CLIAMS:Claims:

1) A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I)

(I)
comprising the steps of:
a) adding 4-Chloro-N-methyl-2-pyridinecarboxamide of Formula II

(II)
and 4-Amino-3-fluorophenol of Formula III

(III)
in an organic solvent in ratio between 3-8 v/w times with respect to compound of formula (II) at a temperature ranging between 20-35°C;
b) reacting the mixture of step a) in presence of sodium/potassium tertiary butoxide in tetrahydrofuran to provide 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV);

(IV)
c) reacting the compound of Formula IV with 4-chloro-3-trifluoromethylisocyanate of Formula V

(V)
in presence of polar solvent in ratio between 3-8 v/w times with respect to compound of formula (IV) to provide 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide(I); and
d) optionally, purifying the 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide using a polar solvent or a mixture of polar and hydrocarbon solvent.

2) A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide according to claim 1, wherein organic solvent used in step a) is selected from amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone, dimethyl acetamide.

3) A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide according to claim 1, wherein polar solvent in step c) and d) are selected from ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone, dimethyl acetamide; alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; water or mixtures thereof.

4) A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide according to claim 1, wherein hydrocarbon solvent used in step d) is selected from toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene dichloride, ethylene chloride, chloroform; or mixtures thereof.

5) A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide according to claim 1, wherein the product obtained is having PXRD pattern having diffraction angle values at 7.2, 8.6, 11.5, 12.0, 13.4, 14.5, 14.8, 15.6, 16.5, 17.2, 17.4, 18.6, 18.8, 19.0, 19.8, 20.0, 20.2, 23.4, 23.8, 24.2, 24.8, 25.8, 25.9, 26.3, 26.4, 26.6, 27.2, 27.4 and 31.6 ± 0.2°2?

6) A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide according to claim 1, wherein the product obtained having purity greater than 99.5%.

7) 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide having purity greater than 99.5% and substantially free from process related impurities:

(A) ; and/or

(B) ; and/or

(C)
8) A process for the purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) comprising the steps of
a) stirring 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide in a polar or mixture of polar and hydrocarbon solvent up to reflux temperature;
b) recovering pure 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide (I) substantially free from process related impurities (A), (B) and (C); and/or
c) optionally, repeating step a) & b) to get desired purity.

9) A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide according to claim 8, wherein polar solvent in step a) are selected from ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone, dimethyl acetamide; alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; water or mixtures thereof; wherein hydrocarbon solvent used in step a) is selected from toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene dichloride, ethylene chloride, chloroform; or mixtures thereof.

10) A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I)

(I)
comprising the steps of:
a) reacting the compound of Formula IV with 4-chloro-3-trifluoromethylisocyanate of Formula V

(V)
in presence of polar solvent in ratio between 3-8 v/w times with respect to compound of formula (IV) to provide 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide(I); and
b) optionally, purifying the 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide using a polar solvent or a mixture of polar and hydrocarbon solvent.

Dated this 09th day of July 2014 Signature:
Dr. A.K.CHATURVEDI
,TagSPECI: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-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib of Formula (I).

(I)
The present invention further relates to a process for the purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I)

BACKGROUND OF THE INVENTION

4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib is low molecular weight, orally available, inhibitor of multiple protein kinases, including kinases involved in tumour angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF, BRAFV600E), and the tumour microenvironment (PDGFR, FGFR). In preclinical studies regorafenib has demonstrated antitumour activity in a broad spectrum of tumour models including colorectal tumour models which is mediated both by its antiangiogenic and antiproliferative effects. Major human metabolites (M-2 and M-5) exhibited similar efficacies compared to Regorafenib both in vitro and in vivo models.

Regorafenib was approved by USFDA in 2012 and is marketed under the brand name Stivarga®, is an important chemotherapeutic agent useful for the treatment of adult patients with metastatic colorectal cancer (CRC) who have been previously treated with, or are not considered candidates for, available therapies. These include fluoropyrimidine-based chemotherapy, an anti-VEGF therapy and an anti-EGFR therapy.

