DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of sorafenib tosylate. Sorafenib tosylate IUPAC nomenclature is 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl amino]phenoxy]-N-methyl-pyridine-2-carboxamide tosylate having following formula:

BACKGROUND OF THE INVENTION
Bayer developed sorafenib for primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), and radioactive iodine resistant advanced thyroid carcinoma.
Sorafenib is disclosed in US7897623B2. The disclosed patent describes a number of synthetic Sorafenib methods.
There are also several other references reporting for the preparation of sorafenib, for example WO2000041698, WO2004113274 and WO2000042012.
The above given reference provide a general process for the preparation of sorafenib which is summarized as below:

Preparation of sorafenib also mentioned in reference WO2009034308, given reference provide a general process for the preparation of sorafenib which is summarized as below:

The tosylate salt of 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl] carbamoyl amino] phenoxy]-N-methyl-pyridine-2-carboxamide is mentioned in WO 03/068228 and WO 03/047579 corresponds to the compound of the formula given below.

Most of the references disclose the use of 4-Aminophenol or its salt for the preparation of Sorafenib or its pharmaceutical acceptable salts. 4-Aminophenol is a known genotoxic material and proper handling is required during commercial production of sorafenib Tosylate. 4-Aminophenol should be controlled in a stringent TTC limit in final drug substance specification. To achieve TTC limit by purification, large amount of solvent is required. Also, it contains regio isomers (like 2-Aminophenol, 3-Aminophenol), which are also genotoxic and need to control in API.
Apart from the cited above problem, another major drawback of the prior art processes is that all the above processes for the preparation of sorafenib tosylate is tedious process and suffers from many disadvantages like poor yield and low purity, to overcome this problem it is necessary to develop simple and cost effective process for the preparation of large scale production of sorafenib tosylate with high purity.
Surprisingly, the inventors of the present invention have discovered an improved process for the preparation of sorafenib and salts thereof which excludes the use of 4-Aminophenol and also provides simple, safe and viable process to prepare highly pure sorafenib and salts thereof.
OBJECTS OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of sorafenib tosylate comprises:

(a) reacting 4-chloro-N-methylpicolinamide hydrochloride with N-(4-hydroxyphenyl)acetamide using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I),

(b) condensing 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I) with 4-chloro-3-(trifluoromethyl)-phenyl isocyanate in suitable solvent to obtain 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide,

(c) purifying sorafenib base using suitable solvent or mixture thereof,

(d) tosylating 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide using p-Toluenesulfonic acid in suitable solvent to obtain 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide tosylate.

In another object of the present invention provides process for the preparation of 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage –I) by reacting 4-chloro-N-methylpicolinamide hydrochloride with N-(4-hydroxyphenyl)acetamide using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I).

In another object of the present invention is to provide process for the preparation of pure sorafenib base by using suitable solvent or mixture thereof.

In another object of the present invention is to provide process for the preparation of 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage I) by reacting 4-chloro-N-methylpicolinamide hydrochloride with compound A using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I).

In yet another object of the present invention provides the use of 4-hydroxyphenyl acetamide for the preparation of Sorafenib or its or its pharmaceutical acceptable salts.

SUMMARY OF THE INVENTION

The main aspect present invention is to provide an improved process for the preparation of sorafenib tosylate comprises:

(a) reacting 4-chloro-N-methylpicolinamide hydrochloride with N-(4-hydroxyphenyl)acetamide using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I),

(b) condensing 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I) with 4-chloro-3-(trifluoromethyl)-phenyl isocyanate in suitable solvent to obtain 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide,

(c) purifying sorafenib using suitable solvent or mixture thereof,

(d) tosylating 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide (Stage-III) using p-Toluenesulfonic acid in suitable solvent to obtain 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide tosylate.

In another aspect of the present invention provides process for the preparation of 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage –I) by reacting 4-chloro-N-methylpicolinamide hydrochloride with N-(4-hydroxyphenyl)acetamide using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I).

In another aspect of the present invention is to provide process for the preparation of pure sorafenib base by using suitable solvent or mixture thereof.

In another aspect of the present invention is to provide process for the preparation of 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage I) by reacting 4-chloro-N-methylpicolinamide hydrochloride with compound A using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I).

In yet another aspect of the present invention provides the use of 4-hydroxyphenyl acetamide for the preparation of Sorafenib or its or its pharmaceutical acceptable salts.

