DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of vemurafenib of formula I

formula I

BACKGROUND OF THE INVENTION
Vemurafenib, chemically known as N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide OR propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4difluoro-phenyl}-amide and is is a B-Raf enzyme inhibitor.
Vemurafenib is commercially marketed by Roche under the brand name of ZELBORAF® for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation. ZELBORAF (vemurafenib) is available as 240 mg tablets for oral use.
The synthesis of the compound of formula I have been described before in US7863288 B2.
However, the known synthesis routes may not be readily adapted for use on an industrial scale.

SUMMARY OF THE INVENTION
In one aspect of the present invention encompasses an improved process for the preparation of vemurafenib of formula I.

formula I
In another aspect of the present invention encompasses novel intermediate of compound of formula II and its use in the preparation of vemurafenib, wherein protecting groups PG are selected from the group comprising but not limited to Carbobenzyloxy, p-Methoxybenzyl carbonyl , tert-Butyloxycarbonyl , 9-Fluorenylmethyloxycarbonyl, Acetyl, Benzoyl , Benzyl, Carbamate , p-Methoxybenzyl , 3,4-Dimethoxybenzyl, p-methoxyphenyl , Tosyl and Other Sulfonamides.

formula II
In another aspect of the present invention encompasses novel intermediate of compound of formula III and its use in the preparation of vemurafenib, wherein R1 is selected from the group comprising alkyl, optionally substituted alkyl, cycloalkyl, aryl and optionally substituted aryl. protecting groups PG is same as defined above.

formula III
In another aspect of the present invention encompasses an improved process for the preparation of compound of formula IV comprising reduction of compound of formula III as shown below, wherein R1 and protecting groups PG are same as defined above.

formula III formula IV

In another aspect of the present invention encompasses an improved process for the preparation of vemurafenib Form-II.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention an improved process for the preparation of vemurafenib of formula I.

formula I
In another embodiment of the present invention encompasses an improved process for the preparation of vemurafenib of formula I comprising the steps;
a. direct carbonylation of compound of formula II’ in the presence of suitable base and suitable solvent to obtain compound formula II,
b. esterification of compound of formula II in the presence of suitable base and suitable solvent to obtain compound of formula III,
c. reduction of compound of formula III to obtain compound of formula IV,
d. alkylation of compound of formula IV with propane sulfonyl chloride in the presence of base and solvent to obtain compound of formula V,
e. hydrolysis of compound of formula V to obtain 2,6-difluoro-3-[(propylsulfonyl)amino]benzoic acid of formula VI,
f. chlorination of 2,6-difluoro-3-[(propylsulfonyl)amino]benzoic acid of formula VI in the presence of chlorinating agent and solvent to obtain 2,6-difluoro-3-[(propylsulfonyl)amino]benzoyl chloride of formula VII,
g. condensation of 2,6-difluoro-3-[(propylsulfonyl)amino]benzoyl chloride of formula VII with 5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine to obtain Vemurafenib of formula I.
In another embodiment of the present invention encompasses an improved process for the preparation of vemurafenib of Formula I comprising the steps;
a. direct carbonylation ofcompound of formula II’ in the presence of n-Butyllithium in THF and carbondioxide or dry ice to obtain compound of formula II,
b. esterification of compound of formula II in the presence of Oxalyl chloride, methanol and methylene chloride to obtain compound of formula III,
c. reduction of compound of formula III in the presence of Pd/C and methanol to obtain compound of formula IV,
d. alkylation of compound of formula IV with propane sulfonyl chloride in the presence of pyridine and MDC to obtain compound of formula V,
e. hydrolysis of compound of formula V in the presence of NaOH and methanol to obtain 2,6-difluoro-3-[(propylsulfonyl)amino]benzoic acid of formula VI,
f. chlorination of 2,6-difluoro-3-[(propylsulfonyl)amino]benzoic acid of formula VI in the presence of oxalyl chloride, MDC and DMF to obtain 2,6-difluoro-3-[(propylsulfonyl)amino]benzoyl chloride of formula VII,
g. condensation of 2,6-difluoro-3-[(propylsulfonyl)amino]benzoyl chloride of formula VII with 5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine in the presence of AlCl3 and MDC to obtain Vemurafenib of formula I.
In another embodiment of the present invention encompasses an improved process comprising direct carbonylation of compound of formula II’ in the presence of suitable base and suitable solvent to obtain compound of formula II. wherein PG is same as defined above.

