Field of the Invention:

The present invention relates to a novel process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[253-b]pyridine-3-carbonyl]-2,4-difluoro-5 phenyl}-amide compound of formula-1, represented by the;follo^ying structure:

Formula-1

The present invention also relates to novel intermediate compounds which are useful in the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-10 b]pyridine-3-carbonyl]-254-difluoro-phenyl}-amide compound of formula-1.

Background of the Invention:

Propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1 is commonly known as 15 Vemurafenib.

Vemurafenib is a BRAF kinase inhibitor, which is marketed under the trade name
ZELBORAF for the treatment of patients with metastatic melanoma with the BRAF V600E
Mutation . Vemurafenib the first oral BRAF inhibitor was approved in 2011 by the U.S Food
And Drug Administration (FDA) for the first-line, treatment of patients with unresectable or
20 metastatic melanoma with BRAFV600E mutation. Vemurafenib is not indicated for people
with wild-type BRAF melanoma Vemurafenib and process for its preparation was first disclosed in US 7,863,288 B2 (herein after referred as "US 288").

The said "US 288" patent discloses the process for the preparation of propane-1-25 sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro- phenyl}-amide compound of formula-1 comprising ;of reacting N-(3-(5-bromo-lH- pyirolo[23-b]pyridine-3-carbonyl)-2,4-difluoro^ with 4-chloro phenylboronic acid in a microwave instrument at elevated temperatures in the presence of tetrakis(triphenylphosphine)palladium and potassium carbonate to provide compound of

formula-1, which is schematically represented as below:.

5 Scheme-I:

Formula-1

"US 288" patent also discloses another process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[253-b]pyridihe-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1, comprising of reacting 5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine with N-(2,4-difluoro-3-formylphenyl)propane-l-sulfonamide in the presence of a base in a solvent to provide compound of formula-1 which is schematically represented as below:
Scheme-II:
The above said processes suffers from several drawbacks such as low yields and low purities, and further the desired compound of formula-1 was isolated using column chromatography which is tedious and time consuming, hence these processes are not suitable for commercial scale.

Therefore there is a need in the art for an improved, economical viable and efficient process that provides propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1 with enhanced yields and high purity.

Brief description of the Invention:

The first aspect of the present invention is to provide a novel process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-6.

The third aspect of the present invention relates to noyel (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-6.

The fourth aspect of the present invention relates to novel N-protected (5-(4- chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of general formula-7.

The fifth aspect of the present invention is to provide novel process for the preparation of N-protected (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro- 3-nitrophenyl)methanone compound of general formula-7.

The sixth aspect of the present invention is to provide a process for the preparation of N-protected (3-amino-256-difluorophenyl)(5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3- yl)methanone compound of general formula-8.

Detailed description of the Invention:

The present invention relates to novel process for the preparation of propane-1- sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1 and further the present invention also relates to novel intermediate compounds which are useful in the preparation of compound of formula-1.

The term "suitable solvent" used in the present linvention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, pentane, cycloheptane, methyl cyclohexane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofiiran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy
ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethyl formamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichlorqethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone ' and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2- trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.

The term "suitable base" used herein the present invention until unless specified is selected from inorganic bases like "alkali metal hydroxides" such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; "alkali< metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide,' potassium tert-butoxide and the like; ammonia, methanolic ammonia; and organic bases such as triethyl amine, methyl amine, ethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo(4.3.0)non- 5-ene (DBN), lithium dioisoporpylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

The suitable "hydrochloric acid source" is selected from HC1 gas, aqueous HC1, dry HC1, ethyl acetate-HCl, IPA-HC1, ethanol-HCl, methanol-HCl.
The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 4d. Ed., Wiley & Sons, 2007, which is incorporated herein by reference in its entirety.

As used herein the term "Pg" in the entire document of the present invention is referred to as suitable amino protecting group.

