DETAILED DESCRIPTION

Description of drawings:

Fig. 1 represent X-ray powder diffraction pattern of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid sodium salt [Fevipiprant sodium salt]

Fig. 2 represents X-ray powder diffraction pattern of 2-[2 -methyl- l-[[4-methylsulfonyl -2-(trifluoromethyl) phenyl]methyl]pyrrolo [2, 3 -b] pyridine -3 -yl] acetic acid potassium salt [Fevipiprant potassium salt]

Fig. 3 represents X-ray powder diffraction pattern of 2-[2 -methyl- l-[[4-methylsulfonyl -2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid calcium salt [Fevipiprant calcium salt]

Fig. 4 represents X-ray powder diffraction pattern of 2-[2 -methyl- l-[[4-methylsulfonyl -2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid barium salt [Fevipiprant barium salt]

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

Accordingly, in main embodiment, the present invention provides the novel compounds of Formula IV,

Formula IV

wherein A is SOiMc. halogen or a leaving group.

In another embodiment, the leaving group is selected from the group that can easily be replaced by any other leaving group such as halogen and/or is replaced by methane sulfonyl group via sulfonylation reaction. The leaving group may be selected from, but not limited to, the group comprising of p-toluene sulfonyl, nitro, halogen, and the like.

In another embodiment, the present invention provides novel compounds of Formula IV which are represented as compounds of Formula IVa and IVb,

Formula IVa Formula IVb

wherein X is selected from chloro, bromo, iodo and fluoro.

In another embodiment, the novel compounds of Formula IV comprises of the compounds of Formula IVa - IVf as represented below:

Formula IVa Formula IVc Formula IVd

In one another embodiment, the present invention provides a process for the preparation of compounds of Formula IV, wherein said process comprising the steps of:

i) N-alkylation of 2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula II,

Formula II,

with compound of Formula III in presence of base,

Formula III,

wherein A is SOiMc. halogen or a leaving group,

to give compound of Formula IV,

Formula IV

wherein A is SOiMc. halogen or a leaving group.

In a preferred embodiment, the N-alkylation of compound of Formula II is carried out presence of organic or inorganic base selected from, but not limited to, the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, cesium bicarbonate, triethyl amine, dimethyl amino pyridine, diisopropyl amine, diisopropyl ethyl amine, sodamide, lithium tert-butoxide, n-butyl lithium, sodium tert-butoxide, potassium tert-butoxide, alkali tert-butoxide and mixture thereof.

In another preferred embodiment, the N-alkylation may be carried out in presence of phase transfer catalyst selected from, but not limited to, tetra n-butyl ammonium bromide, tetra n-butyl ammonium iodide, l2-crown-4, l5-crown-5, l8-crown-6, dibenzo-l8-crown-6, and diaza- 18 -crown-6.

In another embodiment, the N-alkylation is carried out in presence of solvent selected from, but not limited to, the group comprising of dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N-methyl pyrrolidine, acetamide, acetone, methanol, ethanol, tert-butanol, n-butanol, dichloromethane, o/m/p-xylene, dichloroethane, dichlorobenzene, acetonitrile, tert-butyl acetate, propyl acetate, iso-propyl acetate, ethyl acetate and mixture thereof. Preferably, the solvent is selected from dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, and N-methyl pyrrolidine.

In one another embodiment, the N-alkylation of compound of Formula II is carried out at a temperature in the range of 60 to l80°C.

In another embodiment, compound of Formula II may be prepared by any of the conventional methods such as disclosed in US 3,320,268 or any other method known from the prior art references; or can be purchased from any of the commercial source.

In another embodiment, compound of Formula III may be prepared by any of the conventional methods or any other method known from the prior art references; or can be purchased from any of the commercial source.

In one another embodiment, the compound of Formula IV is converted to 2-[2-methyl-l-[ [4-methylsulfonyl-2-(trifluoromethyl) phenyl] methyl] pyrrolo [2, 3 -b] pyridine -3 -yl] acetic acid of Formula I.

