DESC:Field of invention

The present invention relates to process for the preparation of crystalline form III of sorafenib tosylate.

Background of the invention

Sorafenib tosylate, 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methyl pyridine-2-carboxamide 4-methylbenzenesulfonate of the following formula (I)

is marketed as Nexavar® by Bayer for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received "Fast Track" designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer).

WO 00/41698 A1 discloses sorafenib and its salts, such as the tosylate salt and a process for preparation thereof. WO 00/41698 A1 in Example C1a discloses method for the preparation of sorafenib base. In this method, sorafenib base is obtained in one crystal polymorph. X-ray diffraction pattern is as depicted in fig II.

WO 00/042012 A1 describes sorafenib base, pharmaceutically acceptable salts and their use.
WO 06/034796 A1 discloses processes for preparing sorafenib base and its tosylate salt.
WO 06/034797 reports crystalline forms of sorafenib tosylate, forms I, II, and III, methanol solvate, ethanol solvate and preparation thereof. Crystalline sorafenib tosylate form III is characterized by a PXRD pattern having peaks selected from a list consisting of: 7.7, 8.5, 9.8, 10.6, 12.0, 12.3, 12.9, 13.4, 13.5, 15.4 and 16.0, 16.5, 16.9, 17.3, 17.8, 18.7, 18.8, 19.3, 19.9, 20.3, 20.8, 21.2, 21.6, 22.5, 23.0, 23.4, 24.2, 24.5, 24.8, 25.2, 25.9, 26.9, 27.5, 27.7, 28.2, 29.2, 29.4, 29.8, 30.3, 31.4, 32.2, 33.5, 34.0, 35.2, 36.1, 37.2, and 37.7+0.2 degrees 2theta. Crystalline sorafenib tosylate methanol solvate is characterized by a PXRD pattern having peaks selected from a list consisting of: 8.0, 8.4, 9.3, 11.2, 12.2, 13.0, 13.4, 15.8, 16.3, 16.9, 17.7, 18.3, 18.7, 19.0, 19.4, 20.2, 20.5, 20.9, 21.4, 21.7, 22.3, 22.4, 23.8, 24.0, 24.4, 24.7, 24.9, 25.2, 25.7, 26.0, 26.1, 26.4, 26.9, 27.0, 27.5, 27.7, 28.1, 28.3, 28.8, 29.1, 29.7, 30.2, 30.4, 30.7, 30.8, 31.4, 31.6, 31.9, 32.3, 32.6, 32.9, 33.4, 33.8, 34.0, 34.2, 34.5, 34.9, 36.2, 36.6, 37.2, and 37.7+0.2 degrees 2theta. Crystalline sorafenib tosylate ethanol solvate is characterized by a PXRD pattern having peaks selected from a list consisting of: 7.9, 8.4, 9.3, 9.5, 11.2, 12.0, 12.2, 12.8, 13.4, 15.9, 16.1, 16.8, 17.4, 17.7, 18.1, 18.3, 18.6, 18.8, 19.4, 20.0, 20.4, 21.0, 21.2, 21.5, 21.7, 22.3, 22.4, 22.8, 23.3, 23.6, 23.8, 24.3, 24.7, 25.3, 25.8, 25.9, 26.4, 26.9, 27.3, 27.6, 28.3, 28.8, 29.1, 29.5, 29.7, 30.2, 30.4, 30.9, 31.4, 32.0, 32.6, 32.9, 33.2, 33.7, 33.9, 34.5, 35.5, 36.0, 36.3, 36.6, 37.1, and 37.7+0.2 degrees 2theta.

WO2009092070 discloses process for the preparation of sorafenib tosylate crystalline form III, methanol solvate and ethanol solvate. According to process of WO2009092070 crystalline form III is obtained by drying of methanol solvate which is obtained by combining sorafenib tosylate, p-toluene sulfonic acid (PTSA) and solvent such as methanol, a mixture of methanol and dimethyulsulfoxide (DMSO) and a mixture of methanol and N-methyl pyrollidine (NMP).

