Claims:We claim:
1. A process for preparation of Regorafenib tosylate (VI), comprising steps of
a. reacting 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (V) in an organic solvent or mixture of organic solvent at temperature ranging 25 - 50 °C;

b. addition of p-toluenesulphonic acid in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C; and
c. isolation of Regorafenib tosylate (VI) by filtration.

2. A process for the preparation of regorafenib form I, comprising the steps of

a. reacting 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) with imidazole complex of imidazole-1- carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (VII) in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 40 °C to get regorafenib base,

b. purifying the base by converting into its tosylate salt followed by basification, extraction to isolate regorafenib;
c. followed by hot leaching in an organic solvent.

3. The process of claims 1 or 2, wherein organic solvent is selected from the group consisting of acetone, N,N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethyl acetamide (DMA), ethyl acetate or mixtures thereof.

4. A process for preparation of Regorafenib tosylate (VI) according to claim 1, wherein process for the preparation of 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) comprising of
a. reaction of 4-amino-3-fluorophenol (II) with 4-chloro-N-methyl-2-pyridinecarboxamide (III) in organic solvent or mixture of organic solvents at temperature ranging from about 75-90 °C;

b. evaporation of volatile solvent, neutral pH adjustment, isolation of product by filtration; and
c. purification in alcoholic or ester solvent.

5. The process according to claim 4, wherein the alcoholic or ester solvent is selected from the group comprising of methanol, ethanol, isopropanol and ethyl acetate or mixtures thereof.

6. The process for the preparation of regorafenib form I according to claim 2, wherein the form 1 has PXRD pattern as shown in figure 1.
, Description:TECHNICAL FIELD OF THE INVENTION
The present invention provides a process for the preparation of Regorafenib form I, with purity not less than 99.7%. The invention also provides the process for the preparation of Regorafenib tosylate salt.

BACKGROUND ART
The compound Regorafenib (I) also known as 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide.

Regorafenib was approved in 2012 by US FDA for the treatment of patients with metastatic colorectal cancer (CRC). It was developed and marketed by Bayer Healthcare under the brand name Stivarga®. It is a multiple protein kinase inhibitor drug involved in oncogenesis, tumor angiogenesis and tumor microenvironment.

Synthesis of Regorafenib and its salts like hydrochloride, mesylate and phenyl sulphonate was first disclosed by U.S. patent No. 8,637,553 B2 starting from 3-fluoro-4-nitrophenol. The final condensation between 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxylic acid methylamide with 4-chloro-3-(trifluoromethyl)phenylisocyanate was reported in toluene for 72 hrs to get Regorafenib in 47% yield after triturating with diethyl ether.