In one another embodiment, the present invention provides a process for the preparation of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl] methyl] pyrrolo [2,3-b]pyridine-3-yl] acetic acid of Formula I,

Formula I

comprising the steps of:

i) adding compound of Formula IV in a suitable solvent,

Formula IV

wherein A is SOiMc, halogen or a leaving group; and

ii) converting the compound of Formula IV to 2-[2-methyl-l-[[4-methylsulfonyl-2- (trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid of Formula I.

In a preferred embodiment, when A is SOiMc. the compound of Formula IV is hydrolysed in presence of acid to give compound of Formula I,

In yet another embodiment, when A is halogen, the compound of Formula IV is converted to compound of Formula I by sulfonylation of compound of Formula IV followed by hydrolysis in presence of acid,

In preferred embodiment, the halogen is replaced by sulfonylation in presence of sulfonylating agent. The above said reaction is carried out in presence of solvent such as polar and non-polar solvent selected from, but hot limited to, the group comprising of dimethyl formamide, dimethyl sulfoxide, acetamide, dimethyl acetamide, N-methyl pyrrolidine and the like.

In another embodiment, the sulfonylating agent is selected from, but not limited to, the group comprising of sodium methane sulfmate, methyl sulfonyl chloride, methane sulfonic acid, methyl sulfone, and the like.

In a preferred embodiment, the compound obtained after halogen replacement of compound of Formula IV, is hydrolysed in presence of acid to give compound of Formula I, i.e. Fevipiprant.

In another embodiment, the acid used for hydrolysis of compound of Formula IV (wherein A is -SCriMe) is selected from, but not limited to, the group comprising of hydrochloric acid, sulphuric acid, acetic acid, formic acid, propanoic acid, methane sulfonic acid, nitric acid and the like.

In another embodiment, the hydrolysis is performed in presence of suitable solvent selected from, but not limited to, the group comprising of dichloromethane, dichloroethane, acetone, methyl isobutyl ketone, ethyl acetate, acetonitrile, methanol, ethanol, isopropyl alcohol, butanol, tert-butanol, butyl acetate, tert-butyl acetate, isopropyl acetate, propyl acetate, dimethyl formamide, N-methyl acetamide, dimethyl sulfoxide, tetrahydrofuran, methyl ethyl ether, methyl tert butyl ether, dimethyl ether, diethyl ether, water, and mixture thereof.

In one of the preferred embodiment, the compound of Formula I is isolated with purity above 98.0% and wherein said compound of Formula I is substantially free of impurities wherein each impurity is less than about 0.15% w/w and total impurities are less than about 1.5% w/w.

In another embodiment, the present invention provides a novel process for the preparation of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl] methyl] pyrrolo [2,3-b]pyridine-3-yl] acetic acid of Formula I,

Formula I

comprising the steps of:

i) N-alkylation of 2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula II,

Formula II,

with compound of Formula III in presence of base,

Formula III,

wherein A is SOiMc. halogen or a leaving group,

to give compound of Formula IV,

Formula IV,

wherein, A is as defined above,

wherein when A is SChMc. compound of Formula IV is represented as Formula IVa, when A is halogen, compound of Formula IV is represented as Formula IVb; and ii) a) hydrolysis of the compound of Formula IVa to give compound of Formula I; or b) sulfonylation of the compound of Formula IVb to obtain compound of Formula IVa; and hydrolysis of the compound of Formula IVa to give compound of Formula I.

In further embodiment, the reaction step (b) i.e. sulfonylation of the compound of Formula IVb followed by hydrolysis to give compound of Formula I may be carried out in one pot without isolation of intermediate of Formula IVa.

In further embodiment, the N-alkylation of compound of Formula II can also be carried out by reacting compound of Formula II with 4-(halo)-2-(trifluoromethyl)benzaldehyde (represented as Formula Ilia), to give compound of Formula IV;

Formula Ilia

wherein A is SOiMc. halogen or a leaving group.

In an alternate embodiment, the compound of Formula IV can be prepared by reacting pyridinium N-oxide derivative of compound of Formula II with compound of Formula III or, compound of Formula Ilia to give compound of Formula IV as described below:

ormu a

Formula Ilia Fevipiprant wherein A is as defined above.

