Field of the Invention:
The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenox carboxamide compound of formula-1, and its crystalline polymorph-1 which is represented by the following structural formula:

Further, the present invention provides a novel DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 and its process for the preparation.

Background of the Invention:
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide commonly known as Regorafenib. Regorafenib is marketed under the brand name Stivarga by Bayer Healthcare. It is approved in United States as Regorafenib monohydrate on 27th Sep 2012. Regorafenib is indicated for the treatment of patients with metastatic colorectal cancer (CRC).

U.S. Patent No. 7,351,834 Bl generically discloses Regorafenib, a pharmaceutical^ acceptable salt thereof, but there is no specific disclosure of Regorafenib in said patent or its equivalents. The patent discloses a process for the preparation of desfluoro analog of Regorafenib i.e. Sorafenib, involving the reaction of 4-chloro-3-(trifluoromethyl) phenyl isocyanate with 4-(2-(N-methylcarbamoyl)-4- pyridyloxy)aniline in dichloromethane.

U.S. patent No. 8,637,553 B2 Al specifically discloses Regorafenib,pharmaceutically acceptable salts thereof and its composition thereof Also discloses the process for the preparation of Regorafenib by reacting 4-(4-amino-3- fluorophenoxy) pyridine-2-Qarboxylic acid methylamide in toluene with 4-chloro-3- (trifluoromethyl) phenyl isocyanate. The reaction mass was concentrated under reduced pressure and the residue was triturated with diethyl ether. The resulting solid was collected by filtration and dried to afford Regorafenib.

WO 2005/009961 disclosed Regorafenib and its process for the preparation. The monohydrate of said compound is disclosed in WO 08/043446.WO 2005/009961 is also disclosed polymorph-I of Regorafenib, US2010/0113533A1 disclosed the polymorph-II of Regorafenib and US2010/0063112A1 disclosed polymorph-III of Regorafenib and process for the preparation thereof.
Polymorphism is the occurrence of different solid state forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids having the same molecular formula and different physical properties such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with desired solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction and by other methods such as, infrared spectrometry and differential scanning calorimetry. Solvent medium and mode of crystallization play very important role in obtaining a polymorphic form over the other.

Most of the prior reported processes for the preparation of Regorafenib compound of formula-1 provide Regorafenib with higher level of impurities which are toxic in nature. Especially, 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 remains as impurity in the final API. Further it requires number of purifications to reduce or remove the said impurity.

In view of the above, there is a need in the art to develop a process for the preparation of Regorafenib compound of formula-1 which controls the level of above said genotoxic impurities and enhances the purity of the desired compound thereby useful for the pharmaceutical composition.

The present inventors have developed a process for the preparation of Regorafenib and surprisingly got Regorafenib with desired purity by simple modifications.

The present invention relates to a process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 through its DMSO solvate of compound of formula-1 which controls the level of genotoxic impurities thereby meets the desired ICH quality.
Brief description of the Invention:
The first aspect of the present invention is to provide a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4.

The second aspect of the present invention relates to DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1, hereinafter designated as crystalline Form-M.
The third aspect of the present invention is to provide a process for the preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoro phenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)T 3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1.
The fifth aspect of the present invention relates to an improved process for the

preparation of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4.
Brief description of Drawings:
Figure 1: Illustrates the powder X-ray diffractogram of DMSO solvate (crystalline fprm-M)
of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-
methylpyridine-2-carboxamide compound of formula-1.
Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofiiran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl 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, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, t-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "polar solvents" such as water; formic acid, acetic acid or mixture of any of the aforementioned solvents.
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, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium 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, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as

sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine, diisopropyl mine, diisopropylethylamine, diisobutylamine, triethylamine, triisoprppyl amine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-methylimidazole, l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene(DBN), N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA) and the like; "organosilicon bases" such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like or their mixtures.
As used herein "substantially free of genotoxic impurities" refers to compound of formula-1 containing genotoxic impurity i.e., compound of formula-4, in an amount of less than about 0.005 area%, preferably in an amount less than 0.001 area% by HPLC.
The first aspect of the present invention is to provide a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4, comprising of:
a) Reacting 4-chloro-N-methylpicolinamide compound of formula-2 with 4-amino-3-fluorophenol compound of formula-3 in presence of a suitable base in a suitable solvent in presence or absence of a suitable catalyst provides 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4,
b) adding the compound of formula-4 to the first lot of l-chloro-4-cyanatp-2-(trifluoro methyl)benzene compound of formula-5 in dichloromethane,
c) stirring the reaction mixture at a suitable temperature,
d) adding second lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,