DETAILED DESCRIPTION

The main embodiment of the present invention is to provide an improved process for the preparation of sorafenib tosylate comprises:

(a) reacting 4-chloro-N-methylpicolinamide hydrochloride with N-(4-hydroxyphenyl)acetamide using inorganic base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I),

(b) condensing 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I) with 4-chloro-3-(trifluoromethyl)-phenyl isocyanate in suitable solvent to obtain 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide,

(c) purifying sorafenib using suitable solvent or mixture thereof,

(d) tosylating 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide (Stage-III) using p-Toluenesulfonic acid in suitable solvent to obtain 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide tosylate.

In another embodiment of the present invention provides process for the preparation of 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage –I) by reacting 4-chloro-N-methylpicolinamide hydrochloride with N-(4-hydroxyphenyl)acetamide using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I).

In another embodiment of the present invention is to provide process for the preparation of pure sorafenib base by using suitable solvent or mixture thereof.

In another embodiment of the present invention is to provide process for the preparation of 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage I) by reacting 4-chloro-N-methylpicolinamide hydrochloride with compound A using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I).

In yet another embodiment of the present invention provides the use of 4-hydroxyphenyl acetamide for the preparation of Sorafenib or its or its pharmaceutical acceptable salts.

Paracetamol i.e. 4-hydroxyphenyl)acetamide is a well-known API and it is available commercially with high purity and easy to handle on commercial scale.

In general, suitable solvents for above steps are water, hydrocarbon solvents , e.g., benzene, toluene, xylene, methylbenzene, dimethylbenzene, hexane, heptanes, cyclohexane and the like; an alkanol, e.g., methanol, ethanol, 1-butanol, isopropanol and the like; a ketone, e.g., 2-propanone, 4-methyl-2-pentanone, acetone and the like; an ether, e.g., Diethyl ether, dimethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,1'-oxybisethane and the like; an ester ethyl acetate, methyl acetate and like, a dipolar aprotic solvent, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like; a halogenated hydrocarbon, e.g. dichloromethane, 1,2-dichloroethane, trichloromethane and the like; a nitrile e.g. acetonitrile, propionitrile and like, carboxylic acids e.g. acetic acid, propanoic acid and like or a mixture of such solvents.

In general, suitable bases for above steps are an alkali or an earth alkaline metal carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide, acetate or oxide, e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert. butoxide, sodium hydride, sodium amide, sodium hydroxide, sodium acetate, calcium carbonate, calcium hydroxide, potassium hydroxide, calcium oxide and the like; alkali metal iodide such as sodium iodide, potassium iodide and like or an organic base, such as, for example, an amine, e.g., N,N-diethylethanamine, N,N-(1-methylethyl)-2-propanamine, triethylamine, diethylamine, 4-ethylmorpholine, pyridine, morpholin, piperidine and the like or a mixture of such bases.

In general, suitable phase transfer catalyst for the stage-I are tetrabutylammonium chloride, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium methanesulfonate, tetrabutylammonium bromide, tetrabutyl ammonium iodide, Tetrabutylammonium nitrate or the like.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

EXAMPLES

Example 1: Preparation of Stage-I

To a mixture of THF and N-(4-hydroxyphenyl) acetamide, water was added at 25 to 35°C under stirring followed by addition of Potassium hydroxide, Tetrabutyl ammonium bromide & Potassium carbonate. Heat the reaction mass up to 68 to 720C. 4-chloro-pyridine-2-carboxylic acid methyl amide HCl (50 gm) was added at 68 to 720C. Stir the mass at 65 to 700C for 16 to 18 hrs. Cool reaction mass to 0 to 10°C and add slowly HCl at same temperature. Reaction mass pH was adjusted between 3.5 to 4.0 with 5 % NaOH by maintaining temperature 0 to 10°C. Isopropanol was added at 25 to 35°C in the obtained solid product and heated upto 70 to 75°C. Obtained solid was dried in vacuum tray dryer at 50 to 60°C for 8 to 10 hours (Practical Yield (%): 50%).

Example 2: Preparation of Sorafenib base

Add 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (25 gm) (Stage-I) into MDC: DMF solution. The reaction mass was stirred for 10 to 15 minutes at 25 to 35°C followed by cooling at 10 to 15°C. 4-chloro-(3-trifluoromethyl) phenyl isocyanate solution was added slowly in MDC: DMF solution at 10 to 15°C within in 15 to 30 minutes. Reaction mass was stir at 10 to 15°C for 4 to 5hrs. Obtained solid cake was washed with water followed by drying wet cake in dryer at 50 to 60°C for 8 to 10 hours (Practical Yield (%): 84 %).
Example 3: Purification of Sorafenib base

Add obtained sorafenib base (36mg), acetone & DMF in RB flask at 25 to 35oC. The reaction mass was heated at 50 to 55oC & stirred for 15-20 minutes. Reaction mass was cooled for 25 to 30°C and washed with acetone followed by drying wet cake in dryer at 50 to 60°C for 6 to 8 hours (Practical Yield (%): 72 %).

