) within the composition.

22. A composition of claim 21 which further comprises the monohydrate of the compound of the formula (I) and the amount of each anilinic substance is greater than 0.0001% by weight based on the weight of the compound of the formula (I) within the composition.

23. A process for preparing the compound of the formula (I)

which comprises the step of treating a salt of the compound of the formula (I) with an aqueous basic solution to precipitate the monohydrate of the compound of the formula (I).

24. The process of claim 23 wherein the monohydrate of the compound of the formula (I) precipitates at a temperature of from 35° C. to 45° C.

25. The process of claim 23 additionally comprising the step of drying the monohydrate of the compound of the formula (I) under reduced pressure until the compound of the formula (I) is formed.

Assignees

• Bayer Healthcare Llc

Inventors

• Stiehl Juergen
• Heilmann Werner
• Lögers Michael
• Rehse Joachim
• Gottfried Michael
• Wichmann Saskia

Classifications

• C07D213/81 Primary

  Amides; Imides · CPC title

• A61K31/4412

  having oxo groups directly attached to the heterocyclic ring · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title