DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
.

INTRODUCTION
Aspects of the present application relate to alternate processes for the preparation of diphenyl urea derivatives and novel intermediates thereof. The present application specifically relates to processes for the preparation of diphenyl urea derivatives such as Regorafenib and its desfluoro analog, Sorafenib.
Diphenyl urea derivatives are known compounds with kinase inhibitory activity. A class of ?-carboxyl aryl substituted diphenyl urea and their use for treating various cancers is reported in U.S. Patent No. 7,351,834 B1. Regorafenib and its des-fluoro analog, Sorafenib are among the small molecular multi-kinase inhibitors marketed by Bayer for the treatment of various cancer treatments.
Sorafenib is approved as its Tosylate salt and is marketed as Nexavar for the treatment of advanced renal cell carcinoma and Hepatocellular carcinoma. Sorafenib tosylate has the chemical name 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido} phenoxy) N-methyl pyridine-2-carboxamide 4-methylbenzenesulfonate. Each Nexavar tablet contains 274 mg of Sorafenib tosylate equivalent to 200 mg of Sorafenib free base.
U.S. Patent No. 7,351,834 B1 specifically discloses Sorafenib and its pharmaceutically acceptable salts thereof. U.S. Patent No. 7,351,834 B1 discloses process for the preparation of Sorafenib comprising reacting picolinic acid with thionyl chloride in dimethyl formamide to form corresponding acid chloride salt. This salt is reacted with methyl amine to form corresponding carboxamide derivative, which on further reaction with p-amino phenol provides 4–(4-aminophennoxy)-N-methylpicolinamide. This methylpicolinamide compound is reacted with 4-chloro-3-trifluoromethyl phenyl isocyanate to obtain Sorafenib.
WO 2006034796 A1 also disclosed a similar process for the preparation of Sorafenib or its tosylate salt.
Regorafenib is the second generation oral multi-kinase inhibitor and marketed as Stivarga for the treatment of metastatic colorectal cancer and gastrointestinal stromal tumor (GIST). Regorafenib monohydrate is the drug substance in Stivarga and it has the chemical name of 4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}3-fluorophenoxy) N-methyl pyridine-2-carboxamide monohydrate. Each Stivarga tablet contains 40 mg of Regorafenib in the anhydrous state, which corresponds to 41.49 mg of Regorafenib monohydrate.
U.S. Patent No. 7,351,834 B1 generically discloses Regorafenib, a pharmaceutically 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 8,637,553 B2 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-carboxylic 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.
U.S. patent application No. 20130116442 A1 specifically discloses the process for preparation of Regorafenib by reacting 4-imino-3-fluoro phenol with 4-chloro-N-methylpicolinamide to obtain 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide followed by reaction with 4-chloro-3-(trifluoromethyl) phenyl isocyanate. During workup, the reaction mixture was then treated with an acid to obtain corresponding salt of Regorafenib, wherein the acid is generated in situ by adding an alcohol, such as methanol and an acid precursor, such as acetyl chloride. Optionally, the salt of Regorafenib was then treated with aqueous basic solution to obtain monohydrate form of Regorafenib and dried under reduced pressure to obtain Regorafenib.
U.S. patent applications No. 2013060043 A1 and WO 2010144499 A1 discloses various other processes for the preparation of deuterated analogs of Regorafenib.
Prior art processes for the preparation of Regorafenib or its desfluoro analog, Sorafenib are suffering from process disadvantages such as the use of lengthy and hazardous procedures to practice which may not be viable at industrial scale. The prior art processes result in low yield and low quality of the product. Hence, there remains a need for alternate processes for the preparation of Regorafenib or its desfluoro analog, Sorafenib in an industrially viable manner.
SUMMARY
Aspects of the present application provide alternate processes for the preparation of diphenyl urea derivatives such as Regorafenib, its desfluoro analog (Sorafenib) and novel intermediates thereof.
In an aspect, the application provides a process for the preparation of Regorafenib or its desfluoro analog (Sorafenib), comprising the steps of:
a) N-formylating 4-amino phenol of formula (II), wherein R1 may be fluorine or hydrogen

to obtain 4-N-formylamino phenol of formula (III);
b) reacting 4-N-formylamino phenol of formula (III) with 4-chloro-N-methylpicolinamide of formula (IV)

to obtain 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V);
c) optionally, de-formylating 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to obtain 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI);

d) converting 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) or 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).

wherein, R1 may be hydrogen or fluoro.
In another aspect, the application provides a process for the preparation of Regorafenib or its desfluoro analog (Sorafenib), comprising the steps of:
a) converting 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) or 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII), wherein R1 may be fluorine or hydrogen;

b) converting 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).

wherein, R1 may be hydrogen or fluoro.
In another aspect, the present application provides process for the preparation of Regorafenib or its desfluoro analog (Sorafenib), comprising the steps of
a) N-formylating 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) to obtain 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula
b) converting 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII);

c) converting 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).

wherein, R1 may be hydrogen or fluoro.
In another aspect, the application provides a process for the preparation of Regorafenib, comprising the steps of:
a) converting 4-chloro-3-(trifluoromethyl)aniline of formula (VIII) to 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate of formula (IX)

b) reacting 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate of formula (IX) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) to obtain thiourea compound of formula (X)

c) converting thiourea compound of formula (X) to compound of formula (Ia), Regorafenib.

In another aspect, the present application provides novel intermediates useful in preparation of Regorafenib or its desfluoro analog (Sorafenib) having formula (V) and (VII) wherein R1 may be fluorine or hydrogen.

and compound of formula (X)

In another aspect, the application provides processes for the preparation of novel intermediates for formula (V), (VII) and (X) as described in any of the previous aspects.
In still another aspect, the present application provides pharmaceutical compositions containing a therapeutically effective amount of Regorafenib or its desfluoro analog, Sorafenib obtained by the processes of any of the aspects of application.

DETAILED DESCRIPTION
In aspects, the present application provides alternate processes for the preparation of diphenyl urea derivatives such as Regorafenib or its desfluoro analog, Sorafenib.
In an aspect, the application provides a process for the preparation of Regorafenib or its desfluoro analog (Sorafenib), comprising the steps of:
a) N-formylating 4-amino phenol of formula (II), wherein R1 may be fluorine or hydrogen

to obtain 4-N-formylamino phenol of formula (III);
b) reacting 4-N-formylamino phenol of formula (III) with 4-chloro-N-methylpicolinamide of formula (IV)

to obtain 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V);
c) optionally, de-formylating 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to obtain 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI);

d) converting 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) or 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).

