Field of the Invention:
The present invention relates to an improved process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-5 phenyl}-amide compound of formula-1, represented by the following structure:
Background of the Invention:
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 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 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 reacting N-(3-(5-bromo-lH-pyrrolo[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide with 4-chlorophenyl boronic acid in a microwave instrument at elevated temperatures in the presence of tetrakis(triphenylphosphine)palladium and potassium carbonate to provide compound of formula-1.

The above said processes suffers from several drawbacks including 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 not suitable for commercial scale process.
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 high yield
and purity.
i
Brief description of the Invention:
The first aspect of the present invention is to provide an improved 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 an improved process for the preparation of methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3, comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-2 in presence of dimethyl i sulfate in a suitable base and a suitable solvent to provide compound of formula-3.
The third aspect of the present invention is to provide a process for the preparation of N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide compound of formula-10, comprising of reacting N-(3-(5-bromo-lH-pyrrolof2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propanc-l-sulfonamide compound of formula-9 with 2,6-dimethyoxybenzoyl chloride in presence of a suitable base in a suitable solvent to provide compound of formula-10.
The fourth aspect of the present invention is to provide a process for the preparation
I of N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-
carbonyl)-2,4-difluoro phenyl)propane-l-sulfonamide compound of formula-12, comprising
reacting N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-
2,4-difluorophenyl)propane-l -sulfonamide compound of formula-10 with 4-chlorophenyl

boronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride in a suitable base in a suitable solvent to provide compound of formula-12.
The fifth aspect of the present invention is to provide a 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. Brief description of Figures:
Figure 1: Illustrates the PXRD pattern of HPMC-AS amorphous solid dispersion of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[233-b]pyridine-3-carbonyl]-2J4-difluoro-phenyl}-amide obtained according to example-9.
Detailed description of the Invention:
The present invention relates to an improved 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.
The term "suitable solvent" used in the present invention 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 and the like; "ether solvents" such as dimethoxy methane, 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, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone 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,
A

diethylene glycol monoethyl ether, cyclohexanol 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 (DIPA), diisopropylethylamine (DIPEA), N-methyl morpholine (NMP), N-ethylmorpholine, piperidine, dimethylaminopyridine (DMAP), 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.
As used herein the term suitable "chlorinating agent" include but are not limited to chlorine, oxalyl chloride, sulforyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, pivaloyl chloride, 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 aluminum chloride, boran trichloride, ferric chloride, tin tetrachloride and TiCLj.
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, UAIH4, L1BH4, diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as Pd/C, Pt/C, PtCh, Pd(OH)2, Raney nickel, Rhodium, sulfides, alkali metal dithionite, alkali metal dithionate and sodium amalgam.

The first aspect of the present invention provides an improved 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 2,6-difluoro-3-nitrobenzoic acid compound of formula-2 with dimethyl sulfate in presence of a suitable base in a suitable solvent to provide methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3,
b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide methyl 3-amino-2,6-difluorobenzoate compound of formula-4,
c) reacting the compound of formula-4 with propane sulfonyl chloride in presence of a suitable base in a suitable solvent to provide methyl 2,6-difluoro-3 -(propyl sulfonamido)benzoate compound of formula-5,
d) hydrolyzing the compound of formula-5 with a suitable base in a suitable solvent to provide 2,6-difluoro-3-(propylsulfonamido)benzoic acid compound of formula-6,
e) reacting the compound of formula-6 with a suitable chlorinating agent in a suitable solvent to provide 2,6-difluoro-3-(propylsulfonamido)benzoyl chloride compound of formula-7,
f) reacting the compound of formula-7 with 5-bromo-1 H-pyrrolo[2,3-b]pyridine compound of formula-8 in presence of a suitable Lewi's acid in a suitable solvent to provide N-(3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1 -sulfonamide compound of formula-9,
g) reacting the compound of formula-9 with 2,6-dimethyloxybenzoyl chloride in presence of a suitable base in a suitable solvent to provide N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-254-difluorophenyl) propane-1-sulfonamide compound of formula-10,.
h) reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride in a suitable base in a suitable solvent to provide N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-12,

