FIELD OF THE INVENTION

The present invention relates to a process for the preparation of compound of Formula II and use of said compound in the preparation of fevipiprant,

Formula II
wherein R is SO2Me or a leaving group.

The present invention further provides a process for the preparation of amorphous form of fevipiprant.

BACKGROUND OF THE INVENTION
The compound, 2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl] methyl]pyrrolo [2,3-b]pyridine-3-yl]acetic acid is an antagonist of the G-protein coupled chemokine receptor homologous molecule that is useful for the treatment of an obstructive or inflammatory airway of disease such as asthma and atopic dermatitis. It is also known as Fevipiprant and is represented by structure of Formula I:
.

The compound of Formula I is disclosed in US patent 7,666,878. US’878 also discloses a method of synthesis of compound of Formula I as represented in the scheme-1 below:

Scheme-1
.

IN 201614033159, discloses method of preparation of compound of Formula I by cyclizing the pyrrolo ring after coupling with trifluoro methane sulfonyl benzyl side chain and is represented in the scheme-2 below:

Scheme 2

CN 106188040 discloses process of preparation of compound of Formula-I by using acetyl malonate methyl ester as cyclizing reagent as represented in the scheme 3 below:

Scheme-3

IN 201741017103 discloses process for the preparation of fevipiprant as represented in the scheme 4 below:

Scheme 4

Although several methods are known in prior published references for the synthesis of compound of Formula I, the present invention is concentrated towards the development of a new method for synthesizing compound of Formula I which is simple and cost effective and is reproducible at large scale production.

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 compounds of Formula IV, its preparation, preparation of compounds of Formula II and conversion to Fevipiprant of Formula I thereof, and other object of the present invention as disclosed in the following embodiments are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, any other embodiment defined herein.

OBJECT OF THE INVENTION
Main object of the present invention is to prepare a compound of Formula II and use of said compound in the preparation of 2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-b]pyridine-3-yl]acetic acid (Fevipiprant) of Formula I.

Another object of the present invention is to develop a method of synthesizing fevipiprant of Formula I, which is simple and cost effective and is reproducible at large scale production.

Another object of the present invention is to provide amorphous solid dispersion of fevipiprant with pharmaceutical acceptable excipients and process of preparation thereof.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of compounds of Formula II,

Formula II
wherein R is SO2Me or a leaving group,
comprising the steps of:
a) protecting hydroxyl group of compound of Formula III,
,
wherein R is as defined above,
with hydroxyl protecting reagent to get compound of Formula IV,
,
wherein PG is hydroxyl protecting group and R is as defined above; and
b) converting compound of Formula IV to compound of Formula II by reacting with 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula V,
.

In another aspect, the present invention provides a process for the preparation of fevipiprant of Formula I,

comprising the steps of:
a) adding compound of Formula IV and 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula V in a suitable solvent to get compound of Formula II,

,
wherein PG and R are as defined above; and
b) converting the compound of Formula II to fevipiprant of Formula I.

In one another aspect, the present invention provides compounds of Formula IV,

wherein PG is hydroxyl protecting group, R is SO2Me or a leaving group.

In one another aspect, the present invention provides compounds of Formula IV represented as compounds of Formula IVa, IVb, IVc, IVd, IVe, IVf, and IVg;

wherein PG is a suitable hydroxyl protecting group and R1 represents hydrogen, or (un) substituted alkyl group.

In another aspect, the present invention provides a process for the preparation of amorphous form of fevipiprant of Formula I, wherein said process comprising the steps of:
a) adding fevipiprant of Formula I to a suitable solvent, and
b) lyophilizing to get amorphous form of fevipiprant.

DETAILED DESCRIPTION
Definitions:
The term “Base” or “suitable base” as used in the context of the present invention refers to one or more organic and inorganic base selected from, but not limited to, triethyl amine, dimethyl amine, dimethyl amino pyridine, diisopropyl amine, diisopropyl ethyl amine, methyl ethyl amine, pyridine, piperidine, N-methyl piperidine, N-phenyl piperidine, aniline, magnesium carbonate, cesium bicarbonate, potassium sodium carbonate, barium oxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, tetramethyl ammonium hydroxide, guanidine, magnesium hydroxide, copper hydroxide, calcium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, magnesium bicarbonate, potassium carbonate, sodamide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, calcium tert-butoxide, magnesium tert-butoxide, sodium hydride, and the like.

