Field of the Invention:
The present invention relates to an improved process for the preparation of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide hemitosylate, which corresponds to the compound of formula-1.
Further, the present invention relates to an improved process for the preparation of crystalline methanol solvate, ethanol solvate and crystalline Form-Ill of 4-(4-{3-[4-Chloro-3 (trifluoromethyl)phenyl]ureido}phenoxy)-N-2-methylpyridine-2-carboxamide 4-methyl benzenesulfonate compound of formula-2.
Background of the Invention:
Sorafenib tosylate has the chemical name 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido}phenoxy)-N -methylpyridine-2-carboxamide benzenesulfonate. Sorafenib, marketed as NEXAVAR by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer) and advanced hepatocellular carcinoma (primary liver cancer). NEXAVAR is the tosylate salt of Sorafenib. In the label of USFDA,
NEXAVAR is chemically mentioned as 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido}phenoxy)-N-2-methylpyridine-2-carboxamide-4-methylbenzene sulfonate that is Sorafenib tosylate.
WO2009106825 (Al) discloses amorphous Sorafenib free base and process for preparation thereof.
WO2013175483 (Al) discloses Sorafenib free base polymorph-I and preparation thereof.
WO06/034796A1 discloses processes for preparing sorafenib and its tosylate salt.
WO2006034797 (Al) discloses crystalline forms of Sorafenib tosylate form 1, II and III, methanol solvate, ethanol solvate and preparation thereof.
The prior art processes for the preparation of Sorafenib tosylate ethanol solvate involve treating Sorafenib free base with p-toluene sulfonic acid mono hydrate in presence of solvents like methanol or ethanol to form a polymorphic form of Sorafenib tosylate and then conversion of obtained polymorph to Sorafenib tosylate ethanol solvate.
None of the prior art processes involve the direct conversion of Sorafenib free base to Sorafenib tosylate ethanol solvate. Moreover, prior art processes are tedious. All these reaction conditions are difficult to achieve at industrial scale.
Keeping in view of the difficulties in commercialization of the above reported processes for the preparation of Sorafenib tosylate ethanol solvate, the present inventors have developed a simple and economical process for commercial production of Sorafenib tosylate ethanol solvate from Sorafenib free base.
Brief description of the Invention:
Accordingly the main objective of the present invention is to provide an improved process for the preparation of Sorafenib hemitosylate, Sorafenib tosylate ethanol solvate, Sorafenib tosylate methanol solvate and crystalline Form-Ill of Sorafenib tosylate.
The first aspect of the present invention is to provide an improved process for the preparation of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2- methylpyridine-2-carboxamide hemitosylate compound of formula-1.
The second aspect of the present invention is to provide an improved process for the preparation of methanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl] ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2.
The third aspect of the present invention is to provide an improved process for the preparation of ethanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido} phenoxy)-N -methylpyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2.
The forth aspect of the present invention is to provide a process for the preparation of crystalline Form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate.
Advantageous of the present Invention:
• The present invention provides Sorafenib hemitosylate with high yield and purity when compare to the yield and purity of the prior art processes.
• As per the present invention, the process for the preparation of Sorafenib tosylate ethanol solvate is completed in 10-12 hrs which is very less when compared to prior-art processes.
• The process for the preparation of Sorafenib tosylate ethanol solvate is simple and economical for commercial purpose.
Brief description of Drawings:
Figure-1: Illustrates the powder X-ray diffractogram of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-2-methylpyridine-2-carboxamide hemitosylate.
Figure-2: Illustrates the powder X-ray diffractogram of crystalline ethanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-2-methylpyridine-2-carboxarnide4-methylbenzenesulphonate.
Figure-3: Illustrates the powder X-ray diffractogram of crystalline methanol solvate of 4-(4- {3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-2-methylpyridine-2- carboxamide4-methylbenzenesulphonate.