i) reacting the compound of formula-12 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, j) optionally, purifying the compound of formula-1 with a suitable solvent or a solvent mixture to provide pure compound of formula-1. Wherein,
in step-a), c), d), g), h) & i) the suitable base is selected from organic or inorganic
base;
in step-b) 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 (SnC12), NaBFL*, UBH4,
diborane, borane-THF complex, hydrazine hydrate, hydrogenation catalysts such as
Pd/C, Pt/C, Pt02, Pd(OH)2, Raney nickel, Rhodium, sulfides, alkali metal dithionite,
alkali metal dithionate and sodium amalgam;
in step-e) 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;
in step-f) the suitable Lewi's acid is selected from aluminium chloride, boran
trichloride, ferric chloride, tin tetrachloride, stibium penta chloride and TiCU;
in step-a) to j) the suitable solvent is selected from alcohol solvents, chloro solvents,
ester solvents, hydrocarbon solvents, ketone solvents, ether solvents, polar aprotic
solvents, nitrile solvents and polar solvents such as water or mixtures thereof
The preferred embodiment of the present invention provides an improved process for the preparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyirolo[2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1, comprising of the following steps:

a) Reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-2 with dimethyl sulfate in presence of sodium bicarbonate in acetone to provide methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3,
b) reducing the compound of formula-3 with iron in acetic acid in methanol to provide methyl 3-amino-2,6-difluorobenzoate compound of formula-4,
c) reacting the compound of formula-4 with propane sulfonyl chloride in presence of pyridine in toluene to provide methyl 2,6-difluoro-3-(propyIsulfonamido)benzoate compound of formula-5,
d) hydrolyzing the compound of formula-5 with aqueous sodium hydroxide in toluene to provide 2,6-difluoro-3-(propylsulfonamido)benzoic acid compound of formula-6,
e) reacting the compound of formula-6 with oxalyl chloride in dichloromethane to provide 2,6-difluoro-3-(propylsulfonamido)benzoyl chloride compound of formula-7,
f) reacting the compound of formula-7 with 5-bromo-l H-pyrrolo[2,3-b]pyridine compound of formula-8 in presence of aluminium chloride in dichloromethane to provide N-(3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1 -sulfonamide compound of formula-9,
g) reacting the compound of formula-9 with 2,6-dimethyloxy benzoyl chloride in presence of diisopropylethylamine and dimethylamino pyridine in a mixture of dichloromethane and toluene to provide N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-254-difluorophenyl)propane-l-sulfonamide compound of formula-10,
h) reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride in aqueous sodium carbonate in a mixture of tetrahydrofuran and cyclohexane to provide N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l -sulfonamide compound of formula-12,
i) reacting the compound of formula-12 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.

The second aspect of the present invention provides an improved process for the preparation of methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3, comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-2 in presence of dimethyl sulfate in a suitable base and a suitable solvent to provide compound of formula-3.
Wherein, the suitable base is selected from organic or inorganic base and suitable solvent is same as defined in the first aspect of the present invention.
The preferred embodiment of the present invention provides an improved process for the preparation of methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3, comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-2 in presence of dimethyl sulfate and sodium bicarbonate in acetone to provide compound of formula-3.
When the inventors of the present invention carried out the methylation of compound of formula-2 using methyl iodide, sulfuric acid and methanol etc., they found that the reaction was incomplete and required longer period of time to complete the reaction. This resulted the decrease in the yield and purity of the desired compound of formula-3 as well as increase in the cost of the manufacturing process.
In order to overcome the problems associated with the prior art, inventors of the present invention has carried out the reaction in the presence of dimethyl sulfate, a cheaper chemical reagent. Surprisingly, they have found that the time cycle of the reaction was reduced to 2-3 hours and further the yield and purity of compound of formula-3 was increased when compared to prior art. Hence the present invention is more advantageous over the prior art processes.
The third aspect of the present invention provides a process for the preparation of N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide compound of formula-10, comprising of reacting N-(3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-

