POLYMORPH III

Field of the Invention:

The present invention relates to an improved process for the preparation of Sorafenib tosylate form III with high purity and high yield. The present process controls the genotoxic impurities content in final API.

Background of the Invention:

Sorafenib tosylate is chemically known as 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido }phenoxy)N2methylpyridine-2-carboxamide 4-methylbenzenesulfonate and structurally represented as below.

Sorafenib tosylate is marketed as Nexavar® by Bayer for treatment of advanced renal cell carcinoma (primary kidney cancer).

Sorafenib and its salts, such as the tosylate salt and a process for preparation thereof are disclosed in US7351834.

US8877933 described Polymorph I, Polymorph II, Polymorph III, methanol solvate and ethanol solvate of sorafenib tosylate. According to this patent, sorafenib tosylate polymorph III can be prepared by suspending sorafenib tosylate form II in methanol at room temperature, maintained for one week and then filtered to obtain a residual solid. The residual solid was heat-treated at 150° C, for 30 minutes to obtain sorafenib tosylate polymorph III.

As per US8217061 patent, sorafenib tosylate polymorph III can be prepared by providing a suspension comprising sorafenib tosylate and a solvent selected from methanol, a mixture of methanol and N-methyl-2-pyrrolidone, a mixture of methanol and dimethyl sulfoxide to obtain sorafenib tosylate methanol solvate and then drying the sorafenib tosylate methanol solvate at 80 to 90° C. WO2014118807A1 describes sorafenib tosylate form III preparation from sorafenib tosylate ethanol solvate.

The present inventors have found a novel process for the preparation of Sorafenib tosylate form III with high purity. The present process is cost effective and feasible in large scale production also. The present process controls the genotoxic impurities content in final API.

Summary of the Invention:

The main aspect of the present invention is to provide a novel process for the preparation of sorafenib tosylate form III from sorafenib base through sorafenib tosylate methanol solvate.

One aspect of the present invention is to provide a process for the preparation of Sorafenib tosylate form III, comprising the steps of:

a) adding sorafenib base in methanol,

b) adding methanolic solution of para toluene sulfonic acid to step (a) solution, c) isolating sorafenib tosylate methanol solvate and

d) drying the solid of step (c) to obtain sorafenib tosylate form III.

Another aspect of the present invention is to provide a process for the preparation of sorafenib tosylate form III, comprising the steps of:

a) adding sorafenib base in methanol,

b) adding methanolic solution of para toluene sulfonic acid to step (a) at 55- 60°C, c) isolating sorafenib tosylate methanol solvate at 40-45°C,

d) optionally washing the methanol solvate with methanol,

e) drying sorafenib tosylate methanol solvate in fluid bed drier at 80-95°C to obtain sorafenib tosylate form III.

Detailed description of the Invention:

The present invention is related to a process for the preparation of Sorafenib tosylate form III, wherein suspending sorafenib base in methanol, adding methanolic solution of para toluene sulfonic acid to this solution, isolating sorafenib tosylate methanol solvate and drying sorafenib tosylate methanol solvate to obtain sorafenib tosylate form III. One embodiment of the present invention is to provide a process for the preparation of Sorafenib tosylate form III, comprising the steps of:

a) adding sorafenib base in methanol,

b) adding methanolic solution of para toluene sulfonic acid to step (a) solution, c) isolating sorafenib tosylate methanol solvate and

d) drying the solid of step (c) to obtain sorafenib tosylate form III.

Another embodiment of the present invention is to provide a process for the preparation of sorafenib tosylate form III, comprising the steps of:

a) adding sorafenib base in methanol,

b) adding methanolic solution of para toluene sulfonic acid to step (a) at 55- 60°C, c) isolating sorafenib tosylate methanol solvate at 40-45°C,

d) optionally washing the methanol solvate with methanol,

e) drying sorafenib tosylate methanol solvate in fluid bed drier at 80-95°C to obtain sorafenib tosylate form III.

According to the present invention, Sorafenib base and methanol is charged into a four necked round bottom flask. The reaction mass is heated to 55-60°C. Solution of p- toluene sulfonic acid in Methanol [p- toluene sulfonic acid in of cold methanol (~0-5°C)] is added to the above solution at 55-60°C in 15-20 minutes. The reaction mass is heated to 60- 65°C and maintained for 2h. The reaction mass is cooled to 40-45°C and maintained for 45- 60 minutes. The solid is filtered and washed with methanol. Solid (methanol solvate) is dried in fluid bed dryer at 25-35°C for 60 minutes and then dried at 85-90°C for 12h to get sorafenib tosylate form III.

According to the present invention, methyl p-toulene sulfonate is a potentially genotoxic impurity. This impurity limitation is achieved through drying sorafenib tosylate methanol solvate in fluid bed drier.

Advantages of the present Invention:

• The genotoxic impurity is very well controlled in final API.

• The present process is cost effective and feasible in large scale production also. Brief description of drawings:

Fig-1 : Powder X-ray diffractogram of sorafenib tosylate form III.

The below examples are provided for illustrative purpose only and are not intended to limit the scope of invention.

Experimental section:

Example-1: Preparation of Sorafenib tosylate form III

Sorafenib base (125 g, 0.269 mole) and methanol (1875 ml) were charged into a 3.0L four necked round bottom flask. The reaction mass was heated to 55-60°C. Solution of p- toluene sulfonic acid in methanol [56.2g p-toluene sulfonic acid (0.296 mole) in 90 ml of cold methanol (~0-5°C)] was added to the above solution at 55-60°C in 15-20 minutes. The reaction mass was heated to 60-65°C and maintained for 2h. The reaction mass was cooled to 40-45°C and maintained for 45-60 minutes. The solid was filtered and washed with methanol. Solid (methanol solvate) was dried in fluid bed dryer at 25-35°C for 60 minutes and then dried at 85-90°C for l2h to get Sorafenib tosylate form III. (Yield: 144.7g, theoretical 84.5%)

Methyl-p-toluene sulfonate: Below detection limit.

HPLC purity: 99.98%

Example-2: Preparation of Sorafenib tosylate form III

Sorafenib base (50 g, 0.108 mole) and methanol (625 ml) were charged into a 2.0L four necked round bottom flask. The reaction mass was heated to 55-60°C. Solution of p- toluene sulfonic acid in methanol [21.5 g p-toluene sulfonic acid (0.113 mole) in 35 ml of cold methanol (~0-5°C)] was added to the above solution at 55-60°C in 15-20 minutes. The reaction mass was heated to 60-65°C and maintained for 2h. The reaction mass was cooled to 40-45°C and maintained for 45-60 minutes. The solid was filtered and washed with methanol. Solid (methanol solvate) was dried in fluid bed dryer at 25-35°C for 60 minutes and then dried at 85-90°C for 12h to get Sorafenib tosylate form -III. (Yield is 54.18 g, Theoretical 79.1%)

Methyl-p-toluene sulfonate: Below detection limit.

HPLC purity: 99.97%