The term “Suitable hydroxyl protecting reagent” as used in the context of the present invention refers to the compounds that react with hydroxyl group and converting it to a suitable nucleophile that can easily be replaced during condensation reaction. The hydroxyl protecting reagent is selected from, but not limited to, mesyl chloride, tosyl chloride, triflic acid and (un) substituted alkyl group.

The term “hydroxyl protecting group” as used in the context of the present invention are selected from the group, but not limited to, mesyl chloride, tosyl chloride, triflic acid and (un) substituted alkyl group.

The term “solvent” or “suitable solvent” as used in the context of the present invention refers to the group comprising of dimethyl formamide, dimethyl sulfoxide, N-methyl acetamide, dimethyl acetamide, N-methyl pyrrolidine, acetamide, acetone, methyl isobutyl ketone, methyl t-butyl ketone, methanol, ethanol, tert-butanol, n-butanol, isopropyl alcohol, n-propyl alcohol, dichloromethane, toluene, o/m/p-xylene, dichloroethane, dichlorobenzene, chlorobenzene, acetonitrile, propionitrile, tert-butyl acetate, butyl acetate, propyl acetate, iso-propyl acetate, ethyl acetate, propenyl acetate, tetrahydrofuran, methyl-tetrahydrofuran, 1,4-dioxane, methyl ethyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether, water and the mixture thereof.

The term “leaving group” as used in the context of the present invention is selected from, but not limited to, tosylate, triflate, halogens, -SR1, and -OR1, wherein R1 represents hydrogen or (un) substituted alkyl group.

“Pharmaceutically acceptable excipient” as used in the context of the present invention may include, but not limited to, an inorganic oxide such as silicon dioxide, titanium dioxide, zinc oxide, zinc dioxide, aluminium dioxide and zeolite; and organic polymers such as polyvinyl pyrrolidinone, cross linked cellulose acetate phthalate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethyle/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, povidone, povidone K-30, povidone K-60, Povidone K-90, Co-povidone, polyvinyl pyrrolidone vinyl acetate, polyvinyl alcohol, polysorbate 80, polyethylene glycol, methyl cellulose, Eudragit S-100, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, gelucire 44/14, ethyl cellulose, D-alphatocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose, cellulose derivatives; polyethylene glycol, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like.

In one embodiment, the present invention provides a process for the preparation of compounds of Formula II,

Formula II
wherein R is SO2Me or a leaving group,
comprising the steps of:
a) protecting hydroxyl group of compound of Formula III,
,
wherein R is as defined above,
with a suitable hydroxyl protecting reagent to get compound of Formula IV,
,
wherein PG is hydroxyl protecting group and R is as defined above; and
b) converting compound of Formula IV to compound of Formula II by reacting with 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula V,
.

In another embodiment, the compound of Formula III is reacted with hydroxyl protecting reagent in presence of base which are as defined above.

In another embodiment, the present invention provides compounds of Formula IV,
,
wherein PG is hydroxyl protecting group, R is SO2Me or a leaving group, wherein leaving group is as defined above.

In a preferred embodiment, the present invention provides a process for the preparation of fevipiprant of Formula I,

comprising the steps of:
a) adding compound of Formula IV and 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula V in a suitable solvent to get compound of Formula II,
,
wherein R is as defined above; and
b) converting the compound of Formula II to fevipiprant of Formula I.

In one another embodiment, the conversion of compound of Formula IV to compound of Formula II is carried out at a temperature in the range of 20 to 180oC.

In one another embodiment, the present invention provides a process for the preparation of fevipiprant of Formula I,

comprising the steps of:
a) protecting hydroxyl group of compound of Formula III,
,
wherein R is SO2Me or a leaving group,
with hydroxyl protecting reagent to get compound of Formula IV,
,
wherein PG is hydroxyl protecting group and R is as defined above;
b) converting compound of Formula IV to compound of Formula II by reacting with 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula V,
,
wherein R is as defined above; and
c) converting the compound of Formula II to Fevipiprant of Formula I.

In another embodiment, compound of Formula V 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 a preferred embodiment, when R is SO2Me, the compound of Formula II is hydrolysed in presence of suitable reagent to give compound of Formula I,
.

In yet another embodiment, when R is a leaving group, the compound of Formula II is converted to compound of Formula I by sulfonylation of compound of Formula II followed by hydrolysis in presence of suitable reagent,
.

In preferred embodiment, the leaving group is replaced by sulfonylation in presence of sulfonylating agent wherein said sulfonylating agent is selected from, but not limited to, the group comprising of sodium methane sulfinate, methyl sulfonyl chloride, methane sulfonic acid, methyl sulfone, and the like.