In one another embodiment, the present invention provides an alternate process for the preparation of compound of Formula I comprising the steps of:

Formula I

a) reacting 2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)acetic acid of Formula V,

Formula V

with 4-(halo)-2-(trifluoromethyl)benzyl bromide of Formula VI,

Formula VI

wherein X is halogen,

in presence of base to give compound of Formula VII,

Formula VII ; and

b) sulfonylation of compound of Formula VII optionally in presence of catalyst to give compound of Formula I.

In one another embodiment, the N-alkylation of compound of Formula V is carried out in presence of organic or inorganic base selected from, but not limited to, the group comprising of inorganic bases such as hydroxides, carbonates, bicarbonates, organic amines such as primary, secondary and tertiary amines.

In preferred embodiment, the N-alkylation of compound of Formula V is carried out in presence of base selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, cesium bicarbonate, triethyl amine, dimethyl amino pyridine, diisopropyl amine, diisopropyl ethyl amine, and so on.

In another preferred embodiment, the N-alkylation may be carried out in presence of phase transfer catalyst selected from, but not limited to, tetra n-butyl ammonium bromide, tetra n-butyl ammonium iodide and the like.

In another embodiment, the N-alkylation is carried out in presence of solvent selected from, but not limited to, the group comprising of dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, acetone, methanol, ethanol, tert-butanol, n-butanol, dichloromethane, o/m/p-xylene, dichloroethane, dichlorobenzene, acetonitrile, tert-butyl acetate, propyl acetate, iso-propyl acetate, ethyl acetate and mixture thereof. Preferably, the solvent is selected from dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, and N-methyl pyrrolidine.

In further embodiment, the halogen of compound of Formula VII is replaced by sulfonylation in presence of sulfonylating agent such as sodium methane sulfmate and the like to give compound of Formula I. The above said reaction is carried out in presence of solvent such as polar and non-polar solvent selected from the group comprising of dimethyl formamide, dimethyl sulfoxide, N-methyl pyrrolidine, acetamide, dimethyl acetamide and the like.

In another embodiment, the N-alkylation is carried out at a temperature range of 80-l80°C.

In another embodiment, the N-alkylation of compound of Formula II and/ or V may be carried out in continuous flow reactor like plug flow reactor, micro reactor and the like.

In another alternate embodiment, the compound of Formula V can be prepared by following the scheme as mentioned below:

Acetic acid

Formula VIII Formula IX

Acetic acid

Formula V

In a preferred embodiment, compound of Formula V may be prepared by any of the conventional methods such as disclosed in US 3,320,268 or can be purchased from the commercial source.

Moreover, compound of Formula Ilia can either be purchased from any of the commercial source or can be prepared by any of the conventional methods or any other method known from prior published references.

In one another embodiment, the present invention further provides substantially pure compound of Formula I, wherein said compound of Formula I is free from impurities of Formula 1-9 and wherein each impurity is less than about 0.15% w/w,

Formula 6 Formula 7 Formula 8 , and

Formula 9

In further embodiment, the present invention provides a compound of Formula I i.e. Fevipiprant, substantially free of impurities of Formula 1 to 9 and compound of Formula IVf.

In further embodiment, the present invention provides compound of Formula I substantially free of impurities of Formula 1 to 9 and compound of Formula IVf, wherein each impurity is less than about 0.15% w/w and total impurities are less than about 1.5% w/w.

In further embodiment, the present invention provides compound of Formula I having purity above 98.0% and is substantially free of impurities wherein each impurity is less than about 0.15% w/w and total impurities are less than about 1.5% w/w.

In other embodiment, the compound of Formula I may be converted into salt form or salt form may be converted into free form of Formula I, by any of the conventional methods. The compound of Formula I in free or salt form can be obtained in form of hydrates or solvates. The compound of Formula I in free or salt form can be obtained in amorphous or any of the crystalline form.

