DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESS FOR THE PREPARATION OF FEVIPIPRANT

INTRODUCTION
Aspects of the present application relate to process for the preparation of Fevipiprant and intermediates thereof.
Fevipiprant is the adopted name of drug compound having a chemical name: 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid and structure as below.

Novartis is developing Fevipiprant, also known as QAW-039, a prostaglandin D2 receptor (PD2/CRTh2) antagonist, as an oral capsule formulation for the potential treatment of asthma and moderate to severe atopic dermatitis. The research, funded by Novartis Pharmaceuticals, National Institute for Health Research (NIHR) and the EU (AirPROM) and carried out by scientists at Leicester University, demonstrated that Fevipiprant pill significantly decreased the symptoms of asthma, improved lung function, reduced inflammation and repaired the lining of airways.
US 7666878 B2 discloses Fevipiprant [1-(4-Methanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid] its composition and use for treating inflammatory or allergic condition for which antagonism of the CRTh2 receptor is useful such as intrinsic asthma, extrinsic asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma or bacterial infection induced asthma.
US 7666878 B2 discloses the preparation of Fevipiprant according the scheme-1 as depicted below.

Prior art process may not suitable at a large scale to obtain the product with desired quality and yield. Hence, there remains need for the preparation of Fevipiprant with an inexpensive, environmentally friendly solvents and economical process that is better suited for industrial application. Further, there remains a need for a reproducible and stable solid form of Fevipiprant.

SUMMARY
In an aspect, the present application provides a process for the preparation of Fevipiprant of formula I, comprising the steps of
a) acylation of pyrrolo[2,3-b]pyridine of formula (II) with ethyl 2-chloro-2-oxoacetate to obtain acylated pyrrolo[2,3-b]pyridine of formula (III);

b) optionally reducing the acylated pyrrolo[2,3-b]pyridine of formula (III) to pyrrolo[2,3-b]pyridine of formula (IV);

c) reacting pyrrolo[2,3-b]pyridine of formula (III) or (IV) with 1-(bromomethyl)-2-(trifluoromethyl)benzene of formula (V) to obtain ethyl ester of formula (Ia) o (Ib), wherein R is selected from the group comprising of methylsulfane or methylsulfonyl;

d) optionally reducing the ethyl ester of formula (Ia) to obtain compound of formula (Ib)

e) sulfoxidation of ethyl ester of formula (Ib), when R is methylsulfane.
f) hydrolyzing the ethyl ester of formula (Ib), wherein R is methylsulfonyl, to Fevipiprant of formula (I).

In another aspect, the present application provides a pharmaceutical composition comprising Fevipiprant obtained according to process of previous aspect, together with atleast one pharmaceutically acceptable excipient.

DETAILED DESCRIPTION
Aspects of the present application provide process for the preparation of Fevipiprant and intermediates thereof.
In an aspect, the present application provides a process for the preparation of Fevipiprant of formula I, comprising the steps of
a) acylation of pyrrolo[2,3-b]pyridine of formula (II) with ethyl 2-chloro-2-oxoacetate to obtain acylated pyrrolo[2,3-b]pyridine of formula (III);

b) optionally reducing the acylated pyrrolo[2,3-b]pyridine of formula (III) to pyrrolo[2,3-b]pyridine of formula (IV);

c) reacting pyrrolo[2,3-b]pyridine of formula (III) or (IV) with 1-(bromomethyl)-2-(trifluoromethyl)benzene of formula (V) to obtain ethyl ester of formula (Ia) o (Ib), wherein R is selected from the group comprising of methylsulfane or methylsulfonyl;

d) optionally reducing the ethyl ester of formula (Ia) to obtain compound of formula (Ib)

e) sulfoxidation of ethyl ester of formula (Ib), when R is methylsulfane.
f) hydrolyzing the ethyl ester of formula (Ib), wherein R is methylsulfonyl, to Fevipiprant of formula (I).

Starting materials used in this aspect may be prepared according to any of the processes known in the art or by following to the procedure described or exemplified in the instant application. Alternatively, the starting material may be obtained from any of the commercially available sources. In embodiments, the starting materials may be used after purifying according to any of the suitable purification methods that include but not limited to crystallization, chromatography, acid-base treatment, fractional distillation, or the like.
Step a) of the present aspect may be carried out by acylating pyrrolo[2,3-b]pyridine of formula (II) with ethyl 2-chloro-2-oxoacetate to obtain acylated pyrrolo[2,3-b]pyridine of formula (III).

