Process for the preparation of regorafenib and its crystalline forms

Patent metadata

Field	Value
Publication number	US-9790185-B2
Application number	US-201515324683-A
Country	US
Kind code	B2
Filing date	Jul 6, 2015
Priority date	Jul 9, 2014
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib (I).

The present invention further relates to a process for the purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib (I) to provide highly pure material.
The present invention further relates to a process for the preparation stable crystalline material of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide or Regorafenib (I) useful in the preparation of pharmaceutical compositions for the treatment of cancer.

First claim

The invention claimed is:

1. A process for the preparation of Regorafenib (I)

comprising the steps of:
a) adding 4-Chloro-N-methyl-2-pyridinecarboxamide of Formula II

and 4-Amino-3-fluorophenol of Formula III

in an organic solvent in ratio between 3-8 v/w times with respect to compound of formula (II) at a temperature ranging between 20-35° C;
b) reacting the mixture of step a) in presence of sodium/potassium tertiary butoxide in tetrahydrofuran to provide 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV);

c) reacting the compound of Formula IV with 4-chloro-3-trifluoromethylisocyanate of Formula V

in presence of polar solvent in ratio between 3-8 v/w times with respect to compound of formula (IV) to provide Regorafenib (I); and
d) optionally, purifying the Regorafenib using a polar solvent or a mixture of polar and hydrocarbon solvent, wherein the degree of purity is 99.5%.

2. A process for the preparation of Regorafenib according to claim 1 , wherein organic solvent used in step a) is selected from amide solvents formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2-pyrrolidone, dimethyl acetamide.

3. A process for the preparation of Regorafenib according to claim 1 , wherein polar solvent in step c) and d) are selected from ketone solvents acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2-pyrrolidone, dimethyl acetamide; alcohols, methanol, ethanol, isopropanol; ethers tetrahydrofuran, dioxane; water or mixtures thereof.

4. A process for the preparation of Regorafenib according to claim 1 , wherein hydrocarbon solvent used in step d) is selected from toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons methylene dichloride, ethylene chloride, chloroform; or mixtures thereof.

5. A process for the preparation of Regorafenib according to claim 1 , wherein the product obtained is having PXRD pattern having diffraction angle values at 7.2, 8.6, 11.5, 12.0, 13.4, 14.5, 14.8, 15.6, 16.5, 17.2, 17.4, 18.6, 18.8, 19.0, 19.8, 20.0, 20.2, 23.4, 23.8, 24.2, 24.8, 25.8, 25.9, 26.3, 26.4, 26.6, 27.2, 27.4 and 31.6±0.2°2θ.

6. Regorafenib having purity greater than 99.5% and substantially free from process related impurities:

7. A process for the purification of Regorafenib (I)somprising the steps of
a) stirring 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide in a polar or mixture of polar and hydrocarbon solvent up to reflux temperature;
b) recovering pure 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl]carbamoyl}amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide (I) substantially free from process related impurities (A), (B) and (C); and/or
c) optionally, repeating step a) & b) to get the desired purity of 99.5%.

8. A process for the preparation of Regorafenib according to claim 7 , wherein polar solvent in step a) are selected from ketone solvents acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2-pyrrolidone, dimethyl acetamide; alcohols, methanol, ethanol, isopropanol; ethers tetrahydrofuran, dioxane; water or mixtures thereof; wherein hydrocarbon solvent used in step a) is selected from toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons methylene dichloride, ethylene chloride, chloroform; or mixtures thereof.

Assignees

• Shilpa Medicare Ltd

Inventors

• Rampalli Sriram
• Upalla Lav Kumar
• Ramachandrula Krishna Kumar
• Purohit Prashant
• Akshay Kant Chaturvedi

Classifications

• C07D213/81 Primary

  Amides; Imides · CPC title