In another embodiment, the present invention provides various salts of compound of Formula I, specifically pharmaceutically acceptable salts. The pharmaceutically acceptable salts of compound of Formula I include acid addition salts such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, diphenylacetic acid, triphenyl acetic acid, carprylic acid, dichloroacetic acid, trifluoroacetic acid, hippuric acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, furmaric acid, glutamic acid, maleic acid and the like. The pharmaceutical acceptable salts further includes pharmaceutically acceptable bases such as alkali metal or alkaline earth metal salts, organic and heterocyclic bases and wherein said pharmaceutical acceptable bases are selected from sodium, potassium, magnesium, calcium, zinc, barium, benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl)morpholine, l-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine.

In a preferred embodiment, the compound of Formula I is converted to its pharmaceutical acceptable salts selected from sodium, potassium, calcium, barium, oxalate, citrate and tartarate salts. More preferably, the compound of Formula I is converted to its pharmaceutical acceptable salts selected from sodium, potassium, calcium and barium.

In one another embodiment, the present invention provides a process for the preparation of pharmaceutical acceptable salt of compound of Formula I wherein said process comprising the steps of:

i) heating compound of Formula I in an alcohol to get clear solution;

ii) cooling the clear solution to room temperature and reacting with aqueous solution of metal base; and

iii) filtering and isolating to get salt of compound of Formula I.

In further embodiment, the alcohol used in preparation of various salts of compound of Formula I is selected from, but not limited to, the group comprising of methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, tert-butanol, pentanol and mixture thereof.

In further embodiment, the metal base used for preparing various salts of compound of Formula I is selected from, but not limited to, calcium hydroxide, barium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonates, potassium carbonate, cesium carbonate, calcium carbonate, barium carbonate and the like.

In further embodiment, the heating of compound of Formula I in an alcohol is carried out at a temperature in the range of 40-90°C.

In further embodiment, the isolation of salts of compound of Formula I is carried out by a process selected from drying under vacuum, filtration under suction, lyophilization, spray drying, centrifugation, and freeze drying.

In another embodiment, the present invention provides pharmaceutical acceptable salts of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl] pyrrolo [2,3-b]pyridine-3-yl] acetic acid selected from the group comprising of:

i) sodium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo[2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 4.99, 12.44, 14.48, 15.76, and 21.90±0.2°2Q; ii) potassium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo[2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 10.18, 20.25, and 28.5 l±0.2°20;

iii) calcium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo[2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 10.05, 15.43, 20.16, 23.39, and 29.38±0.2°20; and iv) barium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo[2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 10.32, 12.68, 21.42, and 23.92±0.2°20.

In further embodiment, the present invention provides sodium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 4.99, 12.44, 14.48, 15.76, and 21.90±0.2°2Q. In an embodiment, the present invention provides sodium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl] methyl] pyrrolo [2,3-b]pyridine-3-yl] acetic acid having one or more additional peaks at about 5.79, 7.47, 8.66, 11.57, 13.25, 14.93, 16.60, 17.06, 17.34, 17.79, 19.05, 19.38, 20.10, 20.94, 21.27, 21.45, 22.62, 22.97, 23.54, 25.12, 26.12, 26.99, 27.60, 29.16, 31.53, 32.16, 33.52±0.2°20. In an embodiment, the present invention provides sodium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern as represented in Fig. 1.

In further embodiment, the present invention provides potassium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 10.18, 20.25, and 28.5 l±0.2°20. In an embodiment, the present invention provides potassium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid having one or more additional peaks at about 11.78, 15.96, 21.39, 26.53, 30.5 l±0.2°20. In an embodiment, the present invention provides potassium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern as represented in Fig. 2.

In further embodiment, the present invention provides calcium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 10.05, 15.43, 20.16, 23.39, and 29.38±0.2°20. In an embodiment, the present invention provides calcium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl] methyl] pyrrolo [2,3-b]pyridine-3-yl] acetic acid having one or more additional peaks at about 6.39, 10.81, 11.91, 12.80, 14.44, 16.16, 16.81, 18.98, 19.29, 20.55, 20.77, 21.18, 21.92, 22.66, 23.87, 24.48, 24.94, 25.53, 26.22, 26.61, 27.12, 27.71, 30.46, 31.75, 32.24, 32.68, 34.47, 34.71, 39.40 ±0.2°20. In an embodiment, the present invention provides calcium salt of 2-[2-methyl-l-[ [4-methylsulfonyl-2-(trifluoromethyl) phenyl] methyl] pyrrolo [2, 3 -b] pyridine -3 -yl] acetic acid characterized by X-ray powder diffraction pattern as represented in Fig. 3.