sulfonamide compound of formula-9 with 2,6-dimethyoxybenzoyl chloride in presence of a suitable base in a suitable solvent to provide compound of formula-10.
Wherein, the suitable base is selected from organic or inorganic base and suitable solvent is same as defined in the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of N-(3-(5-bromo-l-(2?6-dimethoxybenzoyl)-lH-pyrrolo[253-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-10, comprising of reacting N-(3-(5-bromo-lH-pyrrolo[2?3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-9 with 2,6-dimethyoxybenzoyl chloride in presence of diisopropyl ethylamine and dimethylamino pyridine in a mixture of dichloromethane and toluene to provide compound of formula-10.
According to US7863288 B2 N-(3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1 -sulfonamide compound of formula-9 is reacted with 4-chlorophenylboronic acid compound of formula-11 in a microwave instrument at elevated temperatures to provide propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyixolo[2,3-b] pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1 with low yield and purity with undesired byproducts and impurities. Further, the obtained crude compound of formula-1 is purified by column chromatography which is tedious, time consuming and increases the cost of the production which is not recommended for commercial scale.
Inventors of the present invention had overcame the problem, by initially protecting the nitrogen atom of pyrrole compound of formula-9 with a suitable protecting group such as 2,6-dimethyloxy benzoyl chloride to provide compound of formula-10 and then followed by reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 to provide compound of formula-12, which on subsequently underwent deprotected with a suitable base to provide compound of formula-1 with increased yield and purity and reduced the number of purification steps and which further thereby reduced the consumption of large quantities of solvent. Hence making the present process simple,

economically and commercially viable. Therefore the present invention is more advantageous when compared with the prior art process.
The fourth aspect of the present invention provides a process for the preparation of N-(3-(5-(4-chlorophenyl)-l-(256-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-12, comprising reacting N-(3-(5-bromo-l-(256-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-254-difluorophenyl)propane-l-sulfonamide compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine) palladium(ii) dichloride in a suitable base and a suitable solvent to provide compound of formula-12.
Wherein, the suitable base is selected from organic or inorganic base and suitable solvent is same as defined in the first aspect of the present invention.
The preferred embodiment of the present invention provides a process for the preparation of N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b] pyridine-3-carbonyl)-2,4-difluoro phenyl)propane-l-sulfonamide compound of formula-12, comprising reacting N-(3-(5-bromo-l-(2?6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1 -sulfonamide compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine) palladium(ii) dichloride in aqueous sodium carbonate in a mixture of tetrahydrofuran and cyclohexane to provide compound of formula-12.
In the above aspect, the compound of formula-12 can also be prepared by reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of [l,r-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride - [Pd(dppf)Cl2] and inorganic base in a suitable solvent selected from hydrocarbon solvent, ether solvents and polar solvents such as water or mixtures thereof.
The fifth aspect of the present invention provides a 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 N-(3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-9 with 2,6-dimethyloxybenzoyl chloride in presence of a suitable base in a suitable solvent to provide N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2?3-b]pyridine-3-carbonyl)-254-difluoro phenyl)propane-l-sulfonamide compound of formula-10,
b) reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride in a suitable base and a suitable solvent to provide N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1 -sulfonamide compound of formula-12,
c) treating the compound of formula-12 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]-254-difluoro-phenyl}-amide compound of formula-1.
Vherein,
in step-a), b) and c) the suitable base is organic or inorganic base; in step-a), b) and c) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
The preferred embodiment of the present invention provides a process for the ►reparation of propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-arbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1, comprising of the following teps:
a) Reacting N-(3-(5-bromo-lH-pyrrolo[2?3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1 -sulfonamide compound of formula-9 with 2,6-dimethyloxybenzoyl chloride in presence of diisopropylethylamine and dimethylamino pyridine in a mixture of dichloromethane and toluene to provide N-(3-(5-bromo-l-(2,6-dimethoxy benzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide compound of formula-10,
b) reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride in aqueous