e) stirring the reaction mixture at a suitable temperature and filtering the precipitated solid,
f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
g) adding second lot of l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 to the reaction mixture and stirring the reaction mixture at a suitable temperature,
h) adding methanol to the reaction mixture, i) stirring and cooling the reaction mixture, j) filtering the precipitated solid and drying to get DMSO solvate of 4-(4-amino-3-
fluorophenoxy)-N-methylpicolinamide compound of formula-1, k) dissolving DMSO solvate obtained in step-(j) in dimethylsulfoxide, 1) adding methanol to the reaction mixture and filtering the reaction mixture, m) stirring the reaction mixture at -15 to -25°C, n) filtering the precipitated solid and drying the compound to get compound of
formula-1, o) optionally, slurrying the solid obtained in step-(n) with methanol to provide
compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-
3-fluorophenoxy)-N-methylpicolinamide compound of formula-4. Wherein, the suitable base used in step-(a) is selected from organic or inorganic base
defined as above. The suitable solvent is selected from the list of solvents defined as above. The suitable catalyst used in step-(a) is selected from tetraalkyl/aryl ammonium halides,
tetraalkyl/aryl ammonium hydroxides and the like.
The preferred embodiment of the present invention provides a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoro phenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4, comprising of:
a) Reacting 4-chloro-N-methylpicolinamide compound of formula-2 with 4-amino-3-
fluorophenol compound of formula-3 in presence of a suitable base in a suitable

solvent in presence or absence of a suitable catalyst provides 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4,
b) adding 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to first lot of l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in dichloromethane,
c) stirring the reaction mixture at 0-5°C,
d) adding second lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
e) stirring the reaction mixture at 0-5°C and filtering the precipitated solid,
f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
g) adding second lot of l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 to the reaction mixture and stirring the reaction mixture at 19°C-23°C,
h) adding methanol to the reaction mixture, i) stirring and cooling the reaction mixture, j) filtering the precipitated solid and drying to get DMSO solvate of 4-(4-amino-3-
fluorophenoxy)-N-methylpicolinamide compound of formula-1, k) dissolving DMSO solvate obtained in step-(j) in dimethylsulfoxide, 1) adding methanol to the reaction mixture and filtering the reaction mixture, m) stirring the reaction mixture at -15 to -25°C,
n) filtering the solid and drying the compound to get compound of formula-1, o) slurrying the solid obtained in step-(n) with methanol provides compound of formula-
1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-
methylpicolinamide compound of formula-4.
The second aspect of the present invention provides DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1, hereinafter designated as crystalline Form-M. Further, the crystalline form-M is characterized by:
a) its powder X-ray diffraction pattern having peaks at 7.3, 9.2, 11.0, 13.5, 14.6, 14.9,
16.5, 17.0, 17.3, 18.1, 19.0, 19.5, 19.9, 21.6, 23.8, 24.6, 24.9, 25.1, 26.1 and 27.5± 0.2
degrees of 2-theta; and

b) its powder X-ray diffraction pattern as illustrated in figure-1.
The third aspect of the present invention is to provide a process for the preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1, comprising of:
a) Reacting 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula^ 4 with l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in a suitable solvent,
b) stirring the reaction mixture at a suitable temperature,
c) adding another lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
d) stirring the reaction mixture at a suitable temperature,
e) filtering the solid obtained in step-(d),
f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
g) adding a suitable solvent to the reaction mixture,
h) stirring and cooling the reaction mixture,
i) filtering the solid and drying to get DMSO solvate of compound of formula-1
Wherein, the suitable solvent is selected from chloro solvents, polar-aprotic solvents and alcohol solvents defined as above.
The preferred embodiment of the present invention provides a process for the preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl]carbamoyl} amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1, comprising of:
a) Reacting 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 with l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in dichloromethane,
b) stirring the reaction mixture at 0-5°C,
c) adding another lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
d) stirring the reaction mixture at 0-5°C,