wherein, R1 may be hydrogen or fluoro.
The individual steps of this aspect are described herein below.
4-amino phenol of formula (II) may be prepared by the procedures known in art or the procedures described and exemplified in present application.
The starting materials can be purified by techniques known in art like column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
In an embodiment, 4-amino phenol of formula (II) may be prepared by the reduction of 4-nitro phenol using suitable reducing agents. Suitable reducing agents may be hydrogen on Palladium-carbon or Raney Nickel; Fe/ ammonium chloride; Fe/ acetic acid, sodium dithionate or the like. In preferred embodiment, reduction may be carried out using Fe / ammonium chloride.
Reaction may be carried out in the presence of a suitable solvent. In preferred embodiment, the reaction may be carried out in alcohol such as methanol, ethanol, or isopropyl alcohol.
Reaction may be carried out at a suitable temperature for the reduction of 4-nitro phenol to 4-amino phenol at about 25ºC to boiling point of the solvent and for sufficient time to complete the reaction.
Step (a) of this aspect may be carried out by N-formylating 4-amino phenol of formula (II).
In embodiments, step (a) may be carried out by reacting 4-amino phenol of formula (II) with a suitable N-formylating agent. Suitable N-formylating agents may include, but not limited to formic acid, formic acid / I2, formic acid / Lewis acid catalyst such as ZnCl2, formic acid / ethyl formate, , formic acid / Amberlite IR-120 and other formic acid derivatives such as formic anhydride, acetic formic anhydride, formyl chloride, formyl fluoride, formamide; N-formyl alkyl amines such as 2-(N-methyl N-formylamino)pyridine, N-formyl piperidine, N-formyl morpholine; carbon monoxide/ acid; formic acid / dehydrating agents such as DCC and the like. Preferably, the reaction may be carried out using formic acid.
In preferred embodiment, the reaction may be carried out in the presence of a metal oxide such as Zinc oxide.
Optionally, N-formylation of 4-amino phenol of formula (II) may be carried out in the presence of suitable inert solvent.
Reaction may be carried out at suitable temperatures at about ambient temperature to boiling point of reaction medium. The step of N-formylation of 4-amino phenol of formula (II) may be carried out at about 50°C and above. Preferably, reaction may be carried out at about 70°C and above.
Reaction may be carried out for sufficient time to complete N-formylation of 4-amino phenol of formula (II). Preferably, the reaction may be carried out for 15 hours or more.
The reaction product of step (a), 4-N-formylamino phenol of formula (III) may be isolated by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Purification of the N-formylated product prepared by the process of step (a) may be effected, if desired, by any suitable procedure. Alternatively, the product may be used as such for the next reaction.
Step (b) of this aspect may be carried out by reacting 4-N-formylamino phenol of formula (III) with 4-chloro-N-methylpicolinamide of formula (IV) to obtain compound of formula (V), 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide.
4-chloro-N-methylpicolinamide of formula (IV) is commercially available or can be prepared according to any of the processes known in the art.
In embodiments, the reaction between 4-chloro-N-methylpicolinamide of formula (IV) and 4-N-formylamino phenol of formula (III) may be carried out in the presence of a suitable inert solvent. In preferred embodiment, the reaction may be carried out in the presence of N-methyl pyrrolidone.
Reaction between 4-chloro-N-methylpicolinamide of formula (IV) and 4-N-formylamino phenol of formula (III) may be carried out in the presence of a suitable base. Suitable bases for the reaction include, but are not limited to organic bases such as triethyl amine, diethyl amine, diisopropyl amine, pyridine; inorganic bases such as metal carbonates like sodium carbonate, potassium carbonate; metal bicarbonates like sodium bicarbonate, potassium bicarbonate; metal hydroxide like sodium hydroxide, potassium hydroxide; metal alkoxides like potassium tertiary butoxide, sodium methoxide and the like. Preferably, suitable base may be potassium tertiary butoxide.
Reaction between 4-chloro-N-methylpicolinamide of formula (IV) and 4-N-formylamino phenol of formula (III) may be carried out at suitable temperatures of about ambient to boiling point of solvent. Preferably, reaction may be carried out at about 80°C and above.
Reaction between 4-chloro-N-methylpicolinamide of formula (IV) and 4-N-formylamino phenol of formula (III) may be carried out for sufficient time till the completion of reaction to obtain 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V). In preferred embodiments, the reaction may be carried out for about 8 hours or more.
The reaction product of step (b), 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) may be isolated by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Purification of the reaction product prepared by the process of step (b) may be effected, if desired, by any suitable procedure. Alternatively, the reaction mass containing the product may be used as such for the next reaction.
Step (c) of this aspect may be carried out optionally by de-formylation of 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI).
De-formylation of 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) may be carried out by reacting with suitable de-formylating agents such as acids like hydrochloric acid, sulphuric acid, acetic acid or bases like metal hydroxides such as sodium hydroxide, potassium hydroxide; metal carbonates such as sodium carbonate, potassium carbonate; metal bicarbonates such as sodium bicarbonate, potassium bicarbonate. In preferred embodiments, de-formylation reaction may be carried out with acid such as hydrochloric acid.
De-formylation reaction may be carried out in the presence of suitable solvent. In preferred embodiment, the reaction may be carried out in the presence of an alcohol such as methanol.
De-formylation reaction may be carried out for sufficient time to complete de-formylation of the starting material. Preferably, reaction may be carried out for about 24 hours or more.
De-formylation reaction may be carried out at suitable temperature at about ambient temperature to boiling point of the solvent. Preferably, reaction may be carried out at about 25°C and above.
The reaction product obtained by the de-formylation of 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) may be isolated by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Purification of the reaction product prepared by the process of step (c) may be effected, if desired, by any suitable procedure. Alternatively, the product may be used as such for the next reaction.
Step (d) of this aspect may be carried out by converting the compound of formula (V) or formula (VI) to Regorafenib or its desfluoro analog, Sorafenib of formula (I) according to any known method or procedures described or exemplified in present application.
In an embodiment, step (d) may carried out by reacting the compound of formula (V) or formula (VI) with 4-chloro-3-trifluoromethyl aniline or its suitable reactive derivatives such as corresponding isocyanate or carbamate ester derivatives according to any suitable procedure known in art or method described or exemplified in the present application.
4-chloro-3-trifluoromethyl aniline or its reactive derivatives such as corresponding isocyanate or carbamate ester derivatives may be prepared by suitable methods known in art or procedures described or exemplified in the present application.
In an embodiment, step (d) may be carried out by reacting the compound of formula (V) with 4-chloro-3-trifluoromethyl aniline in the presence of suitable reagents. Suitable reagents may include, but not limited to: metal complexes such as copper complexes like Copper (II) triflate (Cu (OTf) 2) optionally in presence of tertiary butyl hydroperoxide (TBHP); Cobalt complexes such as Cobaltous acetyl acetonate (Co(acac)2 or Ruthenium complexes like Dichloro tris(triphenylphosphine) ruthenium(II).

In another embodiment, step (d) may be carried out by reacting compound of formula (VI) either with phenyl 4-chloro-3-trifluoromethyl phenyl carbamate or 4-chloro-3-trifluoromethyl phenyl isocyanate by following suitable methods known in the art or procedure described or exemplified in the present application.
In embodiments, reaction may be carried out by reacting 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) with 4-chloro-3-trifluoromethyl phenyl isocyanate.