The process of present invention provides process for the preparation of crystalline form III of sorafenib tosylate by providing a solution of sorafenib base, p-toluene sulfonic acid in mixture of alcohol and ketone. The crystalline form III of sorafenib tosylate as obtained by the process of present invention is free from other impurities and stable.

Object of the invention

The object of the present invention is to provide process for the preparation of crystalline form III of sorafenib tosylate comprising steps of :
a) providing a solution of Sorafenib and p-toluene sulfonic acid in a mixture of alcohol and ketone;
b) optionally seeding crystals of form III of sorafenib tosylate;
c) recovering crystalline sorafenib tosylate alcohol solvate;
d) drying crystalline sorafenib tosylate alcohol solvate to obtain crystalline form III of sorafenib tosylate.

The crystalline form III of sorafenib tosylate obtained by the process of present invention is characterized by a PXRD patterns having the peaks selected from: 7.6, 8.5, 9.8, 10.6, 12.0, 12.3, 12.9, 13.3, 16.0, 16.8, 17.3, 17.7, 18.7,19.3, 19.9, 20.2, 20.8, 21.6, 22.5, 22.9, 23.3, 24.2, 24.8, 25.9, 26.8, 27.7, 28.1, 29.4, 29.8, 31.5, 32.1, 32.9, 33.5, 34.0, 35.2, 36.1, 37.1, 37.7 + 0.2 theta (?) as depicted in fig I.

Description of drawing

Figure I: XRD of form III of Sorafenib tosylate
Figure II: XRD of Sorafenib Base
Figure III: XRD of Methanol solvate of Sorafenib tosylate

Detailed description of the invention
The embodiment of present invention provides process for the preparation of crystalline form III of sorafenib tosylate comprising steps of :
a) providing a solution of Sorafenib and p-toluene sulfonic acid in a mixture of alcohol and ketone;
b) optionally seeding crystals of form III of sorafenib tosylate;
c) recovering crystalline sorafenib tosylate alcohol solvate;
d) drying crystalline sorafenib tosylate Alcohol solvate to obtain crystalline form III of sorafenib tosylate.

Alcohol solvents as used here includes ethanol, methanol,1-propanol, isopropanol, 1-butanol, 2-butanol, tert. butanol, 1-pantenol, tert-pantenol.

Ketone solvents as used here include acetone, 3-pentanone, methyl isobutyl ketone, methyl ethyl ketone.

In the process of present invention seed crystal means crystals of form III of sorafenib tosylate obtained by the prior art process or by the process of the present invention (Example III). It was also unexpectedly found that a very high reproducibility of the product characteristics can be obtained by seeding of the solution with seeds consisting of sorafenib tosylate in crystalline form III.

Another embodiment of the present invention also provides the process for the preparation of Sorafenib intermediates and process for purification thereof.

The compound of formula (II) is preferably reacted with 4-aminophenol (III) to give the compound of formula (IV) in the presence of a base in a suitable solvent at a temperature from 10° C. to the reflux temperature of the solvent, preferably from 80 to 90° C., within 1 to 4 hours, preferably within 1 to 2 hours. In order to achieve a higher purity, of the compound of formula (IV), reaction mass is neutralized with acid in situ, and then the compound of formula (V) is isolated. Resulting solid is further purified by dissolving the compound of formula (V) in Isopropylalcohol and admixing with cyclohexane at temperature from 25° C to the reflux temperature, preferably at 65 to 85° C. A suitable solvent in the reaction is a dipolar aprotic solvent. Preference is given to dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane or mixture thereof. Particular preference is given to dimethyl sulfoxide. Suitable bases in the reaction are alkali metal carbonates and alkali metal alkoxides. Preference is given to potassium carbonate, potassium tert-butoxide.

Sorafenib free base obtained by reacting the compound of the formula (IV) with 4-chloro-3-trifluoromethylphenyl isocyanate (V), wherein the reaction is carried out in a chlorinated organic solvent, inert towards isocyanates at a temperature of 0° C. to the reflux temperature of the solvent, preferably from 0 to 5° C, more preferably at 20 to 300C . Preference is given to dichloromethane as a chlorinated solvent. Resulting solid was further purified by dissolving the compound of formula (V) in acetone at temperature of 25° C. to the reflux temperature, preferably at 50 to 60° C.