In another embodiment, the sulfonylation is carried out in presence of catalyst selected from copper iodide, sodium iodide, and the like.

In a preferred embodiment, the compound obtained after sulfonylation (i.e. Formula II with R = SO2Me), is hydrolysed in presence of suitable reagent to give compound of Formula I, i.e. Fevipiprant.

In another embodiment, the hydrolysis of compound of Formula II (wherein R is –SO2Me) is carried out in presence of suitable reagent wherein said reagent is an acid 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 one of the preferred embodiment, the compound of Formula I prepared as per the process of the present invention 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 0.3% w/w and total impurities are less than about 1.5% w/w.

In one another embodiment, the present invention provides a process for the preparation of fevipiprant by using novel compounds of Formula II and IV as represented in the scheme 5 below:

Scheme 5

In another embodiment, the compound of Formula IV is prepared as per the process as represented in scheme below:

Scheme 6

wherein R is as defined above .

In one another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of fevipiprant, comprising the steps of:
a) providing a solution of fevipiprant in a suitable solvent;
b) adding atleast one pharmaceutically acceptable excipient to the solution obtained in step a); and
c) isolating the amorphous solid dispersion of fevipiprant.

In further embodiment, the fevipiprant described herein, for the preparation various amorphous solid dispersion are either amorphous, or crystalline in nature. Even the reaction mixture containing fevipiprant can be used for preparing solid dispersions.

In another embodiment, the isolation in step c) above may be done using techniques such as direct filtration, or by shaking the container, removal of the solvent include using a rotational distillation device such as a buchi rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like, or other techniques specific to the equipment used.

In one another embodiment, the present invention provides a pharmaceutical composition comprising fevipiprant prepared as per process of the present invention along with at least one pharmaceutical acceptable excipient thereof, wherein said fevipiprant is either amorphous or solid amorphous solid dispersion in nature.

In another embodiment, the present invention provides a process for the preparation of amorphous form of fevipiprant of Formula I, wherein said process comprising the steps of:
a) adding fevipiprant of Formula I to a suitable solvent, and
b) lyophilizing to get amorphous form of fevipiprant.

In one another embodiment, the present invention provides a process for the preparation of amorphous form of fevipiprant of Formula I, wherein said process comprising the steps of:
a) adding fevipiprant of Formula I to a suitable solvent,
b) optionally heating at a temperature in the range of 35-150oC, and
c) adding another solvent and isolating to get amorphous form of fevipiprant of Formula I.

In another embodiment, the another solvent used in step c) above, for isolating amorphous form of fevipiprant is selected from halogenated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride; hydrocarbons such as cyclohexane, n-heptane, n-hexane; ketones such as acetone, methyl isobutyl ketone; ethers such as ethyl acetate, propyl acetate and water.

In another preferred embodiment, the compound of Formula I, i.e. Fevipiprant is characterized by the particle size distribution wherein, d90 is between 0.1µm to 200µm.

In a preferred embodiment, the compound of Formula I, i.e. Fevipiprant is characterized by particle size distribution wherein, d90 is between 2.0 µm to 150µm.

EXAMPLES
EXAMPLE 1.0: Preparation of 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid [Fevipiprant]
1.1 Preparation of tert-butyl (3-methylpyridin-2-yl)carbamate of Formula VII:
Charged 100.0g (0.925 mole) of 2-amino-3-methyl pyridine in 650.0ml of tetrahydrofuran. Added 241.9g (1.11mole) of di-tert-butyl dicarbonate in above reaction mixture and stirred the reaction mass at reflux for 20.0 hrs. The reaction mixture was evaporated under reduced pressure and crystallized the residue so obtained in hexane: ethyl acetate (1:4) to give tert-butyl (3-methylpyridin-2-yl)carbamate (168.7 g, yield: 87.3%) as white solid.

