Claims:We Claim
1. A process for the preparation of Sorafenib of Formula I or a pharmaceutically acceptable salt thereof,

comprising

a. reacting 4-(4- aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3- (trifluoromethyl)phenylisocyanate (IV) or imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (V) in organic solvent or mixture of organic solvents at temperature ranging from about 25 – 50 °C to get crude sorafenib, and

b. isolation of Sorafenib base of formula (I) by leaching with organic solvent or mixture of organic solvents at temperature ranging from about 25 – 50 °C.

2. A process for the preparation of Sorafenib of Formula I or a pharmaceutically acceptable salt thereof, comprising

a. reacting 4-chloro-3-(trifluoromethyl)aniline of formula VI with carbonyldiimidazole (CDI) (VII) in organic solvent or mixture of organic solvents at temperature ranging from 25 - 50 °C,
b. adding 4-(4- aminophenoxy)-N-methylpicolinamide (III) to step a, at temperature ranging from 25 - 50 °C, and
c. isolation of Sorafenib base.

3. The process according to claims 1 and 2, wherein the organic solvent is selected from the group comprising of N,N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethyl acetamide (DMA) or a mixture thereof.

4. The process according to claims 1 and 2, wherein the reaction is carried out in DMF at a temperature of about 25 - 50 °C, preferably at 25 -30 °C.

5. The process according to claims 1 and 2, wherein the reaction is carried out in THF at temperature of about 25 to 45 °C.

6. The process according to claims 1 and 2, wherein the reaction is carried out in a solvent mixture of DMF and THF at a temperature of about 25 - 50 °C, preferably at 30 - 35 °C.

7. The process according to claims 1 and 2, wherein the isolation of sorafenib base (I) is carried out by leaching in an organic solvent, selected from the group comprising of acetone, ethyl acetate, dichloromethane, methanol or a mixture thereof at a temperature of about 25 to 30 °C.

8. The process according to claims 1 and 2, wherein the Sorafenib base (I) is characterized by a single peak ranging between 202° to 220°C with onset range 210°C, chemical assay of 99.93% using perchloric acid and HPLC purity of > 99.5 % with individual impurities < 0.05%.

9. A process according to claim 1, wherein the process for preparation of imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula V comprises of

a. reacting 4-chloro-3-(trifluoromethyl)aniline of formula VI with carbonyldiimidazole (CDI) (VII) in organic solvent or mixture of organic solvents at temperature ranging from 25 - 50 °C, and
b. isolation of compound of formula V by leaching with organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C followed by filtration.

10. The process according to claim 9, wherein the Isolation of compound of formula V is carried out by leaching in an organic solvent, selected from the group consisting of n-hexane, n-pentane, ethyl acetate, Diisopropyl ether and mixtures thereof at a temperature of about 25 to 30 °C.

11. A process for the preparation of Sorafenib tosylate salt of Formula II, comprising:

a. combining Sorafenib base (I) with p-toluenesulfonic acid in organic solvent at temperature ranging about 25 - 50 °C to obtain sorafenib tosylate (II)

12. A process for the preparation of Sorafenib tosylate salt of Formula II, comprising:
a. by reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-(trifluoromethyl) phenylisocyanate (IV) in organic solvent or mixture of organic solvent at temperature ranging about 25 - 50 °C,
b. addition of PTSA in organic solvent or mixture of organic solvents at temperature ranging about 25 - 50 °C, and
c. isolation of Sorafenib PTSA salt.

13. The process according to claims 11 and 12, wherein organic solvent is selected from the group comprising of Tetrahydrofuran (THF), Acetone, Ethyl acetate, Ethanol, Methanol, Ethyl methyl ketone or a mixture thereof.

14. The process according claims 11 and 12, wherein the Sorafenib tosylate (II) is characterized by a single endothermic peak ranging between 225° to 240 °C with onset range 236 °C and HPLC purity of > 99.5 % with individual impurities < 0.05%.
, Description:TECHNICAL FIELD
The invention relates to process for the preparation of Sorafenib i.e. 4-{4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide and the salts thereof. More particularly the invention relates to process for the preparation of Sorafenib and its tosylate salt.