In embodiments, acylation of pyrrolo[2,3-b]pyridine of formula (II) may be carried out under Friedal-Craft’s acylation conditions. Acylation may be carried out in the presence of Lewis acid catalyst such as ZnCl2, BF3, SnCl4, AlCl3 and MeAlCl2.
Reaction of pyrrolo[2,3-b]pyridine of formula (II) with ethyl 2-chloro-2-oxoacetate may be carried out by adding ethyl 2-chloro-2-oxoacetate gradually in single lot or in multiple lots.
In embodiments, the acylation step may be carried out in the presence of an inert solvent such as dichloromethane, dichloroethane, N-methyl pyrrolidine, nitromethane, Tetrahydrofuran or mixtures thereof.
In embodiments, the acylation may be carried out at suitable temperature of about -30°C to reflux temperature of the solvent used and for sufficient time to complete the acylation for atleast one hour or more.
Step b) of this aspect may be optionally carried by reducing the acylated pyrrolo[2,3-b]pyridine of formula (III) of step a) to alkylated pyrrolo[2,3-b]pyridine of formula (IV).

In embodiments, the reduction of acylated pyrrolo[2,3-b]pyridine of formula (III) may be carried out in the presence of a suitable reducing agent. Suitable reducing agent includes, but not limited to alkylsilanes such as Triethyl silane (Et3SiH), Triethyl silane (Et3SiH) – trifluoroacetic acid (TFA), alkylsiloxanes such as Polymethylhydrosiloxane (PMHS), Diethoxymethylsilane (DEMS), phenylsilane (PhSiH3) and halosilanes such as trichlorosilane or the like.
In embodiments, reduction may be carried out optionally in the presence of an inert solvent Inert solvent includes, but not limited to ethers such as tetrahydrofuran, 1,4-dioxane or hydrocarbons such as dichoromethane, or mixtures thereof. In an embodiment, the reduction may be carried out using Triethyl silane (Et3SiH) - trifluoroacetic acid (TFA), without any other solvent.
In embodiments, reduction may be carried out at suitable temperature of about 0°C to reflux temperature of the solvent used and for sufficient time to complete the reduction for atleast one hour or more.
Step c) of this aspect may be carried out by reacting pyrrolo[2,3-b]pyridine of formula (III) or (IV) with 1-(bromomethyl)-2-(trifluoromethyl)benzene of formula (V) to obtain ethyl ester of formula (Ia), wherein R is selected from the group comprising of methylsulfane or methylsulfonyl.
In embodiments, pyrrolo[2,3-b]pyridine of formula (III) may be alkylated with 1-(bromomethyl)-2-(trifluoromethyl)benzene of formula (V) to obtain ethyl ester of formula (Ia), wherein R is selected from the group comprising of methylsulfane or methylsulfonyl.

In embodiments, pyrrolo[2,3-b]pyridine of formula (IV) may be alkylated with 1-(bromomethyl)-2-(trifluoromethyl)benzene of formula (V) to obtain ethyl ester of formula (Ib), wherein R is selected from the group comprising of methylsulfane or methylsulfonyl.

In embodiments, the alkylation may be carried out in the presence of a suitable base. Suitable base includes, but not limited to 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP).
In embodiments, the alkylation may be carried out in the presence of an inert solvent. Inert solvent includes, but not limited to dimethylformamide, dimethyl acetamide, n-methyl pyrrolidone, dimethyl sulfoxide, or mixtures thereof.
In embodiments, alkylation may be carried out at suitable temperature of about 0°C to reflux temperature of the solvent used and for sufficient time to complete the reduction for atleast one hour or more.
Step d) of this aspect may be carried out by reducing the ethyl ester of formula (Ia) to obtain corresponding ethyl ester of formula (Ib).

In embodiments, the reduction may be carried out under conditions similar to the reduction process described at step b). In embodiments, reaction mixture containing ethyl ester of formula (Ib) after reduction may be taken directly without isolation or after isolation and purification, to next steps.
Step e) of this aspect may be carried out by sulfoxidation of ethyl ester of formula (Ib), when R is methylsulfane.

In alternate embodiments, the ethyl ester of formula (Ia), when R is methylsulfane may be subjected to sulfoxidation and then the resulting product is subjected to reduction of keto group.