1.2 Preparation of 2-methyl-1H-pyrrolo[2,3-b]pyridine of Formula VIII:
tert-butyl (3-methylpyridin-2-yl)carbamate (30.0 g, 0.143 mole) was dissolved in tetrahydrofuran (500.0 ml) under nitrogen and the mixture was cooled to -10 ºC. Added n-Butyllithium (2.5 M in hexane 168.0 ml 0.42 mole) over 30.0 min with stirring and the mixture was stirred for 1.0 hrs at -10 ºC followed by addition of N-methoxy-N-methylacetamide (22.8 g, 0.22 mole). After completion of reaction, the reaction mixture was cooled to -10 ºC, and then quenched with 78.0 ml of concentrated hydrochloric acid and then stirred at 50ºC for 90.0 min. The organic phase was extracted twice with 2N hydrochloric acid. The combined aqueous was basified with 32% sodium hydroxide solution and extracted with ethyl acetate (x3). The organics were washed with brine dried over anhydrous sodium sulphate, filtered and evaporated under reduce pressure. The residue was purified using hexane: ethylacetate (60:40) to give 2-methyl-1H-pyrrolo[2,3-b]pyridine (15.8 g, yield 83.0 %)

1.3 Preparation of N,N-dimethyl-1-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine of Formula IX:
To 2-methyl-1H-pyrrolo[2,3-b]pyridine (12.0 g, 0.0902 mole) was added para formaldehyde (2.61 g) and dimethyl amine hydrochloride (8.82 g, 0.108 mole) in acetic acid (150.0 ml) and toluene (40.0 ml) at room temperature. The reaction mixture was refluxed for 2.0 hrs. After completion of reaction, the reaction mixture was evaporated under reduced pressure and basified with 10% sodium hydroxide solution to maintain the pH to 8.0 to 9.0 and extracted with ethyl acetate (x3). The organics were washed with brine and dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give N,N-dimethyl-1-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine (15.6 g, yield 91.7 %).

1.4 Preparation of 2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile of Formula V:
Added N,N-dimethyl-1-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine (13.5 g, 0.0718 mole) in N, N dimethyl formamide (40.0 ml) followed by addition of the mixture of potassium cyanide (5.6 g, 0.0861 mole) in water (32.0 ml). Added acetic acid (4.0 ml) to the mixture in a drop wise manner and the resulting solution was heated at 110.0 ºC for 3.0 hrs. After completion of reaction, cooled the reaction mixture at room temperature and diluted with saturated potassium carbonate followed by extraction with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to give a pale yellow solid (11.6 g, yield 96.5 %).

1.5 Preparation of 4-(methylsulfonyl)-2-(trifluoromethyl)benzaldehyde of Formula XII (R is SO2Me):
To 4-Fluoro-2-(trifluoromethyl) benzaldehyde (25.0 g 0.1302 mole) was added sodium sulfonate (15.96 g, 0.1562 mole) and copper iodide (0.494 g, 0.0026 mole) in dimethyl sulfoxide (150.0 ml) at room temperature. Stirred the reaction mixture at 90ºC for 9-10 hrs. The reaction mixture was cooled and poured on to ice water (400.0 ml). The resulting precipitates were collected by filtration and dried under high vacuum to give the 4-(methylsulfonyl)-2-(trifluoromethyl)benzaldehyde as white solid (31.6 g, yield 96.3 %).
1H NMR (DMSO): d3.41(s, 3H); 8.32-8.37 (m, 2H); 8.43-8.45 (d, 1H); 10.33 (s, 1H).

1.6 Preparation of (4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol of Formula XIII (R is SO2Me):
Dissolved 4-fluoro-2-(trifluoromethyl)benzaldehyde (20.0 g, 0.0793 mole) in methanol (150.0 ml) at 0ºC under an inert atmosphere of nitrogen was added sodium borohydride (3.6 g, 0.0947 mole). After stirring at room temperature for 3.0 hrs, the reaction mixture was poured carefully on to ice water (400.0ml) and acidified to pH 1-2 with 1N HCl. The resulting mixture suspension was extracted with ethylacetate and the organic portion was combined and washed with brine. Dried the organic layer over MgSO4, concentrated the organic layer under vacuum to give the 4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]methanol (19.6 g, yield 97.8 %).
1H NMR (DMSO): d3.32 (s, 3H); 4.76 (s, 2H); 5.79 (t, 1H); 8.06-8.09 (d, 1H); 8.15 (s, 1H); 8.24-8.26 (d, 1H).

1.7 Preparation of 4-(methylsulfonyl)-2-(trifluoromethyl)benzyl methanesulfonate of Formula IV (R is SO2Me; PG is SO2Me):
A suspension of [4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]methanol (10.0 g, 0.0393) in dichloromethane at 0ºC was added triethyl amine (8.24 ml, 0.059 mole) and methanesulfonyl chloride (5.38 g, 0.0472 mole). After stirring at room temperature for 2.0 hrs, the reaction mixture was washed with saturated sodium bicarbonate solution (200.0ml) and the organic portion was washed with brine. Dried the organic layer over MgSO4 and concentrated under vacuum to give the 4-(methylsulfonyl)-2-(trifluoromethyl)benzyl methanesulfonate (12.2 g, yield 93.8 %).
1H NMR (DMSO): d3.35 (s, 3H); 3.36 (s, 3H); 5.51 (s, 2H); 8.04-8.06 (d, 1H); 8.27 (s, 1H); 8.32-8.34 (d, 1H).