Figure-4: Illustrates the powder X-ray diffractogram of Form-Ill of 4-(4-{3-[4-Chloro-3-
(trifluoromethyl)phenyl]ureido}phenoxy)-N-2-methylpyridine-2-carboxamide 4-methyl benzenesulfonate.
Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/or mixtures thereof.
The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, tributylamine, pyridine, 4-dimethyl aminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropyl amide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and/or mixtures thereof.
The first aspect of the present invention provides an improved process for the preparation of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methyl pyridine-2-carboxamide hemitosylate compound of formula-1, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in a suitable solvent,
b) adding paratoluenesulfonic acid monohydrate and water to the reaction mixture,
c) heating the reaction mixture to reflux temperature,
d) filtering the reaction mixture at reflux temperature,
e) cooling the reaction mixture, stirring and filtering,
f) washing the obtained compound with a suitable solvent,
g) drying the compound under reduced pressure to get. the compound of formula-1.
Wherein, in step-a) the suitable solvent is selected from ketone solvent, preferably methyl ethyl ketone:
In a preferred embodiment of the present invention provides an improved process for the preparation of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide hemitosylate compound of formula-1, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in methylethylketorie,
b) adding paratoluenesulfonic acid monohydrate and water to the reaction mixture,
c) heating the reaction mixture at 75 °C±5°C,
d) filtering the reaction mixture at 75°C ±5°C,
e) cooling the reaction mixture to 30°C±5°C, stirring and filtering the reaction mixture,
f) washing the obtained compound with a mixture of methylethylketone and water,
g) drying the compound to get the compound of formula-1.

The second aspect of the present invention is to provide an improved process for the preparation of methanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido} phenoxy)-N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in a suitable solvent,
b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) slowly adding a solution of p-toluehe sulfonic acid in methanol to the reaction mixture,
e) stirring the reaction mixture and filtering the reaction mixture,
f) washing the obtained compound with methanol and drying to get the methanol solvate compound of formula-2.
Wherein,
in step-a) the suitable solvent is selected from polar aprotic solvents, preferably, N,N-dimethylformamide and dimethylacetamide.
In a preferred embodiment of the present invention provides an improved process for the preparation of methanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido} phenoxy) N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in N,N-dimethylformamide,
b) stirring the reaction mixture for 5-10 minutes at 30±5°C,
c) filtering the reaction mixture,
d) slowly adding a solution of p-toluene sulfonic acid in methanol to the reaction mixture,
e) stirring the reaction mixture for 6-8 hrs at 30°C±5°C and filtering the reaction mixture,
f) washing the obtained compound with methanol and drying to get the methanol solvate compound of formula-2.
The third aspect of the present invention provides an improved process for the preparation of ethanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido} phenoxy)-N -methylpyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2, which is characterized by X-ray diffactogram pattern having peaks at 7.82, 9.1, 11.8, 15.7, 18.1,20.8, 21.37, 24.6 and 25.1 ±0.2 degrees of 2-theta, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)N2-methylpyridine-2-carboxamide in a suitable solvent,
b) adding ethanol to the reaction mixture,
c) filtering the reaction mixture,
d) slowly adding a solution of p-toluene sulfonic acid mono hydrate (PTSA.H20) in ethanol to the reaction mixture in lot wise,
e) seeding the reaction mixture with crystalline Sorafenib tosylate ethanol solvate,
f) filtering the obtained solid and drying it to get ethanol solvate compound of formula-2.
Wherein,
in step a), the suitable solvent is selected from polar aprotic solvents, preferably, dimethylsulfoxide. in step d), the p-toluene sulfonic acid mono hydrate (PTSA.H2O) solution is added to the reaction mixture in lot-wise manner.