In embodiments, reaction mixture containing ethyl ester of formula (Ib) may be taken directly without isolation or after isolation and purification, to next step.
In embodiments, sulfoxidation of ethyl ester of formula (Ia) or (Ib) may be carried out in the presence of a suitable oxidizing agent. Suitable oxidizing agent includes but not limited to peroxy acids such as peroxy acetic acid, trifluoroperoxy acetic acid, m-chloro peroxybenzoic acid (mCPBA), peroxides such hydrogen peroxide, urea-hydrogen peroxide, tert-butyl hydroperoxide, or the like.
Sulfoxidation of ethyl ester of formula (Ia) or (Ib) may be carried out in the presence of an inert solvent such as hydrocarbons such as dichloromethane or ethers such as tetrahydrofuran, 1,4-dioxane; or mixtures thereof.
Sulfoxidation may be carried out at suitable temperature of about 0°C to reflux temperature of the solvent used and for sufficient time to complete the reduction for atleast one hour or more.
Step f) of this aspect may be carried out by hydrolyzing the ethyl ester of formula (Ib), wherein R is methylsulfonyl, to obtain Fevipiprant of formula (I).
In embodiments, hydrolysis of the ester of formula (Ib) may be carried out in the presence of an acid or a base. In embodiments, the hydrolysis may be carried out in the presence of a suitable base. Suitable base includes, but not limited to hydroxides, carbonates or bicarbonates of alkaline metals such as sodium, lithium, potassium, calcium, magnesium or ammonia.

In embodiments, the hydrolysis may be carried out in the presence of an inert solvent such as acetonitrile, tetrahydrofuran, dichloromethane, water or mixtures thereof.
Sulfoxidation may be carried out at suitable temperature of about 0°C to reflux temperature of the solvent used and for sufficient time to complete the reduction for atleast one hour or more.
In embodiment, Fevipiprant obtained in step f) may be dried under suitable drying conditions at temperature and time where Fevipiprant is stable and not affected at 30°C or above for atleast one hour or more.
In embodiments, Fevipiprant obtained in step f) may be optionally purified through methods known in the art or procedures described or exemplified in the instant application. Fevipiprant obtained in step f) may be obtained as a crystalline or amorphous solid.
In another aspect, the present application provides a pharmaceutical composition comprising Fevipiprant obtained according to process of previous aspect, together with atleast one pharmaceutically acceptable excipient.
In another aspect, the present application provides Fevipiprant or pharmaceutical composition comprising Fevipiprant or a salt thereof having a chemical purity of atleast 99% by HPLC or atleast 99.5% by HPLC or atleast 99.9% by HPLC.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagent s under conditions that cause the chemical reaction indicated to take place.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called“aromatic.” Examples of “C5-C8aliphatic or aromatic hydrocarbons” include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.
A “nitrile” is an organic compound containing a cyano -(C=N) bonded to another carbon atom. “C2-C6Nitriles” include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

EXAMPLES
Example-1: Preparation of 4-(methylthio)-2-(trifluoromethyl) benzaldehyde

4-Fluoro-2-trifluoromethylbenzaldehyde (150 g) was dissolved in dimethyl formamide (750 mL) at 28°C and the reaction mixture was cooled to 0°C. Sodium thiomethoxide (65.6g) was added and heated the reaction mixture to 90°C. The mixture was stirred at the same temperature for 2 hours. Chilled water (1500 mL) was added to the reaction mixture after the completion of the reaction. Extracted the reaction mixture with ethyl acetate (2 x 750 mL) and washed the organic layer with brine solution (2 x 750 mL). The organic layer was dried over sodium sulphate and removed the solvent under reduced pressure at 50°C to obtain the title compound as light yellow residue. Yield: 141.0 g

Example-2: Preparation of (4-(methylthio)-2-(trifluoromethyl)phenyl) methanol

4-(methylthio)-2-(trifluoromethyl)benzaldehyde (140 g) was dissolved in 700 mL at 28°C and the solution was cooled to 0°C. Sodium borohydride (28.86 g) was slowly added at 10°C and then the temperature of the reaction mixture was raised to 28°C. The mixture was stirred at the same temperature for 2 hours. The solvent was removed under reduced pressure at 50°C. Dichloromethane (1400 mL) and 1 N HCl (1400 mL) was added to the crude reaction product and separated the organic layer. The organic layer was washed with brine solution (2 x 700 mL) and dried over sodium sulphate. The solvent was removed completely under reduced pressure to obtain the title compound as yellowish residue. Yield: 139 g and Purity by HPLC: 98.97%