formula II’ formula II
In another embodiment of the present invention encompasses an improved process comprising direct carbonylation of compound of formula II’ in the presence of n-Butyllithium, THF and carbondioxide to obtain compound of formula II.
In another embodiment of the present invention encompasses an improved process comprising esterification of compound of formula II in the presence of suitable base and suitable solvent to obtain compound of formula III. wherein PG and R are same as defined above.

formula II formula III
In another embodiment of the present invention encompasses an improved process comprising esterification of compound of formula II in the presence of Oxalyl chloride, methanol and methylene chloride to obtain compound of formula III.
In another embodiment of the present invention encompasses an improved process for the preparation of compound of formula IV comprising reduction of compound of formula III as below.

formula III formula IV
In another embodiment of the present invention encompasses an improved process for the preparation of compound of formula IV comprising reduction of compound of formula III in the presence of Pd/C and methanol.
In another aspect of the present invention encompasses novel intermediate of compound of Formula II and its use in the preparation of vemurafenib.

formula II
In another aspect of the present invention encompasses novel intermediate of compound of Formula III and its use in the preparation of vemurafenib.

formula III
In another aspect of the present invention encompasses an improved process for the preparation of vemurafenib Form-II comprising the steps of;
1. providing a solution of Vemurafenib in solvent,
2. filtering the reaction mixture,
3. cooling the reaction mixture to obtain vemurafenib Form-II.

The term "solvent" includes any solvent or solvent mixture, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The solvent may be selected from the group consisting of water, alkanols, esters, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms.
Suitable alkanol solvents include methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG and butanol. Examples of ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include tetrahydrofuran and the like. A suitable polar aprotic solvent includes N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. A solvent may also preferably be 1,1,3,3-tetramethylurea, Benzotrifluoride.

The present invention is depicted in the scheme as below:

The term "solvent" includes any solvent or solvent mixture, for example, water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.
The solvent may be selected from the group consisting of water, alkanols, esters, ketones, ethers, polar aprotic solvents, or mixtures thereof. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms.
Suitable alkanol solvents include methanol, ethanol, n-propanol, 2-propanol, ethylene glycol, PEG and butanol. Examples of ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include tetrahydrofuran and the like. A suitable polar aprotic solvent includes N,N-dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. A solvent may preferably be a mixture of water with alkanol, for example, a mixture of water with methanol, ethanol, or 2-propanol.
Suitable base includes but not limited to an inorganic base or organic base selected from the group comprising of carbonates, bicarbonates, hydroxides, hydrides and alkoxides of alkali or alkaline earth metals and the like, phosphates such as dipotassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, diammonium monohydrogen phosphate, ammonium dihydrogen phosphate and triammonium phosphate; acetates such as potassium acetate, sodium acetate and ammonium acetate; formates such as potassium formate and sodium formate; n-butyllithium, n-hexyllithium, sodium hydride and , HMDS, lithium diisopropylamide. These inorganic bases may be used singly, or in combination of two or more kinds thereof. The organic base is selected from the group comprising of lutidine, diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n-propylamine, tri-n-butylamine, piperidine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N,N-diethylaniline, N-ethyl-N-methylaniline, diisopropylethylamine, 3-methylimidazole, 1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine; and metal alcoholates such as sodium methoxide and sodium ethoxide. Other bases are known to the person skilled in the art.
Suitable protecting groups PG are selected from but not limited to Carbobenzyloxy, p-Methoxybenzyl carbonyl , tert-Butyloxycarbonyl , 9-Fluorenylmethyloxycarbonyl, Acetyl, Benzoyl , Benzyl, Carbamate , p-Methoxybenzyl , 3,4-Dimethoxybenzyl, p-methoxyphenyl , Tosyl and Other Sulfonamides
Suitable reducing agents are selected from but not limited to palladium, platinum, Raney Nickel, Rhodium. Other reducing agents known to the person skilled in the art.
In the following section, embodiments are described by way of examples to illustrate the process of invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.