The preferred embodiment of the present invention provides an improved process for the preparation of ethanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl] ureido}phenoxy)-N -methyl pyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2, which is characterized by X-ray diffactogram pattern having peaks at 7.82, 9.1, 11.8, 15.7, 18.1, 20.8, 21.37, 24.6 and 25.1 ± 0.2 degrees of 2-theta, comprising of following steps:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in dimethylsulfoxide,
b) adding ethanol to the reaction mixture,
c) filtering the reaction mixture,
d) slowly adding a solution of p-toluene sulfonic acid mono hydrate (PTSA.H20) in ethanol to the reaction mixture,
e) seeding the reaction mixture with crystalline sorafenib tosylate ethanol solvate,
f) filtering the obtained solid and drying it to get ethanol solvate compound of formula-2.
The forth aspect of the present invention provides a process for the preparation of
Form-Ill of 4-(4- {3 - [4-Chloro-3 -(trifluoromethyl)phenyl]ureido} phenoxy)-N2-methy 1
pyridine-2-carboxamide 4-methylbenzenesulfonate, comprising of drying methanol solvate
of 4-(4- { 3 - [4-Chloro-3 -(trifluoromethyl)phenyl]ureido} phenoxy)-N2-methy lpyridine-2 -
carboxamide 4-methylbenzenesulfonate compound of formula-2 under reduced pressure at a suitable temperature for a suitable time period.
Wherein a suitable temperature is 80±5°C and suitable time period is 20-24 hrs.
In a preferred embodiment of the present invention provides a process for the preparation of Form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N -methylpyridine-2-carboxamide 4-methylbenzenesulfonate, comprising of drying methanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2 under reduced pressure at 80±5°C for 20-24 hrs.
In another preferred embodiment of the present invention provides an improved
process for the preparation of crystalline form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)
phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate
compound of formula-2, comprising of:
a) Dissolving 4-(4- {3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in N,N-dimethylformamide at 30±5°C,
b) optionally, filtering the reaction mixture,
c) slowly adding a solution of p-toluene sulfonic acid in methanol to the reaction mixture obtained in step-b),
d) stirring the reaction mixture for 6-8 hrs at 30°C±5°C and filtering the reaction mixture,
e) washing the obtained compound with methanol and drying at 80±5°C to get the crystalline form-Ill of compound of formula-2.
In another preferred embodiment of the present invention provides an improved process for the preparation of crystalline form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido}phenoxy)-N -methylpyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2, comprising of: ">•-
a) Dissolving p-toluene sulfonic acid in methanol at 30±5°C,
b) optionally, filtering the reaction mixture,
c) slowly adding 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in N,N-dimethylformamide to the filtrate obtained in step-b),
d) stirring the reaction mixture for 6-8 hrs at 30°C±5°C and filtering the reaction mixture,
e) washing the obtained compound with methanol and drying at 80±5°C to get the crystalline form-Ill of compound of formula-2.
The crystalline form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido} phenoxy)-N -methylpyridine-2-carboxamide 4-methylbenzenesulfonate compound of formula-2 obtained from the above aspect can be purified by slurring the obtained compound of formula-2 in methanol to get the pure compound of formula-2.
The starting material 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N -methylpyridine-2-carboxamide may be obtained by any of the methods known in the prior art.
The crystalline Sorafenib tosylate ethanol solvate, Sorafenib tosylate methanol solvate of the present invention are useful in the preparation of crystalline Form-Ill of Sorafenib tosylate.
The crystalline forms of Sorafenib tosylate obtained according to the present invention can be useful in the preparation of pharmaceutical composition.
P-XRD Method of Analysis:
PXRD analysis of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
The compounds produced by the present invention can be further micronized by using conventional technique or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The best mode of carrying out the present invention is illustrated by the following examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido} phenoxy)-N-2-methylpyridine-2-carboxamidehemitosylate(Formula-l)
4-(4- { 3- [4-Chloro-3 -(trifluoromethyl)phenyl]ureido} phenoxy)-N-2-methylpyridine-2-carboxamide (70 gm), paratoluene sulfonic acid monohydrate (35 gm) and water (84 ml) were added to methylethylketone (210 ml). The reaction mixture was refluxed at 70-75°C for 20 minutes. Filtered the reaction mixture, stirred the filtrate at 25°C-30°C for 2 hrs and then filtered it again. The obtained compound was washed with methylethylketone. Dried under reduced pressure for 6 hrs at 55-60°C to get the title compound. Yield: 82.9 g; % yield: 78.4-90.4%, water content: The Powder X-ray diffraction pattern of the obtained compound is shown in figure-1.