According to some embodiments, the amino protecting group. "Pg" is benzyloxy carbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc),: 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylphenylsulfonyl) ethoxycarbonyl (Tsc), t-butoxy carbonyl (BOC), 1-adamantyl oxycarbonyl, (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yl oxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1 -dimethyl-2,2,2-trichloroethoxy carbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2~nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridyl methyl, N',N'-dimethylhydrazinyl, methoxy methyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP), l-(ethoxy) ethyl, p-methoxy benzyl, triphenylmethyl, diphenylmethyl, hydroxymethyl, methoxymethyl, and t-butyldimethylsilylmethyl, N-pivaloyloxymethyl (POM), 1,1-diethoxymethyl, tri(C 1 -4-alkyl)silyl, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, 9-Fluorenylmethyloxy carbonyl (FMOC) group, Acetyl (Ac) group, Benzoyl (Bz) group, C1-C6 alkoxy substituted benzoyl group, Benzyl (Bn) group, p-methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM).

According to some embodiments, the amino protecting group "Pg" is selected from -C(0)OCi-C6 alkyl, such as, for example, carboethoxy, carbomethoxy and t-butoxycarbonyl; optionally substituted -C(0)OCrC6 aryl, such as, for example, benzyloxy-carbonyl and p-methoxybenzyloxycarbonyl; optionally substituted -C1-C12 aryl(Ci-C3)alkyl such as, for example, benzyl, phenethyl, p-methoxy benzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl and 9-fluorenylmethyl; optionally substituted C7-C11 aryl carbonyl, such as, for example, benzoyl; C1-C6 alkanoyl, such as, for example, formyl, acetyl, and propionyl; C1-C6 alkylsulfonyl, such as, for example, mesyl.

According to some embodiments, the amino protecting group "Pg" is selected from optionally substituted phenylsulfonyl, such as, for example, benzenesulfonyl, toluenesulfonyl (tosyl) and 3-nitrobenzenesulfonyl; -Ci-Ce alkylcarbamoyl, such as for example dimethyl carbamoyl; and optionally substituted -C7-C10 arylalkyl carbamoyl, such as, for example, benzyl carbamoyl.

As used herein the term suitable "chlorinating agent" include but are not limited to chlorine, oxalyl chloride, sulfuryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, pivaloyl chldride, antimony pentachloride, iodine trichloride, sulfur dichloride, disulfur dichloride, manganese tetrachloride and the like.

As used herein the term suitable "lewi's acid" is selected from aluminium chloride, boron trichloride, ferric chloride, tin tetrachloride, stibium pentachloride and TiCU.

As used herein the term suitable "reducing agent" is selected from Fe, Fe in acidic media like NH4CI or HC1 or acetic acid, Sn in acidic media like HC1, Zn dust, Zn in acidic media like HC1 or NH4CI or acetic acid, stannous chloride (SnCh), NaBFLi, LIAIH4, UBH4, diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Pd/C, Pt/C, PtC>2, Pd(OH)2, Raney nickel, Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate such as sodium dithionite and sodium amalgam.

The first aspect of the present invention provides a novel process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-254-difluoro-phenyl}-amide compound of-formula-1, comprising of the following steps:

a) Reacting 5-bromo-lH-pyrrolo[2,3-b]pyridine compound of formula-2 with 4-chloro phenylboronic acid compound of formula-3 in presence of tetrakis(triphenylphosphine) palladium and a suitable base in a suitable solvent to provide 5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine compound of formula-4, ' ;

b) optionally, purifying the compound of formula-4 using a suitable solvent,

c) reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-10 with chlorinating agent in a suitable solvent to provide 2,6-difluoro-3-nitrobenzoyl chloride compound of formula-5, which further reacts with compound of formula-4 in presence of lewi's acid in a suitable solvent to provide (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitro phenyl)methanone compound of formula-6,

d) reacting the compound of formula-6 with a suitable amine protecting group in presence of a suitable base and a suitable catalyst in a suitable solvent to provide N-protected (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of general formula-7,

e) reducing the nitro group of compound of general formula-7 with a suitable reducing agent in a suitable solvent to provide N-protected (3-amino-2,6-difluorophenyl)(5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)methanone compound of general formula-8,
f) optionally, purifying the compound of general formula-8 using a suitable solvent,
g) reacting the compound of general formula-8 with propane- 1-sulfonyl chloride in presence of a suitable base in a suitable catalyst in a suitable solvent to provide N-protected N-(3-(5-(4-chlorophenyl)-lH-pyrrolo[253-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane- 1-sulfonamide compound of general formula-9,

h) treating the compound of general formula-9 with a suitable base in a suitable solvent to provide propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1.