Regorafenib is chemically known as 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I).
Regorafenib is a white to slightly pink or slightly brownish solid substance with the empirical formula C21H15ClF4N4O3 and a molecular weight of 482.82. Regorafenib is practically insoluble in water, dilute alkaline solution, dilute acid solution, n-heptane, glycerine and toluene. It is slightly soluble in acetonitrile, dichloromethane, propylene glycol, methanol, 2-propanol, ethanol and ethyl acetate. It is sparingly soluble in acetone and soluble in PEG 400 (macrogol). Regorafenib is not hygroscopic.

Regorafenib is generically disclosed in US 7351834, and specifically disclosed in US 8637553. US ‘553 disclose a process for the preparation of Regorafenib starting from 3-fluoro-4-nitrophenol. The process is as demonstrated below:

US 2010173953 disclose Regorafenib monohydrate and crystalline Form I of Regorafenib. This patent application further discloses that crystalline Form I of Regorafenib stated in this application is obtained as per the process disclosed in WO 2005009961 A2 (Equivalent to US ‘553). The compound obtained was having a melting point of 186-206° C.

This patent publication discloses a process for the preparation of Regorafenib monohydrate comprises dissolving Regorafenib Form I obtained as per WO ‘961 in acetone and the solution is filtered, followed by addition of water until precipitation, which was filtered and dried at room temperature

US 2010/0113533 discloses crystalline Form II of Regorafenib, comprises dissolving Regorafenib Form I obtained as per WO ‘961 in ethyl acetate, the suspension was heated to 40-45°C, addition of isocyanate solution (isocyanate in ethyl acetate) and is cooled to room temperature to yield the crystals, which was filtered, washed with ethyl acetate and dried at room temperature.

US 2010/0063112 discloses Form III of Regorafenib, process comprises of heating Regorafenib monohydrate at 100°C or 60 min, and further 15 min at 110°C, followed by cooling to room temperature.

The present inventors has repeated the above process and found the following disadvantages:
? In most of the patent literature, toluene is used as solvent in coupling stage, which is tedious for the removal.
? Unwanted reactions are observed during the formation of Regorafenib, due to the involvement time lagging process.
? Incomplete reactions were observed with excessive impurity formation due to incomplete conversion.

In view of the above and to overcome the prior-art problems the present inventors had now developed an improved process for the preparation of Regorafenib, using industrially feasible and viable process, with the use of industrially friendly solvents, which does not include tedious work up and time lagging steps.

OBJECTIVE OF THE INVENTION

The main objective of the invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib (I).

Yet another objective of the invention relates to a process for the purification of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I)

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I)

(I)
comprising the steps of:
a) adding 4-Chloro-N-methyl-2-pyridinecarboxamide of Formula II

(II)
and 4-Amino-3-fluorophenol of Fomula III

(III)
in an organic solvent in ratio between 3-8 v/w times with respect to compound of formula (II) at a temperature ranging between 20-35°C;
b) reacting the mixture of step a) in presence of sodium/potassium tertiary butoxide in tetrahydrofuran to provide 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV);

(IV)
c) reacting the compound of Formula IV with 4-chloro-3-trifluoromethylisocyanate of Formula V

(V)
in presence of polar solvent in ratio between 3-8 v/w times with respect to compound of formula (IV) to provide 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide(I); and
d) optionally, purifying the 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide using a polar solvent or a mixture of polar and hydrocarbon solvent.

In another aspect of the invention relates to 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide having purity greater than 99.5% and substantially free from process related impurities:

(A) ; and/or

(B) ; and/or

(C)

In yet another aspect of the invention relates to a process for the purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) comprising the steps of
a) stirring 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide in a polar or mixture of polar and hydrocarbon solvent up to reflux temperature;
b) recovering pure 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide (I) substantially free from process related impurities (A), (B) and (C) ; and/or
c) optionally, repeating step a) & b) to get desired purity.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib (I) obtained according to the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide or Regorafenib (I) comprising adding 4-Chloro-N-methyl-2-pyridinecarboxamide (II) and 4-Amino-3-fluorophenol (III) in an organic solvent selected from amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone; in the ratio between 3-8 v/w times with respect to compound of formula (II) at a temperature ranging between 20-35°C. The obtained reaction mixture was heated to 110-115°C and then a solution of sodium/potassium tertiary butoxide in tetrahydrofuran was added slowly over a period of 3 to 4 hours. Distill off the solvent without vacuum, followed by pH adjustment with Hydrochloric acid to obtain crude 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV). The obtained crude material finally recrystallized with ethyl acetate to provide 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV).

