DESC:CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of earlier Indian provisional patent application No. IN 202041027268, filed on Jun 26, 2020; the entire contents of each of which are incorporated by reference herein.
FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Favipiravir using novel intermediate.
DESCRIPTION OF THE RELATED ART

Favipiravir, sold under the brand names Avigan, Abigan and FabiFlu, is an antiviral medication used to treat influenza. It was developed and manufactured by Toyama Chemical (Fujifilm group) and was approved for medical use in Japan in 2014 for the treatment of Influenza. It is also being studied to treat a number of other viral infections including Covid 19. It is represented by formula 1 shown below:

Formula 1

Favipiravir was disclosed in U.S Patent 6787544 B2 which is hereby incorporated by reference.

There are many methods known in the art for the preparation of Favipiravir. Still there is a requirement for an improved process for the preparation of Favipiravir, which is cost effective, easy to handle and produce pure Favipiravir in good yield.

SUMMARY OF THE INVENTION.
The main aspect of the present invention provides an improved process for the preparation of Favipiravir using novel intermediate.
In one aspect, the present invention provides ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile, represented by formula II below:

Formula II

In yet another aspect, the present invention provides crystalline ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile, characterized by PXRD spectrum having peaks at 7.8, 13.8, 15.7, 19.4, 23.7,26.3, 29.0, 33.1 and 33.8 ± 0.2° 2theta, represented by Fig. 1.

In yet another aspect, the present invention provides a process for the preparation of ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile.

In yet another aspect, the present invention provides a process for the preparation of 6-fluoro-3-hydroxypyrazine-2-carboxamide [Favipiravir] using ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile.

DRAWINGS:

FIGURE 1: PXRD pattern of crystalline ammonium salt of 6-Fluoro-3-hydroxypyrazine-
2-carbonitrile.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Favipiravir using novel intermediate.

In one embodiment, the present invention relates to ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile, represented by formula II below:

Formula II
In another embodiment, the present invention relates to crystalline ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile, characterized by PXRD spectrum having peaks at 7.8, 13.8, 15.7, 19.4, 23.7,26.3, 29.0, 33.1 and 33.8 ± 0.2° 2theta.

In yet another embodiment, the present invention relates to crystalline ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile as shown in Fig-1.

In yet another embodiment, the present invention relates to a process for the preparation of ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile comprising the steps of:
a) converting 3,6-difluoropyrazine-2-carbonitrile to 6-Fluoro-3-hydroxypyrazine-2-carbonitrile,
b) adding aqueous ammonia, and
c) isolating ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile

According to the present invention, 3,6-difluoropyrazine-2-carbonitrile taken as such or in an organic solvent such as toluene may be added with sodium acetate in presence of an organic solvent such as dimethyl sulfoxide and heat the contents to about 50°C. After completion of the reaction, the reaction mixture may be cooled to about 25°C and added with water. The pH of the reaction mixture may be adjusted to about 1.6 using Hydrochloric acid. To the resultant reaction mixture, ethyl acetate may be added, and the layers may be separated. The organic layer may be dried and concentrated and dissolved in suitable solvents such as acetone, toluene or mixtures thereof and added with aqueous ammonia. The resultant reaction mixture may be maintained at about 25°C for about two hours. The solid formed may be filtered to obtain ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile.

In yet another embodiment, the present invention relates to a process for the preparation of 6-fluoro-3-hydroxypyrazine-2-carboxamide [Favipiravir] from ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile as represented by the scheme below:

In yet another embodiment, the present invention relates to the purification of Favipiravir by treating Favipiravir with sodium hydroxide and acidification with HCl.

In yet another embodiment, the present invention relates to pharmaceutical composition comprising Favipiravir prepared according to the present invention and pharmaceutically acceptable excipient.

The examples are given solely for illustration and are not to be construed as limitations as many variations are possible without departing from spirit and scope of the invention.

EXAMPLES

Example 1: Preparation of 6-Fluoro-3-hydroxypyrazine-2-carnitrile Ammonia salt.