The spectral differentiation of Regorafenib monohydrate and its form I is disclosed in U.S. patent application No. 20100173953 A1. The characteristic X-ray diffractogram, IR spectrum, Raman spectrum, FIR spectrum, NIR spectrum and a 13C-solid state-NMR spectrum for both the polymorphic forms was disclosed.
Regorafenib polymorph II and polymorph III iss disclosed in U.S. patent application No.’s 20100113533 A1 and 20100063112 A1 respectively with characteristic X-ray diffraction peaks, melting point and the characteristic IR wave numbers. WO2015011659A1 discloses the process for the synthesis of crystalline Regorafenib polymorphic forms A, B, C and D. This patent also discloses the preparation of polymorph I of Regorafenib. WO2015049698A2 provides a process for the preparation of a crystalline solid of Regorafenib tosylate and Regorafenib Polymorph I by in-situ condensing 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide with 4-chloro-3- (trifluoromethyl)aniline in presence of 1,1-carbonyldiimidazole in DCM solvent to get crude Regorafenib. The reaction time is 55 hrs. The obtained residual mass was further reacted with p-toluenesulfonic acid to obtain Regorafenib tosylate in nearly 54% of yield with purity 97.8%. Regorafenib Polymorph I was achieved by dissolving Regorafenib tosylate in water and an ester solvent followed by basification, solvent evaporation and by heating the residual solid in ketonic solvent. Prolonged time and less yield of the reaction are not suitable for industrial scale preparation. WO2016005874A1 discloses the process for preparation Regorafenib and its crystalline forms. In this application Regorafenib form 1 was prepared by condensing 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide with 4-chloro-3-trifluoromethylisocynate (1.5 - 2 equivalent) in acetone for 3 - 4 hrs followed by with or without addition of toluene to the reaction mass. Though the purity of the product mentioned is 99.5 %, this procedure fails in terms of cost effectiveness at industrial scale due to use of excess equivalent of isocynate derivative.
WO2017/125941A1 discloses the process for preparation Regorafenib form I by condensing 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide with 4-chloro-3-trifluoromethylisocynate in THF for 12 hrs followed by carbon treatment in acetone (44 volumes) to get crude Regorafenib form I. Purification in acetone at 55 0C yielded nearly 57- 60 % of Regorafenib form I. Use of high volumes of solvent, long reaction time and moderate yield procedure fails in terms of industrial production.
Thus, there is a need to address the various drawbacks of prior disclosed processes, by developing the suitable industrial scale methodology in terms of good purity, yield and cost-effectiveness.
SUMMARY OF THE INVENTION
The invention disclosed herein relates to improved process for the preparation of the regorafenib form I and regorafenib tosylate salt which has faster reaction rate, high yield and high purity.
The invention relates to a process for preparation of Regorafenib tosylate (VI), comprising steps of
a. reacting 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (V) in an organic solvent or mixture of organic solvent at temperature ranging 25 - 50 °C;

b. addition of p-toluenesulphonic acid in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50°C; and
c. isolation of Regorafenib tosylate (VI) by filtration.
The organic solvent is selected from the group consisting of acetone, N,N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethyl acetamide (DMA), ethyl acetate or mixtures thereof.
The invention disclosed herein also provides an improved industrially suitable process for the synthesis of regorafenib form I with improved yield, good purity and substantially free from any process related impurities. The regorafenib form I prepared according to the process as disclosed herein has a purity > 99.5 % with individual impurities < 0.1%. The process for the preparation of regorafenib form I, comprises the steps of

a. reacting 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) with imidazole complex of imidazole-1- carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (VII) in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 40°C to get regorafenib base,

b. purifying the regorafenib base by converting into its tosylate salt followed by basification, and extraction to isolate regorafenib; and
c. hot leaching in an organic solvent.
The regorafenib form I has PXRD pattern as shown in figure 1.
The organic solvent is selected from the group consisting of acetone, N,N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethyl acetamide (DMA), ethyl acetate or mixtures thereof.
The process for the preparation of 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) comprises of
a. reaction of 4-amino-3-fluorophenol (II) with 4-chloro-N-methyl-2-pyridinecarboxamide (III) in organic solvent or mixture of organic solvents at temperature ranging from about 75-90 °C;

b. evaporation of volatile solvent, neutral pH adjustment, isolation of product by filtration; and
c. purification in alcoholic or ester solvent.
The alcoholic or ester solvent is selected from the group comprising of methanol, ethanol, isopropanol and ethyl acetate, or a mixture thereof.
BREIF DESCRIPTION OF DRAWINGS
Figure 1 is an X-ray powder diffraction spectrum obtained according to the process of preparation for Regorafenib form I as disclosed herein.
Figure 2 is DSC isotherm obtained according to the process of preparation for Regorafenib form I as disclosed herein.
DETAILED DESCRIPTION
As set forth herein, the embodiments of the invention provide an industrial suitable process for the synthesis of Regorafenib form I in improved yield, good purity and free from its process related impurities.