Example-2: Preparation of ethanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyI) phenyl]ureido}phenoxy)-N-2-metb.ylpyridine-2-carboxamide 4-methylbenzenesulfonate (Formula-2) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)N2-methyl pyridine-2-carboxamide (50 gm) in dimethylsulfoxide (75 ml) at 25-30°C. Ethanol (50 ml) was added to the reaction mixture at 25-30° C. The reaction mixture was filtered through hyflow bed and washed with ethanol. A solution of paratoluene sulfonic acid (24.5 gm of PTSA.H20 in 675 ml of ethanol) was slowly added in lot wise to the reaction mixture at 25-30° C. After the addition of 4th lot, the reaction mixture was seeded with crystalline Sorafenib tosylate ethanol solvate (2.5 gm) and addition of the rest of the lots continued. After completion of addition stirred the reaction mixture for 2 hrs at 25-30°C. Filtered the precipitated solid, washed with ethanol and dried to get the title compound. Yield: 64 g. Purity: 99.19%.
Ethanol solvent content: 6.7% ppm. Particle size distribution: D (0.1): 10.43 urn; D(0.5): 25.84 um; D(0.9): 51.10 urn; Specific surface area: 0.785 m2/g. The Powder X-ray diffraction pattern of the obtained compound is shown in figure-2.
Example-3: Preparation of methanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido}phenoxy)-N-2-methylpyridine-2-carboxamide 4-methyl benzenesulfonate (formula-2)
Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)N2-methyl pyridine-2-carboxamide (50 gm) in dimethylformamide (75 ml) and stirred for 10 minutes at 25-30°C. The reaction mixture was filtered through filter paper for particle free and washed the filter paper with dimethylformamide. The solution of paratoluene sulfonic acid (24.5 gm) in methanol was added slowly to the reaction mixture at 25-30°C and stirred the reaction mixture for 8 hrs at the same temperature. Filtered the reaction mixture at 25-30°C and washed with methanol to get the title compound. Yield: 70.g; The Powder X-ray diffraction pattern of the obtained compound is shown in figure-3.
Example-4: Preparation of methanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl) phenyl]ureido}phenoxy)-N-2-methylpyridine-2-carboxamide 4-methyl benzenesulfonate
(formula-2)
Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)N2-methyl pyridine-2-carboxamide (5 gm) in dimethylacetamide (7.5 ml) and stirred for 15 minutes at 25-30°C. Methanol (5 ml) was added to the reaction mixture and stirred for 10 minutes at 25-30°C. The reaction mixture was filtered through high flow bed and washed with methanol. The solution of paratoluene sulfonic acid (2.5 gm) in methanol was slowly added in lot wise to the reaction mixture at 25-30°C and stirred the reaction mixture for 4 hrs at the same temperature. Filtered the obtained solid, washed with methanol and dried to get the title compound. Yield: 5.2 gm;
Example-5: Preparation of Form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]
ureido}phenoxy)-N-2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate
(formula-2)
The methanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido} phenoxy)-N-2-methylpyridine-2-carboxamide 4-methylbenzenesulfonate obtained in example-3 or example-4 was kept for drying under reduced pressure at 80-85°C for 24 hrs to to get the title compound. Yield: 68.5 g; % yield: 78.3-98.3% The Powder X-ray diffraction pattern of the obtained compound is shown in figure-4.
Example-6: Preparation of crystalline form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-methylpicolinamide-4-methylbenzene sulfonate (formula-2)
PTSA (24.5 gm) was dissolved in methanol (500 ml). Filtered the reaction mixture and washed with methanol (50 ml). The mixture of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido} phenoxy)-N-2-methylpyridine-2-carboxamide (50 gm) and DMF (75 ml) was stirred at 25-30°C for 10 minutes. Filtered the reaction mixture and washed with DMF. The obtained filtrate was added to above PTSA solution at 25-30°C and stirred for 8 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and dried at 80-85°C for 24 hrs to get the title compound. Yield: 65 gm; MR: 187-192°C.
