# US 9,518,020 B2 · Process for Regorafenib

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- Number: US 9,518,020 B2
- Document ID: US9518020B2
- Status: Granted
- Kind: B2
- Application number: 15/026,694
- Filed: 2014-09-29
- Published: 2016-09-01
- Granted: 2016-12-13
- Earliest claimed: 2013-10-04
- Assignees: Hetero Research Foundation
- Applicants: Hetero Research Foundation
- Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Thungathurthy Srinivasa Rao; Bandi Vamsi Krishna
- Web page: https://patentgrep.com/patent/US9518020B2

## CPC

- C07D 213/81: Amides; Imides
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention provides processes for the preparation of i) Regorafenib (4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, BAY 73-4506, Stivarga®) and its pharmaceutically acceptable salt thereof; ii) a crystalline solid of Regorafenib tosylate; iii) Regorafenib Polymorph I from Regorafenib tosylate, and iv) a pure 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide from 4-amino-3-fluorophenol and 4-chloro-N-methylpicolinamide in the presence of potassium tert-butoxide.

## Claims

### Claim 1

A process for the preparation of Regorafenib Polymorph I, which comprises:
a) dissolving Regorafenib tosylate in water and an ester solvent;
b) adjusting the pH to about 9.0 to 10.0 with a base;
c) removing the solvent from the reaction mass;
d) adding a ketonic solvent to the residual solid obtained in step (c);
e) heating the suspension obtained in step (d) at reflux; and
f) isolating Regorafenib Polymorph I.

### Claim 2 (depends on 1)

The process according to claim 1, wherein the ester solvent used in step (a) is selected from group comprising of ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate and ethyl formate.

### Claim 3 (depends on 1)

The process according to claim 1, wherein the base used in step (b) is selected from group comprising of sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, calcium carbonate and calcium bicarbonate.

### Claim 4 (depends on 1)

The process according to claim 1, wherein the ketonic solvent used in step (d) is selected from group comprising of acetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, methyl isobutyl ketone and methyl tert-butyl ketone.