Wherein, in step-a), d), g), and h) the suitable base is selected from organic or inorganic base; in step-c) the suitable chlorinating agent is selected from chlorine, oxalyl chloride, sulfuryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, pivaloyl chloride, antimony pentachloride, iodine trichloride, sulfur dichloride, disulfur dichloride, manganese tetrachloride and the like; and suitable lewis acid is selected from aluminium chloride, Boron trifluoride, boron trichloride, ferric chloride, tin tetrachloride, stibium penta chloride, AsFs, ASF3, and TiCU; in step-d) the suitable amino protecting group is same as defined above; in step-e) the suitable reducing agent is selected from Fe, Fe in acidic media like NH4CI or HC1 or acetic acid, Sn in acidic media like HC1, Zn dust, Zn in acidic media like HC1 or NH4CI or acetic acid, stannous chloride (SnCfe), NaBFLj,' UAIH4, LiBH*, diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Pd/C, Pt/C, PtCh, Pd(OH)2, Nickel, Raney nickel, Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate such as sodium dithionite and sodium amalgam; in step-d) and g) the suitable catalyst is dimethyl amino pyridine; in step-a) to h) the suitable solvent is selected from alcohol solvents, chloro solvents, ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture thereof.

The preferred embodiment of the present invention provides a novel process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1, comprising of the following steps:

a) Reacting 5-bromo-lH-pyrrolo[2,3-b]pyridine compound of formula-2 with 4-chloro phenylboronic acid compound of formula-3 in presence of tetrakis(triphenylphosphine) palladium and potassium carbonate in a mixture of 1,4-dioxane and water to provide 5-(4-chlorophenyl)-lH-pyrrolo [2,3-b]pyridine compound of formula-4,

b)purifying the compound of formula-4 using a mixture of methyl tertiary butyl ether and cyclohexane, ,
c) reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-10 with oxalyl chloride in presence of a mixture of dichloromethane and dimethyl formamide to provide 2,6-difluoro-3-nitrobenzoyl chloride compound of formula-5, which further reacts with compound of formula-4 in presence of aluminium chloride in dichloromethane to provide (5-(4-chlorophenyl)-lH-pyn,olo[23-b]pyridin-3-yl)(256-diflu6ro-3^nitrophenyl) methanone compound of formula-6,

d)reacting the compound of formula-6 with 2,6-dimethoxy benzoyl chloride in presence of diisopropyl ethylamine and dimethyl amino pyridine in a mixture of dichloromethane and toluene to provide (5-(4-chlorophenyl)-l-(2,6-dim'ethoxybenzoyl)-lH-pyrrolo[2,3-b] pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-7a,

e) reducing the nitro group of compound of formula-7a with sodium dithionite in a mixture of water and tetrahydrofuran to provide (3-(3-amino-2,6-difluorobenzpyl)-5-(4-chloro phenyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)(2J6-dimethoxyphenyl)methanone compound of formula-8a,

f) purifying the compound of formula-8a using a mixture of ethyl acetate and cyclohexane,

g) reacting the compound of formula-8a with propane-1-sulfonyl chloride in presence of pyridine and dimethyl amino pyridine in 1,4-dioxane to provide N-(3-(5-(4-chloro phenyl)- l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro phenyl)propane-l-sulfonamide compound of formula-9a,

h) treating the compound of formula-9a with methanolic ammonia in dimethyl acetamide to provide propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1.

US7863288 B2 patent discloses the process for the preparation of propane-1-sulfonic acid {3-[5-(4-cWorophenyl)-lH-pyrrolo[2s3-b]pyridine-3-carbonyl]-2J4-difluoro-phenyl}-amide compound of formula-1 by reacting N-(3-(5-bromo-lH-pyrrolo[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide with; 4-chlorophenylbQronic acid in a microwave instrument at elevated temperatures.

When the same reaction was carried out, it was found that formation of impurities is more rather than the formation of desired compound of formula-1. Such formation of impurities would demand the process to undergo exhaustive purifications which is tedious, time consuming and increases the cost of production, hence it is not suitable for the commercial scale.

Moreover conducting the reactions on microwave is a critical job to perform and further not suitable for commercial scale-up.