sodium carbonate in a mixture of cyclohexane and tetrahydrofiiran to provide N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-12, c) treating the compound of formula-12 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.
According to the present 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,-having a purity greater than 99.75%; more preferably greater than 99.85%; most preferably greater than 99.95% as measured by HPLC.
Propane-1-sulfonic acid {3-[5-(4-chIorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1 obtained according to the present invention is having bromo acid impurity and bromo impurity in non-detectable level as measured by HPLC.
The invention also encompasses pharmaceutical compositions comprising compound of formula-1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include 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 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.

The process described in the present invention was demonstrated in examples 5 illustrated below. 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 methyl 2,6-difluoro-3-nitrobenzoate (Formula-3)

Sodium bicarbonate (82.7 gms) was added to a mixture of acetone (1000 ml) and 2,6-difluoro-3-nitrobenzoic acid (100 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Dimethyl sulfate (74.7 gms;) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 5 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Water was added to the obtained wet solid at 25-30°C and stirred for 1 XA hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 101 gms; M.R: 60-65°C; Purity by HPLC: 99.87%.
Example-2:
Preparation of methyl-3-amino-2,6-difluorobenzoate (Formula-4)
Iron powder (309 gms) and acetic acid (496.8 gms) were added to a mixture of methanol (3000 ml) and methyl 2,6-difluoro-3-nitrobenzoate (300 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 60-65°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Hyflow was added to the reaction mixture at 25-30°C and stirred for 1 hour at the same temperature. Filtered the reaction mixture and washed with methanol. Distilled off the solvent completely from filtrate under reduced pressure. Ethyl acetate and water were added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through high flow bed and washed with ethyl acetate. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium bicarbonate solution. Further, organic layer was washed with water and followed by aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure to get the title compound. Yield: 240 gms; Purity by HPLC: 99.6%.
Example-3:
Preparation of methyl 2,6-difluoro-3-(propylsulfonamido)benzoate (Formula-5)
Pyridine (126.8 gms) was added to a mixture of toluene (2000 ml) and methyl-3-amino-2,6-difluorobenzoate (200 gms) at 25-30°C and stirred for 10 minutes at the same

temperature. Propane-1-sulfonyl chloride (182.9 gms) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 5 hours at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure. Methanol (200 ml) was added to the obtained compound at 50-55°C and distilled off the solvent from the reaction mixture under reduced pressure. Water (1000 ml) was added to the obtained compound at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 320 gms; M.R: 95-100°C; Purity by HPLC: 99.59%.
Example-4:
Preparation of 2,6-difluoro-3-(propylsulfonamido)benzoic acid (Formula-6)
Aqueous sodium hydroxide solution (13.6 gms sodium hydroxide and 250 ml water) was slowly added to a mixture of toluene (250 ml) and methyl 256-difluoro-3-(propylsulfonamido)benzoate (50 gms) at 25-30°C and stirred for 5 hours at the same temperature. Filtered the reaction mixture through high flow bed and washed with water. Both the organic and aqueous layers were separated and aqueous layer was washed toluene. Cooled the aqueous layer to 10-15°C. Aqueous hydrochloric acid solution (45 ml hydrochloric acid and 115 ml water) was slowly added to aqueous layer at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 44 gms; M.R: 206-208°C; Purity by HPLC: 99.56%.
Example-5:
Preparation of N-(3-(5-bromo-lH-pyrroIo[2,3-b]pyridine-3-carbonyI)-2,4-
difluorophenyl) propane-l-sulfonamide (FormuIa-9)
Dimethyl formamide (1ml) was added to a mixture of 2,6-difluoro-3-(propyl sulfonamido)benzoic acid (42.5 gms) and dichloromethane (225 ml) at 25-30°C. Oxalyl chloride solution (13.2 ml of oxalyl chloride in 25 ml dichloromethane) was slowly added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. A mixture of 5-Bromo-7-azaindole (25 gms), aluminum chloride (84.5 gms) and dichloromethane (225 ml)