Example-1
Preparation of N,N-dibenzyl-2,4-difluoroaniline
To a stirred solution of 2, 4-difluoroaniline (100.0 g, 0.775 moles) in DMF (1.0 lit) was charged N, N-diisopropylethylamine (350 g, 2.710 moles) at 25-30°C. To this solution was added benzyl bromide (331.17 g, 1.936 moles) at 25-30°C. The reaction mixture was heated to 80-85°C for 3 hrs. After cooling the reaction mixture to 25-30°C, water was charged into the reaction mixture. The product was extracted with toluene, concentrated under reduced pressure and isolated by 5 % water in methanol to get the 203 g (85% yield) of the title compound.

Example-2
Preparation of 3-(Dibenzylamino)-2,6-difluorobenzoic acid
To a chilled THF at -80° was added 2.5 M n-butyllithium in hexane (420 mL, 0.421 moles) at -80°C to -70°C under nitrogen atmosphere. The solution of N,N-dibenzyl-2,4-difluoroaniline (100.0 g, 0.324 moles) in THF was added into THF at -80°C to -70°C. Stir the reaction mixture for 1 hour at -80°C to -70°C. Carbon dioxide gas was purged into reaction mass at -80° to -70°C. Reaction completion was monitored by TLC. The reaction mass was quenched by adding 10 % aqueous HCl at temperature below -50°C. The reaction mass was allowed to come to room temperature. Concentrated the reaction mass under reduced pressure and filtered the reaction mass. Dried the product at 50-55°C under reduced pressure to get 110 g (96% yield) of the title compound.

Example-3
Preparation of Methyl 3-(dibenzylamino)-2,6-difluorobenzoate
To a stirred solution of 3-(1, 3-diphenylpropan-2-yl)-2, 6-difluorobenzoic acid (100 g, 0.283 moles) in MDC (1.0 lit.) was added oxalyl chloride (53.94 g, 0.425 moles) at 25-30°C. Stirred the reaction mass for 3 hrs. The reaction mass was quenched by adding methanol (500 mL) and further stirred for 1 hour at 25-30°C. Concentrated the reaction mass under reduced pressure and the product was isolated by adding 50% toluene in n-Heptane (500 mL). Dried the product under reduced pressure at 50-55°C to get the 93 g (90% yield) of title compound.

Example-4
Preparation of 2,6-Difluoro-3-[(propylsulfonyl)amino]benzoic acid
The solution of methyl 3-(dibenzylamino)-2,6-difluorobenzoate (100.0g, 0.272 moles) in methanol was hydrogenated by using 10 % palladium on carbon (10 g) at 4-5 Kg/cm2 hydrogen pressure for 3 hrs. Filtered the reaction mixture through celite bed. The filterate was concentrated under reduced pressure. Charged MDC (500 mL) into the residual mass at 25-30°C. Charged pyridine (43 g, 0.544 moles) followed by 1-Propanesulfonyl chloride (46.57 g, 0.327 moles) into the reaction mass at 25-30°C. The reaction mass was stirred at 25-30°C for 16 hours at 25-30°C. The reaction mass after aqueous work up was concentrated atmospherically. To the residual product was charged 5 % aqueous methanol (550 mL) at 25-30°C. Charged sodium hydroxide (21.78 g, 0.544 moles) into the reaction mass. The reaction mass was stirred at 55°C for 3 hrs. After cooling the reaction mass to 25-30°C, pH of the reaction mass was adjusted to 2.5 by Conc. HCl solution. Stirred the reaction mass for 1 hour at 25°C. The reaction mass was filtered. Dried the solid at 55°C under reduced pressure to get (64 g, 84% yield) of the title compound.

Example-5
Preparation of Vemurafenib
To a stirred solution of 2, 6-difluoro-3-[(propylsulfonyl)amino]benzoic acid (100.0 g, 0.358 moles) in MDC was charged N,N-dimethylformamide (2.88 g, 0.039 moles). Added oxalyl chloride (50 g, 0.394 moles) into the reaction mass within 1 hr at 20-25°C. Reaction mixture stirred for 3 hours at 20-25°C. In another reaction flask, aluminium chloride (190.5 g, 1.432 moles) was charged into a chilled MDC (200 mL). The slurry was stirred at 0-5°C for 30 minutes. After heating the slurry to 20°C, the slurry of 5-(4-chlorophenyl)-1H-pyrrolo [2,3-b] pyridine (73.62 g, 0.322 moles) in MDC was added at 20-25°C. To this resultant reaction mass was added acid chloride solution prepared above at 20-25°C. Stirred the reaction mass at 20-25°C for 3 hours. The reaction mass was quenched in ice. MDC was distilled out atmospherically from the reaction mass. The reaction mass was extracted in ethyl acetate and THF at 50°C. The solvents were distilled off under reduced pressure and the residual product was crystallized from THF and n-heptane to get 105 g (60% yield) of Vemurafenib.