In further embodiment, the present invention provides barium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 10.32, 12.68, 21.42, and 23.92±0.2°2Q. In an embodiment, the present invention provides barium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid having one or more additional peaks at about 3.89, 4.39, 5.20, 6.46, 9.69, 10.73, 11.70, 13.21, 13.70, 15.49, 16.65, 17.01, 18.02, 18.80, 19.40, 19.95, 20.74, 21.96, 22.88, 23.53, 25.11, 25.58, 25.85, 26.93, 27.13, 26.93, 27.13, 28.85, 29.27, 32.32, 33.72, 34.11±0.2°20. In an embodiment, the present invention provides barium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern as represented in Fig. 4.

In another embodiment of the present invention, the 2-[2 -methyl- l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl] methyl] pyrrolo [2,3-b]pyridine-3-yl]acetic acid [fevipiprant] of Formula I used for preparation of various salts of Fevipiprant, may be prepared either by any of the conventional methods or by the methods known in the prior published references or by the methods of the present invention.

In one another embodiment, the present invention provides a pharmaceutical composition comprising pharmaceutical acceptable salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2, 3 -b] pyridine -3 -yl] acetic acid along with at least one pharmaceutical acceptable excipient thereof, wherein said pharmaceutical acceptable salt is prepared as per the process of the present invention.

In another preferred embodiment, the compound of Formula I, i.e. Fevipiprant is characterized by the particle size distribution wherein, ds>o is between 0. 1 pm to 200pm.

In a preferred embodiment, the compound of Formula I, i.e. Fevipiprant characterized by particle size distribution wherein, ds>o is between 2.0 pm to l50pm.

In still another embodiment, the present invention provides a pharmaceutical composition comprising compound of Formula I and at least one pharmaceutical acceptable excipient thereof.

In still another embodiment, the present invention provides method of treating an obstructive or inflammatory airway of disease such as asthma and atopic dermatitis by administration of Fevipiprant wherein said fevipiprant is prepared as per the process of the present invention.

EXAMPLES:

EXAMPLE 1.0: Preparation of 2-(2-methyl-l-(4-(methylsulfonyl)-2- (trifluoromethyl)foenzyI)-lH-pyrrolo[2,3-b]pyridin-3-yl)acetic add [Fevipiprant]

1.1 Preparation of ethyl 2-methyl- lH-pyrrolo [2, 3-b]pyridine-3-carboxylate:

Charged 4.0g of 3-bromopyridin-2-amine, 18.0g of ethyl acetoacetate, 0.4g of copper iodide, 15.2g of cesium carbonate and 0.662g of BINOL in 60.0 ml of dimethyl sulfoxide and stirred at l00-l20°C till completion of reaction. After completion of reaction, quenched the reaction with DM water and extracted the compound in ethyl acetate (2x). Combined the organic layer and concentrated under vacuum to give 3.8 g of ethyl 2-methyl- lH-pyrrolo [2,3-b]pyridine-3 -carboxylate .

1.2 Preparation of 2-methyl-lH-pyrrolo[2,3-b]pyridine-3-carboxylic acid:

Charged 3.5g of ethyl 2-methyl-lH-pyrrolo[2,3-b]pyridine-3-carboxylate in autoclave in 20.0 ml of methanol and added 60.0 ml of 20% NaOH solution under N2 pressure at 5.0 psi. After completion of reaction, quenched the reaction with water and distilled the solvents. Added ethyl acetate and washed the organic layer with DM water. Concentrated the organic layer to give 2.6g of 2-methyl- 1 //-pyrrolo| 2.3% |pyridinc-3-carboxylic acid.