The invention disclosed herein further provides a process for the one pot preparation of Regorafenib tosylate (VI), comprising steps of - a. reacting 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (V) in an organic solvent or mixture of organic solvent at temperature ranging from about 25 - 50 °C; addition of p-toluenesulphonic acid in organic solvent or mixture of organic solvent at temperature ranging 25 - 50 °C; and isolation of Regorafenib tosylate (VI) by filtration.
According to one embodiment, 4-chloro-3-(trifluoromethyl)phenylisocyanate in acetone (4 vol) was added to pre stirred solution 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide in acetone (10 vol) at 25-30 °C. During the course of the reaction crude regorafenib solid was separate in reaction mixture. Reaction mass was stirred for 4 - 5 hrs. Absence of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide was confirmed by HPLC. Reaction time was about 4 hrs for completion. p-toluenesulphonic acid in acetone (4 vol) was added to above mass at 25-30 °C in 10-15 min to get cleared solution and then salt was separates out. Stirred mass for 2 -3 hrs at room temperature and Regorafenib tosylate was isolated by filtration followed by acetone washing in an around 90 – 93 % yield with HPLC purity > 99 %.
According to another embodiment, 4-chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide in DMF (6 vol) solvent for 6 hrs. After completion of reaction, crude regorafenib was isolated by extraction and then converted into its tosylate salt with HPLC purity > 99.5 %.
The invention disclosed herein also provides a process for the preparation of regorafenib form I, by reacting 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) with imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (VII) in DMF for 12 hrs to get crude regorafenib base, which was purified by converting into its tosylate salt followed by basification, extraction and hot leaching in acetone.
The invention disclosed herein also provides a process for the preparation of regorafenib form I, by dissolving its tosylate salt in ethyl acetate and water mixture under heating condition. pH made basic using caustic lye solution. Combined organic layer was treated with carbon at a temperature ranging from about 60-65 °C, celite filtration followed by evaporation of solvent gives regorafenib base. Hot leaching in acetone, cooling and filtration yields regorafenib form I in 80-85 % yield with purity around 99.8 % with no process related impurities. Reacting 4-chloro-3-(trifluoromethyl)phenylisocyanate with 4-(4-amino-3-fluorophenoxy)-N-methylpicolin amide in acetone, in-situ salt formation followed by basification method is beneficial in terms of good yield as well as excellent purity.

The synthesized regorafenib according to the process disclosed herein was analyzed by DSC isotherm and PXRD. DSC isotherm was found to be a single peak, ranging between 212° to 217°C with onset range 213°C. The PXRD pattern having diffraction angle values (± 0.2° 2 Theta) are given in table 1.

Table 1
In summary, present invention provide the improved process for the preparation of the regorafenib form I and regorafenib tosylate salt in terms of faster reaction rate, high yield and excellent purity.
According to the process disclosed herein, regorafenib form I having purity > 99.5 % with individual impurities < 0.1% and which compliance with the regulatory requirements.
The invention disclosed herein provides a process for the preparation of 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (IV) comprising, reaction of 4-amino-3-fluorophenol (II) with 4-chloro-N-methyl-2-pyridinecarboxamide (III) in organic solvent or mixture of organic solvents at temperature ranging from about 75-90 °C followed by purification in alcoholic or ester solvent.

According to one embodiment, the mixture of 4-amino-3-fluorophenol, 4-chloro-N-methyl-2-pyridinecarboxamide and potassium carbonate in N,N-dimethylformamide (DMF) was initially heated to a temperature ranging from about 80 – 90 °C. The solution of potassium t-butoxide (t-BuOK) in tetrahydrofuran (THF) was added to above mass in 10 - 15 min at a temperature ranging from about 80-85 °C. Reaction mass further reflux at a temperature ranging from about 70 - 72 °C for 4 hrs. Evaporate THF completely from the reaction mass under reduced pressure to obtained residue. Water was drop wise added to above residue at room temperature and pH of the reaction was made neutral using 1N HCl solution. Obtained solid was stirred for 30 min at room temperature, filtered and washed with 20 – 50 volumes of water. The dried crude 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide was further purified using hot leaching with alcoholic or ester solvent to get 97- 98% pure product depending upon choice and volume of solvent in 65 -70 % over all yield from 4-chloro-N-methyl-2-pyridinecarboxamide. Use of 1.5 eq of 4-amino-3-fluorophenol, 1.6 eq of potassium t-butoxide, 0.5 eq of potassium carbonate in mixture of solvents like DMF (4 vol) and THF (5 vol) is the preferred method for getting 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide.