e) filtering the solid obtained in step-(d),
f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
g) adding methanol to the reaction mixture,
h) stirring and cooling the reaction mixture,
i) filtering the solid and drying to get DMSO solvate of compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1, comprising of:
a) Dissolving DMSO solvate of compound of formula-1 in dimethylsulfoxide,
b) adding anti-solvent to the reaction mixture,
c) stirring and cooling the reaction mixture at a suitable temperature,
d) filtering the solid and drying the compound to get crystalline polymorph-I of compound of formula-1,
e) optionally, slurrying the solid obtained in step-(d) with a suitable solvent to provide crystalline polymorph-I of compound of formula-1.
Wherein, the suitable solvent is selected from polar-aprotic solvents and alcohol solvents defined as above.
The preferred embodiment of the present invention provides a process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1, comprising of:
a) Dissolving DMSO solvate of compound of formula-1 in dimethylsulfoxide,
b) adding methanol to the reaction mixture,
c) stirring and cooling the reaction mixture at -15 to -25°C,
d) filtering the solid and drying the compound to get crystalline polymorph-I of compound of formula-1,
e) optionally, slurrying the solid obtained in step-(d) with methanol to provide crystalline polymorph-I of compound of formula-1.
Most of the prior reported process for the preparation of Regorafenib compound of

formula-1 provides Regorafenib with higher level of impurities which are toxic in nature and not suitable for use in the pharmaceutical composition. The present inventors have developed an improved process i.e., re-reaction technique for the preparation of Regorafenib compound of formula-1 which controls the level of genotoxic impurities thereby meets the desired ICH quality. Hence, it can be known that, the process of the present invention is more advantageous than the prior art processes.
The fifth aspect of the present invention is to provide an improved process for the preparation of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4, comprising of reacting 4-chloro-N-methylpicolinamide compound of formula-2 with 4-amino-3-fluorophenol compound of formula-3 in presence of a suitable base in a suitable solvent in presence or absence of a suitable phase transfer catalyst provides 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4.
Wherein, the suitable base is selected from organic or inorganic base defined as above; the suitable solvent is selected from the list of solvents defined as above.
The suitable phase transfer catalyst is selected from tetraalkyl/aryl ammonium halides, tetraalkyl/aryl ammonium hydroxides and the like;
The preferred embodiment of the present invention provides an improved process for the preparation of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4, comprising of reacting 4-chloro-N-methylpicolinamide compound of formula-2 with 4-amino-3-fluorophenol compound of formula-3 in presence of potassium, tert.butoxide, potassium carbonate and tetrabutylammoniumbromide in acetonitrile provides 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4.
HPLC Method of Analysis:
4-[4-({[4-chloro-3-(trifluoromethyl)phenyI]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide:
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Kromacil 100-C18, 250 x 4.6 mm, 5 |im (or) equivalent; Flow rate: 1.2ml/min; Wavelength: 240 nm; Column Temperature: 30°C;

Injection volume: 10 fxL; Run time: 52 mins; Diluent: Acetonitrile : Water (98 : 02) v/v; Needle wash: Acetonitrile : Water (90 : 10) v/v; Elution: Gradient; Mobile phase-A: Buffer : Methanol (95 : 05 v/v); Mobile phase-B: Acetonitrile : Water (90 : 10) v/v. Weigh accurately about 1.36g of potassium dihydrogen orthophosphate in 1000ml of Milli-Q-water and filtered this solution through 0.22^im Nylon membrane filter paper.
Amine impurity, Ghloro impurity, Methyl ester impurity and Trifluoro impurity content by HPLC:
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength PDA-detector; Column: Hyperclone BDS CI8, 250 x 4.6 mm, 5 jam (or) equivalent; Wavelength: 210 nm & 240 nm; Column Temperature: 25PC; Injection volume: 15 |iL; Diluent: Methanol: Tetrahydrofuran; Needle wash: Acetonitrile : Water (90 : 10) v/v; Elution: Gradient; Mobile phase-A: Buffer (100 %); Mobile phase-B: Acetonitrile : Water (90 : 10) v/v. Transfer accurately 1.5 mL of Perchloric acid into a lOOOmL of Milli-Q water and filter this solution through 0.22(im nylon membrane filter paper.
PXRD analysis of the 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide of the present invention was carried out by using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.
The 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoro
phenoxy]-N-methylpyridine-2-carboxamide which is obtained by the present invention can be further micronized 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 (4-(3-fluoro-4-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy} phenyl) carbamoyl]amino}phenoxy)-N-methylpyridine-2-carboxamide) is known as "Dimer impurity" having the following structure:

The 4-chloro-3-(trifluoromethyl)aniline is known as "Trifluoro impurity" having the
following structure:
. The methyl 4-chloropicolinate is known as "Methyl ester impurity" having the following
structure:
The process of the present invention controlled above said Dimer impurity, Trifluoro impurity & Methyl ester impurity to 0.01%, preferably to non-detectable level.
The present invention is schematically represented as below: Scheme-I:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (Formula-4)
4-amino-3-fluorophenol (18.62 g), potassium tert.butoxide (20.6 g), potassium carbonate (10.2 g) & tetrabutylammonium bromide (9.5 g) were added to a pre-cooled acetonitrile (100 ml) at -10°C to -15°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 0°C to 5°C and stirred for 15 minutes. 4-chloro-N-methylpicolinamide (25 g) was added to the reaction mixture at the same temperature. Heated the reaction mixture to 80°C-85°C and stirred for 6 hours at the same temperature. Distilled off the 60% volume of the solvent under reduced pressure and cooled the reaction mixture to 25°C-30°C. Pre-cooled water (150 ml) followed by dichloromethane (375 ml) were added to the reaction mixture and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Separated both the aqueous and organic layers and extracted aqueous layer with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely and co-distilled the

reaction mixture with acetonitrile. Added acetonitrile to the obtained compound at 25PC-30°C and cooled the reaction mixture to 0°C to 5°C and stirred for 60 minutes at the same temperature. Filtered the reaction mixture and washed the obtained compound with chilled acetonitrile. Water was added to the obtained compound and stirred the reaction mixture for 2 hours at 25°C-30°C. Filtered the solid, washed with water and dried the compound to get the title compound. Yield: 25.25 g; M.R: 136-142°C.
Example-2: Preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]
carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of
formula-1
Step-a): Preparation of compound of formula-1
4-chIoro-3-(trifloromethyl)phenyl isocyanate (318.0) and 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (125 g) were added to a pre-cooled dichloromethane (2500 ml) at 0°C to 5°C under nitrogen atmosphere. Stirred the reaction mixture for 60 minutes at the same temperature. Another lot of 4-(4-amino-3-fluorophenoxy)-N-methyl picolinamide (125 g) was added to the reaction mixture at 0°C to 5°C and stirred the reaction mixture for 3 hours. Filtered the solid and washed with dichloromethane and dried the compound at 35°C to 40°C for 4 hours to get the title compound. Yield: 350 g;
Content of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide: 704.13 ppm (0.070 % by HPLC) Step-b): Preparation of DMSO solvate of compound of formula-1 (Re-reaction)
The compound obtained in step-(a) was added to a pre-cooled dimethylsulfoxide (1400 ml) at 19°C to 23°C. Second lot of 4-chloro-3-(trifloromethyl)phenyl isocyanate (29.67 g) was added to the reaction mixture at 19°C to 23°C and stirred for 1 hour. Raised the temperature of the reaction mixture to 25°C to 30°C and stirred the reaction mixture for 2 hours. Methanol (5600 ml) was slowly added to the reaction mixture at 25°C to 30°C. Cooled the reaction mixture to -10°C to -15°C and stirred the reaction mixture for 2 hours at same temperature. Filtered the solid, washed with methanol and dried the compound to get Regorafenib [DMSO solvate]. Yield: 275 g; M.R: 196-202°C. DMSO content: 18%.
Content of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide: 7.45 ppm (0.000745 % by HPLC); Dimer impurity: 0.01%.