The present invention is further illustrated in detail by the below examples which are however not limit to the scope of the invention.

Example-I
Preparation of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (IV)

A cold solution of 4-aminophenol (56.56 g) in DMSO (100 mL) was treated with potassium tert-butoxide (70.0 g), and reaction mixture was stirred at 250C for 1 h. The contents were treated with 4-chloro-N-methyl-2-pyridinecarboxamide (100.0 g) and K2CO3 (85.68 g) in DMSO (100 ml) and then heated at 850C for 2 h. The mixture was cooled to room temperature and conc HCl (28-35 % w/w) (16 ml) was added and separated between MDC (800 mL) and water (500 mL). The aqueous phase was back-extracted with MDC (500 mL * 2). The combined organic layers were washed with water (4×500 mL) and concentrated under reduced pressure. The resulting material was suspended in IPA (250 mL) and then heated at 750C till clear solution was obtained. Cyclohexane (500 ml) was added slowly in the resulting mixture and then heated at 750C for 30 min. The mixture was cooled to room temperature and stirred for 4 h. The resulting solid was isolated, washed with cyclohexane (100 ml x 2) and dried under reduced pressure at 40oC for 4 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. (92 g).

Example-II
Preparation of sorafenib base

In a cold solution of 4-chloro-3-(trifluromethylphenyl) isocyanate(101.19 g) in dichloromethane (100 g in 550 mL), 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)amine (100 gm) was added at 150C. Reaction mass was stirred for 1 h at 250C. The resulting solid was suspended in acetone (3800 mL), heated at 550C till clear solution was obtained. The clear solution thus obtained was treated with activated carbon (5.0 g), passed through hyflow and concentrated under reduced pressure. The resulting mass was stirred for 2 h; solid was isolated and washed with acetone (100 ml x 3). The resulting solid was dried to afford N-(4-chloro-3-(trifluromethyl) phenyl-N’-4-(N-methylcarbamoyl)-4-pyridyloxy) phenyl (145 g).

Example- III
Preparation of sorafenib tosylate polymorph III
Sorafenib base (100 g) was suspended in a mixture of methanol (100 ml) and acetone (1800 ml) followed by dropwise addition of p-toluenesulfonic acid monohydrate solution in methanol at 650C. The resulting solution was treated with charcoal (2 g), stirred for 15 min and passed through hyflow. The solution was seeded with crystal of polymorph III (0.5 g) and stirred for 15 min at 650C. Reaction mass was cooled to 25oC and stirred for 1 h. The solid was filtered off and washed with methanol. In a mixture of methanol (500 ml) and water (50 ml), obtained solid was added and heated to 60oC and stirred for 1 h. Reaction mass was cooled and solid was isolated. Again in a mixture of methanol (500 ml) and water (50 ml), obtained solid was added and heated to 60oC and stirred for 1 h. Reaction mass was cooled, solid was isolated as sorafenib tosylate methanol solvate. The obtained methanol solvate further dried at 85oC for 20-24 h to afford sorafenib tosylate polymorph III. Yield (105 g). XPRD: form III as depicted in figure 1.

Example IV
Preparation of sorafenib tosylate polymorph III
Sorafenib base (20 g) was suspended in methanol (660 ml) and methyl-tert-butyl ether (20 ml) followed by dropwise addition of p-toluene sulfonic acid monohydrate solution (10 g in 20 ml Methanol) at 45oC. Crystallization was induced by seeding of sorafenib tosylate polymorph III (0.2 g). The suspension was cooled to 2oC and stirred for 2 hrs. The solid was filtered off and washed with methanol. Obtained crystals of sorafenib tosylate methanol solvate were dried at 80 oC under vacuum tray drier for 16-20 hrs to obtain sorafenib tosylate polymorph III. Yield (25 g). XPRD: form III depicted in figure 1.