The present inventors have identified the following potential impurities which are formed in the prior art process. And these impurities are not been reduced to not detectable levels to meet the ICH quality. The impurities are as follows
"US 288" patent also discloses another process for the preparation of propane-1- sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrTolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1, comprising of reacting 5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine with N-(234-difluoro-3-formylphenyl)propane-l-sulfonamide in the presence of a base in a solvent and subsequently undergoes further reactions to provide compound of formula-1.

When the same reaction was carried out, it has been observed that the reaction was incomplete and requires more time to complete, which leads to the formation of impurities and undesired byproducts in the reaction thereby decreased the yield and purity of the desired compound of formula-1.

The present process over comes the difficulties associated with the prior art processes by proceeding through the novel intermediates. The formation1 of the above said potential impurities are avoided and are observed to not detectable levels. Hence, the present process is more advantageous when compared to the prior art processes.

It is known that synthetic compounds can contain • extraneous : compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself, or during the preparation of the API. Impurities in Vemurafenib or any active pharmaceutical ingredient (API) are undesirable and might be harmful, as they would be carried over to pharmaceutical compositions, used for human consumption.

The second aspect of the present invention provides a process for the preparation of (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-6, comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-10 with a suitable chlorinating agent in a suitable solvent to provide 2,6-difluoro-3-nitrobenzoyl chloride compound of formula-5, which further reacts with compound of formula-4 in presence of Lewi's acid in a suitable solvent to provide (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-6.

Wherein, the suitable chlorinating agent, lewi's acid and |solvent are same as defined in step-c) of the first aspect of the present invention.

The preferred embodiment of the present invention provides a process for the preparation of (5-(4-cMorophenyl)-lH-pyrTolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitro phenyl)methanone compound of formula-6, comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-10 with oxalyl chloride in presence of a mixture of dichloromethane and dimethyl formamide to provide 2,6-difluoro-3-nitrobenzoyl chloride compound of formula-5, which further reacts with compound of formula-4 in presence of aluminium chloride in dichloromethane to provide (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-6.

The third aspect of the present invention relates to novel (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(256-difluoro-3-nitrophenyl)methanone compound of formula-6.
Formula-6
The fourth aspect of the present invention relates to novel N-protected (5-(4-cWorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone 0 compound of general formula-7.
Formula-7 Wherein "Pg" is a suitable amino protecting group
Novel intermediate compound of formula-6 and general formula-7 of the present 5 invention are useful in the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-
pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1.
i
The fifth aspect of the present invention provides process a process for the preparation of N-protected (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-0 3-nitrophenyl)methanone compound of general formula-7, comprising of reacting (5-(4-chlorophenyl)-lH-pyrrolo[233-b]pyridin-3-yl)(2,6-difluoro-^3-nitrophenyl)methanone

compound of formula-6 with a suitable amino protecting group in presence of a suitable base and suitable catalyst in a suitable solvent to provide compound of general formula-7.

Wherein, the suitable amino protecting group is same as defined above; and suitable base, suitable catalyst, suitable solvent is same as defined in the step-d) of the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of (5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridin-3-yl) (2,6-difluoro-3-nitrophenyl) methanone compound of formula-7a, comprising of reacting the compound of formula-6 with 2,6-dimethoxy benzoyl chloride! in presence of diisopropyl ethylamine and dimethyl amino pyridine in a mixture of dichloromethane and toluene to provide (5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-7a.
The sixth aspect of the present invention provides a process for the preparation of N-protected (3-amino-2,6-difluorophenyl)(5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl) methanone compound of general formula-8, comprising of treating N-protected (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin«3-yl)(2,6-difluoro43-nitrbphenyl)methanone compound of general formula-7 with a suitable reducing agent in a suitable solvent to provide N-protected (3-amino-256-difluorophenyl)(5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]
pyridin-3-yl)methanone compound of general formula-8.
Wherein, the suitable reducing agent and suitable solvent is same as defined in step-e) of the first of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of (3-(3-amino-2,6-difluorobenzoyl)-5-(4-chlorophenyl)-lH-pyrrolo[2,3-b] pyridin-1 -yl)(2,6-dimethoxyphenyl)methanone compound of formula-8a, comprising of treating (5-(4-chlorophenyl)-l-(2,6-dimethoxyben2oyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formulaj-7a with sodium dithionite in a mixture of water and tetrahydrofuran to provide compound of general formula-8a.