The PXRD of obtained compound is depicted in figure-1.
Example-3: Preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyI] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1
4-chloro-3-(trifloromethyl)phenyl isocyanate (318.0) and 4-(4-amino-3-fluorop henoxy)-N-methylpicolinamide (125 g) were added to a pre-cooled dichloromethane (2500 ml) at 0°C to 5°C under nitrogen atmosphere. Stirred the reaction mixture for 60 minutes at the same temperature. Another lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (125 g) was added to the reaction mixture at 0°C to 5°C and stirred the reaction mixture for 3 hours. Filtered the solid and washed with dichloromethane and suck dry the compound. The obtained wet compound was added to a pre-cooled dimethylsulfoxide (1400 ml) at 19°C to 23°C. Raised the temperature of the reaction mixture to 25°C to 30°C and stirred the reaction mixture for 2 hours. Methanol (5600 ml) was slowly added to the reaction mixture at 25°C to 30°C. Cooled the reaction mixture to -10°C to -15°C and stirred the reaction mixture for 2 hours at same temperature. Filtered the solid, washed with methanol and dried the compound to get Regorafenib [DMSO solvate]. Yield: 275 g; M.R: 196-202°C. DMSO content: 18 %.
Content of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide: 7.45 ppm (0.000745 % by HPLC); Dimer impurity: Not detected.
The PXRD of obtained compound is depicted in figure-1.
Example-4: Preparation of polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1
Dissolved Regorafenib (125 g) in dimethylsulfoxide (500 ml) at 25°C to 3Q°C under nitrogen atmosphere. Methanol (1625 ml) was added to the reaction mixture at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Cooled the reaction mixture to -15°C to -20°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the solid, washed with methanol.
Methanol (234.4 ml) was added the above wet compound at 25°C to 30°C and stirred the reaction mixture for 2 hours. Cooled the reaction mixture to 0°C to 5°C and stirred for 2

hours. Filtered the solid, washed with methanol and dried the compound to get Regorafenib. Yield: 106.25 g; M.R: 199-206°C. Purity: 99.98% by HPLC; Particle size distribution D90: 46.6 jam. D[4,3]: 23.8 jim.
Content of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (Amine impurity): 2.0 ppm (0.0002% by HPLC); Chloro impurity compound of formula-2: 1.4 ppm (0.00014 % by HPLC); 4-amino-3-fluorophenol impurity compound of formula-3: Not detected; Trifluoro impurity: Not detected; Methylester impurity: Not detected; Dimer impurity: Not detected.
The PXRD of the obtained compound is matching with polymorph-I of Regorafenib disclosed in US201073953A1.
Example-5: Preparation of polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1
Dissolved Regorafenib (20 g) in methylethyl ketone (240 ml) at 25°C to 30°C. Heated the reaction mixture to 70°C to 75°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and washed with methylethyl ketone. Cooled the filtrate to 0°C to 5°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with methylethyl ketone and dried to get the title compound. Yield: 15.2 g; M.R: 198-206°C.
The PXRD of the obtained compound is matching with polymorph-I of Regorafenib disclosed in US201073953A1.

We Claim:
1. A process for the preparation of 4-[4-({[4-Qhloro-3-(trifluoromethyl)phenyl]carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4, comprising of: a) Reacting 4-chloro-N-methylpicolinamide compound of formula-2
with 4-amino-3-fluorophenol compound of formula-3
in presence of a suitable base in a suitable solvent in presence or absence of a suitable catalyst provides 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4,
b) adding the compound of formula-4 to the first lot of l-chloro-4-cyanato-2-(trifluoro methyl) benzene compound of formula-5

in dichloromethane,
c) stirring the reaction mixture at a suitable temperature,
d) adding second lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
e) stirring the reaction mixture at a suitable temperature and filtering the precipitated solid,
f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
g) adding second lot of l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 to the reaction mixture and stirring the reaction mixture at a suitable temperature,
h) adding methanol to the reaction mixture, i) stirring and cooling the reaction mixture, j) filtering the precipitated solid and drying to get DMSO solvate of 4-(4-amino-3-
fluorophenoxy)-N-methylpicolinamide compound of formula-1, k) dissolving DMSO solvate obtained in step-(j) in dimethylsulfoxide, 1) adding methanol to the reaction mixture and filtering the reaction mixture, m) stirring the reaction mixture at -15 to -25°C, n) filtering the precipitated solid and drying the compound to get compound of
formula-1, o) optionally, slurrying the solid obtained in step-(n) with methanol to provide
compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-
3-fluorophenoxy)-N-methylpicolinamide compound of formula-4.
2. A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl} amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4, comprising of:
a) Reacting 4-chloro-N-methylpicolinamide compound of formula-2 with 4-amino-3-fluorophenol compound of formula-3 in presence of a suitable base in a suitable solvent in presence or absence of a suitable catalyst provides 4-(4-amino-3-