Reaction between 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) and 4-chloro 3-trifluoromethyl phenyl isocyanate may be carried out in the presence of a suitable solvent. In preferred embodiment, reaction may be carried out in the presence of an ether solvent such as tetrahydrofuran and / or a hydrocarbon solvent such as toluene.
Reaction between 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) and 4-chloro 3-trifluoromethyl phenyl isocyanate may be carried out at suitable temperature at about 25°C to boiling point of the solvent for sufficient time to complete the reaction.
Alternatively, reaction may be carried out by reacting 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) with phenyl 4-chloro 3-trifluoromethyl phenyl carbamate.

In preferred embodiments, this reaction may be carried out in the presence of a base such as organic base like Triethyl amine or diisopropyl ethyl amine.
Reaction between 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) and phenyl 4-chloro 3-trifluoromethyl phenyl carbamate may be carried out in the presence of a suitable solvent. Preferably, the reaction may be carried out in the presence of an ether solvent such as tetrahydrofuran and / or a hydrocarbon solvent such as toluene.
Reaction between 4-(4-N-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) and phenyl 4-chloro 3-trifluoromethyl phenyl carbamate may be carried out at suitable temperature at about 25°C to boiling point of the solvent for sufficient time to complete the reaction.
Regorafenib or its desfluoro analog, Sorafenib of formula (I) obtained by the above process may be isolated by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Sutiable solvents that may be used in any of the steps of this aspect include, but not limited to: aliphatic or cyclic C2-C6 ethers, aliphatic or aromatic hydrocarbons, C1-C6 alcohols, C5-C8, ethers, C3-C6 esters, C1-C6 amides, C2-C6 nitriles, C3-C6 ketones, halogenated hydrocarbons or mixtures thereof.
In another aspect, the application provides a process for the preparation of Regorafenib or its desfluoro analog (Sorafenib), comprising the steps of:
a) converting 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) or 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII), wherein R1 may be fluorine or hydrogen;

b) converting 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).

wherein R1 may be hydrogen or fluoro.
The individual steps of this aspect are described herein below.
4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) or 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) may be prepared by any known methods or the procedures described and exemplified in present application.
The starting materials may be purified by techniques known in art like column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
Step (a) of this aspect may be carried out by converting 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) or 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII).
In one embodiment, step (a) may be carried out by reacting 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) with a source of dichlorocarbene to 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII).

It is well known, that dichlorocarbene is most commonly generated in-situ by reacting chloroform or trichloro ethyl acetate with a suitable base. Suitable base may include, but not limited to: potassium tertiary butoxide, sodium methoxide or aqueous sodium hydroxide. Preferably, base may be aqueous sodium hydroxide.
In preferred embodiments, reaction may be carried out in the presence of a phase transfer catalyst such as benzyl triethyl ammonium chloride, benzyl triethyl ammonium bromide, benzyl triethyl ammonium hydroxide, triethyl benzyl ammonium chloride, trimethyl benzyl ammonium hydroxide, tertiary butyl ammonium bromide, tertiary butyl ammonium chloride, tetra n-butyl phosphonium bromide and tetra phenyl phosphonium bromide or the like.
In embodiments, step (a) may be carried out at suitable temperature of about ambient to boiling point of solvent. Preferably, reaction may be carried out at about 25°C and above. Reaction may be carried out for sufficient time for the completion of reaction. Preferably, for about 4 hours or more.
In another embodiment, step (a) may be carried out by reacting 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) with a suitable dehydrating agent to obtain to 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII).

Suitable dehydrating agent may include, but not limited to: phosphorus oxychloride, phosgene, diphosgene, triphosgene or the like. Preferably, dehydrating agent may be triphosgene.
In preferred embodiments, reaction may be carried out in the presence of a suitable base. Suitable base may be an organic base such as triethyl amine, di isopropyl ethyl amine; an inorganic base such as metal carbonates, metal bicarbonates, metal hydroxides or the like. Preferably, base may be an organic base such as triethyl amine.
In embodiments, reaction may be carried out at suitable temperature of about ambient temperature to boiling point of solvent. Preferably, reaction may be carried out at about 25°C and above. Reaction may be carried out for sufficient time for the completion of reaction. Preferably, for at least about 1 hour or more.
This step may be carried out in the presence of a suitable solvent. In preferred embodiment, the reaction may be carried out in halogenated hydrocarbons such as dichloromethane.
The reaction product obtained in this step may be isolated by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Purification of the reaction product prepared by the process step (a) may be effected, if desired, by any suitable procedure. Alternatively, the product may be used as such for the next reaction.
Step (b) of this aspect may be carried out by converting the 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).
Step (b) may carried out by the reacting the 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII) with 4-chloro 3-trifluoromethyl aniline of formula (VIII) according to any suitable method known in art or procedure described or exemplified in the present application.
In an embodiment, step (b) may be carried out by the reacting the 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII) with 4-chloro 3-trifluoromethyl aniline of formula (VIII) in the presence of suitable catalyst such as Copper acetate, Cobalt (II) acetylacetonate under suitable reaction conditions.
In another embodiment, step (b) may be carried out by oxidation of 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII) to corresponding isocyanate derivative using suitable agent such as dimethyl sulphoxide in the presence of trifluoroacetic anhydride and then treating with 4-chloro 3-trifluoromethyl aniline of formula (VIII) to obtain Regorafenib or its desfluoro analog (Sorafenib) of formula (I).
Reaction may be carried out in the presence of a suitable solvent. In preferred embodiment, the reaction may be carried out in the presence of a halogenated hydrocarbon such as dichloromethane.
Reaction may be carried at suitable temperature of about -80ºC and above, preferably at about -60ºC to 30ºC and for sufficient time to complete the reaction.
The reaction product obtained in the above process may be isolated and purified by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Sutiable solvents that may be used in any of the steps of this aspect include, but not limited to: aliphatic or cyclic C2-C6 ethers, aliphatic or aromatic hydrocarbons, C1-C6 alcohols, C5-C8, ethers, C3-C6 esters, C1-C6 amides, C2-C6 nitriles, C3-C6 ketones, halogenated hydrocarbons or mixtures thereof.

In another aspect, the present application provides process for the preparation of Regorafenib or its desfluoro analog (Sorafenib), comprising the steps of
a) N-formylating 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) to obtain 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V), wherein R1 may be fluorine or hydrogen;

b) converting 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII);

c) converting 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).