Presence of THF during pH adjustment drastically reduces the product precipitation and there by alter the yield of reaction. It is beneficial to wash crude solid product with excess of water to remove colored impurities formed during the reaction.

The crude 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide was further purified using hot leaching with alcoholic or ester solvents. The solvents or mixture of solvents was selected from a group comprising of methanol, ethanol, isopropanol, ethyl acetate hexane and water. According to one embodiment the mixture of Ethanol and ethyl acetate is the preferred solvent mixture in terms of yield and purity of the product.
EXAMPLES:
Example 1: Preparation of 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide
4-chloro-N-methyl-2-pyridinecarboxamide (75 gm, 0.44 moles) and 4-amino-3-fluorophenol (84 gm, 0.66 moles) was dissolved in DMF (300 mL). K2CO3 (30.44 g, 0.22 mole) was added to the mixture and mass was heated to 85 - 90°C. Chilled water was circulated through the condenser and t-BuOK (79.06 g, 0.70) in THF (375 mL) was added to reaction mass within 10-15 minutes. Vigorous reaction occurs during addition time and temperature was drop down to 70-75°C. After 4-5 hrs, THF was totally distilled out from the reaction mass and it was cooled to room temperature. Water (750 mL) was added and pH of the mass was adjusted to neutral with 1N HCl. Solid was filtered, washed with water (3 x 15 V) and dried in oven for 4 hrs. Obtained 108.6 gm of crude product was hot triturated with Ethyl acetate (450 mL) for 30 - 45 minutes. Mixture was cooled to 0°C and stirred for 1 hr. Product was filtered and dried in oven to get 77.6 gm (67.3 %) of product. HPLC purity: 97.5 %.
Example 2: Purification of 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide in ethanol
30 gm crude of product (Example 1) was hot triturated with Ethanol (120mL) for 30 - 45 minutes. Mixture was cooled to 0°C and stirred for 1 hr. Product was filtered and dried in oven to get 18.3 gm of product. HPLC purity: 96.63 %.
Example 3: Purification of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide in methanol
5 gm crude of product (Example 1) was hot triturated with methanol (15 mL) for 30 - 45 minutes. Mixture was cooled to 0°C and stirred for 1 hr. Product was filtered and dried in oven to get 3.25 gm of product. HPLC purity: 95.2 %.
Example 4: Preparation of Regorafenib form I
To a stirred solution of 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (77 gm, 0.29 mole, example 1) in acetone (770 mL) was added 4-chloro-3-trifluoromethylisocyanate (81.6, 0.36 mole) in acetone (308 mL) in 15-20 minutes by maintaining the temperature below 30 - 35°C. Solid material separates after 1 hr. Stirred mass for 5 hrs at 25 -30°C. Progress of reaction was monitored by HPLC for the complete absence of 4-(4-aminophenoxy)-N-methylpicolinamide. After completion of the reaction, p- toluenesulfonic acid monohydrate (61.65 g, 0.32 mole) in acetone (308 ml) was added within 10-15 min at 25 -30°C. During addition clear solution was observed followed by salt precipitation. Reaction mass was further stirred at 30°C for 2.5 hrs. Obtained solid was filtered and washed with acetone (2 X 308 ml). Product was further dried for 3 hrs to get 172.4 gm of regorafenib tosylate salt. (HPLC purity: 99.43%).
The dried salt (172 gm, 0.26 mole) was further stirred with the mixture of ethyl acetate (12 v) and water (5v). The suspension was heated to 55°C and pH of the solution was adjusted to 8 – 9 using caustic lye solution. Organic layer was separates and aq. layer was extracted with ethyl acetate (1 x 1206 mL). Combined organic layer was treated with activated carbon at 65°C for 30 minutes and filtered in hot through celite. Mother liquor was evaporate under reduced pressure to obtained crude regorafenib solid, which was hot triturated with acetone (625 mL) for 30 minutes. Mixture was cooled to -5 °C for 1 hr and solid was filtered and dried for 2 hrs to get 112.8 gm of regorafenib from 1 in 82.5% yield. HPLC purity: 99.75 %