Example-6
Preparation of 5-(4-Chlorophenyl)-1H-pyrrolo[2, 3-b]pyridine
To a stirred solution of 5-Bromo-7-azaindole (100g, 0.508 moles) in acetonitrile and water was charged 4-chlorophenylboronic acid (95.22 g, 0.609 moles), potassium carbonate (210.31 g, 1.524 moles) and Tetrakis(triphenylphosphine)palladium(0)(17.6 g) at 25-30°C. The reaction mass was heated for 6 hours at 80-85°C. Cooled the reaction mass to 25-30°C. The pH of the reaction mass was adjusted to 1.0 by Conc.HCl solution and reaction mass was extracted with ethyl acetate. Concentrated the organic layer under reduced pressure. The residual mass was treated with n-heptane at 25°C. Filtered the reaction mass. Dried the solid at 55°C under reduced pressure to get 92 g (79% yield) of title compound.

Example-7
Preparation of 5-(4-Chlorophenyl)-1H-pyrrolo[2, 3-b]pyridine
To a stirred mixture of 5-Bromo-7-azaindole (100g, 0.508 moles) in acetonitrile and water was charged 4-chlorophenylboronic acid (95.22 g, 0.609 moles), potassium carbonate (210.31 g, 1.524 moles) and palladium acetate (5.70 g) at 25-30°C. The reaction mass was heated for 6 hrs at 82°C. Cooled the reaction mass to 25-30°C. The pH of the reaction mass was adjusted to 1.0 by Conc.HCl solution and reaction mass was extracted with ethyl acetate. Concentrated the reaction mass under reduced pressure. The residual mass was treated with n-heptane at 25°C. Filtered the reaction mass. Dried the solid at 55°C under reduced pressure to get 92 g (79% yield) of title compound.

Example-8
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (3.0 g) and 1,4-Dioxane (36 mL) was heated to 95°C to get the clear solution. After filtering the reaction mixture through celite bed, the reaction mixture was cooled to 25°C from 95°C.The reaction mixture was stirred at RT for 12 hrs. The separated material was filtered and washed with 1, 4-Dioxane. The material was dried at 50°C under reduced pressure to get 1.56 g of Vemurafenib Form-II.

Example-9
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (1.0 g) and methanol (500 mL) was heated to 65°C to get the clear solution. After getting the clear solution, the solvent was distilled off under reduced pressure upto haziness. The reaction mixture was cooled to RT. Stirred the reaction mixture for 2 hrs at 25-30°C. The reaction mixture was filtered and washed the wet material with methanol. The material was dried at 50°C under reduced pressure to get 0.9 g of Vemurafenib Form-II.

Example-10
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) was dissolved in 1,1,3,3-tetramethylurea (6.0 mL) at RT. Water (30.0 ml) was added into the reaction mixture at RT. The reaction mixture was stirred at RT for 2 hrs. The separated solid was filtered and washed with water. The material was dried at 40°C for 6 hrs to get 1.67 g of Vemurafenib Form-II.

Example-11
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) was dissolved in 1,1,3,3-tetramethylurea (6.0 mL) at 25-30°C. The solution was added into water (30 mL) at RT. The reaction mixture was stirred at RT for 2 hrs. The separated solid was filtered and the wet material was washed with water. The material was dried at 40°C for 6 hrs to get 1.71 g of Vemurafenib Form-II.

Example-12
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) was dissolved in N-methyl-2-pyrolidinone (6.0 mL) at 25-30°C. Water (30.0 ml) was added into the reaction mixture at RT. The reaction mixture was stirred at RT for 2 hrs. The separated solid was filtered and the wet material was washed with water. The material was dried at 40°C for 6 hrs to get 1.67 g of Vemurafenib Form-II.