BACKGROUND ART
The compound sorafenib also known as 4- {4 - [({[4-chloro-3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy} -N- methylpyridine-2-carboxamide.

It was co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar. It is a kinase inhibitor drug and approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), and radioactive iodine resistant advanced thyroid carcinoma.
WO 00/42012, describes synthesis of ?-Carboxylaryl substituted diphenyl ureas including Sorafenib synthesis and its pharmaceutically acceptable salts. Patents WO 03/068228 and WO 03/047579 also disclosed Sorafenib tosylate of formula II in their patent applications.
Organic Process Research & Development, 2002, 6, 777-781 by Bankston et al. discloses a process for the preparation of Sorafenib. Method 1 describes the reaction of 4-(4-aminophenoxy)-N-methylpicoiinamide with 4-chloro-3-(trifluoromethyl)phenyl isocyanate in chlorinated solvent and method 2 describes the in-situ reaction of 4-(4-aminophenoxy)-N-methylpicoiinamide with 4-chloro-3-(trifluoromethyl) aniline and CDI in chlorinated solvent. The reaction time for both reactions is 16 hrs and 34 hrs respectively.
US2009/0253913, disclosed the reaction between 4-chloro-3-(trifluoromethyl) aniline and CDI in chlorinated solvent to form imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide in 76 % yield after 16 hrs, which further reacted with of 4-(4-aminophenoxy)-N-methylpicoiinamide for 16 hrs to yield sorafenib.
As per above disclosures, sorafenib precipitates in reaction after 15 min and which further stirred for 16-18 hrs. To our observation precipitation of product during the reaction lower the rate of the reaction due to the saturation and nearly 2 - 5 % of 4-(4-aminophenoxy)-N-methylpicoiinamide remains unreacted even after longer hours of stirring. Even additional amount of 4-chloro-3-(trifluoromethyl)phenyl isocyanate addition cannot take reaction to the completion, due to saturation.
Purification to remove 4-(4-aminophenoxy)-N-methylpicoiinamide from sorafenib needs additional efforts of crystallization and it leads to loss in yield, indicates the unsuitability of the process for industrial scale production.
WO 2013175483 disclosed synthesis of crystalline sorafenib and its tosylate salt by reacting 4-chloro-3-trifluoromethylisocyanate (1.64 eq) with 4-(4-aminophenoxy)-N-methylpicolinamide in ethyl methyl ketone (MEK) at 80-85°C in 75% of yield. Though the product purity is reported to be 99.5 %, this process may not be of cost effectiveness at industrial scale due to use of excess equivalent of isocynate derivative and less yield of the product.

SUMMARY
Accordingly, an improved industrially suitable process for the synthesis of Sorafenib base of Formula (I) (also referred to as Sorafenib base (I)) and its pharmaceutically acceptable tosylate salt (II) thereof with improved yield, high purity and free from any undesired impurities is disclosed herein.

According to one aspect of the invention, the process for the preparation of Sorafenib base of Formula (I) comprises of, reaction of 4-(4-aminophenoxy)-N- methylpicolinamide (III) with 4-chloro-3-(trifluoromethyl)phenylisocyanate (IV) in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C to get crude Sorafenib base (I) after leaching in an organic solvent.

According to another aspect of the invention the process for the preparation of Sorafenib base (I) comprises of reacting 4-(4- aminophenoxy)-N-methylpicolinamide (III) with imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (V) in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C to get Sorafenib base (I) after leaching in organic solvent.

According to another aspect of the invention, the process for the preparation of Sorafenib base (I) is a one pot process comprising of (a) reacting 4-chloro-3-(trifluoromethyl)aniline (VI) with carbonyldiimidazole (CDI) (VII) in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C, (b) adding 4-(4- aminophenoxy)-N-methylpicolinamide (III) to step (a), at temperature ranging from about 25 - 50 °C and get Sorafenib base (I) after leaching in organic solvent.