1.8 Preparation of 2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile of Formula II (R=-SO2Me):
To a stirred solution of 2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (5.5g, 0.0321 mole) in acetone (27.5 ml) was added potassium carbonate (13.31g, 0.0964 mole) and 4-(methylsulfonyl)-2-(trifluoromethyl)benzyl methanesulfonate (12.8 g, .0385 mole) at room temperature. Stirred the reaction mixture at 70 ºC for 6.0 hrs, cooled and then poured into ice water. The aqueous layer was extracted with ethyl acetate and organic layer were combined, dried over MgSO4 and concentrated under vaccum to give the 2-methyl-1-[4-(methylsulfonyl)-2-(trifluoromethyl)benzyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}acetonitrile. Purified the crude residue so obtained by column chromatography and eluted with ethyl acetate: hexane (15:85) to give (10.6 g, yield 80.7 %) of pure compound of Formula X.

1.9 Preparation of Fevipiprant:
Added 2-methyl-1-[4-(methylsulfonyl)-2-(trifluoromethyl)benzyl]-1H-pyrrolo[2,3-b]pyridin-3- yl}acetonitrile (10.0g, 0.0245mole) in concentrated hydrochloric acid (50.0 ml) at 50 ºC for 3-4 hrs. The reaction mixture was cooled to room temperature, poured in to ice water and adjusted to pH 4-5 using 10% sodium hydroxide solution. The aqueous layer extracted with ethyl acetate 2-3 time combined the organic layer, dried over MgSO4 and concentrated under vacuum to give fevipiprant (7.9 g, yield 75.2 %).

EXAMPLE 2.0: Process for the preparation of Fevipiprant:
2.1 Preparation of 4-fluoro-2-(trifluoromethyl)benzyl methanesulfonate of Formula IV (R is F; PG is SO2Me):
A suspension of [4-(fluoro)-2-(trifluoromethyl)phenyl]methanol (10.0g) in dichloromethane at 0ºC was added triethyl amine (8.24 ml) and methanesulfonyl chloride (5.38 g). After stirring at room temperature for 2.0 hrs, the reaction mixture was washed with saturated sodium bicarbonate solution (200.0ml) and the organic portion was washed with brine. Dried the organic layer over MgSO4 and concentrated under vacuum to give the 4-(fluoro)-2-(trifluoromethyl)benzyl methanesulfonate (11 g).

2.2 Preparation of 1-(4-fluoro-2-(trifluoromethyl)benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile of Formula II (R=F):
To a stirred solution of 2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile (5.0g) in acetone (27.5 ml) was added potassium carbonate (12.5g) and 4-(fluoro)-2-(trifluoromethyl)benzyl methanesulfonate (11 g) at room temperature. Stirred the reaction mixture at 70 ºC for 6.0 hrs, cooled and then poured into ice water. The aqueous layer was extracted with ethyl acetate and organic layer were combined, dried over MgSO4 and concentrated under vacuum to give the 1-(4-fluoro-2-(trifluoromethyl)benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (3.9g).

2.3 Preparation of 2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile of Formula II (R=-SO2Me):
To a stirred solution of 1-(4-fluoro-2-(trifluoromethyl)benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (2g) in dimethyl sulfoxide was added copper iodide (1.0 eq) and sodium sulfonate (2.0 eq) at room temperature. Stirred the reaction mixture at 80 ºC for 6.0-8.0 hrs, cooled and then poured into ice water. The resulting precipitates were filtered to give 2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.

2.4 Preparation of Fevipiprant:
Added 2-methyl-1-[4-(methylsulfonyl)-2-(trifluoromethyl)benzyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}acetonitrile (1g) in concentrated hydrochloric acid (5 ml) at 50 ºC for 3-4 hrs. The reaction mixture was cooled to room temperature, poured into ice water and adjusted to pH 4-5 using 10% sodium hydroxide solution. The aqueous layer extracted with ethyl acetate 2-3 time combined the organic layer, dried over MgSO4 and concentrated under vacuum to give fevipiprant.