According to the present invention, propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[253-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1, having a purity greater than 99.75%; more preferably greater than 99.85%; most preferably greater than 99.95% as measured by HPLC.
The invention also encompasses pharmaceutical ; compositions comprising Vemurafenib or salts thereof of the invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Pharmaceutical compositions containing the Vemurafenib of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants. Various modes of administration of the pharmaceutical compositions of! the invention can be selected
i I
depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1! produced by the present invention can be further micronized or milled by the conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size
i i
reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the
product.
These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of 5-(4-Chlorophenyl)-lH-pyrrolo[2,3-b]pyridine (Formula-4)
1,4-Dioxane (500 ml) was added to 5-bromo-lH-pyrrolo[2,3-b]pyridine (50 gms) compound of formula-2 at 25-30°C. 4-Chlorophenylbororiic acid (51.56 gms) and followed
by aqueous potassium carbonate {potassium carbonate (105.2 gms) in water (250 ml)} solution was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Tetrakis(triphenylphosphine)palladium (2.92 gms) was added to the reaction mixture at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 100-105°C and stirred for 5 hours at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure. Cooled the reaction mixture to 25-30°C,and water was added to it. Stirred the reaction mixture for 3 hours at.25-30°C and filtered: the solid. To the obtained solid, methyl tertiary butyl ether (12.5 ml) and cyclohexane (237.5 ml) were added at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid and dried to get the title compound.
Yield: 68 gms; Melting point: 205-210°C.
Example-2:
Preparation of (5-(4-Chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yI)(2,6-difluoro-3-nitro
phenyl)methanone (Formula-6) | .
Dimethyl formamide (0.5 ml) was added to a mixture of dichloromethane (100 ml) and 2,6-difluoro-3-nitrobenzoic acid (15.13 gms) compound of formula-5 at 25-30°C. Oxalyl chloride (8.33 gms) and dichloromethane (20 ml) were slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40°C and :stirred for 4 hours at the same temperature. Quenched the reaction mixture in methanol. The obtained reaction mixture was slowly added to a mixture of aluminium chloride (23.4 gms) and dichloromethane (100 ml) and 5-(4-Chlorophenyl)-lH-pyrrolo[2,3-b]pyridine (10 gms) compound of formula-4 at 25-30°C. Stirred the reaction mixture for 12 hours at 25-30°C. Quenched the reaction mixture

with ice cold water at 0-5°C and stirred for 1 hour at the same temperature. Filtered the
precipitated solid and washed with water. To the obtained wet! compound, water (100 ml)
was added at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid
and washed with water. To the obtained wet compound, methanol (100 ml) was added at 25-
30°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with
methanol and dried to get the title compound. . ;
Yield: 14.2 gms; Melting point 294-296°C.
Example-3:
Preparation of (5-(4-Chlorophenyl)-l-(2,6-dimethoxyph|enyl)-lH-pyrroIo [2,3-b]
pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone(Formula-7a)
Dimethyl formamide (0.5 ml) was added to a mixture of 2.6-dimethoxybenzoic acid (13.22 gms) and toluene (200 ml) at 25-30°C. A mixture of oxalyl chloride (7.99 gms) and toluene (40 ml) were slowly added to the above reaction mixture: at 25;30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C. A mixture of diisopropylethyl amine (9.35 gms) and dichloromethane (40 ml) was slowly added to the reaction mixture at 0-5°C. Dimethyl amino pyridine (0.6 gms) and toluene (40 ml) were added to a mixture of (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone (20 gms) compound of formula-6 and toluene (200 ml) at 25-30°C. Cooled the reaction mixture to 15-20°C and the above reaction mixture was slowly added to it at the same temperature. Stirred the reaction mixture for 4 hours at 15-20°C. Then added diisopropylethyl amine (9.35 gms) to the reaction mixture at 15-20°C and stirred for 3 hours at the same temperature. Quenched the reaction mixture in water and ethyl acetate was added to the reaction mixture. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the both organic layers and washed with 5% aqueous hydrochloric acid solution and then followed by water. Distilled off the solvent completely from the organic layer under reduced pressure. Methyl tertiary butyl ether (100ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid and washed with methyl itertiary butyl ether. To the obtained solid, mixture of methanol (180 ml) and acetonitrile (20 ml) was added at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 30 minutes at the same