fluorophenoxy)-N-methylpicolinamide compound of formuIa-4,
b) adding 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formuIa-4 to first lot of l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in dichloromethane,
c) stirring the reaction mixture at 0-5 °C,
d) adding second lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
e) stirring the reaction mixture at 0-5°C and filtering the precipitated solid,
f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
g) adding second lot of l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 to the reaction mixture and stirring the reaction mixture at 19°C-23°C.
h) adding methanol to the reaction mixture, i) stirring and cooling the reaction mixture, j) filtering the precipitated solid and drying to get DMSO solvate of 4-(4-amino-3-
fluorophenoxy)-N-methylpicolinamide compound of formula-1, k) dissolving DMSO solvate obtained in step-(j) in dimethylsulfoxide, 1) adding methanol to the reaction mixture and filtering the reaction mixture, m) stirring the reaction mixture at -15 to -25°C,
n) filtering the solid and drying the compound to get compound of formula-1, o) slurrying the solid obtained in step-(n) with methanol provides compound of
formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluoro
phenoxy)-N-methylpicolinamide compound of formula-4.
3. DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)'3-fluoro phenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1.
4. Crystalline form-M of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1 is characterized by:

a) its powder X-ray diffraction pattern having peaks at 7.3, 9.2, 11.0, 13.5, 14.6, 14.9, 16.5, 17.0, 17.3, 18.1, 19.0, 19.5, 19.9, 21.6, 23.8, 24.6, 24.9, 25.1, 26.1 and 27.5* 0.2 degrees of 2-theta; and
b) its powder X-ray diffraction pattern as illustrated in figure-1.
5. A process for the preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)
phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
compound of formula-1, comprising of:
a) Reacting 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 with l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in a suitable solvent,
b) stirring the reaction mixture at a suitable temperature,
c) adding another lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
d) stirring the reaction mixture at a suitable temperature,
e) filtering the solid obtained in step-(d),
f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
g) adding a suitable solvent to the reaction mixture,
h) stirring and cooling the reaction mixture,
i) filtering the solid and drying to get DMSO solvate of compound of formula-1.
6. The process for the preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)
phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
compound of formula-1, comprising of:
a) Reacting 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 with l-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in dichloromethane,
b) stirring the reaction mixture at 0-5°C,
c) adding another lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
d) stirring the reaction mixture at 0-5°C,

e) filtering the solid obtained in step-(d),
f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
g) adding methanol to the reaction mixture,
h) stirring and cooling the reaction mixture,
i) filtering the solid and drying to get DMSO solvate of compound of formula-1.
7. A process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoro
methyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
compound of formula-1, comprising of:
a) Dissolving DMSO solvate of compound of formula-1 in a suitable solvent,
b) adding anti-solvent to the reaction mixture,
c) stirring and cooling the reaction mixture at a suitable temperature,
d) filtering the solid and drying the compound to get crystalline polymorph-I of compound of formula-1,
e) optionally, slurrying the solid obtained in step-(d) with a suitable solvent to provide crystalline polymorph-I of compound of formula-1.
8. A process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoro
methyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
compound of formula-1, comprising of:
a) Dissolving DMSO solvate of compound of formula-1 in dimethylsulfoxide,
b) adding methanol to the reaction mixture,
c) stirring and cooling the reaction mixture at -15 to -25°C,
d) filtering the solid and drying the compound' to get crystalline polymorph-I of compound of formula-1,
e) optionally, slurrying the solid obtained in step-(d) with methanol to provide crystalline polymorph-I of compound of formula-1.
9. The process according to any of the preceding claims, the 4-[4-({[4-chloro-3-(trifluoro
methyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
compound of formula-1 substantially free of impurities such as 4-(4-amino-3-
fluorqphenoxy)-N-methylpicolinamide compound of formula-4 (amine impurity), chloro impurity compound of formula-2, 4-amino-3-fluorophenol impurity compound of formula-3, trifluoro impurity, methyl ester impurity and dimer impurity.
10. The DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 useful in the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(triflupromethyl)phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1.