Example-3: Preparation of (4-(methylsulfonyl)-2-(trifluoromethyl)phenyl) methanol

(4-(methylthio)-2-(trifluoromethyl)phenyl) methanol (138 g) was dissolved in dichloromethane (3450 mL) at 28°C and cooled the solution to 10°C. m-chloro peroxybenzoic acid (321.48 g) was added to the mixture at 15°C and allowed the mixture to warm to 27°C and stirred at the same temperature for 21 hours. 10% sodium thiosulphate solution (1380 mL) to the reaction mixture and separated the organic layer and washed it with 1N sodium hydroxide solution (2760 mL), brine solution (2 x 1380 mL) and then dried over sodium sulphate. The solvent was removed under reduced pressure at 50°C to obtain the title compound as off-white solid. Yield: 136.5 g and Purity by HPLC: 92.95%.
Example-4: Preparation of 1-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl)benzene

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol (135 g) was dissolved in dichloromethane (2700 mL) and cooled the solution to 5°C. Triphenylphosphine (208.9 g) and carbontetrabromide (264.16 g) was added the 5°C and stirred for 1 hour at the same temperature. Water (1350 mL) was added to the reaction mixture after the completion of reaction and separated the organic layer. Organic layer was washed with brine solution (2 x 675 mL) and dried over sodium sulphate. The solvent was removed completely under reduced pressure at 50°C and methyl tert.butyl ether (675 mL) was added. Stirred the reaction mixture for 20 minutes at 28°C and the solid was filtered. The solid was washed with methyl tert.butyl ether (2 x 540 mL). Crude product was purified by column chromatography using mixture of ethyl acetate - hexane as eluent to obtain the title compound as white colour solid.
Yield: 95.2 g
Example-5: Preparation of ethyl 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetate

A mixture of Aluminum chloride (161.4 g) and nitromethane (500 mL) was cooled to -10°C and a solution of 2-methyl-1H-pyrrolo[2,3-b]pyridine (50 g) dissolved in 1,2-dichloro ethane (500 mL) was added slowly to the above reaction mixture at -10°C. The reaction mixture was stirred for 15 minutes at -10°C and ethyl 2-chloro-2-oxoacetate (67.15 g) was added slowly at the same temperature. The reaction mixture was stirred for 3 hours at -8°C and the reaction mixture was added to chilled water (100 mL) at 5°C and stirred for 10 minutes at the same temperature. The organic layer was separated and the aqueous layer was extracted to dichloromethane (2 x 300 mL). The combined organic layer was washed with brine solution (300 mL) and dried on sodium sulphate. The solvent was removed from the organic layer under reduced pressure at 50°C. n-hexane (100 mL) was added to the reaction mixture and stirred for 15 minutes at 27°C. The solid was filtered and washed with n-hexane (2 x 20 mL). The solid was dried under reduced pressure at 27°C for 30 minutes to obtain the title compound as pale yellow solid.
Yield: 69.2 g and Purity by HPLC: 99.80%

Example-6: Preparation of ethyl 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate

A solution of 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetate (50 g) in trifluoroacetic acid (TFA) (500 mL) is added to a solution of triethylsilane (90.12 g) in trifluoroacetic acid (TFA) (250 mL) at 27°C and heated to 60°C. Stirred the reaction mixture at 63°C for 18 hours and the solvent was removed under reduce pressure at 50°C after the completion of the reaction. Ethanol (300 mL) & 10 % sodium bicarbonate solution (500 mL) was added to the crude product at 27°C and stirred for 2 hours at the same temperature. The reaction mixture was then extracted with dichloromethane (3 x 125 mL) and combined organic layer was washed with brine solution (100 mL). The organic layer was dried over sodium sulphate and removed the solvent under reduced pressure at 45°C. n-hexane (100 mL) was added to the product at 27°C and cooled to 10°C. Stirred the mixture for 10 minutes at the same temperature and the solid was filtered. The solid was washed with n-hexane (50 mL) and dried under reduced pressure at 45°C for 1 hour to obtain the title compound.
Yield: 24.2 g and Purity by HPLC: 99.51%

Example-7: Preparation of ethyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate

Ethyl 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (23 g) was dissolved in dimethylformamide (345 mL) at 27°C and cooled the solution to 10°C. 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) (28.9 g) was added slowly to the reaction mixture at 10°C and the reaction mixture was stirred at the same temperature for 40 minutes. A solution of 1-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl) benzene (50.12 g) in dimethylformamide (115 mL) was added slowly to the reaction mixture at 8°C. After the completion of addition, the reaction mixture was allowed to warm to 27°C and stirred at the same temperature for 16 hours. After the completion of the reaction, the mixture was added to chilled water (100 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic layer was washed with cold water (200 mL) and then with brine solution (200 mL). The organic layer was dried over sodium sulphate and the solvent was removed under reduced pressure at 45°C to obtain crude product. The crude product was purified by column chromatography using 20% ethyl acetate – dichloromethane as eluent to obtain the title compound as off-white solid.
Yield: 15.1 g and Purity by HPLC: 99.14%

Example-8: Preparation of Fevipiprant

A solution of sodium hydroxide (2.64 g) in water (75 mL) was added to a mixture of Ethyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (15 g), etrahydrofuran (150 mL) and water (225 mL) at 27°C and stirred the reaction mixture for 16 hours at the same temperature . After the completion of the reaction, the solvent was removed from the mixture under reduced pressure at 45°C and the pH of reaction mixture was adjusted to 2.0 with 6N HCl at 20°C. The reaction mixture was then extracted with dichloromethane (3 x 200 mL) and the combined organic layer was dried over sodium sulphate. The solvent was removed under reduced pressure at 40°C and added ethyl acetate (20 mL) and methyl tert.butyl ether (20 mL). Stirred the mixture at 27°C for 15 minutes and the solid was filtered. The solid was washed with methyl tert. butyl ether (10 mL) and dried under reduced pressure at 40°C for 2 hours to obtain the title compound as off-white solid.
Yield: 11.2 g and Purity by HPLC: 99.88 %

Example-9: Preparation of ethyl 2-(2-methyl-1-(4-(methylthio)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetate

Ethyl 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (2 g) was dissolved in dimethylformamide (30 mL) at 27°C and cooled to 10°C. 2-tert-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) (2.36 g) was added slowly to the reaction mixture at 10°C and the reaction mixture was stirred at the same temperature for 40 minutes. A solution of (4-(bromomethyl)-3-(trifluoromethyl)phenyl)(methyl)sulfane (2.95 g) in dimethylformamide (10 mL) was added slowly and then the reaction mixture was warmed to 27°C and stirred for 16 hours at the same temperature. The reaction mixture was added to chilled water (100 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with cold water (20 mL) and brine solution (20 mL). The organic layer was dried on sodium sulphate and removed the solvent under reduced pressure at 45°C. The crude product was purified by column chromatography using 20% ethyl acetate-hexane as eluent to obtain the title compound as pale yellow residue. Yield: 1. 0 g

Example-10: Preparation of ethyl 2-(2-methyl-1-(4-(methylthio)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate.

To a solution of ethyl 2-(2-methyl-1-(4-(methylthio)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-oxoacetate (1 g) in trifluoroacetic acid (10 mL), a solution of triethyl silane (0.96 g) in trifluoroacetic acid (10 mL) was added at 27°C. The mixture was heated to 60°C and stirred at the same temperature for 20 hours. The solvent was removed from the reaction mixture under reduced pressure at 45°C. Adjusted the pH of the reaction mixture with sodium bicarbonate solution to 8.8 and extracted the reaction mixture with dichloromethane (2 x 15 mL). The organic layer was washed with brine solution (10 mL) and dried over sodium sulphate. The solvent was removed from the reaction mixture under reduced pressure at 40°C and the crude product was purified by column chromatography using 20% ethyl acetate-hexane as eluent to obtain the title compound as pale yellow residue. Yield: 0.32 g

Example-11: Preparation of ethyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate.