In one embodiment, the present inventors surprisingly found that use of an organic solvent in the ratio between 3-8 v/w times with respect to compound of formula (II) leads to provide 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV) in higher yields compare to the prior-art process.

On the other hand, the prior art processes involves the use of excess solvent greater than 8 v/w times, which involves distillation of solvent at high temperature leads in the decomposition of product and lowering the quantity of yield. The present inventors also found that the use of excess solvent also leads in the conversion of reactant in the range of 70-75% only, which means that the reaction becomes incomplete.

The present inventors also found that the use of an organic solvent in the ratio between 3-8 v/w times with respect to compound of formula (II) is advantageous while removing the solvent after completion of the reaction, which is very easy and does not require any cumbersome workup.

In another embodiment, the present inventors surprisingly found that the use of sodium/potassium tertiary butoxide in tetrahydrofuran instead of anhydrous sodium/potassium tertiary butoxide is advantageous over prior art, as the reaction completes within hours and conversion is also greater than 95%. This is due to the decomposition activity of anhydrous sodium/potassium tertiary butoxide, which is overcome by using a solution of sodium/potassium tertiary butoxide completes the reaction within hours, which is industrially feasible and economical. Further, use of sodium/potassium tertiary butoxide solution completes the reaction within hours also helps in avoiding the unwanted reactions and minimizes the formation of impurity in the formation 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV).

4-chloro-3-trifluoromethylisocyanate was added slowly over a period of 5 to 10 minutes to the solution of 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV), wherein the solution was obtained by dissolving 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV) in a polar solvent selected from ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone; alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; water or mixtures thereof in ratio between 3-8 v/w times with respect to compound of formula (IV) at a temperature ranging from 25-30°C; by continuous stirring for 3 to 4 hours; followed by washing with toluene to provide 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I);

In an another embodiment, the present inventors surprisingly found that the use of polar solvent in the condensation of 4-chloro-3-trifluoromethylisocyanate (V) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV) completes the reactions within 3 to 5 hours, which is industrially feasible and economical.

The present inventors also found that the use of polar solvent in the condensation of 4-chloro-3-trifluoromethylisocyanate (V) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV) leads to provide higher yields, compare to the prior processes known in the art, which is more advantageous in industrial scale.

The present inventors also found that the use of polar solvent in the condensation of 4-chloro-3-trifluoromethylisocyanate (V) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (IV) leads to formation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I), immediately after completion of the reaction and does not require cumbersome workup.

4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) obtained above is purified using a polar solvent selected from selected from ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone; alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; water or mixtures thereof or a mixture of polar and hydrocarbon solvent selected from selected from toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene dichloride, ethylene chloride, chloroform; or mixtures thereof; at a temperature ranging from 60-110°C, by stirring the reaction mixture for 15 to 45 minutes, cooling to room temperature and continued stirring for 30 minutes to 2 hours; the obtained reaction mixture was filtered and washed with toluene to yield pure 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-65°C for a time ranging from 12 to 16 hours depending upon the physical attributes of the end product obtained i.e. Pure Regorafenib. 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib obtained according to the present invention is having purity greater than 99.5%.

The obtained pure 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib having purity greater than 99.5% and substantially free from process related impurities:

(A) ; and/or

(B) ; and/or

(C)
4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib obtained according to the present invention is analyzed by PXRD and obtained PXRD pattern having diffraction angle values at 7.2, 8.6, 11.5, 12.0, 13.4, 14.5, 14.8, 15.6, 16.5, 17.2, 17.4, 18.6, 18.8, 19.0, 19.8, 20.0, 20.2, 23.4, 23.8, 24.2, 24.8, 25.8, 25.9, 26.3, 26.4, 26.6, 27.2, 27.4 and 31.6 ± 0.2°2?

