Process for the preparation of sorafenib tosylate

The present invention provides a process for the preparation of sorafenib tosylate.

Sorafenib tosylate is the tosylate salt of 4-(4-{3-[4-chloro-3-(trifluoromethyl) phenyl]ureido}phenoxy)-N 2 -methylpyridine-2-carboxamide, having the structure as represented by Formula I.

Sorafenib tosylate is an inhibitor of the enzyme rafkinase. It is marketed in the United States under the brand name Nexavar® for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma.

WO 2006/034796, which is incorporated herein by reference, describes a process for the preparation of sorafenib tosylate in polar solvents.

The use of water, without using any other solvent, for the preparation of sorafenib tosylate is not described in the literature.

The present inventors have developed a process for the preparation of sorafenib tosylate which involves reaction of sorafenib free base with p-toluenesulphonic acid in water.

A first aspect of the present invention provides a process for the preparation of sorafenib tosylate of Formula I

comprising contacting sorafenib free base with p-toluenesulphonic acid in water.

A second aspect of the present invention provides a process for the preparation of sorafenib tosylate of Formula I

comprising contacting sorafenib free base with p-toluenesulphonic acid in water wherein 1.5 mole equivalents of p-toluenesulphonic acid are added per mole equivalent of sorafenib free base.

A third aspect of the present invention provides a process for the preparation of sorafenib tosylate of Formula I

comprising contacting sorafenib free base with p-toluenesulphonic acid in water wherein more than 1.5 mole equivalents of p-toluenesulphonic acid are added per mole equivalent of sorafenib free base.

A fourth aspect of the present invention provides high purity sorafenib tosylate.

FIG. 1 : XRD pattern of sorafenib tosylate prepared by the process of the present invention.

FIG. 2 : DSC thermogram of sorafenib tosylate prepared by the process of the present invention.

FIG. 3 : TGA curve of sorafenib tosylate prepared by the process of the present invention.

Sorafenib free base to be used for the preparation of sorafenib tosylate may be obtained by any of the methods known in the literature such as those described in WO 00/42012, WO 2006/034796, WO 2006/034797, WO 2009/034308, WO 2009/054004, WO 2009/106825 and WO 2009/092070, which are incorporated herein by reference.

In general, sorafenib free base may be prepared by the reaction of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy) aniline with 4-chloro-3-(trifluoromethyl)phenyl isocyanate. The starting sorafenib free base may be obtained as a solution directly from a reaction in which sorafenib is formed and used as such without isolation.

The p-toluenesulphonic acid may be used either in anhydrous form or in the form of hydrates. Preferably, p-toluenesulphonic acid monohydrate may be used.

The amount of p-toluenesulphonic acid required for the conversion of sorafenib base to its tosylate salt may be greater than or equal to the molar equivalent(s) of sorafenib free base used for carrying out the reaction.

In one embodiment, sorafenib free base and p-toluenesulphonic acid may be reacted in 1:1 molar ratio. In another embodiment, sorafenib free base and p-toluenesulphonic acid may be reacted in 1:1.5 molar ratio. In another embodiment, sorafenib free base and p-toluenesulphonic acid may be reacted in 1:2 molar ratio. In another embodiment, sorafenib free base and p-toluenesulphonic acid may be reacted in 1:12 molar ratio. In yet another embodiment, sorafenib base may be reacted with a saturated solution of p-toluenesulphonic acid in water. In a further embodiment, sorafenib free base obtained as a solution directly from a reaction in which sorafenib free base is formed, is reacted with p-toluenesulphonic acid in water as such without isolation.

The term “contacting” may include dissolving, slurrying, stirring or a combination thereof.

The reaction of sorafenib free base with p-toluenesulphonic acid may be carried out at a temperature of about 25° C. to about 100° C.

In one embodiment, the reaction may be carried out at a temperature of about 25° C. to about 35° C. In another embodiment, the reaction may be carried out at a temperature of about 50° C. to about 60° C. In yet another embodiment, the reaction may be carried out at a temperature of about 75° C. to about 85° C.

The reaction mixture may be stirred for about 2 hours to about 20 hours.

In one embodiment, the reaction mixture may be stirred for about 2 hours. In another embodiment, the reaction mixture may be stirred for about 10 hours to 12 hours. In another embodiment, the reaction mixture may be stirred for about 12 hours to 15 hours. In yet another embodiment, the reaction mixture may be stirred for about 15 hours to 18 hours.

Isolation may be accomplished by concentration, precipitation, cooling, filtration or centrifugation, or a combination thereof followed by drying under reduced pressure.

The process of the invention preferably produces sorafenib tosylate of high purity.

In the foregoing section, embodiments are described by way of examples to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Methods

Instrument: Panalytical

Mode: Expert PRO

Detector: Xcelerator

ScanRange: 3-40

Range: 3-40° 2θ

DSC Mettler Toledo instrument

TGA TA instruments (Q 500)