Ethyl 2-(2-methyl-1-(4-(methylthio)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (0.3 g) was dissolved in dichloromethane (12 mL) at 27°C and cooled the solution to 10°C. m-chloro peroxybenzoic acid (0.36 g) was added to the mixture at 8°C and allowed the mixture to warm to 27°C and stirred at the same temperature for 16 hours. Reaction mixture was added to chilled water (50 mL) and separated the organic layer. The organic layer was washed with 10% sodium bicarbonate solution (2 x 15 mL), brine solution (10 mL) and then dried over sodium sulphate. The solvent was removed under reduced pressure at 40°C and purified by column chromatography using 30% ethyl acetate – hexane as eluent to obtain the title compound as pale yellow solid. Yield: 0.15 g

Example-12: Preparation of Fevipiprant

A solution of sodium hydroxide (2.64 g) in water (0.75 mL) was added to a mixture of Ethyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl) benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (0.15 g), tetrahydrofuran (1.5 mL) and water (2.25 mL) at 27°C and stirred the reaction mixture for 16 hours at the same temperature . After the completion of the reaction, the solvent was removed from the mixture under reduced pressure at 45°C and the pH of reaction mixture was adjusted to 3.0 with 6N HCl at 20°C. The reaction mixture was then extracted with dichloromethane (3 x 20 mL) and the combined organic layer was dried over sodium sulphate. The solvent was removed under reduced pressure at 40°C and added methyl tert.butyl ether (5 mL). Stirred the mixture at 27°C for 15 minutes and the solid was filtered. The solid was washed with methyl tert. butyl ether (5 mL) and dried under reduced pressure at 45°C for 2 hours to obtain the title compound as off-white solid.
Yield: 0.11 g and Purity by HPLC: 99.76 %
,CLAIMS:We claim
1. A compound of formula (Ia)

wherein, R is selected from the group consisting of methylsulfane or methylsulfonyl.
2. A compound having the structure

3. A process for the preparation of formula (Ia) comprising reacting pyrrolo[2,3-b]pyridine of formula (III) with 1-(bromomethyl)-2-(trifluoromethyl)benzene of formula (V) to obtain ethyl ester of formula (Ia)

wherein, R is selected from the group consisting of methylsulfane or methylsulfonyl.
4. A process for the preparation of formula (Ib) comprising reacting pyrrolo[2,3-b]pyridine of formula (IV) with 1-(bromomethyl)-2-(trifluoromethyl)benzene of formula (V) to obtain ethyl ester of formula (Ib).

wherein, R is selected from the group consisting of methylsulfane or methylsulfonyl.
5. A process for the preparation of formula (Ib) comprising reducing the formula (Ia) to obtain compound of formula (Ib)

wherein, R is selected from the group consisting of methylsulfane or methylsulfonyl.
6. A process for the preparation of Fevipiprant of formula (I) comprising;
a) reducing the ethyl ester of formula (Ia) to obtain compound of formula (Ib),

b) sulfoxidation of ethyl ester of formula (Ib), when R is methylsulfane.
c) hydrolyzing the ethyl ester of formula (Ib), wherein R is methylsulfonyl, to Fevipiprant of formula (I).

7. A process for the preparation of Fevipiprant of formula I, comprising the steps of
a) acylation of pyrrolo[2,3-b]pyridine of formula (II) with ethyl 2-chloro-2-oxoacetate to obtain acylated pyrrolo[2,3-b]pyridine of formula (III);

b) optionally reducing the acylated pyrrolo[2,3-b]pyridine of formula (III) to pyrrolo[2,3-b]pyridine of formula (IV);

c) reacting pyrrolo[2,3-b]pyridine of formula (III) or (IV) with 1-(bromomethyl)-2-(trifluoromethyl)benzene of formula (V) to obtain ethyl ester of formula (Ia) o (Ib), wherein R is selected from the group consisting of methylsulfane or methylsulfonyl;

d) optionally reducing the ethyl ester of formula (Ia) to obtain compound of formula (Ib)

e) sulfoxidation of ethyl ester of formula (Ib), when R is methylsulfane.
f) hydrolyzing the ethyl ester of formula (Ib), wherein R is methylsulfonyl, to Fevipiprant of formula (I).

8. The process of claim 5, 6 or 7, wherein the reducing agent is selected from the group consisting of triethyl silane (Et3SiH), polymethyl hydrosiloxane (PMHS), diethoxymethyl silane (DEMS), phenylsilane (PhSiH3) or trichlorosilane.
9. The process of claim 6 or 7, wherein the oxidizing agent is selected from the group consisting of peroxy acetic acid, trifluoroperoxy acetic acid, m-chloro peroxybenzoic acid (mCPBA), hydrogen peroxide, urea-hydrogen peroxide or tert-butyl hydroperoxide.
10. The process of claim 6 or 7, wherein the hydrolysis is carried out in the presence of hydroxides, carbonates or bicarbonates of alkaline metals such as sodium, lithium, potassium, calcium, magnesium or ammonia.