Example 4: Preparation of Sorafenib Tosylate Form-III

Add purified sorafenib base (12mg) and methanol in RB flask at 25 to 35oC and stirred reaction mass for 10 to 15 minutes. Add PTSA solution slowly at 25 to 35 °C in 15 to 30 minutes. Cool reaction mass to 0 to 5°C and stir for 4 Hrs. Filter the product and wash with methanol. Dry the product under vacuum at 85 to 95°C (Practical Yield (%): 98%).

The process of present invention is depicted in following schemes:-
SCHEME 1

The process of present invention is depicted in following schemes.
SCHEME 2

,CLAIMS:WE CLAIM:

1. An improved process for the preparation of sorafenib tosylate which comprises steps of;

(a) reacting 4-chloro-N-methylpicolinamide hydrochloride with N-(4-hydroxyphenyl)acetamide using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I),

(b) condensing 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I) with 4-chloro-3-(trifluoromethyl)-phenyl isocyanate in suitable solvent to obtain 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide,

(c) purifying sorafenib using suitable solvent or mixture thereof,

(d) tosylating 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide (Stage-III) using p-Toluenesulfonic acid in suitable solvent to obtain 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methylamide tosylate.

2. An improved process for the preparation of sorafenib tosylate which comprises steps of;

(a) reacting 4-chloro-N-methylpicolinamide hydrochloride with N-(4-hydroxyphenyl)acetamide using inorganic base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I)

(b) converting 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I) to Sorafenib tosylate by any conventional method.

3. A process for the preparation of 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage I) comprising a step of reacting 4-chloro-N-methylpicolinamide hydrochloride with compound A using suitable base, phase transfer catalyst in suitable solvent to obtain 4-(4-Amino-phenoxy)-pyridine-2-carboxylic acid methylamide (Stage-I).

4. Use of 4-hydroxyphenyl acetamide for the preparation of sorafenib or its pharmaceutical acceptable salts.

5. A process as claimed in any of preceding claims, wherein suitable base is selected from an alkali or an earth alkaline metal carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide, acetate or oxide, e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert. butoxide, sodium hydride, sodium amide, sodium hydroxide, sodium acetate, calcium carbonate, calcium hydroxide, potassium hydroxide, calcium oxide and the like; alkali metal iodide such as sodium iodide, potassium iodide and like or an organic base, such as, for example, an amine, e.g., N,N-diethylethanamine, N,N-(1-methylethyl)-2-propanamine, triethylamine, diethylamine, 4-ethylmorpholine, pyridine, morpholin, piperidine and the like or a mixture of such bases.

6. A process as claimed in any of preceding claims, wherein phase transfer catalyst is selected from tetrabutylammonium chloride, tetrabutylammonium acetate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium methanesulfonate, tetrabutylammonium bromide, tetrabutyl ammonium iodide or Tetrabutylammonium nitrate.

7. A process as claimed in any of preceding claims, wherein suitable solvents is selected from water, hydrocarbon solvents, e.g., benzene, toluene, xylene, methylbenzene, dimethylbenzene, hexane, heptanes, cyclohexane and the like; an alkanol, e.g., methanol, ethanol, 1-butanol, isopropanol and the like; a ketone, e.g., 2-propanone, 4-methyl-2-pentanone, acetone and the like; an ether, e.g., Diethyl ether, dimethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,1'-oxybisethane and the like; an ester ethyl acetate, methyl acetate and like, a dipolar aprotic solvent, e.g., N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone and the like; a halogenated hydrocarbon, e.g. dichloromethane, 1,2-dichloroethane, trichloromethane and the like; a nitrile e.g. acetonitrile, propionitrile and like, carboxylic acids e.g. acetic acid, propanoic acid and like or a mixture of such solvents.

8. A process as claimed in any of preceding claims, wherein suitable base most preferably selected from Potassium hydroxide, Potassium carbonate or mixtures thereof.

9. A process as claimed in any of preceding claims, wherein most preferred selected suitable phase transfer catalyst is tetrabutyl ammonium bromide.

10. A process as claimed in any of preceding claims, wherein suitable solvent most preferably selected from THF, IPA, water, MDC, DMF, Acetone, Methanol, Ethanol or mixtures thereof.