temperature. Cooled the solid to 25-30°C. Filtered the solid,; washed with a mixture of methanol and acetonitrile and dried to get the title compound. Yield: 21.0 gms; Melting point: 229-231°C.
Example-4:
i . : Preparation of (3-amino-2,6-difluorophenyl)(5-(4|-chIorophehyI)-l-(2,6-dimethoxy
phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)methanone (FormuIa-8a)
Tetrahydrofuran (190 ml) was added to (5-(4-chlorophenyl)-l-(2,6-dimethoxy phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrpphenyl)methanone (15 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Sodium dithionite (67.74 gms) and water (190 ml) were added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 60-65 °C and stirred for 5 hours at the same temperature. Cooled the reaction mixture to 25-30°]C. Basifying the reaction mixture using 10% aqueous sodium bicarbonate solution. Ethyl acetate was added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated and extracted the aqueous layer with a mixture of tetrahydrofuran and ethyl acetate. Combined both the organic layers and washed with purified water. Distilled off the solvent completely from the organic layer under reduced pressure. To the obtained solid, ethyl acetate (67.5 ml) and cyclohexane (7.5 ml) were added at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with cyclohexane and dried to get the title compound. Yield: 11.0 gms; Melting point: 178-180°C. Example-5:
Preparation of N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxyphenyl)-lH-pyrrolo[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide (Formula-9a)
Dimethyl amino pyridine (0.02 gms) and pyridine (0.57 gms) were added to a mixture of (3-amino-2,6-difluorophenyl)(5-(4-chlorophenyl)-l-(2,6-dimethoxyphenyl)-lH-pyrrolo [2,3-b]pyridin-3-yl)methanone (2 gms) compound of formula-8a and 1,4-dioxane (18 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Propane- 1-sulfonyl chloride (0.52 gms) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 95-100°C and stirred for 3 hours at the same temperature. Pyridine (0.57 gms) and
propane-1-sulfonyl chloride (0.52 gms) was added to the reaction mixture at 95-100°C and

stirred for 3 hours at the same temperature. Distilled off the solvent completely from the
reaction mixture. Cooled the reaction mixture to 25-30°C. Water and ethyl acetate was added
to the reaction mixture and stirred for 15 minutes at the same temperature. Both the organic
and aqueous layers were separated and aqueous layer was extracted with ethyl acetate.
Combined both the organic layers and washed with purified water. Distilled off the solvent
completely from the organic layer under reduced pressure to get the title compound.
Yield: 1.8 gms; Melting point 140-145°C.
ExampIe-6: ! ' ;
Preparation of propane-l-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]
pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide(Formula-l)
Methanol (1.87 ml) and dimethyl acetamide (3.75 ml) was added to N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxyphenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2J4-difluorophenyl)propane-l-sulfonamide (1.5 gms) compound of formula-9a at 25-30°C and stirred for 15 minutes at the same temperature. Methanolic ammonia (0.93 ml) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 24

hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. To the obtained compound, methanol (5.4 ml) was added at 25-30°C and distilled off the solvent completely under reduced pressure. Methanol (10.8 ml) was added to the obtained compound at 40-45°C. Cooled the; reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 1.0 gms; Melting point 265-270°C; Purity by HPLC: 99.96%

1. I
We Claim:
1. Novel process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[23-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amicie compound of formula-1, comprising of the following steps:
a) Reacting 5-bromo-lH-pyrrolo[2,3-b]pyridine compound of formula-2 with 4-chloro phenylboronic acid compound of formula-3 in presence of tetrakis(triphenyl phosphine)palladium and a suitable base in a suitable solvent to provide 5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine compound of formula-4,

b) optionally, purifying the compound of formula-4 using a suitable solvent,

c) reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-10 with chlorinating agent in a suitable solvent to provide 2,6-difluoro-3-nitrobenzoyl chloride compound of formula-5, which further reacts with compound of formula-4 in presence of lewi's acid in a suitable solvent to provide (5-(4-chlorophenyl)-,lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-6,

d) reacting the compound of formula-6 with a suitable amine protecting group in presence of a suitable base and optionally in the presence of a suitable catalyst in a suitable solvent to provide N-protected (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b] pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of general formula-7,

e) reducing the nitro group of compound of general formula-7 with a suitable reducing agent in a suitable solvent to provide N-protected (3-amino-2,6-difluoro phenyl)(5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)metharione ' compound of general formula-8,

f) optionally, purifying the compound of general formula-8 using a suitable solvent,

g) reacting the compound of general formula-8 with propane-1-sulfonyl chloride in ! ! presence of a suitable base in a suitable catalyst in a suitable solvent to provide N-
protected N-(3-(5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-
difluorophenyl)propane-l-sulfonamide compound of general formula-9,

h) treating the compound of general formula-9 with af suitable base in a suitable solvent
to provide propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo [2,3-b]
pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1.