The organic solvent used in the process of preparation of Sorafenib base (I) as disclosed herein is selected from the group comprising of N,N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethyl acetamide (DMA) or a mixture thereof. The reaction in the process of preparation of Sorafenib base (I) as disclosed herein is carried out in an organic solvent at a temperature of ranging from about 25 – 50 oC.

The isolation of sorafenib base (I) is carried out by leaching in an organic solvent, selected from the group comprising of acetone, ethyl acetate, dichloromethane, methanol or a mixture thereof at a temperature of about 25 to 30 °C.

The Sorafenib base (I) obtained by using the process disclosed herein is characterized by a single peak ranging between 202° to 220°C with onset range 210°C, chemical assay of 99.93% using perchloric acid and HPLC purity of > 99.5 % with individual impurities < 0.05%.

The process for the preparation of imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl) phenyl amide of formula V comprises of reacting 4-chloro-3-(trifluoromethyl)aniline of formula VI with carbonyldiimidazole (CDI) (VII) in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C. Solid material obtained was leach with organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C followed by filtration.

The isolation of compound of formula V is carried out by leaching in an organic solvent selected from the group comprising of n-hexane, n-pentane, ethyl acetate, Diisopropyl ether and mixtures thereof at a temperature ranging from about 25 to 30 °C.
According to another aspect of the invention, the process for the preparation of Sorafenib tosylate salt (II), comprises of combining Sorafenib base (I) with p-toluenesulfonic acid in organic solvent at temperature ranging from about 25 - 50 °C to obtain Sorafenib tosylate (II)

According to another aspect of the invention, the process for preparation of Sorafenib tosylate salt (II) is a one pot process, comprising of (a) reacting 4-(4-aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3-(trifluoromethyl) phenylisocyanate (IV) in organic solvent or mixture of organic solvent at temperature ranging from about 25 - 50 °C (b) addition of PTSA in organic solvent or mixture of organic solvent at temperature ranging from about 25 - 50 °C, and (c) isolation of Sorafenib tosylate (PTSA) salt (II) by filtration.

The organic solvent used in the process of preparation of Sorafenib tosylate salt (II) as disclosed herein is selected from the group comprising of Tetrahydrofuran (THF), Acetone, Ethyl acetate, Ethanol, Methanol, Ethyl methyl ketone or a mixture thereof.

The Sorafenib tosylate salt (II) obtained as per the processes disclosed herein is characterized by a single endothermic peak ranging between 225° to 240 °C with onset range 236 °C and HPLC purity of > 99.5 % with individual impurities < 0.05%.
Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.
In addition, the materials, methods and examples described in this invention are illustrative only and are not intended to be limited.

DETAILED DESCRIPTION
As set forth herein embodiments of the invention disclosed herein provide an industrial suitable process for the synthesis of Sorafenib base (I) and its pharmaceutically acceptable tosylate salt (II) thereof with improved yield, good purity and free from any undesired impurities.
In one of the embodiment the process for the preparation of Sorafenib base of formula I comprises of
a. reacting 4-(4- aminophenoxy)-N-methylpicolinamide (III) with 4-chloro-3- (trifluoromethyl)phenylisocyanate (IV) in organic solvent or mixture of organic solvents at temperature ranging from about 25 – 50 °C to get crude sorafenib, and