Example V
Preparation of sorafenib tosylate polymorph III
Sorafenib base (20 g) was suspended in Methanol (660 ml) and Acetonitrile (20 ml) followed by dropwise addition of p-tolunesulfonic acid monohydrate solution (10 g in 20 ml Methanol). Crystallization was induced by seeding of sorafenib tosylate polymorph III (0.2 g). The suspension was cooled to 0oC and stirred for 2 h. The solid was filtered off and washed with methanol. Obtained crystals of sorafenib tosylate methanol solvate were dried at 80 oC under vacuum tray drier for 16-20 h to obtain sorafenib tosylate polymorph III. Yield (26 g). XPRD: form III depicted in figure 1.

Example VI
Preparation of sorafenib tosylate polymorph III
Sorafenib Tosylate (5 g) was suspended in mixture of methanol (50 ml) and acetone (5 ml). The suspension was seeded with sorafenib tosylate polymorph III (50 mg) and stirred at 20oC for 4 h. The solid was filtered off and washed with methanol (5 ml x 2). Obtained crystals of sorafenib tosylate methanol solvate were dried at 80 oC under vacuum tray drier for 16-20 hrs to obtain sorafenib tosylate polymorph III. Yield (4.3 g).
XPRD: form III depicted in figure 1.

Example VII
Preparation of sorafenib tosylate polymorph III
Sorafenib hemi tosylate (5 g) was suspended in mixture of methanol (50 ml) and acetone (5 ml). Charged p-Toluene sulfonic acid (2g) followed by seeding of sorafenib tosylate polymorph III (50 mg). The suspension was stirred at 23 oC for 4 h. The solid was filtered off and washed with methanol (5ml x 2). Sorafenib tosylate methanol solvate was isolated as off white solid (wt 4.0 g, 80 %). Sorafenib tosylate methanol solvate (4.0 g) was dried at 80oC in rotary evaporator under vacuum for 16-20 h to obtain Sorafenib Tosylate polymorph III.

Example VIII
Preparation of sorafenib tosylate polymorph III
Sorafenib Tosylate polymorph III (5 g) was suspended in methanol (50 ml) and stirred at 20-25 oC for 1 h. The solid was filtered off and washed with methanol (10 ml). Sorafenib tosylate methanol solvate was isolated as off white solid (wt 4.7 g, 94 %). Sorafenib tosylate methanol solvate (28 g) was dried at 80 oC under vacuum for 16-20 h to obtain sorafenib tosylate polymorph III. (wt. 25.0 g).
,CLAIMS:1. A process for preparing crystalline sorafenib tosylate characterized by a PXRD pattern having picks selected from the list consisting of: 7.6, 8.5, 9.8, 10.6, 12.0, 12.3, 12.9, 13.3, 16.0, 16.8, 17.3, 17.7, 18.7,19.3, 19.9, 20.2, 20.8, 21.6, 22.5, 22.9, 23.3, 24.2, 24.8, 25.9, 26.8, 27.7, 28.1, 29.4, 29.8, 31.5, 32.1, 32.9, 33.5, 34.0, 35.2, 36.1, 37.1, and 37.7±0.2 degrees 2theta;
the said process comprising
(a) providing a solution of sorafenib and p-toluene sulfonic acid in a mixture of
alcohol and ketone;
(b) optionally seeding crystals of form III of sorafenib tosylate;
(c) recovering crystalline sorafenib tosylate alcohol solvate;
(d) drying crystalline sorafenib tosylate alcohol solvate to obtain crystalline form III of sorafenib tosylate.
2. The process according to claim 1, wherein the alcoholic solvent is methanol, ethanol,
1-propanol, isopropanol, 1-butanol, 2-butanol, tert. butanol, 1-pantenol, 2-pantenol.
3. The process according to claim 1, wherein the ketone solvent is acetone, 3-pentanone, methyl isobutyl ketone, methyl ethyl ketone.
4. The process as claimed in claim 2, wherein the alcoholic solvent is methanol.
5. The process as claimed in claim 3, wherein the ketone solvent is acetone.