1.3 Preparation of (2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)methanol:

To 2.6g of 2 -methyl- li/-pyrrolo [2, 3 -6]pyridine-3 -carboxylic acid was added methanol followed by addition of sodium borohydride. Stirred the reaction solution at room temperature till completion of reaction. Quenched the reaction with water and extracted the compound in dichloromethane. Separated the layers and concentrated the dichloromethane layer to give 2.0g of (2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)methanol.

1.4 Preparation of 3-(chloromethyl)-2-methyl-lH-pyrrolo[2,3-b]pyridine:

To 2.0g of (2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)methanol was added 4.37g of thionyl chloride in 25.0 ml of dichloromethane. Stirred the reaction at room temperature for 3-4 hrs.

After completion of reaction, distilled the solvents and added water to the crude so obtained. Extracted the compound in dichloromethane and separated the layers followed by concentration of dichloromethane layer under vacuum to give 2.2 g of 3-(chloromethyl)-2-methyl- l//-pyrrolo 12.3 -A | py ridine .

1.5 Preparation of 2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile:

Charged 2.0g of 3-(chloromethyl)-2-methyl- l//-pyrrolo| 2,3- 1 pyridine in dimethyl formamide and added 1.08 g of potassium cyanide to the above solution. Heated the reaction to 80-90°C under stirring till completion of reaction. After completion of reaction, quenched the reaction with water and added ethyl acetate. Separated the layers and concentrated the ethyl acetate layer under vacuum to get 1.2 of 2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile.

1.6 Preparation of (4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol:

Charged 10. Og of 4-(methylsulfonyl)-2-(trifluoromethyl)benzaldehyde in methanol and added 1.5 eq of sodium borohydride at 0°C. Heated the reaction to room temperature and stirred for 2hrs. After completion of reaction, quenched the reaction with water and extracted the compound in ethyl acetate (3x). Combined the organic layers and concentrated under vacuum to give 10. Og of (4-(methyl sulfonyl)-2-(trifluoromethyl)phenyl)methanol.

1.7 Preparation of 2-methyl-lH-pyrrolo[2,3-b]pyridine:

Charged 5.0g of 2-aminopyridine in water (50 ml) followed by addition of 4. l4g of 2-chloroacetone. Stirred at room temperature for 1 hour and to the above aqueous solution of nitrogen-(2-chloroethyl) erythio-2-imine was added sodium acetate (6.51 g) slowly and then the temperature was raised to l00°C. Stirred for 5 hours at 25°C and filtered the resulting precipitates. Dried the precipitates to give 4.1 g of 2-methyl-lH-pyrrolo[2,3-b]pyridine.

1.8 Preparation of N,N-dimethyl-l-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)methanamine :

Charged 4.0g of 2-methyl- l//-pyrrolo| 2.3-A |pyridine and 0.8g of paraformaldehyde in butanol followed by slow addition of 4.0g of N,N-dimethyl amine. Heated the reaction solution at reflux condition till completion of reaction. After completion of reaction, quenched the reaction with water and extracted the compound in ethyl acetate (3x).

Combined the organic layers and concentrated the layers 3.7g of /V./V-di methyl- 1 -(2-methyl-l//-pyrrolo [2,3 -6] pyridin-3 -yl)methanamine .

1.9 Preparation of 2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile:

To 3.7g of A. '-di methyl- 1 -(2-methyl- 17/-pyrrolo| 2 -b |pyridin-3-yl)methan amine was added l.46g of potassium cyanide in 40 ml of water. Heated the reaction mass to reflux till completion of reaction. Quenched the reaction with water and extracted the compound in dichloromethane (3x). Combined the organic layer and concentrated under vacuum to give the 2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile.

1.10 Preparation of l-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl) benzene:

Charged 10. Og of (4-(methyl sulfonyl)-2-(trifluoromethyl)phenyl)methanol was added 32.2g of phosphorus tribromide in 120 ml of dichloromethane at 40°C. After completion of reaction, quenched the reaction with sodium bicarbonate solution and extracted the compound in ethyl acetate (3x). Combined the organic layers and concentrated under vacuum to give 11.5 g of l-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl)benzene.