b. isolation of Sorafenib base of formula (I) by leaching with organic solvent or mixture of organic solvents at temperature ranging from about 25 – 50 °C.
In the processes reported in the state of the art, the product precipitates during the course of the reactions between intermediate III with intermediate IV in different solvents, which results in lowering the rate of the reaction and due to the saturation nearly 2 - 5 % of 4-(4-aminophenoxy)-N-methylpicoiinamide (III) remains unreacted even after longer hours of stirring. Even additional amount of 4-chloro-3-(trifluoromethyl)phenyl isocyanate cannot take reaction to the completion there after.
Removal of 4-(4-aminophenoxy)-N-methylpicoiinamide (III) residual impurity from Sorafenib (I) final API, needs additional efforts of crystallization, which resulted in yield loss.
The above problem of saturation during the reaction between intermediate III and intermediate IV is overcome by process for the preparation of Sorafenib base of formula I as disclosed herein with the use of organic solvent or a mixture thereof which also improves the rate of reaction, yield and over all purity of the end product.
The organic solvent used in this reaction is selected from the group comprising of N, N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethylacetamide (DMA) and or a mixture thereof.
Organic solvents like N, N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethylacetamide (DMA) and mixtures thereof used in this reactions of the invention are very much advantageous in terms of faster reaction rate and yield. The amount of unreacted 4-(4-aminophenoxy)-N- methylpicolinamide (III) found in the final API is negligible or less than 0.05%.
The volumes of solvent used in this reaction ranges between 6 to 15 volumes with respect to the 4-(4-aminophenoxy)-N-methylpicolinamide (III),
In another embodiment, 4-(4-aminophenoxy)-N-methylpicolinamide (III) was taken in DMF and 4-chloro-3- (trifluoromethyl)phenylisocyanate (IV) in DMF was added at 25 - 30 ° C. Stirred clear solution for 6-8 hrs and progress of reaction was monitored by HPLC.
In another embodiment, 4-(4-aminophenoxy)-N-methylpicolinamide (III) was taken in THF (10 v), mixture was heated to 40 - 45 °C to obtained clear solution, 4-chloro-3- (trifluoromethyl)phenylisocyanate (IV) in THF (5 V) was added at 40 - 45 °C. Stirred clear solution for 5 -7 hrs and progress of reaction was monitored by HPLC.
In another embodiment, 4-(4-aminophenoxy)-N-methylpicolinamide (III) was taken in DMF (4 v), and 4-chloro-3- (trifluoromethyl)phenylisocyanate (IV) in THF (4 V) was added at RT . Clear solution for 12 hrs and progress of reaction was monitored by HPLC.
According to another embodiment of the invention disclosed herein, the process for the preparation of Sorafenib base of formula I comprises of,
a. reacting 4-(4- aminophenoxy)-N-methylpicolinamide (III) with imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (V) in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C to get crude sorafenib.

b. Isolation of Sorafenib base of formula (I) by leaching with organic solvent or mixture of organic solvents at temperature ranging from 25 - 50 °C.

The organic solvent used in this reaction is selected from the group comprising of N, N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethylacetamide (DMA) and or a mixture thereof.

Organic solvents like N, N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethylacetamide (DMA) and mixtures thereof used in this reactions of the present invention are very much advantageous in terms of faster reaction rate. The amount of unreacted 4-(4-aminophenoxy)-N- methylpicolinamide (III) found in the final API is negligible or less than 0.05%.

According to one of the embodiment of the invention, 4-(4- aminophenoxy)-N-methylpicolinamide (III) is reacted with imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (V) in DMF at 25 - 30 °C.

According to another embodiment of the invention, 4-(4- aminophenoxy)-N-methylpicolinamide (III) is reacted with imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (V) in DMF –THF mixture at 25 - 30 °C.

Isolation of the product was done using water workup followed by extraction with organic solvent like ethyl acetate. Water workup again has advantage in this particular step to remove any of the inorganic things present. The obtained sorafenib base (I) using this methodology have the purity of > 99 % by chemical assay and one can easily take this material for salt formation without any further filtration.

Sorafenib base (I) synthesized according to the above methodology was characterized using DSC isotherm and found to be a single peak, ranging between 202° to 220°C with onset range 210°C. The chemical assay using perchloric acid was found to be 99.93 %. HPLC purity was more > 99.5 % with individual impurities < 0.05%.

According to another embodiment of the invention the process for the preparation of Sorafenib of formula I is a one pot process comprising of,

a. reacting 4-chloro-3-(trifluoromethyl)aniline of formula VI with carbonyldiimidazole (CDI) (VII) in organic solvent or mixture of organic solvents at temperature ranging from 25 - 50 °C,
b. adding 4-(4- aminophenoxy)-N-methylpicolinamide (III) to step a, at temperature ranging from 25 - 50 °C, and
c. isolation of Sorafenib base (I).