The Powder X-ray diffraction pattern of the obtained compound is shown in figure-4.
Example-7: Preparation of crystalline form-Ill of 4-(4-{3-[4-ChIoro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-methylpicolinamide-4-methylbenzene sulfonate (formula-2)
The mixture of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-2-methylpyridine-2-carboxamide (50 gm) and DMF (75 ml) was stirred at 25-30°C for 10 minutes. Filtered the reaction mixture and washed with DMF.
PTSA (24.5 gm) was dissolved in methanol (500 ml). Filtered the reaction mixture and washed with methanol (50 ml). PTSA solution was added to the above reaction mixture at 25-30°C and stirred for 8 hrs at the same temperature. Filtered the precipitated solid, washed with methanol and dried at 80-85°C for 24 hrs to get the title compound. Yield: 65 gm; MR: 187-192°C. The Powder X-ray diffraction pattern of the obtained compound is shown in figure-4.
Example-8: Purification of crystalline form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-methylpicolinamide-4-methylbenzene sulfonate (formula-2)
Methanol (500 ml) was added to the crystalline form-Ill of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N-methylpicolinamide-4-methylbenzene sulfonate (50 gm) at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the reaction mixture, washed with methanol and dried to get the pure compound of formula-2. Yield: 48 gm; Purity: 99.9 % by HPLC.
We Claim:
1. A process for the preparation of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]
ureido}phenoxy)-N2-methyl pyridine-2-carboxamide hemitosylate compound of formula-
1, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-rnethylpyridine-2-carboxamide in a suitable solvent,
b) adding paratoluenesulfonic acid monohydrate and water to the reaction mixture,
c) heating the reaction mixture to reflux temperature,
d) filtering the reaction mixture,
e) cooling the reaction mixture, stirring and filtering,
f) washing the obtained compound with a suitable solvent,
g) drying the compound to get the compound of formula-1.
2. The process for the preparation of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]
ureido}phenoxy)-N2-methylpyridine-2-carboxamide hemitosylate compound of formula-
1, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in methylethylketone,
b) adding paratoluenesulfonic acid monohydrate and water to the reaction mixture,
c) heating the reaction mixture at 75°C ±5°C,
d) filtering the reaction mixture,
e) cooling the reaction mixture at 30°C ±5°C, stirring and filtering the reaction mixture,
f) washing the obtained compound with a mixture of methylethylketone and water,
g) drying the compound to get the compound of formula-1.
3. A process for the preparation of methanol solvate of 4-(4-{3-[4-Chloro-3-
(trifluoromethyl)phenyl]ureido} phenoxy)-N2-methylpyridine-2-carboxamide 4-methy 1
benzenesulfonate compound of formula-2, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-
methylpyridine-2-carboxamide in a suitable solvent,
b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) slowly adding a solution of p-toluene sulfonic acid in methanol to the reaction mixture,
e) stirring the reaction mixture and filtering the reaction mixture,
f) washing the obtained compound with methanol and drying to get the methanol solvate compound of formula-2.
4. The process for the preparation of methanol solvate of 4-(4-{3-[4-Chloro-3-
(trifluoromethyl)phenyl]ureido} phenoxy)-N2-methylpyridine-2-carboxamide 4-methy 1
benzenesulfonate compound of formula-2, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methyl pyridine-2-carboxamide in N,N-dimethylformamide,
b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) slowly adding a solution of p-toluene sulfonic acid in methanol to the reaction mixture,
e) stirring the reaction mixture for 6-8 hrs at 30°C ±5°C and filtering the reaction mixture,
f) washing the obtained compound with methanol and drying to get methanol solvate compound of formula-2.