4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI may be prepared by the procedures known in art or the procedures described and exemplified in present application.
The starting materials can be purified by techniques known in art like column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
Step (a) of this aspect may be carried out by N-formylating 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI).
In embodiments, step (a) may be carried out by reacting 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) with a suitable N-formylating agent. Suitable N-formylating agents may include, but not limited to formic acid, formic acid / I2, formic acid / Lewis acid catalyst such as ZnCl2, formic acid / ethyl formate, , formic acid / Amberlite IR-120 and other formic acid derivatives such as formic anhydride, acetic formic anhydride, formyl chloride, formyl fluoride, formamide; N-formyl alkyl amines such as 2-(Nmethyl-N-formy1amino)pyridine, N-formyl piperidine, N-formyl morpholine; carbon monoxide/ acid; formic acid / dehydrating agents such as DCC and the like. Preferably, the reaction may be carried out using formic acid.
In preferred embodiment, the reaction may be carried out in the presence of a metal oxide such as zinc oxide.
Optionally, N-formylation of 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) may be carried out in the presence of a suitable solvent.
Reaction may be carried out at suitable temperatures at about ambient temperature to boiling point of reaction medium. The step of N-formylation of 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) may be carried out at about 50°C and above. Preferably, reaction may be carried out at about 70°C and above.
Reaction may be carried out for sufficient time to complete N-formylation of 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI). Preferably, the reaction may be carried out for 5 hours or more.
The reaction product of step (a), 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) may be isolated by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Purification of the N-formylated product prepared by the process of step (a) may be effected, if desired, by any suitable procedure. Alternatively, the product may be used as such for the next reaction.
Step (b) may be carried out by reacting 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) with a suitable dehydrating agent to obtain to 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII).

Suitable dehydrating agent may include, but not limited to: phosphorus oxychloride, phosgene, diphosgene, triphosgene or the like. Preferably, dehydrating agent may be triphosgene.
In preferred embodiments, reaction may be carried out in the presence of a suitable base. Suitable base may be an organic base such as triethyl amine, di isopropyl ethyl amine; an inorganic base such as metal carbonates, metal bicarbonates, metal hydroxides or the like. Preferably, base may be an organic base such as triethyl amine.
In embodiments, reaction may be carried out at suitable temperature of about ambient to boiling point of solvent. Preferably, reaction may be carried out at about 25°C and above. Reaction may be carried out for sufficient time for the completion of reaction. Preferably, for atleast 1 hour or more.
This step may be carried out in the presence of a suitable solvent. In preferred embodiment, the reaction may be carried out in the presence of halogenated hydrocarbons such as dichloromethane.
The reaction product obtained in this step may be isolated by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Purification of the reaction product prepared by the process step (a) may be effected, if desired, by any suitable procedure. Alternatively, the product may be used as such for the next reaction.
Step (c) of this aspect may be carried out by converting the 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).
Step (c) may carried out by the reacting the 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII) with 4-chloro 3-trifluoromethyl aniline of formula (VIII) according to any suitable method known in art or procedure described or exemplified in the present application.
In an embodiment, step (b) may be carried out by the reacting the 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII) with 4-chloro 3-trifluoromethyl aniline of formula (VIII) in the presence of suitable catalyst such as Copper acetate, Cobalt (II) acetylacetonate under suitable reaction conditions.
In another embodiment, step (b) may be carried out by oxidation of 4-(4-Isocyano-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VII) to corresponding isocyanate derivative using suitable agent such as dimethyl sulphoxide in the presence of trifluoro acetic anhydride and then treating with 4-chloro 3-trifluoromethyl aniline of formula (VIII) to obtain Regorafenib or its desfluoro analog (Sorafenib) of formula (I).
Reaction may be carried out in the presence of a suitable inert solvent. In preferred embodiment, the reaction may be carried out in the presence of a halogenated hydrocarbon such as dichloromethane.
Reaction may be carried at suitable temperature of about -80ºC and above, preferably at about -60ºC to 30ºC and for sufficient time to complete the reaction.
The reaction product obtained in the above process may be isolated and purified by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Sutiable solvents that may be used in any of the steps of this aspect include, but not limited to: aliphatic or cyclic C2-C6 ethers, aliphatic or aromatic hydrocarbons, C1-C6 alcohols, C5-C8, ethers, C3-C6 esters, C1-C6 amides, C2-C6 nitriles, C3-C6 ketones, halogenated hydrocarbons or mixtures thereof.
In another aspect, the application provides a process for the preparation of Regorafenib, comprising the steps of:
a) converting 4-chloro-3-(trifluoromethyl)aniline of formula (VIII) to 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate of formula (IX)

b) reacting 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate of formula (IX) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) to obtain thiourea compound of formula (X)

c) converting thiourea compound of formula (X) to compound of formula (Ia), Regorafenib.

The individual steps of this aspect are described herein below.
The starting material, 4-chloro-3-(trifluoromethyl) aniline of formula (VIII) is commercially available or it may be prepared by the procedures known in art. Starting material can be purified by techniques known in art like column chromatography, fractional distillation, acid-base treatment, slurring or re-crystallization, before using.
Step (a) of this aspect may be carried out by converting 4-chloro-3-(trifluoromethyl)aniline of formula (VIII) to 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate of formula (IX) by employing the methods known in art or procedures described or exemplified in the present application.
In an embodiment, step (a) may be carried out by reacting 4-chloro-3-(trifluoromethyl) aniline of formula (VIII) with any suitable thiocarbonyl transfer reagents known in art. Thiocarbonyl transfer reagents may include, but not limited to thiophosgene, thiocarbonyl ditriazole, thiocarbonyl diimidazole, dipyridyl thionocarbonate and the like. Preferably, suitable thiocarbonyl transfer reagent may be thiophosgene.
The reaction may be carried out in the presence of a suitable base. Suitable bases for the reaction include, but are not limited to inorganic bases such as metal bicarbonates like sodium bicarbonate, potassium bicarbonate; metal carbonates like sodium carbonate, potassium carbonate; metal hydroxide like sodium hydroxide, potassium hydroxide; metal alkoxides like potassium tertiary butoxide, sodium methoxide; organic bases such as triethyl amine, diethyl amine, diisopropyl amine, pyridine and the like. Preferably, suitable base may be an inorganic base such as aqueous sodium bicarbonate.
The reaction may be carried out at suitable temperatures of about -10 and above. Preferably reaction may be carried out at about 0°C to about 40°C.
The reaction may be carried out for sufficient time to complete the reaction for atleast 1 hour or more. Preferably, reaction may be carried out for about 15 hours or more.
Reaction may be carried out in the presence of a suitable inert solvent. Preferably, the reaction may be carried out in the presence of a halogenated hydrocarbon such as dichloromethane.
The reaction product obtained in the above process may be isolated by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Purification of the reaction product prepared by the process step (b) may be effected, if desired, by any suitable procedure. Alternatively, the product may be used as such for the next reaction.
Step (b) of this aspect may be carried out by reacting 4-chloro-3-(trifluoromethyl) phenyl isothiocyanate of formula (IX) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) to obtain thiourea compound of formula (X).
Reaction may be carried out by treating 4-chloro-3-(trifluoromethyl) phenyl isothiocyanate of formula (IX) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) in the presence of a suitable inert solvent. Preferably, the reaction may be carried out in the presence of a ether such as tetrahydrofuran; aromatic hydrocarbons such as toluene; or a mixture thereof.
Reaction may be carried out by treating 4-chloro-3-(trifluoromethyl) phenyl isothiocyanate of formula (IX) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) for sufficient time to complete the reaction for atleast 1 hour or more. Preferably, the reaction may be carried out for about 15 hours or more. Reaction may be carried out at suitable temperatures of about 25°C and above.
Step (c) of this aspect may be carried out by treating thiourea compound of formula (X) with suitable oxidizing agents to obtain Regorafenib of formula (Ia).
Suitable oxidizing agent may include, but not limited to: hydrogen peroxide, potassium monopersulfate, Fe (VI) salts, Ce (IV) salts or any other known oxidizing agents. Preferably, oxidation may be carried out using hydrogen peroxide.
Oxidation may be carried out in the presence of a suitable inert solvent. Preferably, the reaction may be carried out in the presence of a alcohol solvent such as methanol, ethanol or Isopropyl alcohol.
Oxidation may be carried out by at suitable temperatures of about 25°C to boiling point of the solvent. Preferably, oxidation may be carried out at about 80°C or above.
Reaction may be carried out for sufficient time till the completion of reaction for atleast 1 hour or more. Preferably, reaction may be carried out for about 5 hours or more.
The reaction product obtained in the above process may be isolated and purified by performing suitable work-up procedure known in art or methods described or exemplified in the present application.
Sutiable solvents that may be used in any of the steps of this aspect include, but not limited to: aliphatic or cyclic C2-C6 ethers, aliphatic or aromatic hydrocarbons, C1-C6 alcohols, C5-C8, ethers, C3-C6 esters, C1-C6 amides, C2-C6 nitriles, C3-C6 ketones, halogenated hydrocarbons or mixtures thereof.
In another aspect, the present application provides novel intermediates of formula (V) and formula (VII), wherein R1 may be fluorine or hydrogen.