was slowly added to the reaction mixture at 0-5°C under nitrogen atmosphere. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 4 hours at the same temperature. Quenched the reaction mixture with ice cold water at 0-5°C. Stirred the reaction mixture for 1 hour at 25-30°C. Filtered the precipitated solid and washed with water. To the obtained wet compound, water (300 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 (250 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: 53.5 gms; M.R: 240-246°C; Purity by HPLC: 98.33%.
Example-6:
Preparation of N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[253-b] pyridine-3-
carbonyl)-2,4-difluorophenyI)propane-l-suIfonamide (Formula-10)
Dimethyl formamide (1 ml) was added to a mixture of 2,6-dimethoxy benzoic acid (11.13 gms) and toluene (120 ml) at 25-30°C. Cooled the reaction mixture to 18-22°C. Oxalyl chloride solution (5.4 ml of oxalyl chloride in 40 ml of toluene) was slowly added to the reaction mixture. Stirred the reaction mixture for 2 hours at 25-30°C. Cooled the reaction mixture to 0-5°C. Diisopropylethylamine solution (16.92 gms of diisopropylethylamine in 40 ml dichloromethane) was added to the reaction mixture at 0-5°C. A mixture of Dimethylaminopyridine (0.54 gms), N-(3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l -sulfonamide (20 gms) and toluene (200 ml) was added to the reaction mixture 18-22°C and stirred for 3 hours at the same temperature. Quenched the reaction mixture with water at 25-30°C. Ethyl acetate was added to the reaction mixture. Both the aqueous and organic layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous hydrochloric acid solution and followed by 10% aqueous sodium chloride solution. Distilled off the solvent completely from the reaction mixture under reduced pressure. Toluene (60 ml) was added to the obtained wet compound at 65-70°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 26.5 gms; M.R: 105-110°C; Purity by HPLC: 97.34%.

Example-7:
Preparation of N-(3-(5-(4-chIorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3«carbonyl)-2,4-difluorophenyl)propane"l-sulfonamide (Formula-12)
4-Chlorophenyl boronic acid (5.52 gms) compound of formula-11 was added to a mixture of tetrahydrofuran (66.65 ml), N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide (20 gms) and cyclohexane (66.65 ml) at 25-30°C. Sodium carbonate (10.2 gms) was added to the reaction mixture at 25-30°C under nitrogen atmosphere and stirred for 30 minutes at the same temperature. Heated the reaction mixture to 50-55°C. Bis(triphenylphosphine)palladium(ii) dichloride (0.52 gms) was added to'the reaction mixture at 50-55°C. Further, heated the reaction mixture to 60-65°C and stirred for 1 lA hours at the same temperature. Cooled the reaction mixture to 25-30°C. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture and washed with ethyl acetate. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Cyclohexane (200 ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture, washed with cyclohexane and dried for 3 hours at 60-65°C. Toluene (100 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 18.0 gms; M.R: 130-135°C.
Example-8:
Preparation of Propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo [2,3-b]
pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (Formula-1)
Methanol (22.5 ml), N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b] pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide (18 gms) and dimethylacetamide (45 ml) were charged in autoclave vessel at 25-30°C. Methanolic ammonia (10.8 ml) was added to the reaction mixture at 25-30°C. Heated the reaction