The organic solvent used in this reaction selected from the group consisting of N, N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethylacetamide (DMA) and or a mixture thereof.

In the above mentioned embodiment, step a., 4-(4- aminophenoxy)-N-methylpicolinamide (III) is reacted with imidazole (VII) in DMF solvent to give imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (V) in 25 - 30 °C and which in situ reacted with 4-(4- aminophenoxy)-N-methylpicolinamide (III) at 25 - 30 °C to obtain Sorafenib base (I).

The major advantage using DMF as solvent relates to the solubility of the intermediates used and thereby faster reaction rate. The step a., reaction takes place in less than 4 hrs room temperature. In-situ addition of 4-(4- aminophenoxy)-N-methylpicolinamide (III) to this intermediate leads the formation of sorafenib base (I) in < 8 hrs at room temperature in comparative yield and purity.

In another embodiment of the invention is provided a process for the preparation of imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide of formula V comprising of
a. reacting 4-chloro-3-(trifluoromethyl)aniline of formula VI with carbonyldiimidazole (CDI) (VII) in organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C, and
b. isolation of compound of formula V by leaching with organic solvent or mixture of organic solvents at temperature ranging from about 25 - 50 °C followed by filtration.

The organic solvent used in this reaction selected from the group consisting of N, N-dimethyl formamide (DMF), tetrahydrofuran (THF), N,N-dimethylacetamide (DMA) or a mixture thereof. Whereas the isolation of compound of formula V is carried out by leaching in an organic solvent, selected from the group consisting of n-hexane, n-pentane, ethyl acetate , Diisopropyl ether or a mixture thereof at about 25 to 30 °C.

Reaction between 4-chloro-3-(trifluoromethyl)aniline of formula VI with carbonyldiimidazole (CDI) (VII) was carried out in THF at room temperature and product isolation was done by evaporation of THF. Obtained residue, was triturated in n-hexane and ethyl acetate mixture to get solid mass after filtration.
In another embodiment of the invention is provided a process for the preparation of Sorafenib tosylate salt of formula II comprising,
a. combining Sorafenib base (I) with p-toluenesulfonic acid in organic solvent at temperature ranging from about 25 - 50 °C to obtain sorafenib tosylate (II)

The process wherein organic solvent is selected from the group consisting of Tetrahydrofuran (THF), Acetone, Ethyl acetate, Ethanol, Methanol, Ethyl methyl ketone or a mixture thereof.

According to one of the embodiment of the invention, sorafenib base (I) was dissolved in THF at about 40 - 45 °C and p-toluenesulfonic acid in THF was added at same temperature. This procedure does not require any seeding as salt precipitates on its own. Sorafenib tosylate (II) was isolated after cooling the reaction mixture to 0 - 5 °C followed by filtration.

According to another embodiment of the invention, sorafenib base (I) was dissolved in acetone at about 40 - 45 °C and p-toluenesulfonic acid in acetone was added at same temperature. Sorafenib tosylate (II) was isolated after cooling the reaction mixture to - 5 °C followed by filtration.

Sorafenib tosylate (II) synthesized according to the above methodology was characterized using DSC isotherm and found to be a single endothermic peak, ranging between 225° to 240 °C with onset range 236 °C. HPLC purity was > 99.5 % with individual impurities < 0.05%.

In another embodiment of the invention is provided a one-pot process for the preparation of Sorafenib tosylate (I), comprising the steps of:
a. reacting 4-(4-aminophenoxy)-N-methylpicolinamide(III) with 4-chloro-3-(trifluoromethyl) phenylisocyanate (IV) in organic solvent or a mixture thereof at temperature ranging from about 25 - 50 °C,

b. addition of PTSA in organic solvent or a mixture thereof at temperature ranging from about 25 - 50 °C, and

c. isolation of Sorafenib PTSA salt.

The process wherein organic solvent is selected from the group comprising of Tetrahydrofuran (THF), Acetone, Ethyl acetate, Ethanol, Methanol, Ethyl methyl ketone or a mixture thereof.