Example-13
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) was dissolved in N-methyl-2-pyrolidinone (6.0 mL) at 25-30°C. The solution was added into water (30 mL) at RT. The reaction mixture was stirred at RT for 2 hrs. The separated solid was filtered and washed with water. The material was dried at 40°C for 6 hrs to get 1.65 g of Vemurafenib Form-II.

Example-14
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) and ethanol (20 mL) was heated to 75°C. Added 1,1,3,3-tetramethylurea into the reaction mass upto clear solution observed. Into the reaction mass water (10 mL) was added at 75°C.The reaction mass was cooled to 25-30°C. Stirred the reaction mass at 25-30°C for 2 hrs. The separated solid was filtered washed with water. The material was dried at 40°C for 6 hrs to get 1.70 g of Vemurafenib Form-II.

Example-15
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g), acetone (9.2 mL) and absolute ethanol (4.6 mL) was heated to 75°C. Into the reaction mass, it was added 1,1,3,3,-tetramethylurea (10 mL) at 75°C to get the clear solution. Water (7.0 mL) was added into reaction mass at 75°C. The reaction mixture was cooled to RT. The reaction mixture was stirred at RT for 3 hrs. The separated solid was filtered and washed with water. The material was dried at 40°C for 6 hrs to get 1.72 g of Vemurafenib Form-II.

Example-16
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (3.0 g) and 20 % methanol in MDC (45 mL) was heated to 40°C. Further methanol (15 mL) and MDC (15 mL) was charged into the reaction mixture at 40°C. The reaction mixture was stirred for 30 minutes at 40°C. The reaction mixture was cooled to 0-5°C. Stirred the reaction mixture for 1 hr at 0-5°C. The separated solid was filtered washed with MDC and methanol mixture. The material was dried at 55°C for 8 hrs to get 2.0 g of Vemurafenib Form-II.
Example: 17
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (1.0 g) and ethyl acetate (300 mL) was heated to 75°C to get the clear solution. The reaction mixture was concentrated under reduced pressure upto hazy reaction mass. The reaction mixture was cooled to RT. The reaction mixture was stirred for 2 hrs at RT. The separated solid was filtered and washed with ethyl acetate. The material was dried at 50°C for 8 hrs to get 0.56 g of Vemurafenib Form-II.

Example-18
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) and acetone (240 mL) was heated to 62°C. The reaction mass was stirred for 30 mins at 62°C. The reaction mixture was cooled to 5°C. The reaction mixture was allowed to come to RT. Stirred the reaction mixture for 14 hrs at 25-30°C. The reaction mixture was concentrated under reduced pressure. Cooled the reaction mixture to RT. The reaction mixture was stirred for 3 hrs at RT. The separated solid was filtered and washed with acetone. The material was dried at 30°C for 6 hrs to get 1.56 g of Vemurafenib Form-II.

Example-19
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) and Benzotrifluoride (310 mL) was heated to 110°C. The reaction mixture was stirred for 2 hrs at 110°C.The reaction mixture was cooled to RT. The reaction mixture was stirred for 2 hrs at RT. The separated solid was filtered and washed with Benzo trifluoride. The material was dried at 50°C for 6 hrs to get 1.62 g of Vemurafenib Form-II.

Example-20
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) and ethanol (400 mL) was heated to 78°C. The reaction mixture was stirred for 1 hrs at 78°C.The reaction mixture was filtered through celite bed and allowed to come to RT from 78°C. The reaction mixture was stirred for 4 hrs at RT. The separated solid was filtered and washed with ethanol. The material was dried at 50°C for 6 hrs to get 1.15 g of Vemurafenib Form-II.

Example-21
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) and isopropyl alcohol (400 mL) was heated to 84°C. The reaction mixture was stirred for 30 mins at 84°C.The reaction mixture was filtered through celite bed and allowed to come to RT from 84°C. The reaction mixture was stirred for 4 hrs at RT. The separated solid was filtered and washed with isopropyl alcohol. The material was dried at 50°C for 6 hrs to get 0.58 g of Vemurafenib Form-II.