mixture to 50-55°C and stirred for 4 hours at the same temperature. Cooled the reaction
mixture to 25-30°C. Distilled off the solvent completely under reduced pressure. Methanol
was added to the reaction mixture and distilled off the solvent completely under reduced
pressure. Methanol was slowly added to the obtained compound and stirred for 3 hours at 25-
30°C. Filtered the solid, washed with methanol and dried to get the title compound.
Yield: 7.6 gms; M.R: 270-272°C; Purity by HPLC: 99.95%; Boronic acid impurity: Not
detected; HIUI: 0.05%; Bromo impurity: Not detected.
Particle Size Distribution (PSD): D(0.1) is 2.2 |im; D(0.5) is 9.8 |im; D(0.9) is 57.3 urn.
Example-9:
Preparation of HPMC-AS amorphous solid dispersion of propane-l-sulfonic acid {3-[5-
(4-chlorophenyl)-lH-pyrrolo [2,3-b]pyridine-3-carbonyI]-2,4-difIuoro-phenyl}-amide
A mixture of dimethyl acetamide (1320 ml), propane-l-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-254-difluoro-phenyl}-amide (110 gms) and hydroxypropyl methylcellulose acetate succinate (253 gms) was stirred for 10 minutes at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. Reaction mixture was slowly added to the pre-cooled 0.01N hydrochloric acid solution (11 Its) at 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid. 0.01N hydrochloric acid solution (11 Its) was added to the obtained wet compound at 25-30°C and stirred for 10 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 minutes at the same temperature. Filtered the solid and washed with 0.01N hydrochloric acid solution. Water was added to the obtained wet compound at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 60 minutes at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 320.0 gms. The PXRD pattern of the obtained compound is illustrated in figure-1.

We Claim:
1. An improved process for the preparation of propane-1-sulfonic acid {3-[5-(4-chloro phenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1, comprising of the following steps:
a) Reacting 256-difluoro-3-nitrobenzoic acid compound of formula-2 with dimethyl sulfate in presence of a suitable base in a suitable solvent to provide methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3,
b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide methyl 3-amino-2,6-difluorobenzoate compound of formula-4,
c) reacting the compound of formula-4 with propane sulfonyl chloride in presence of a suitable base in a suitable solvent to provide methyl 2,6-difluoro-3-(propyl sulfonamido)benzoate compound of formula-5,
d) hydrolyzing the compound of formula-5 with a suitable base in a suitable solvent to provide 2,6-difluoro-3-(propylsulfonamido)benzoic acid compound of formula-6,
e) reacting the compound of formula-6 with a suitable chlorinating agent in a suitable solvent to provide 2,6-difluoro-3-(propylsulfonamido)benzoyl chloride compound of formula-7,
f) reacting the compound of formula-7 with 5-bromo-lH-pyrrolo[2,3-b]pyridine compound of formula-8 in presence of a suitable Lewi's acid in a suitable solvent to provide N-(3-(5-bromo-lH-pyrrolo[233-b]pyridine-3-carbonyl)-234-difluorophenyl) propane-1-sulfonamide compound of formula-9,
g) reacting the compound of formula-9 with 2,6-dimethyloxybenzoyl chloride in presence of a suitable base in a suitable solvent to provide N-(3-(5-bromo-l-(2,6-dimethoxy benzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-254-difluorophenyl)propane-l-sulfonamide compound of formula-10,
h) reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride in a suitable base in a suitable solvent to provide N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxy

benzoyl)-lH-pyrrolo[253-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-
sulfonamide compound of formula-12, i) reacting the compound of formula-12 with a suitable base in a suitable solvent to
provide propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyrroIo[2,3-b]pyridine-3-
carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1, j) optionally, purifying the compound of formula-1 with a suitable solvent or a solvent
mixture to provide pure compound of formula-1.
2. The process according to claim-1 wherein,
in step-a), c), d), g), h) & i) the suitable base is selected from organic or inorganic base; in step-b) 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 (SnC12), NaBFLj, 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 and sodium amalgam;
in step-e) the suitable chlorinating agent is selected from chlorine, oxalyl chloride, sulfliryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus penta chloride, pivaloyl chloride, antimony penta chloride, iodine trichloride, sulfur dichloride, disulfur dichloride, manganese tetrachloride and the like;
in step-f) the suitable Lewi's acid is selected from aluminum chloride, boran trichloride, ferric chloride, tin tetrachloride, stibium penta chloride and TiCU; in step-a) to j) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar aprotic solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
3. An improved 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 256-difluoro-3-nitrobenzoic acid compound of formula-2 with dimethyl sulfate in presence of sodium bicarbonate in acetone to provide methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3,
b) reducing the compound of formula-3 with iron in acetic acid in methanol to provide methyl 3-amino-2,6-difluorobenzoate compound of formula-4,
c) reacting the compound of formula-4 with propane sulfonyl chloride in presence of pyridine in toluene to provide methyl 2,6-difluoro-3-(propylsulfonamido)benzoate compound of formula-55
d) hydrolyzing the compound of formula-5 with aqueous sodium hydroxide in toluene to provide 2,6-difluoro-3-(propylsulfonamido)benzoic acid compound of formula-6,
e) reacting the compound of formula-6 with oxalyl chloride in dichloromethane to provide 2s6-difluoro-3-(propylsulfonamido)benzoyl chloride compound of formula-75
f) reacting the compound of formula-7 with 5-bromo-lH-pyrrolo[2,3-b]pyridine compound of formula-8 in presence of aluminium chloride in dichloromethane to provide N-(3-(5-bromo-lH-pyrrolo[2J3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-9,
g) reacting the compound of formula-9 with 2,6-dimethyloxy benzoyl chloride in presence of diisopropylethylamine and dimethylaminopyridine in a mixture of dichloromethane and toluene to provide N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[233-b] pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1 -sulfonamide compound of formula-10,
h) reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride and aqueous sodium carbonate in a mixture of cyclohexane and tetrahydrofuran to provide N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2s3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide compound of formula-12,
i) reacting the compound of formula-12 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.

4. A process for the preparation of methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3, comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-2 in presence of dimethyl sulfate in a suitable base and a suitable solvent to provide compound of formula-3, wherein the suitable base is selected from organic or inorganic base and suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents, ketone solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
5. A process for the preparation of methyl 2,6-difluoro-3-nitrobenzoate compound of formula-3, comprising of reacting 2,6-difluoro-3-nitrobenzoic acid compound of formula-2 in presence of dimethyl sulfate and sodium bicarbonate in acetone to provide compound of formula-3.
6. A 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 N-(3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-9 with 2,6-dimethyloxybenzoyl chloride in presence of a suitable base in a suitable solvent to provide N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-10,
b) reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride [or] 1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride in a suitable base and a suitable solvent to provide N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxy benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide compound of formula-12,
c) treating the compound of formula-12 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.

7. The process according to claim-6, wherein,
in step-a), b) and c) the suitable base is organic or inorganic base;
in step-a), b) and c) the suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, hydrocarbon solvents, ketone solvents, ether solvents, polar aprotic solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
8. A 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-19
comprising of the following steps:
a) Reacting N-(3-(5-bromo-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl) propane-1-sulfonamide compound of formula-9 with 2,6-dimethyloxybenzoyl chloride in presence of diisopropylethylamine and dimethyl amino pyridine in a mixture of dichloromethane and toluene to provide N-(3-(5-bromo-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l -sulfonamide compound of formula-10,
b) reacting the compound of formula-10 with 4-chlorophenylboronic acid compound of formula-11 in presence of bis(triphenylphosphine)palladium(ii) dichloride in aqueous sodium carbonate in a mixture of tetrahydrofiiran and cyclohexane to provide N-(3-(5-(4-chlorophenyl)-l-(2,6-dimethoxybenzoyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide compound of formula-12,
c) treating the compound of formula-12 with methanolic ammonia in dimethyl acetamide
to provide propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-lH-pyirolo[2,3-b]pyridine-
3-carbonyl]-2,4-difluoro-phenyl}-amide compound of formula-1.
9. 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 obtained according to the preceding
claims having purity greater than 99.55%; more preferably greater than 99.75%; most
preferably greater than 99.95% as measured by HPLC.
10. 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 obtained according to any

of the preceding claims having particle size distribution of D90 less than 150 \xm, preferably less than 100 nm.