Intermediate 4-(4-aminophenoxy)-N-methylpicolinamide (III) was synthesized in > 99% purity according to the reported methods from literature.
The invention described herein provides an improved process for the preparation of the sorafenib base (I) and Sorafenib tosylate salt with faster reaction rate, high yield and excellent purity.
According to the process of invention disclosed herein, Sorafenib base (I) and Sorafenib tosylate salt (II) having purity > 99.5 % with individual impurities < 0.05% and which compliance with the regulatory requirements.
EXAMPLES:
Example 1: Preparation of Sorafenib base (I) using DMF as solvent
To a stirred solution of 4-(4-aminophenoxy)-N-methylpicolinamide (10 gm, 0.041 mole) in DMF (40 mL) was slowly added 4-chloro-3-trifluoromethylisocyanate (11.85g, 0.053 mole) in DMF (20 mL) maintaining temperature below 40°C. The cleared solution was further stirred for 6-8 hrs at ambient temperature. Progress of reaction was monitored by HPLC. After completion of the reaction, Ethyl acetate (200 mL) was added to reaction mixture and it was washed with water (2 x 200 mL), brine solution (1 x 100 mL). Ethyl acetate layer was further dried over sodium sulphate and evaporate under reduced pressure to obtained crude solid sorafenib. To the obtained crude residue was charged ethyl acetate (50 mL) and mixture was stirred for 1 hr at ambient temperature. Solid material was filtered and washed with ethyl acetate (2 x 25 mL) to obtain 16.9 gm (Yield = 88.5 %) of sorafenib after drying.
HPLC purity: 99.95 %
m.p. 206 - 210 0C
1H-NMR (DMSO-d6, 500 MHz): d = 2.78 - 2.79 (d, J = 5 Hz, 3H), 7.11 - 7.16 (m, 3H), 7.39 (d, J = 2.5 Hz, 1H), 7.58 - 7.67 (m, 4H), 8.11 - 8.12 (d, J= 2.5 Hz, 1H ), 8.48 - 8.49 (d, J= 5.5 Hz, 1H), 8.74 - 8.75 (d, J= 5 Hz, 1H), 8.97 (s, 1H), 9.19 (s, 1H) ;
MS (ESI, CH3CN/H2O): m/e = 465 [M+H]+.
Example 2: Preparation of Sorafenib base (I) using DMF - THF as dual solvent
To a stirred solution of 4-(4-aminophenoxy)-N-methylpicolinamide (1 gm, 0.0041 mole) in DMF (4 mL) was slowly added 4-chloro-3-trifluoromethylisocyanate (1.08 gm, 0.0049 mole) in THF (4 mL) maintaining temperature below 40°C. The cleared solution was further stirred for overnight at ambient temperature. After completion of the reaction, Ethyl acetate (20 mL) was added to reaction mixture and it was washed with water (2 x 20 mL), brine solution (1 x 20 mL). Ethyl acetate layer was further dried over sodium sulphate and evaporate under reduced pressure to obtained crude sorafenib. To the obtained crude residue was charged ethyl acetate (5mL) and mixture was stirred for 1 hr at ambient temperature. Solid material was filtered and washed with ethyl acetate (2 x 2.5 mL) to obtain 1.69 gm (Yield = 89.4 %) of title compound after drying.
HPLC purity: 99.94 %
MS (ESI, CH3CN/H2O): m/e = 465 [M+H]+.
Example 3: Preparation of Sorafenib base (I) using THF as solvent
Stirred solution of 4-(4-aminophenoxy)-N-methylpicolinamide (10 gm, 0.041 mole) in THF (100 mL) was heated to 40 - 45°C under inert atmosphere to get cleared solution. 4-chloro-3-trifluoromethylisocyanate (10.93, 0.049 mole) in THF (50 mL) was added in 15-20 minutes by maintaining the temperature below 50°C. The cleared solution was further heated for 5 hrs at 40 - 45°C. Progress of reaction was monitored by HPLC. After completion of the reaction, THF was evaporated under reduced pressure to get solid residual mass. The obtained crude residue was stirred with ethyl acetate (50 mL) for 1 hr at ambient temperature. Solid material was filtered and washed with ethyl acetate (2 x 25 mL) to obtain 17.8 gm (Yield = 93.2%) of title compound after drying.