and compound of formula (X)

In embodiments of this aspect, the present application provides isolated intermediates of formula (V), (VII) & (X) in free form or in their suitable salt forms. Suitable salt forms may be acid addition salts such as hydrochloride, hydrobromide, sulfate, mesylate, formate, acetate, tosylate, oxalate, citrate, maleate or the like.
In embodiments, the present application provides the use of intermediates of formula (V), (VII) & (X) in the preparation of Regorafenib, its desfluoro analog Sorafenib or acceptable salts thereof and pharmaceutical compositions thereof.
In another aspect, the application provides processes for the preparation of novel intermediates for formula (V), (VII) and (X) as described in any of the aspects of present application.
In another aspect, Regorafenib or its desfluoro analog Sorafenib obtained by the any of the processes of present application may be purified by any suitable procedure known in art such as recrsytallization, column chromatography, acid-base treatment, slurrying or the like.
The present invention encompasses the conversion of Regorafenib or its desfluoro analog, Sorafenib obtained by any of the processes described in the present application to its pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts may include hydrochloride, hydrobromide, sulfate, phosphate, mesylate, formate, acetate, tosylate, oxalate, citrate, fumarate, tartrate, maleate or the like. Further, the present invention also encompasses the conversion of pharmaceutically acceptable salts of Regorafenib or its desfluoro analog, Sorafenib to free compounds of formula (I).
In preferred embodiment, this conversion may be carried out by treating Regorafenib or its desfluoro analog obtained according to any of the processes described or exemplified in the present application with a suitable acid to obtain corresponding Pharmaceutically acceptable salt.
Suitable acid may include, but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid; organic acid such as formic acid, acetic acid, oxalic acid, malonic acid, citric acid, fumaric acid, methane sulphonic acid, maleic acid, tartaric acid or the like.
Pharmaceutically acceptable salts of Regorafenib or its desfluoro analog may be obtained by reacting Regorafenib or its desfluoro analog with an acid in the presence of suitable solvent. Preferably, reaction may be carried out in the presence of alcohol such as methanol, isopropyl alcohol; ether such as methyl tertiary butyl ether or mixtures thereof.
Pharmaceutically acceptable salts of Regorafenib or its desfluoro analog obtained above may be reacted with a suitable base to obtain Regorafenib or its desfluoro analog as a free compound. Pharmaceutically acceptable salts of Regorafenib or its desfluoro analog may be reacted insitu or isolated before reaction with the base.
Suitable base may include but not limited to metal hydroxides such sodium hydroxide, potassium hydroxide; metal carbonates such as potassium carbonate, sodium carbonate; metal bicarbonates such as potassium bicarbonate, sodium bicarbonate and the like. Preferably, acid addition salt of Regorafenib or its desfluoro analog may be treated with aqueous sodium hydroxide.
In preferred embodiments, pharmaceutically acceptable salts may be isolated before reacting with the base to obtain Regorafenib or its desfluoro analog as free compound.
Reaction of Pharmaceutically acceptable salts of Regorafenib or its desfluoro analog with the base may be carried out in the presence of a suitable inert solvent. Preferably, the reaction may be carried out in the presence of ether solvent such as tetrahydrofuran, acetone, water or mixture thereof.
Sutiable solvents that may be used in any of the steps of this aspect include, but not limited to: aliphatic or cyclic C2-C6 ethers, aliphatic or aromatic hydrocarbons, C1-C6 alcohols, C5-C8, ethers, C3-C6 esters, C1-C6 amides, C2-C6 nitriles, C3-C6 ketones, halogenated hydrocarbons or mixtures thereof.
In another aspect, the present application provides Regorafenib and pharmaceutical compositions thereof with purity of greater than about 99%, as determined by using high performance liquid chromatography (HPLC).
The present invention provides industrially viable methods for the preparation of Regorafenib or its desfluoro analog with high yield and quality; which does not involve the lengthy and hazardous procedures.
In another aspect, the present application provides, Regorafenib or its desfluoro analog, Sorafenib obtained according to processes of the present application may be milled or micronized by any of the processes known in the art, such as ball milling, jet milling, wet milling and the like, to produce desired particle sizes and particle size distributions.
In another aspect, the present application provides pharmaceutical compositions containing a therapeutically effective amount of Regorafenib or its desfluoro analog, Sorafenib obtained according to the processes of present application together with one or more pharmaceutically acceptable excipients.

DEFINITIONS
The following definitions are used in connection with the disclosure of the present application, unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
The term "reacting" is intended to represent bringing the chemical reactants together under conditions that cause the chemical reaction indicated to take place.
The following abbreviations and acronyms are used herein and have the indicated definitions:
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexa-fluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, and the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, iso-hexane, 3-methylpentane, 2,3-dimethylbutane, neo-hexane, n-heptane, iso-heptane, 3-methylhexane, neo-heptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neo-octane, cyclohexane, methylcyclohexane, cyclo-heptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, and any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, and the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, and the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6 nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, and the like.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example-1: Preparation of 4-amino 3-fluoro phenol