Example-22
PREPARATION OF VEMURAFENIB FROM-II
Vemurafenib crude (2.0 g) and ethyl acetate (14 mL) was heated to 75°C. Added 1,1,3,3-tetramethylurea (8.0 mL) into the reaction mass to get the clear solution. Into the reaction mass water (7 mL) was added at 75°C.The reaction mass was cooled to RT. The reaction mixture was stirred at RT for 2 hrs. The separated solid was filtered washed with water. The material was dried at 50°C for 6 hrs to get 1.01 g of Vemurafenib Form-II.
,CLAIMS:Claims:
1. A process for the preparation of vemurafenib of formula I

formula I

comprising the steps of;
a. direct carbonylation of compound of formula II’ in the presence of suitable base and suitable solvent to obtain compound formula II,
b. esterification of compound of formula II in the presence of suitable base and suitable solvent to obtain compound of formula III,
c. reduction of compound of formula III to obtain compound of formula IV,
d. alkylation of compound of formula IV with propane sulfonyl chloride in the presence of base and solvent to obtain compound of formula V,
e. hydrolysis of compound of formula V to obtain compound of formula VI,
f. chlorination of compound of formula VI in the presence of chlorinating agent and solvent to obtain compound of formula VII,
g. condensation of compound of formula VII with 5-(4-chlorophenyl)-1H-pyrrolo[2, 3-b]pyridine to obtain Vemurafenib of formula I.

2. A process for the preparation of compound of formula IV

formula IV
comprising the steps of;
a. direct carbonylation of compound of formula II’ in the presence of suitable base and suitable solvent to obtain compound formula II,
b. esterification of compound of formula II in the presence of suitable base and suitable solvent to obtain compound of formula III,
c. reduction of compound of formula III to obtain compound of formula IV.

3. A novel intermediate of compound of Formula II and its use in the preparation of vemurafenib.

formula II

4. A novel intermediate of compound of Formula III and its use in the preparation of vemurafenib.

formula III

5. A process for the preparation of vemurafenib according to claim 1,2,3 and 4 wherein;
suitable protecting groups pg are selected from carbobenzyloxy, p- methoxybenzyl carbonyl , tert-butyloxycarbonyl , 9- fluorenylmethyloxycarbonyl, acetyl, benzoyl , benzyl, carbamate , p- methoxybenzyl , 3,4-dimethoxybenzyl, p-methoxyphenyl , tosyl and other sulfonamides;
and R1 is selected from the group comprising alkyl, optionally substituted alkyl, cycloalkyl, aryl and optionally substituted aryl.

6. A process for the preparation of vemurafenib according to claim 1 and 2, wherein the suitable base are selected from the group comprising of carbonates, bicarbonates, hydroxides, hydrides and alkoxides of alkali or alkaline earth metals, phosphates, acetates, formates, n-butyllithium, n-hexyllithium, sodium hydride ,HMDS, lithium diisopropylamide, lutidine, diisopropylethylamine, dimethylaminopyridine, triethylamine, tri-n- propylamine, tri-n-butylamine, piperidine, pyridine, 2-picoline, 3-picoline, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine, N,N-diethylaniline, N-ethyl-N-methylaniline, diisopropylethylamine, 3-methylimidazole, 1,8- diazabicyclo[5.4.0]- 7-undecene, 1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine and metal alcoholates.

7. A process for the preparation of vemurafenib according to claim 1 and 2, wherein the suitable solvents are selected from the group comprising of alcohols, esters, ketones, ethers, N,N-dimethylformamide, ?,?- dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone and halogenated hydrocarbons.

8. A process for the preparation of vemurafenib according to claim 1 and 2, wherein the suitable reducing agents are selected from the group comprising palladium, platinum, raney Nickel, rhodium.

9. A process for the preparation of vemurafenib Form-II comprising the steps of;
1. providing a solution of Vemurafenib in solvent,
2. filtering the reaction mixture,
3. cooling the reaction mixture to obtain vemurafenib Form-II.

10. A process for the preparation of vemurafenib Form-II according to claim 9, wherein the solvent are selected from the group comprising of water, alcohols, esters, ketones, ethers, halogenated hydrocarbons, N,N- dimethylformamide, ?,?-dimethylacetamide, dimethylsulphoxide, acetonitrile, N-methylpyrrolidone, 1,1,3,3-tetramethylurea, benzotrifluoride, 1,4-Dioxane and N-methyl-2- pyrolidinone.

Dated this 03th day of Feb, 2016

Ananda Babu Thirunavakarasu