HPLC purity: 99.99 %
MS (ESI, CH3CN/H2O): m/e = 465 [M+H]+.
Example 4: Preparation of Sorafenib base (I) using THF as solvent
Stirred solution of 4-(4-aminophenoxy)-N-methylpicolinamide (90 gm, 0.37 mole) in THF (900 mL) was heated to 40 - 45°C under inert atmosphere to get cleared solution. 4-chloro-3-trifluoromethylisocyanate (104.4g, 0.047 mole) in THF (450 mL) was added in 15-20 minutes by maintaining the temperature below 50°C. The cleared solution was further heated for 5 hrs at 40 - 45°C. Progress of reaction was monitored by HPLC. After completion of the reaction, THF was evaporated under reduced pressure to get solid residual mass. The obtained crude residue was stirred with ethyl acetate (450 mL) for 1 hr at ambient temperature. Solid material was filtered and washed with ethyl acetate (2 x 225 mL) to obtain 160.2 gm (Yield = 93.2%) of title compound after drying.
HPLC purity: 99.97 %, Single polymorph by DSC, m.p. = 209 0C (DSC)
1H-NMR (DMSO-d6, 500 MHz): d = 2.82 - 2.83 (d, J = 4.5 Hz, 3H), 7.15 - 7.19 (m, 3H), 7.38 - 7.39 (d, J = 2.5 Hz, 1H), 7.58 - 7.67 (m, 4H, 8.12 (d, J= 2.5 Hz, 1H ), 8.50 - 8.51 (d, J= 6 Hz, 1H), 8.75 - 8.77 (d, J= 4.5 Hz, 1H), 8.99 (s, 1H), 9.21 (s, 1H).
MS (ESI, CH3CN/H2O): m/e = 465 [M+H]+.
Example 5: Preparation Sorafenib tosylate (II)
THF (80 mL) was added to Sorafenib (10 gm, 0.021 mole) at room temperature and mixture was heated to 50 °C to get a clear solution. p- toluenesulfonic acid monohydrate (5.3 g, 0.027 mole) dissolved in THF (20 ml) was added within 10-15 min at 45- 50 °C. Reaction mass was further stirred at room temperature for 4 hrs. Obtained solid was filtered and washed with THF (2 X 25 ml). Product was further dried in oven for 5 hrs to get 11.9 gm (Yield = 86.8 %) of sorafenib tosylate salt.
HPLC purity: 99.9 %
1H-NMR (DMSO-d6, 500 MHz): d 2.289 (s, 3H), 2.79 - 2.80 (d, J = 5 Hz, 3H), 7.12 - 7.13 (d, J = 8 Hz, 2H), 7.17-7.21 (m, 3H), 7.49 - 7.51 (m, 3H), 7.59 – 7.62 (m, 3H), 7.65 - 7.68 (m, 1H), 8.12 (d, J= 2.5 Hz, 1H),8.53 – 8.54 (d, J = 6 Hz, 1H), 8.87 – 8.88 (d, J = 4.5 Hz, 1H), 9.11 (bs, 1H); 9.31 (bs, 1H).
MS (ESI, CH3CN/H2O): m/e = 465 [M+H]+ base
Example 6: Preparation Sorafenib tosylate II (one pot)
Stirred solution of 4-(4-aminophenoxy)-N-methylpicolinamide (5 gm, 0.0205 mole) in THF (50 mL) was heated to 40 - 45°C under inert atmosphere to get cleared solution. 4-chloro-3-trifluoromethylisocyanate (5.91, 0.026 mole) in THF (25 mL) was added in 15-20 minutes by maintaining the temperature below 50°C. The cleared solution was further heated for 5 hrs at 40 - 45°C. p- toluenesulfonic acid monohydrate (5.08 g, 0.0267 mole) dissolved in THF (10 ml) was added within 10-15 min at 45- 50 °C. Reaction mass was further stirred at room temperature for 4 hrs. Obtained solid was filtered and washed with THF (2 X 25 ml). Product was further dried in oven for 5 hrs to get 5.65 gm (Yield = 82.5%) of sorafenib tosylate salt.
HPLC purity: 99.9 %
Example 7 : Preparation of Imidazole Complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (V)