Ammonium chloride (340.7 g), iron powder (177.8 g) and water (1000 mL) were added to a mixture of 4-nitro 3-fluoro phenol (100 g) and Isopropyl alcohol (1000 mL). Reaction mixture was heated to 100°C and stirred for 3 hours at the same temperature. After the completion of reaction, the reaction mixture was cooled to 26°C. Ethyl acetate (500 mL) was added to the reaction mixture and stirred for 30 min at 26°C. Filtered the reaction mixture through celite bed and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 X 500 mL). Combined organic layer was washed with brine solution (500 mL) and dried over anhydrous sodium sulphate. Reaction mass was distillated under vacuum at 45ºC. Hexane (500 mL) was added to the crude product and stirred for 30 min at 26ºC. Solid was filtered and dried to obtain title compound.
Yield: 75 g (92.8%)
Purity by HPLC: 97.83%
Example-2: Preparation of 4-N-formylamino 3-fluoro phenol

To the mixture of 4-amino 3-fluoro phenol (11.5 g) and formic acid (49.96 g), zinc oxide (5.52 g) was added at 27°C. Reaction mixture was heated to 70°C and stirred at 65-70°C for 16 hours. After the completion of reaction, reaction mixture was distilled under reduced pressure at 65°C to remove formic acid and the crude product was quenched with cold water (120 mL) at 5-10°C and the pH of the reaction mixture was adjusted to 7.5 - 8.0 with saturated aqueous sodium bicarbonate solution. The reaction mixture was then filtered on celite bed and washed with ethyl acetate (100 mL). Organic layer was separated and aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure at 50-55°C. The crude product obtained above was purified by column chromatography using 25-30% ethyl acetate-hexane mixture as mobile phase to obtain the title compound.
Yield: 8.0 g (57%)
Purity by HPLC: 98.84%
Example-3: Preparation of 4-(4-N-formylamino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide

4-N-formylamino 3-fluoro phenol (7.5 g) and 4-chloro-N-methylpicolinamide (10.72 g) were dissolved in N-methyl pyrrolidone (100 mL) at 27°C. Potassium tertiary butoxide (27.12 g) was added portion wise to the above solution in 30 min at same temperature. Then the reaction mixture was heated to 90°C and stirred at 90-95°C for 9 hours. After the completion of reaction, the reaction mixture was poured into cold water (175 mL) and extracted with ethyl acetate (3x75 mL). The combined organic layer was washed with water (4x50 mL) and dried over anhydrous sodium sulphate. Then the organic layer was concentrated under reduced pressure at 50-55°C and the crude product was purified by column chromatography using 40-45% ethyl acetate-hexane mixture as mobile phase to obtain the title compound.
Yield: 9.0 g (36%)
Purity by HPLC: 98.90%
Example-4: Preparation of 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide

4-(4-N-formylamino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide (1.0 g) was dissolved in methanol (10 mL) at 27°C. Concentrated hydrochloric acid (3 mL) was added drop wise to the reaction mixture at 27°C and stirred at same temperature for 24 hours. After the completion of reaction, methanol was evaporated under reduced pressure and the reaction mass was diluted with water (10 mL). Then the pH of the reaction mixture was adjusted to 8.0 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3x10 mL). The combined organic layer was washed with brine solution (15 mL) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure at 50-55°C to obtain the title compound.
Yield: 500 mg (55.4%)
Purity by HPLC: 99.29%
Example-5: Preparation of Phenyl 4- chloro 3-trifluoromethyl phenyl carbamate

4-chloro 3-trifluoromethyl aniline (5.0 g) was added to 1:1 mixture of tetrahydrofuran: water (50 mL) at 25°C and stirred for 10 min at same temperature. Slowly added phenyl chloro formate (3.5 mL) at 25°C and added sodium bicarbonate (2.1 g) and stirred at same temperature for 15 minutes. After the completion of reaction, water (50 mL) and ethyl acetate (100 mL) were added and stirred for 10 min at 25°C. Separated the organic layer and extracted the aqueous layer with ethyl acetate (100 mL). Washed the combined organic layer with brine solution and dried over anhydrous sodium sulphate. The organic layer was distilled under reduced pressure at 45°C to obtain the title compound.
Yield: 7.0 g (87.50%)
Purity: 94.09 % by HPLC.
Example-6: Preparation of Regorafenib

4-chloro-3-trifluoromethyl phenyl isocyanate (1.86 g) was dissolved in toluene (2.4 mL) and slowly added to the solution containing 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide (2.0 g) in tetrahydrofuron (20 mL) in 25 min at 27ºC. The reaction mixture was stirred for 3 hours at 27ºC to completion of reaction. Methanol (1.0 mL) and HCl in Isopropyl alcohol (3.0 mL) were added to the reaction mixture at 27ºC and stirred for 1 hour at same temperature. Reaction mass was concentrated under reduced pressure at 45ºC. Methyl tertiary butyl ether (30 mL) was added to the reaction mass and stirred for 18 hours at 27ºC. Filtered the solid and washed with methyl tertiary butyl ether (5 mL). The crude compound was dissolved in a mixture of tetrahydrofuran (20 mL), water (5 mL) and 45% aqueous sodium hydroxide solution (0.8 g) at 40ºC and stirred for 30 min at same temperature. Reaction mass was cooled to 27ºC and water (5 mL) was added. Reaction mass was distilled at 35-45ºC and then subjected to co-distillation with acetone (10mL). Acetone (20 mL) was added to the reaction mixture and cooled to 0ºC. Stirred the reaction mass at 0°C for 30 min. Filtered the reaction mass and washed the solid with mixture of water (5 mL) and acetone (15 mL) to obtain title compound.
Yield: 2.4 g (66.6%)
Purity: 99.25% by HPLC
Example-7: Preparation of Regorafenib

Phenyl 4-chloro 3-trifluoromethyl phenyl carbamate (4.65 g) was dissolved in toluene (17.5 mL) at 28°C and added drop wise to the mixture containing 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide (3.5 g) in tetrahydrofuran (70 mL) at 28ºC. Triethyl amine (5.6 mL) was added to the reaction mixture at 28ºC and stirred for 1 hour. The temperature of the reaction mixture was increased to 100°C and stirred for 20 hours at same temperature. After the completion of reaction, water was added to the reaction mixture and extracted the product into ethyl acetate. Reaction mass was distilled to remove ethyl acetate under reduced pressure at 45°C to obtain crude compound. This crude compound was combined with methanol (6 mL) and cooled to 0°C. Concentrated HCl in isopropyl alcohol (9 mL) was added to the reaction mixture and stirred for 1 hour at 0°C. Concentrated the reaction mixture under reduced pressure and added methyl tertiary butyl ether (15 mL) and filtered at 28°C. A mixture of tetrahydrofuran (16.4 mL), water (4.7 mL) and aqueous sodium hydroxide solution (containing 0.7 g of sodium hydroxide and 1.5 mL water)) were heated to 40°C and slowly added above obtained crude compound portion wise at 40°C and stirred for 30 minutes at same temperature. Water (5mL) was added to the reaction mixture and tetrahydrofuran was distilled out completely at 40°C and co-distilled the reaction mixture with acetone (20 mL). Acetone (16.4 mL) was added and cooled to 0ºC. Stirred the reaction mixture for 1 hour at 0°C and filtered the solid. Washed the solid with mixture of acetone (9 mL) and water (3 mL) and dried to obtain title compound.
Yield: 2.0 g (61.91%)
Purity: 95.02% by HPLC.
Example-8: Preparation of 4-(4-isocyano-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide

4-(4-N-formylamino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide (1.7 g) was dissolved in dichloromethane (100 mL) and triethyl amine (3.30 mL) was added drop wise. To the reaction mixture triphosgene (1.22 g) was added at 27ºC and stirred for 90 min at same temperature. After Completion of reaction, the reaction mixture was quenched with water (10 mL). Organic layer was separated and the aqueous layer was extracted with dichloromethane (2x30 mL).The combined organic layer was washed with water and dried over anhydrous sodium sulphate. The reaction mixture was concentrated and the crude product was purified by column chromatography using 30-35% ethyl acetate-hexane mixture as mobile phase to obtain the title compound.
Yield: 1.2 g (75%)
Purity by HPLC: 91.46%
Example-9: Preparation of 4-(4-isocyano-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide

Combined the mixture of 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide (5.0 g) and dichloromethane (20 mL) with Chloroform (20 mL), triethyl benzyl ammonium chloride (0.5 g) and 50% sodium hydroxide solution (25 mL) at 27°C and sirred the reaction mixture for 4 hours at same temperature. After completion of the reaction, the reaction mixture was filtered on celite bed and washed with dichloromethane (50 mL). Separated the organic layer and extracted the aqueous layer with dichloromethane (50 mL). The combined organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulphate. Then the organic layer was concentrated under vacuum at 40°C and the crude product obtained above was purified by column chromatography using 25-30% ethyl acetate-hexane mixture as mobile phase to obtain the title compound.
Yield: 1.25 g (24%)
Purity by HPLC: 95.32%
Example-10: Preparation of Regorafenib

4-(4-isocyano-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide (0.9 g) was dissolved in dichloromethane (30 mL) at 27°C and cooled to -60°C. Dimethyl sulphoxide (0.25 g) and trifluoro acetic anhydride (0.1 mL) were added to the reaction mixture at -60°C and stirred for 5 min at same temperature. Temperature of the reaction mixture was raised to 27°C and stirred for 10 min. Then the reaction mixture was cooled to -60°C and 4- chloro 3-trifluoromethyl aniline (1.62 g) was added and stirred for 10 min. Temperature of the reaction mixture was then raised to 27°C and stirred for 2 hours at same temperature. After the completion of reaction, the reaction mixture was concentrated under reduced pressure at 40-45°C and diluted with water (20 mL), then extracted with ethyl acetate (3x25 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure at 40°C. The crude product was purified by column chromatography using 40-45% ethyl acetate- hexane as mobile phase to obtain the title compound.
Yield: 1.03 g (64.3%)
Purity by HPLC: 98.44%
Example-11: Preparation of 4-chloro-3-(trifluoromethyl) phenyl isothiocyanate

4-chloro 3-(trifluoromethyl) aniline (1.0 g) was dissolved in dichloromethane (7 mL) and added to solution containing sodium bicarbonate (1.7 g) in water (7 mL) at 27°C and stirred for 5 min. The reaction mixture was cooled to 0°C and thiophosgene (7.17 g) was added. The temperature of the reaction mixture was raised to 27°C and stirred for 16 hours. After the completion of the reaction, saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture and separated the organic layer. The aqueous layer was extracted with dichloromethane (2x25 mL) and the combined organic layer was dried over anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure at 40°C °C to obtain the title compound.
Yield: 1.0 g (83.4%)
Purity by HPLC: 91.84%
Example-12: Preparation of thiourea compound of formula (x)

4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide (0.5 g) was dissolved in tetrahydrofuran (2.5 mL) at 27°C and the solution containing 4-chloro-3-(trifluoromethyl) phenyl isothiocyanate (986 mg) in toluene (1 mL) was added drop wise to the above reaction mixture at 27°C. Resultant reaction mixture was stirred for 16 hours at same temperature. After the completion of reaction, reaction mass was poured into water (5 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure at 40-45°C and the crude product was purified by column chromatography using 45-50% ethyl acetate- hexane as mobile phase to obtain the title compound.
Yield: 450 mg (47.17%)
Example-13: Preparation of Regorafenib

To the mixture containing thiourea compound (430 mg) and ethanol (18 mL), 30% hydrogen peroxide (9.0 mL) was added and the reaction mixture was heated to 80°C. Stirred the reaction mixture for 5 hours at the same temperature and after the completion of reaction, ethanol was evaporated under reduced pressure at 45-50°C. The resultant reaction mass was diluted with water (5mL) and extracted with ethyl acetate (3x15 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure at 50-55°C. The crude product was purified by column chromatography using 45-50% ethyl acetate- hexane as mobile phase to obtain the title compound.
Yield: 50 mg (12%)
Example-14: Preparation of 4-amino phenol

Ammonium chloride (38.4 g), iron powder (20.0 g) and water (50 mL) were added to a mixture of 4-nitro phenol (100 g) and Isopropyl alcohol (100 mL). Reaction mixture was heated to 80-85°C and stirred for 3 hours at the same temperature. After the completion of reaction, the reaction mixture was cooled to 27°C. Ethyl acetate (50 mL) was added to the reaction mixture and stirred for 10 min at 26°C. Filtered the reaction mixture through celite bed and washed the bed with ethyl acetate (2x50 mL) and then the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL). Combined organic layer was washed with brine solution (100 mL) and dried over anhydrous sodium sulphate. Reaction mixture was distillation under vacuum at 50ºC. Hexane (50 mL) was added to the crude product and stirred for 30 min at 27ºC. Solid was filtered and dried to obtain title compound.
Yield: 6.5 g (83%)
Purity by HPLC: 97.14%
Example-15: Preparation of 4-N-formylamino phenol

To the mixture of 4-amino phenol (6.0 g) and formic acid (18 mL), zinc oxide (4.47 g) was added at 27°C. Reaction mixture was heated to 75-80°C and stirred for 6 hours at same temperature. After the completion of reaction, reaction mixture was quenched with water (60 mL) at 27°C and the pH of the reaction mixture was adjusted to basic pH by adding sodium bicarbonate ( 18 g) to the reaction mass. The reaction mixture was then filtered on celite bed and washed with ethyl acetate (60 mL). Organic layer was separated and aqueous layer was extracted with ethyl acetate (3x30 mL). The combined organic layer was washed with water (60 mL), brine solution (60 mL) and dried over anhydrous sodium sulphate and concentrated under reduced pressure at 50°C to obtain the title compound.
Yield: 4.8 g (64%)
Purity by HPLC: 96.78%
Example-16: Preparation of 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide

To a mixture of 4-N-formylamino phenol (4.69 g) in N-methyl pyrrolidone (30 mL), Potassium tertiary butoxide (3.847 g) was added at 27°C and then a solution containing 4-chloro methyl picolinamide (4.5 g) in N-methyl pyrrolidone (15 mL) was slowly added at the same temperature. The reaction mixture was heated to 100°C and stirred for 24 hours. After the completion of reaction, water (175 mL) was poured into the reaction mixture and reaction mixture was filtered on a celite bed and washed with ethyl acetate (100 mL). Separated the organic layer and aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layer was washed with water (4x100 mL) and dried over anhydrous sodium sulphate. Then the organic layer was concentrated under reduced pressure at 50°C to obtain the title compound.
Yield: 6.5 g
Purity by HPLC: 98.90%
Example-17: Preparation of 4-(4-isocyano-phenoxy) pyridine-2-carboxylic acid methylamide

4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide (2.0 g) was dissolved in dichloromethane (100 mL) at 27°C and triethyl amine (4.1 mL) was added drop wise in 10 minutes. To the reaction mixture triphosgene (1.53 g) was added portion wise at 27ºC and stirred for 120 min at same temperature. After Completion of reaction, the reaction mixture was washed with water (100 mL), brine solution and dried on anhydrous sodium sulphate. The reaction mixture was concentrated under reduced pressure at 40°C. The crude product was purified by column chromatography using 30% ethyl acetate-hexane mixture as mobile phase to obtain the title compound.
Yield: 1.24 g (66.6%)
Purity by HPLC: 99.31%
Example-18: Preparation of 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide

To the mixture of 4- amino phenol (081) and N-methyl pyrrolidone (8.0 mL), potassium tertiary butoxide (0.84 g) was added portion wise at 27°C. 4-chloro-N-methylpicolinamide (1.0 g) dissolved in N-methyl pyrrolidone (4.0 mL) was added to the above reaction mixture at 27°C. Then the reaction mixture was heated to 90-100°C and stirred at 90-95°C for 2 hours. After the completion of reaction, the reaction mixture was cooled to 27°C and added water (20 mL) and ethyl acetate (30 mL) to the reaction mixture. The reaction mixture was filtered on celite bed and washed with ethyl acetate (2x10 mL). Aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layer was washed with water (4x10 mL), brine solution (3x10 mL) and dried over anhydrous sodium sulphate. Then the organic layer was concentrated under reduced pressure at 50°C to obtain the title compound.
Yield: 1.3 g
Purity by HPLC: 95.22%
Example-19: Preparation of 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide

To the mixture of 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide (1.3 g) and formic acid (4.0 mL), zinc oxide (0.43 g) was added at 27°C. Reaction mixture was heated to 75-80°C and stirred for 6 hours at same temperature. After the completion of reaction, water (10 mL), ethyl acetate (10 mL) at 27°C and the pH of the reaction mixture was adjusted to basic pH by adding sodium bicarbonate (15 g) to the reaction mass. The reaction mixture was then filtered on celite bed and washed with ethyl acetate (10 mL). Organic layer was separated and aqueous layer was extracted with ethyl acetate (2x10 mL). The combined organic layer was washed with water, brine solution and dried over anhydrous sodium sulphate and concentrated under reduced pressure at 50°C to obtain the title compound.
Yield: 4.8 g (64%)
Purity by HPLC: 96.78%
Example-20: Preparation of 4-(4-isocyano-phenoxy) pyridine-2-carboxylic acid methylamide

4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide (0.77 g) was dissolved in dichloromethane (38.5 mL) at 27°C and triethyl amine (1.5 mL) was added drop wise in 10 minutes. To the reaction mixture triphosgene (0.58 g) was added portion wise at 27ºC and stirred for 120 min at same temperature. After Completion of reaction, the reaction mixture was washed with water, brine solution and dried on anhydrous sodium sulphate. The reaction mixture was concentrated under reduced pressure at 40°C to obtain the title compound.
Yield: 0.73 g
Purity by HPLC: 93.94%
Example: 21: Preparation of Sorafenib

4-(4-isocyano-phenoxy) pyridine-2-carboxylic acid methylamide (0.7 g) was dissolved in dichloromethane (30 mL) at 27°C and cooled to -60°C. Dimethyl sulphoxide (0.215 mL) and trifluoro acetic anhydride (0.08 mL) were added to the reaction mixture at -60°C and stirred for 10 min at same temperature. Temperature of the reaction mixture was raised to 27°C and stirred for 20 min. Then the reaction mixture was cooled to -60°C and 4- chloro 3-trifluoromethyl aniline (1.3 g) was added and stirred for 10 min. Temperature of the reaction mixture was then raised to 27°C and stirred for 2 hours at same temperature. After the completion of reaction, water and saturated solution of sodium bicarbonate were added to the reaction mixture and extracted the reaction mixture with ethyl acetate. Organic layer was separated and washed with water, brine solution and was dried over anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure at 50°C to obtain crude product. The crude product was purified by column chromatography using 50% ethyl acetate- hexane as mobile phase to obtain the title compound.
Yield: 0.70 g (54.68%)
Purity by HPLC: 97.02%
,CLAIMS:WE CLAIM:
1. A process for the preparation of Regorafenib or its desfluoro analog (Sorafenib), comprising the steps of:
a) N-formylating 4-amino phenol of formula (II),

to obtain 4-N-formylamino phenol of formula (III);
b) reacting 4-N-formylamino phenol of formula (III) with 4-chloro-N-methylpicolinamide of formula (IV)

to obtain 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V);
c) optionally, de-formylating 4-(4-N-formylamino-phenoxy)-pyridine-2-carboxylic acid methylamide of formula (V) to obtain 4-(4-N-amino-phenoxy)-pyridine-2-carboxylic acid methylamide of formula (VI);

d) converting 4-(4-N-formylamino-phenoxy)-pyridine-2-carboxylic acid methylamide of formula (V) or 4-(4-N-amino-phenoxy)-pyridine-2-carboxylic acid methylamide of formula (VI) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).
.
wherein, R1 may be hydrogen or fluoro.
2. A process for the preparation of Regorafenib or its desfluoro analog (Sorafenib), comprising the steps of:
a) converting 4-(4-amino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) or 4-(4-N-formylamino-phenoxy) pyridine-2-carboxylic acid methylamide of formula (V) to 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII), wherein R1 may be fluorine or hydrogen;

b) converting 4-(4-isocyanophenoxy)-N-methylpicolinamide of formula (VII) to Regorafenib or its desfluoro analog (Sorafenib) of formula (I).

wherein, R1 may be hydrogen or fluoro.

3. A process for the preparation of Regorafenib, comprising the steps of:
a) converting 4-chloro-3-(trifluoromethyl)aniline of formula (VIII) to 4-chloro-3- trifluoromethyl)phenyl isothiocyanate of formula (IX)

b) reacting 4-chloro-3-(trifluoromethyl)phenyl isothiocyanate of formula (IX) with 4-(4-amino-3-fluorophenoxy) pyridine-2-carboxylic acid methylamide of formula (VI) to obtain thiourea compound of formula (X)

c) converting thiourea compound of formula (X) to compound of formula (Ia), Regorafenib.

4. A compound of formula (V) or salt thereof
.

5. A compound of formula (VII) or salt thereof
.

6. A compound of formula (X) or salt thereof
.