2. The process according to claim-1, wherein,
in step-a), d)5 g), and h) the suitable base is selected from organic or inorganic base; in step-c) the suitable chlorinating agent is selected from chlorine, oxalyl chloride, sulfuryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, pivaloyl chloride, antimony pentachloride, iodine trichloride, sulfur dichloride, disulfur dichloride, manganese tetrachloride and the like; and suitable lewis acid is selected from aluminium chloride, Boron trifluoride, boron trichloride, ferric chloride, tin tetrachloride, stibium penta chloride, AsFs, ASF3, and TiCU;
in step-d) the suitable amino protecting group is benzyloxy carbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethylsilyl)ethoxycartonyl (Teoc), 2-(4-trifluoro methylphenylsulfonyl) ethoxycarbonyl (Tsc), t-butoxy carbonyl (BOC), 1-adamantyl oxycarbonyl (Adoc), 2-adamantylcarbonyl (2-Adoc), 2,4-dimethylpent-3-yl oxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1 -dimethyl-2,2,2-trichloroethoxy carbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonylethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridyl methyl, N',N'-dimethylhydrazinyl, methoxy methyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetrahydropyranyl (THP), 1 -(ethoxy) ethyl, p-methoxy benzyl, triphenylmethyl, j diphenylmethyl, hydroxymethyl, methoxymethyl, and t-butyldimethylsilylmethyl, N-pivaloyloxymethyl (POM), 1,1-diethoxymethyl, tri(Cl-4-alkyl)silyl, p-Methoxybenzyl carbonyl (Moz or MeOZ) group, 9-Fluorenylmethyloxy carbonyl (FMOC) group, Acetyl (Ac) group, Benzoyl (Bz) group, C1-C6 alkoxy substituted benzoyl group, Benzyl (Bn) group, p-methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM).-C(0)OCi-C6 alkyl, such as, for example, carboethoxy, carbomethoxy and t-butoxycarbonyl; optionally substituted -C(0)OCi-C6 aryl, such as, for example, benzyloxy-carbonyl and p-methoxybenzyloxy carbonyl; optionally substituted -C1-C12 aryl(Ci-C3)alkyl such as, for example, benzyl, phenethyl, p-methoxy benzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl and 9-fluorenylmethyl; optionally substituted C7-C11 aryl carbonyl, such as, for example, benzoyl; Ci-Qealkanoyl, such as,
! j * ! '
for example, formyl, acetyl, and propionyl; C1-C6 alkylsulfonyl, such as, for example, mesyl.

in step-e) the suitable reducing agent is selected from Fe, Fe;in acidic media like NH4CI or HC1 or acetic acid, Sn in acidic media like HC1, Zn dust, Zn in acidic media like HC1 or NH4CI or acetic acid, stannous chloride (SnCk), NaBHU, LiAlHU, LiBILj, diborane,
borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Pd/C, Pt/C,
1 ,
: '
PtC>2> Pd(OH)2, Nickel, Raney nickel, Rhodium, sulfides, alkali metal dithionite, alkali
metal dithionate and sodium amalgam;
in step-d) and g) the suitable catalyst is dimethyl amino pyridine;
in step-a) to h) the suitable solvent is selected from jalcohol solvents, chloro solvents,
ketone solvents, polar aprotic solvents, nitrile solvents, ester solvents, polar aprotic
solvents, hydrocarbon solvents, ether solvents and polar solvent like water or mixture
thereof.
3. Novel process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-
P3orolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-19
comprising of the following steps: .
. - i 1 ! ■ '
a) Reacting 5-bromo-lH-pyrrolo[2,3-b]pyridine compound of formula-2 with 4-
chlorophenylboronic acid compound of formula-3 in presence of tetrakis(triphenyl phosphine) palladium and potassium carbonate in a mixture of 1,4-dioxane and water to provide 5-(4-chlorophenyl)-lH-pyrrolo [2,3-b]pyridine! compound of formula-4,
b) purifying the compound of formula-4 using a mixture of methyl tertiary butyl ether and cyclohexane,
c) reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-10 with oxalyl chloride in presence of a mixture of dichloromethane and dimethyl formamide to provide 2,6-difluoro-3-nitrobenzoyl chloride compound of formula-5, which further reacts with compound of formula-4 in presence of aluminium chloride in dichloromethane to provide (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl) (2,6-difluoro-3-nitrophenyl)methanone compound of formula-6,
d) reacting the compound of formula-6 with 2,6-dimethoxy benzoyl chloride in presence of diisopropyl ethylamine and dimethyl amino pyridine in a mixture of
dichloromethane and toluene to provide (5-(4-chlorophenyl)-l-(2,6-dimethoxy
i ' i '