5. The process for the preparation of methanol solvate of 4-(4-{3-[4-Chloro-3-
(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4-methyl
benzenesulfonate compound of formula-2, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in dimethylacetamide,
b) stirring the reaction mixture,
c) filtering the reaction mixture,
d) slowly adding a solution of p-toluene sulfonic acid in methanol to the reaction mixture,
e) stirring the reaction mixture for 4 hrs at 30°C ±5°C and filtering the reaction mixture,
f) washing the obtained compound with methanol and drying to get methanol solvate compound of formula-2.
6. A process for the preparation of ethanol solvate of 4-(4-{3-[4-Chloro-3-(trifluoromethyl)
phenyl]ureido}phenoxy)-N -methylpyridine-2-carboxamide 4-methyl benzenesulfonate
compound of formula-2, which is characterized by X-ray diffactogram pattern having
peaks at 7.82, 9.1, 11.8, 15.7, 18.1, 20.8, 21.37, 24.6 and 25.1 ± 0.2 degrees of 2-theta,
comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)N2-methyl pyridine-2-carboxamide in a suitable solvent,
b) adding ethanol to the reaction mixture,
c) filtering the reaction mixture at 25°C-30°C,
d) slowly adding a solution of p-toluene sulfonic acid mono hydrate (PTSA.H20) in ethanol to the reaction mixture,
e) seeding the reaction mixture with crystalline Sorafenib tosylate ethanol solvate,
f) filtering the obtained solid and drying it to get ethanol solvate compound of formula-2.
7. The process according to claim-6, wherein in step-d), the p-toluene sulfonic acid mono hydrate (PTSA.H2O) solution is added to the reaction mixture in lot-wise manner.
8. The process for the preparation of ethanol solvate of 4-(4-{3-[4-ChIoro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide 4-methyl benzenesulfonate compound of formula-2, which is characterized by X-ray diffactogram pattern having peaks at 7.82, 9.1, 11.8, 15.7, 18.1, 20.8, 21.37, 24.6 and 25.1 ± 0.2 degrees of 2-theta, comprising of following steps:

a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in dimethylsulfoxide,
b) adding ethanol to the reaction mixture,
c) filtering the reaction mixture,
d) slowly adding a solution of p-toluene sulfonic acid mono hydrate (PTSA.H20) in ethanol to the reaction mixture,
e) seeding the reaction mixture with crystalline sorafenib tosylate ethanol solvate,
f) filtering the obtained solid and drying it to get ethanol solvate compound of formula-2.
9. A process for the preparation of crystalline form-Ill of 4-(4-{3-[4-Chloro-3-
(trifluoromethyl) phenyl]ureido}phenoxy)-N -methylpyridine-2-carboxamide 4-
methylbenzenesulfonate compound of formula-2, comprising of:
a) Dissolving p-toluene sulfonic acid in methanol at 30±5°C,
b) optionally, filtering the reaction mixture,
c) slowly adding 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in N,N-dimethylformamide to the filtrate obtained in step-b),
d) stirring the reaction mixture for 6-8 hrs at 30°C±5°C and filtering the reaction mixture,
e) washing the obtained compound with methanol and drying at 80±5°C to get the crystalline form-Ill of compound of formula-2.
10. A process for the preparation of crystalline form-Ill of 4-(4-{3-[4-Chloro-3-
(trifluoromethyl)phenyl]ureido}phenoxy)-N -methylpyridine-2-carboxamide 4-methyl
benzenesulfonate compound of formula-2, comprising of:
a) Dissolving 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide in N,N-dimethylformamide at 30±5°C,
b) optionally, filtering the reaction mixture,
c) slowly adding a solution of p-toluene sulfonic acid in methanol to the reaction mixture obtained in step-b),
d) stirring the reaction mixture for 6-8 hrs at 30°C±5°C and filtering the reaction mixture,
e) washing the obtained compound with methanol and drying at 80±5°C to get the crystalline form-Ill of compound of formula-2.