MS (ESI, CH3CN/H2O): m/e = 483 [M+H]+, 505 [M+Na]
Example 5: Preparation of Regorafenib tosylate
To a stirred solution of 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (5 gm, 0.019 mole, Example 2) in DMF (20 mL) was added 4-chloro-3-trifluoromethylisocyanate (5.3, 0.023 mole) in DMF (10 mL) in 15-20 minutes by maintaining the temperature below 30 - 35°C. Stirred mass for 4 hrs at 25 -30°C. Progress of reaction was monitored by HPLC for the complete absence of 4-(4-aminophenoxy)-N-methylpicolinamide. After completion, the reaction mass was quenched onto water and extracted with (2 x 50 mL) of ethyl acetate. Combined organic layer was washed with brine solution (2 x 20 mL), dried over sodium sulphate and evaporate to dryness to get crude regorafenib. Obtained crude product was dissolved in acetone (50 mL) and p- toluenesulfonic acid monohydrate (4 g, 0.21 mole) in acetone (20 ml) was added within 10-15 min at 25 -30°C. Reaction mass was further stirred at 30°C for 2.5 hrs. Obtained solid was filtered and washed with acetone (2 X 20 ml). Product was further dried for 3 hrs to get 10.25 gm of regorafenib tosylate. HPLC purity: 99.65%.
Example 6: Preparation of Regorafenib form I
The dried salt (10 gm, 0.015 mole, Example 5) was further stirred with the mixture of ethyl acetate (12 v) and water (5v). The suspension was heated to 55°C and pH of the solution was adjusted to 8 – 9 using caustic lye solution. Organic layer was separates and aq. layer was extracted with ethyl acetate (1 x 70 mL). Combined organic layer was treated with activated carbon at 65°C for 30 minutes and filtered in hot through celite. Mother liquor was evaporated under reduced pressure to obtain crude regorafenib solid, which was hot triturated with acetone (42 mL) for 30 minutes. Mixture was cooled to -5 °C for 1 hr and solid was filtered and dried for 2 hrs to get 6.3 gm of regorafenib from 1 in 70 % yield. HPLC purity: 99.91 %
Example 7: Preparation of Regorafenib tosylate
To the mixture of 4-(4-amino-3-fluorophenoxy)-N- methylpicolinamide (5 gm, 0.019 mole, example 1)and imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl) phenyl amide (8.2 g, 0.022 mole ) was added DMF (30 mL). The mixture was stirred further at room temperature till completion of the reaction. Ethyl acetate (150 mL) was added and the mixture was washed with 1N HCl (1 X 20 mL), water (2 x 50 mL) and brine solution (1 x 30 mL). Organic layer was dried over sodium sulphate and evaporate under reduced pressure to get solid mass, which was dissolved in acetone (50 mL) and p- toluenesulfonic acid monohydrate (4 g, 0.21 mole) in acetone (20 ml) was added within 10-15 min at 25 -30°C. Reaction mass was further stirred at 30°C for 2.5 hrs. Obtained solid was filtered and washed with acetone (2 X 20 ml). Product was further dried for 3 hrs to get 9 gm of regorafenib tosylate. HPLC purity: 99.3%.
Example 8: Preparation of Regorafenib form I
The dried salt (9 gm, 0.013 mole, Example 5) was further stirred with the mixture of ethyl acetate (12 v) and water (5v). The suspension was heated to 55°C and pH of the solution was adjusted to 8 – 9 using caustic lye solution. Organic layer was separates and aq. layer was extracted with ethyl acetate (1 x 63 mL). Combined organic layer was treated with activated carbon at 65°C for 30 minutes and filtered in hot through celite. Mother liquor was evaporate under reduced pressure to obtained crude regorafenib solid, which was hot triturated with acetone (42 mL) for 30 minutes. Mixture was cooled to -5 °C for 1 hr and solid was filtered and dried for 2 hrs to get 6.05 gm of regorafenib from 1 in 67 % yield. HPLC purity: 99.42 %.