18g of Sodium acetate was dissolved in 60 ml of water at room temperature and 100 ml of dimethyl sulfoxide was charged to it. 230 ml of Toluene layer containing 20g of 3,6-Difluoropyrazine-2-carbonitrile was added to the reaction mass and then heated to 50°C. Reaction mass was maintained at 50-55°C for 6 hours. Reaction mass was cooled to 25°C and 140 ml water was added. pH of the reaction mass was adjusted to 1.6 with 30 ml of HCl. 200ml Ethyl acetate was charged to the reaction mass and stirred for 30 minutes. Organic layer was separated, and aqueous layer was back extracted with 150 ml of Ethyl acetate. Both the organic layers were combined and washed with 10% sodium chloride aqueous solution. Organic layer was concentrated under vacuum. 46 ml Acetone and 23 ml Toluene was charged to the concentrated reaction mass and 6 ml aqueous ammonia was added to it. It was stirred for 2 hours at 25±3°C and filtered off to get 8.9g Ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile with 99.81% purity. NMR details: 7.32 (br s, 4H), 8.02 – 8.05 (dd, 1H, J=8.4, 1.2)

Example 2: Preparation of Favipiravir.

2.56g of Sodium hydroxide was dissolved in 60 ml of water at room temperature and cooled to 17±2°C. 5g 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonium salt is added to it and then 7.3g of 30% Hydrogen peroxide was added slowly to the reaction mass at 20±5°C. Reaction mass was stirred for 1 hour at 23±3°C, and pH of reaction was adjusted to 3.5 with 9.5g of HCl. Reaction mass was then heated to 43±3°C and maintained for 1 hours. Further it was cooled to 30±3°C and stirred for 1 hours. Reaction mass was filtered and washed with water to get Favipiravir API.

Example 3: Purification of Favipiravir.

1.35g of Sodium hydroxide was dissolved in 60 ml of water and cooled to room temperature. 6.5g of Favipiravir is added to it and stirred for 15 minutes at 27±3°C, 0.2g Activated carbon is charged to reaction mass and stirred for 30 minutes. Reaction mass was filtered off and washed with 5 ml water. pH of reaction was adjusted to 3.5 with 3.25g of HCl. Reaction mass was then stirred for 1 hours at 27±3°C, filtered and washed with water to get Favipiravir API.

Example 4: Preparation of 3,6-Difluoropyrazine-2-carbonitrile.

20g of Potassium fluoride and 7.4 g Tetrabutylammonium bromide was charged to 100 ml of dimethyl sulfoxide followed by 120ml of Toluene. Reaction mixture was heated to 120°C and distilled out 60 ml of Toluene atmospherically and again 60 ml toluene was charged followed distillation, it was repeated for removal of water. Reaction mixture was cooled to 58°C. Solution of 20g of 3,6-Dichloropyrazine-2-carbonitrile dissolved in 20ml of Toluene was added slowly to the reaction mass at 58-60°C. Reaction mass was maintained at 57±3°C for 7 hours and cooled to 25°C. 200ml water and 150 ml toluene was charged to reaction mass and stirred for 25 minutes. Organic layer was separated, and aqueous layer was back extracted with 150 ml of Toluene. Both the organic layers were combined, and 200 ml water was charged to it, pH of aqueous layer was adjusted to 1.5 with HCl. It was stirred for 30 minutes followed by layer separation. Organic layer was treated with activated carbon to get decolored Toluene layer. Same Toluene layer was taken further for the next stage.
,CLAIMS:A compound of formula

2. The process for the preparation of ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-
Carbonitrile as claimed in claim 1, comprising the steps of:
a) converting 3,6-difluoropyrazine-2-carbonitrile to 6-Fluoro-3-hydroxypyrazine-2-carbonitrile,
b) adding aqueous ammonia, and
c) isolating ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile.

3. The process as claimed in claim 2, wherein the conversion of 3,6-difluoropyrazine-2-carbonitrile to 6-Fluoro-3-hydroxypyrazine-2-carbonitrile comprising the steps of:
a) dissolving 3,6-difluoropyrazine-2-carbonitrile in toluene
b) adding sodium acetate solution and dimethylsulfoxide
c) adjusting the pH
d) adding ethyl acetate and separating the layers
e) concentrating the organic layer
f) isolating 6-Fluoro-3-hydroxypyrazine-2-carbonitrile

4. The process as claimed in claim 2, wherein 6-Fluoro-3-hydroxypyrazine-2-carbonitrile is dissolved in acetone-toluene mixture and treated with aqueous ammonia to obtain ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile.

5. The process as claimed in claim 2, further comprises converting ammonium salt of 6-
Fluoro-3-hydroxypyrazine-2-carbonitrile into Favipiravir.

6. The process as claimed in claim 5, further comprises purification of Favipiravir by acid base treatment.

7. Crystalline ammonium salt of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile characterized by PXRD spectrum having peaks at 7.8, 13.8, 15.7, 19.4, 23.7,26.3, 29.0, 33.1 and 33.8 ± 0.2° 2theta.

8. A pharmaceutical composition comprising Favipiravir prepared according to the present invention and a pharmaceutically acceptable excipient.