The process related impurities that appear in the impurity profile of the 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib may be substantially removed by the process of the present invention resulting in the formation of highly pure material. The process of the present invention is as summarized below:


In another embodiment, the Regorafenib obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Regorafenib obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from Regorafenib of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES

Example 1
Preparation of 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide

4-Amino-3-fluorophenol (11g, 0.08 moles) and of 4-Chloro-N-methyl-2-pyridinecarboxamide (8.85 g, 0.05 moles) was added to a reaction flask containing N, N-dimethylacetamide (55 ml) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 110-115°C and then potassium tert-butoxide in tetrahydrofuran (60 ml, 0.06 moles) was added slowly over a period of 3 to 4 hours. Distill off solvent at same temperature, cooled the reaction mass to 25-30°C and water (110 mL) was added slowly over a period of 15 min. Cooled the reaction mass to 0-5°C and then adjusted the pH of the reaction mass in between 7 and 7.5 by using 10% aqueous hydrochloric acid (~7 ml). Stir the reaction mass for 30 min at the same temperature. Filter the product, washed with water (22 mL) and Dried at 50-55°C for 12 hrs. The obtained crude material was added to the flask containing Ethyl acetate (55 mL).The reaction mass was heated to reflux to get a clear solution and stirred for 15 min at reflux. Cooled to 0-5°C, stir for 2hrs at the same temperature. Filter the product, washed with Toluene (9 mL) and dried at 50-55°C for 3-5 hrs.

Above recrystallized material was added to the reaction flask containing methylene dichloride (270 mL) at 25-30°C and stirred for 10-15 min. Activated carbon (1 g) and silica gel (4.4 g) was added to the reaction mass and stir for 1h at the same temperature. Filter the reaction mass through hyflo bed and wash with methylene dichloride (18 mL). Distill off solvent still~1-2 volumes of methylene dichloride remains in the flask and then cooled to 25-30°C. Toluene (20 mL) was added and stirred for 30 min at the same temperature. Filtered the product, washed with Toluene (9 mL) and dried at 50-55°C for 12 h.

Yield: 9 gm
Chromatographic Purity (By HPLC): 98%

Example 2
Preparation of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] Carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib

4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methyl amide (4g, 0.01 moles) was added in to a reaction flask containing acetone (20 ml) at 25-30°C and stirred for 15 minutes. 4-chloro-3-trifluoromethylisocyanate (6.1g, 0.02 moles) was added slowly over a period of 5 to 10 minutes and stirred the reaction mixture 3 to 4 hours. Toluene (20 mL) was added to the reaction mass and stirred for 30 min at 25-30°C.The obtained reaction mass was filtered and washed with toluene (8 mL). Dried the material still constant weight appears to yield title product a crystalline material.

Yield: 5.5 gm
Chromatographic Purity (By HPLC): 97%

Example 3
Purification of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib using acetone and toluene mixture

4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (2 mL) and toluene (3 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and suck dried for 15 min, followed by drying at 50-55oC for 10-12 h to yield Pure 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine -2-carboxamide (I) or Regorafenib.

Yield: 0.88 gm
Chromatographic Purity (By HPLC): 99.3 %

Example 4
Purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib using acetone

4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (5 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 0-5°C and stirred for 1 hour. Filter the material, washed with acetone (1 mL) and suck dried for 15 min. The obtained wet cake was added in to the reaction flask containing acetone (5 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 0-5°C and stirred for 1 hour. Filter the material, washed with acetone (1 mL) and dried at 60-65°C for 12 h to yield Pure 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine -2-carboxamide (I) or Regorafenib.

Yield: 0.7 gm
Chromatographic Purity (By HPLC): 99.77%

Example 5
Double - Purification of 4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib using acetone and toluene mixture

4-[4-({[4-chloro-3-(trifluoromethyl) phenyl] Carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide (I) or Regorafenib (1 g) was added slowly in to the reaction flask containing acetone (2 mL) and toluene (3 mL) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and suck dried for 15 min. The obtained wet cake was added in to the reaction flask containing acetone (2 mL) and toluene (3 mL) mixture at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 50-55°C and stirred the reaction mixture for 30 minutes. Cooled the reaction mass to 25-30°C and stirred for 1 hour. Filter the material, washed with toluene (2 mL) and dry at 60-65°C for 12h.

Yield: 0.80 gm
Chromatographic Purity (By HPLC): 99.79 %

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.