Charged 5.0g of 2-(2-methyl-lH-pynOlo[2,3-b]pyridin-3-yl)acetonitrile in 30.0 ml of dimethyl formamide and added 12.0 g of potassium carbonate and stirred at room temperature for 1 hr. Added 9.26 g of l-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl)benzene at l00°C and stirred the reaction at l00°C for 7-8hrs. The reaction is concentrated under vacuum followed by addition of toluene. Distilled the solution and crude was proceeded to next step without any purification.

To the crude so obtained was added methyl isobutyl ketone followed by addition of 1N HC1 solution at room temperature. Heated the reaction mass at 50°C for 3-4 hrs. Separated the organic layer and charged 50.0 ml of methyl isobutyl ketone. Heated at 80°C for 1.0 hr followed by separation of organic layer which was distilled under vacuum to give 7.2 g of fevipiprant.

EXAMPLE 2: Preparation of sodium salt of compound of Formula I (Fevipiprant sodium salt)

Charged Fevipiprant (500.0 mg) in 50 ml RBF with methanol (8.0 ml) and heated the reaction mass at 50.0°C to get clear solution. Dissolved sodium hydroxide (46.0 mg) in distilled water (4.0 ml) and added the sodium hydroxide solution in above RBF and stirred for 3-4 hrs at room temperature. Solid was separated out filtered and dried under vacuum at 50.0°C to get 430.0 mg of sodium salt of Fevipiprant.

EXAMPLE 3: Preparation of calcium salt of compound of Formula I (Fevipiprant calcium salt)

Charged Fevipiprant (500.0 mg) in 50 ml RBF with methanol (10.0 ml) and heated the reaction mass at 50.0°C to get clear solution. Dissolved calcium hydroxide (43.0 mg) in distilled water (5.0 ml). Added the calcium hydroxide suspension in above RBF and stirred for 9-10 hrs at room temperature. Solid was separated out filtered washed with methanol and dry under vacuum at 50.0°C to give 380. Omg of calcium salt of Fevipiprant.

EXAMPLE 4: Preparation of potassium salt of compound of Formula I (Fevipiprant potassium salt)

Charged Fevipiprant (500.0 mg) in 250 ml RBF with methanol (5.0 ml) and heated the reaction mass at 50.0°C to get clear solution. Dissolved the potassium hydroxide (65.0 mg) in distilled water (20.0 ml). Added potassium hydroxide solution in above RBF and lyophilized the material to get 520.0 mg of Fevipiprant potassium salt.

EXAMPLE 5: Preparation of barium salt of compound of Formula I (Fevipiprant barium salt)

Charged Fevipiprant (500.0 mg) in 50.0 ml RBF with methanol (5.0 ml) and heated the reaction mass at 50.0°C to get clear solution. Dissolved barium hydroxide (200.0 mg) in distilled water (10.0 ml) and added the barium hydroxide solution in above RBF and stirred the reaction mass for 20-30 minutes. White solid was then filtered and washed with distilled water and dried under vacuum at 50.0°C to give 340.0 mg of barium salt of fevipiprant.

CLAIMS:

1. Compounds of Formula IV,

Formula IV

wherein A is SCFIVIc. halogen or a leaving group.

2. The compounds of Formula IV as claimed in claim 1, comprising compounds of Formula IVa and IVb,

Formula IVa Formula IVb

wherein X is selected from chloro, bromo, iodo and fluoro.

3. A process for the preparation of compounds of Formula IV as claimed in claim 1, wherein said process comprising the steps of:

i) N-alkylation of 2-(2-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula

P,

Formula II,

with compound of Formula III in presence of base,

wherein A is SCFIVIc. halogen or a leaving group,

to give compound of Formula IV,

Formula IV

wherein A is as defined above.

4. The process as claimed in claim 3, wherein said base is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, cesium carbonate, cesium bicarbonate, triethyl amine, dimethyl amino pyridine, diisopropyl amine, diisopropyl ethyl amine, sodamide, lithium tert-butoxide, n-butyl lithium, sodium tert-butoxide, potassium tert-butoxide, alkali tert-butoxide and mixture thereof.