To a stirred solution of 4-chloro-3-(trifluoromethyl)aniline (5 g, 0.025 mole) in THF (50 mL) under nitrogen atmosphere, was added CDI (5.51 g; 0.034 mole) in portion at room temperature. The suspension was cleared over a time of period to get clear solution. The reaction mixture was stirred for 16 hours. Evaporate THF under reduced pressure to get solid mass, which was triturated with Hexane: ethyl acetate mixture (25: 5 mL respectively). The Solid was filtered and dried at room temperature to obtained 8.69 g of solid (Yield = 95 %).

Example 8: Preparation of Sorafenib base (I)

To the mixture of 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide (5 g, 0.0205 mole) and imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (7.34 g, 0.0205 mole ) was added DMF (30 mL). The mixture was stirred further at room temperature till completion of the reaction. Ethyl acetate (150 mL) was added and the mixture was washed with 1N HCl (1 X 20 mL), water (2 x 50 mL) and brine solution (1 x 30 mL). Organic layer was dried over sodium sulphate and evaporate under reduced pressure to get solid mass, which was triturated with ethyl acetate (20 mL) to get 7.6 g of sorafenib base. (Yield = 80 %)

Example 9: Preparation of Sorafenib base (I)

To the mixture of 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide (1 g, 0.0041 mole) and imidazole complex of imidazole-1-carboxylic acid 4-chloro-3-(trifluoromethyl)phenyl amide (1.47g, 0.0041 mole) was added THF-DMF mixture (5 mL : 2mL respectively). The mixture was stirred further at room temperature till completion of the reaction. Ethyl acetate (20mL) was added and the mixture was washed with 1N HCl (2 X 5 mL), water (2 x 10 mL) and brine solution (1 x 10 mL). Organic layer was dried over sodium sulphate and evaporate under reduced pressure to get solid mass, which was triturated with ethyl acetate (5 mL) to get 1.6 g of sorafenib base (Yield = 84 %).

Example 10: Preparation of Sorafenib base I (one pot)

To a stirred solution of 4-chloro-3-(trifluoromethyl) aniline (0.8 g, 0.0041 mole) in DMF (5 mL) under nitrogen atmosphere, was added CDI (0.86 g; 0.0053 mole) in portion at room temperature. The mixture was stirred at room temperature for 4 hrs and 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide (1 g, 0.0041 mole) was as such added to above mixture. After completion of reaction, mixture was quenched onto water - brine mixture (30 mL) and extracted with ethyl acetate (2 x 30 mL). Collective organic layer was washed with 1N HCl (2 x 5 mL), water (2 x 10 mL) and brine solution (1 x 10 mL). Organic layer was dried over sodium sulphate and evaporate under reduced pressure to get solid mass, which was triturated with ethyl acetate (5 mL) to get 1.7 g of sorafenib base (Yield = 89 %).
Example 5: Preparation Sorafenib tosylate (II)
Acetone (50 mL) was added to Sorafenib (5 gm, 0.0107 mole) at room temperature and mixture was heated to 45-50 °C to get a suspensioin. p- toluenesulfonic acid monohydrate (2.60 g, 0.0136 mole) dissolved in acetone (10 ml) was added within 10-15 min at 45- 50 °C. Reaction mass was further stirred at room temperature for 4 hrs. Obtained solid was filtered and washed with acetone (2 X 10 ml). Product was further dried in oven for 5 hrs to get 6.56 gm (Yield = 95.7 %) of sorafenib tosylate salt.
HPLC purity: 99.9 %