EXAMPLE 3: Preparation of amorphous solid dispersion of Fevipiprant with hydroxypropyl methyl cellulose:
Fevipiprant (300 mg), hydroxypropyl methyl cellulose (300 mg) and methanol (30 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 15 minutes at 50°C. Cooled the reaction mass to 25°C and then filtered to remove any insoluble particles. Evaporated the solvents under vacuum at 50°C for over 60 minutes to give amorphous solid dispersion of Fevipiprant with hydroxypropyl methyl cellulose.

EXAMPLE 4: Preparation of amorphous solid dispersion of Fevipiprant with Co-povidone:
Fevipiprant (500 mg), Co-povidone (500 mg) and methanol (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 15 minutes at 50°C. Cooled the reaction mass to 25°C and then filtered to remove any insoluble particles. Evaporated the solvents under vacuum at 55°C for over 20 minutes to give amorphous solid dispersion of Fevipiprant with Co-povidone.

EXAMPLE 5: Preparation of amorphous form of fevipiprant:
Fevipiprant (1 g) was dissolved in ethanol (20 mL) at 50°C and filtered the solution to make it particle free. Added n-heptane and filtered the precipitates thus obtained. Dried the precipitates to get title compound.

EXAMPLE 6: Preparation of amorphous form of fevipiprant:
Charged Fevipiprant (1 g) in water (20 mL) and heated at 50oC. Cooled the solution to room temperature and lyophilized to get the title compound.

CLAIMS:

WE CLAIM

1. A process for the preparation of compounds of Formula II,

Formula II
wherein R is SO2Me or a leaving group,
comprising the steps of:
a) protecting hydroxyl group of compound of Formula III,
,
wherein R is SO2Me or a leaving group,
with hydroxyl protecting reagent to get compound of Formula IV,
,
wherein PG is hydroxyl protecting group and R is selected from –SO2Me or a leaving group; and
b) converting compound of Formula IV to compound of Formula II by reacting with 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula V,
.

2. The process as claimed in claim 1, wherein step a) and b) are carried out in presence of solvent selected from dimethyl formamide, dimethyl sulfoxide, N-methyl acetamide, dimethyl acetamide, N-methyl pyrrolidine, acetamide, acetone, methyl isobutyl ketone, methyl t-butyl ketone, methanol, ethanol, tert-butanol, n-butanol, isopropyl alcohol, n-propyl alcohol, dichloromethane, toluene, o/m/p-xylene, dichloroethane, dichlorobenzene, chlorobenzene, acetonitrile, propionitrile, tert-butyl acetate, butyl acetate, propyl acetate, iso-propyl acetate, ethyl acetate, propenyl acetate, tetrahydrofuran, methyl-tetrahydrofuran, 1,4-dioxane, methyl ethyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether, water, and the mixture thereof.

3. Compounds of Formula IV,

wherein PG is hydroxyl protecting group, R is SO2Me or a leaving group.

4. The compounds as claimed in claim 4, wherein said hydroxyl protecting group is selected from mesyl chloride, tosyl chloride, triflic acid and (un) substituted alkyl group; and
wherein said leaving group is selected from the group comprising of tosylate, triflate, halogens, -SR1, and -OR1, wherein R1 represents hydrogen or (un) substituted alkyl group.

5. A process for the preparation of fevipiprant of Formula I,

comprising the steps of:
a) adding compound of Formula IV and 2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)acetonitrile of Formula V in a suitable solvent to get compound of Formula II,

,
wherein PG is hydroxyl protecting group, and R is SO2Me or a leaving group; and
b) converting the compound of Formula II to Fevipiprant of Formula I.

6. The process as claimed in claim 5, wherein when R is SO2Me, the compound of Formula II is hydrolysed in presence of suitable reagent to give compound of Formula I,
.

7. The process as claimed in claim 5, wherein when R is a leaving group, the compound of Formula II is converted to compound of Formula I by sulfonylation of compound of Formula II followed by hydrolysis in presence of suitable reagent,
.

8. A process for the preparation of amorphous form of fevipiprant of Formula I, wherein said process comprising the steps of:
a) adding fevipiprant of Formula I to a suitable solvent, and
b) lyophilizing to get amorphous form of fevipiprant.

9. The process as claimed in claim 8, wherein said suitable solvent is selected from the group comprising of methanol, ethanol, 2-propanol, 1- butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, propenyl acetate, acetonitrile, propionitrile, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, dichlorobenzene, chlorobenzene, chloroform, carbon tetrachloride, toluene, water and mixtures thereof.