5. The process as claimed in claim 3, wherein said N-alkylation is optionally carried out in presence of phase transfer catalyst selected from tetra n-butyl ammonium bromide, tetra n-butyl ammonium iodide, l2-crown-4, l5-crown-5, l8-crown-6, dibenzo-l8- crown-6, and diaza- 18 -crown-6.

6. The process as claimed in claim 3, wherein said compound of Formula IV is converted to 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3- b] pyridine -3 -yl] acetic acid.

7. A process for the preparation of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid of Formula I,

Formula I

comprising the steps of:

i) adding compound of Formula IV in a suitable solvent,

Formula IV

wherein A is SChMc. halogen or a leaving group; and

ii) converting the compound of Formula IV to 2-[2 -methyl- l-[[4-methylsulfonyl-2- (trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid of Formula I.

8. The process as claimed in claim 7, wherein when A is SChMc. the compound of Formula IV is hydrolysed in presence of acid to give compound of Formula I,

The process as claimed in claim 7, wherein when A is halogen, the compound of Formula IV is converted to compound of Formula I by sulfonylation of compound of Formula IV followed by hydrolysis in presence of acid,

Formula I

10. The process as claimed in claim 7, wherein said suitable solvent is selected from the group comprising of dichloromethane, dichloroethane, acetone, methyl isobutyl ketone, ethyl acetate, acetonitrile, methanol, ethanol, isopropyl alcohol, butanol, tert-butanol, butyl acetate, tert-butyl acetate, isopropyl acetate, propyl acetate, dimethyl formamide, N-methyl acetamide, dimethyl sulfoxide, tetrahydrofuran, methyl ethyl ether, methyl tert butyl ether, dimethyl ether, diethyl ether, water, and mixture thereof.

11. The process as claimed in claim 8, wherein said acid is selected from the group comprising of hydrochloric acid, sulphuric acid, acetic acid, formic acid, propanoic acid, methane sulfonic acid, nitric acid and the like.

12. The process as claimed in claim 7, wherein said compound of Formula I is isolated with purity above 98.0% and wherein said compound of Formula I is substantially free of impurities wherein each impurity is less than about 0.15% w/w and total impurities are less than about 1.5% w/w.

13. A pharmaceutical acceptable salt of 2-[2-methyl-l-[[4-methylsulfonyl-2- (trifluoromethyl) phenyl]methyl]pyrrolo [2, 3 -b] pyridine -3 -yl] acetic acid selected from the group comprising of:

i) sodium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 4.99, 12.44, 14.48, 15.76, and 2l.90±0.2°20; ii) potassium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 10.18, 20.25, and 28.51±0.2°20;

iii) calcium salt of 2-[2 -methyl- l-[[4-methylsulfonyl-2-(trifluoromethyl)

5 phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder diffraction pattern having peaks at about 10.05, 15.43, 20.16, 23.39, and 29.38±0.2°20; and

iv) barium salt of 2-[2-methyl-l-[[4-methylsulfonyl-2-(trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid characterized by X-ray powder

10 diffraction pattern having peaks at about 10.32, 12.68, 21.42, and 23.92±0.2°20.

14. The pharmaceutical acceptable salt of 2-[2-methyl-l-[[4-methylsulfonyl-2- (trifluoromethyl) phenyl]methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid as claimed in claim 13, wherein said salt is prepared by a process comprising the steps of:

^5 Formula 1

i) heating compound of Formula I in an alcohol get clear solution;

ii) cooling the clear solution to room temperature and reacting with aqueous solution of metal base; and

iii) filtering and isolating to get salt of compound of Formula I.

20

15. The process as claimed in claim 14, wherein said alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol, iso-butanol, tert-butanol, pentanol and mixture thereof; and wherein said metal In further embodiment, the metal base is selected from calcium hydroxide, barium hydroxide, sodium hydroxide, potassium 25 hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonates, potassium carbonate, cesium carbonate, calcium carbonate, and barium carbonate.