benzoyl)-lH"pyirolo[23-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-7a,
e) reducing the nitro group of compound of formula-7a with sodium dithionite in a
mixture of water and tetrahydrofuran to provide (3-(3-amino-2,6-difluorobenzoyl)-5-
(4-chlorophenyl)-lH-pyrrolo[253-b]pyridin-l-yl)(2s6-dimethoxyphenyl)methanone
compound of formula-8a,
• i >
f) purifying the compound of formula-8a using a' mixture of ethyl acetate and
cyclohexane,
g) reacting the compound of formula-8a with propane-1-sulfonyl chloride in presence of
pyridine and dimethyl amino pyridine in 1,4-dioxane to provide N-(3-(5-(4-chloro
i •
phenyl)-l-(256-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-254-difluorophenyl)propane-l -sulfonamide compound of formula-9a, h) treating the compound of formula-9a with methanolic ammonia in dimethyl acetamide to provide propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-254-difluoro-phenyl}-amide compound of formula-1.
4. Compounds having the structural formulae.
! I
t :
Wherein "Pg" is a suitable amino protecting group
5. A solid compounds of: ' | : !
i. (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(256-difluoro-3-nitrophenyl) methanone.
ii. (5-(4-chlorophenyl)-l-(236-dimethoxyphenyl)-lH-pyrrol6[2,3-b]pyridin-3-yl)(256-
. ■ i ; <
difluoro-3-nitrophenyl)methanone.

6. A process for the preparation of (5-(4-chlorophenyl)-lH-pyrrolo[253-b]pyridin-3-yl) (2,6-difluoro-3-nitrophenyl)methanone compound of formula-6, Comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-10 with a suitable chlorinating agent in a suitable solvent to provide 2,6-difluoro-3-nitrobenzoyl chloride compound of formula-5, which further reacts with compound of formula-4 in presence of Lewi's acid in a suitable solvent to provide (5-(4-chlorophenyl)-l^I-pyrrolo[253-b]pyridin-3-yl) (2,6-difluoro-3-nitrophenyl)methanone compound of formula-6.
7. A process for the preparation of (5-(4-cWorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl) (2,6-difluoro-3-nitro phenyl)methanone compound of formula-6, comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-10 with oxalyl chloride in presence of a mixture of dichloromethane and dimethyl formamide to provide 2,6-difluoro-3-nitrobenzoyl chloride compound of formula-5, which; further reacts with compound of formula-4 in presence of aluminium chloride in dichloromethane to provide (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-6.
8. A process for the preparation of N-protected (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl) methanone compound of general formula-7, comprising of reacting (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)(2,6-difluoro-3-nitrophenyl)methanone compound of formula-6 with a suitable amino protecting group in presence of a suitable base and optionally in the presence of a suitable catalyst in a suitable solvent to provide compound of general formula-7.
' ' ■ !
9. A process for the preparation of N-protected (3-amino-2,6-difluorophenyl)(5-(4-
chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)methanone compound of general formula-8,
comprising of treating N-protected (5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)
(2,6-difluoro-3-nitrophenyl)methanone compound of general formula-7 with a suitable
reducing agent in a suitable solvent to provide N-protected (3-amino-2,6-difluoro
phenyl)(5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)methanone compound of
general formula-8. ;

10. The compound of formula-1, obtained according to any one of the proceeding claims, having purity greater than 99.75%; more preferably greater than 99.85%; most preferably greater than 99.95% as measured by HPLC.