Claims:1. An improved process for the synthesis of 3,6-difluoropyrazine-2-carbonitrile, a key intermediate in the synthesis of Favipiravir, which process comprises;
a) reacting 3,6-dichloropyrazine-2-carbonitrile with potassium fluoride in presence of a solvent selected from N-methyl-2-pyrrolidone or N,N-Dimethylacetamide and 18-crown-6 as catalyst, at a temperature range of 40-140°C; and
b) isolating 3,6-difluoropyrazine-2-carbonitrile from the reaction mass by extracting into low boiling solvents.

2. The process as claimed in claim 1, wherein, the low boiling solvents are selected from the group consisting of DCM, hexane, methyl-tert-butyl ether, diethyl ether , isobutyl methyl ether.

3. The process as claimed in claim 2, wherein, the low boiling solvent is methyl-tert-butyl ether.

4. The process as claimed in claim 1, wherein, the 18-crown-6 catalyst can be used in an amount of from 0.05 to 0.25 eq, to facilitate the reaction.

5. The process as claimed in claim 4, wherein, the 18-crown-6 is used preferably in 0.1 eq of the 3,6-dichloropyrazine-2-carbonitrile.

6. The process as claimed in claim 1, wherein, the N-methyl-2-pyrrolidone (NMP) or N,N-dimethylacetamide is used from 3 volumes to 15 volumes with reference to 3,6-dichloropyrazine-2-carbonitrile.

7. The process as claimed in claim 6, wherein, the solvent is used in 10 volumes with reference to 3,6-dichloropyrazine-2-carbonitrile.

8. The process as claimed in claim 1, wherein, the potassium fluoride is used in 2 to 6 eq with reference to 3,6-dichloropyrazine-2-carbonitrile.

9. The process as claimed in claim 8, wherein the potassium fluoride is used in 4 eq.

10. A process for synthesis of Favipiravir, which process comprises;
a) preparing 3,6-difluoropyrazine-2-carbonitrile, as claimed in claim 1;
b) reacting the 3,6-difluoropyrazine-2-carbonitrile in 1,4-dioxane with aq. solution of sodium acetate, at temperature of 50-60°C, followed by acidification to obtain 6-fluoro-3-hydroxypyrazine-2-carbonitrile; and
c) treating the 6-fluoro-3-hydroxypyrazine-2-carbonitrile in 6% aq. NaOH with 30% hydrogen peroxide at room temperature, followed by acidification to obtain Favipiravir.
, Description:Technical filed:
The present invention relates to an efficient synthesis of 3,6-difluoropyrazine-2-carbonitrile, which is a key intermediate, in the preparation of Favipiravir. The invention further relates to synthesis of Favipiravir.

Background and prior art:
3,6-difluoropyrazine-2-carbonitrile is a fluorinated building block and production intermediate useful in the synthesis of Favipiravir.

Favipiravir is known to be very effective against a variety of viruses, and particularly the influenza virus. 3,6-difluoropyrazine-2-carbonitrile is the key intermediate for synthesis of Favipiravir. Though there are number of methods reported for the synthesis of this intermediate available in the literature, however, they suffer with low yield and tedious workup procedure. Most of these reported methods use dimethyl sulfoxide as reaction solvent for the preparation of 3,6-difluoropyrazine-2-carbonitrile from 3,6-dichloropyrazine-2-carbonitrile.

Example II- 13 of WO01/60834 discloses the synthesis of Favipiravir, wherein, the conversion of 3,6-dichloropyrazine-2-carbonitrile into 3,6-difluoropyrazine-2-carbonitrile, is carried out in presence of KF/ tetra-n-butylammonium bromide in DMSO as a solvent. In this step, the recommended workup suggests the isolation of the product by extraction of an acidic solution. However, this organic layer does not contain appreciable amounts of product. Moreover, the product is not isolated. The toluene layer is taken as such for next reaction.

The synthesis is shown in scheme 1 below.
Scheme 1:

Another improved method for the preparation of 6-fluoro-3-hydroxy-pyrazine-2-carboxamide (t-705) by Sagar V. Beldar and Ulrich Jordis, reported in 13th electronic conference on synthetic organic chemistry, wherein, 3,6-dichloro pyrazine-2-carbonitrile in DMSO is reacted with vacuum dried KF and BuN+ Br-, to obtain 3,6-difluoropyrazine-2-carbonitrile. The work reported in this article specifically excludes the acidification step to prevent the loss of the product, 3,6-difluoropyrazine-2-carbonitrile and thus preferred the extraction of the basic aqueous phase omitting the addition of HCl. The reaction is shown in scheme 2 below.
scheme 2

US8586741b2 discloses the synthesis of 3,6-difluoropyrazine-2-carbonitrile in step 1 of reference example. In this example, DMSO is used in combination with toluene as a reaction solvent in presence of potassium fluoride and tetrabutylammonium bromide. Here also, the product is not isolated.

CN107226794 also reported similar conversion of dichloro intermediate to difluro intermediate by treating the dichloro intermediate with KF/TBAB in DMSO.

CN106866553 also reported similar conversion of dichloro intermediate to difluro intermediate by treating dichloro intermediate with KF/TBAB in DMSO /toluene.
As is evident from the above, use of DMSO as solvent medium for this conversion is heavily reported in all the prior arts; however is not favourable for the use on commercial scale considering explosive decomposition of DMSO even with slight acidity.

Moreover, the above reported literature uses tetrabutyl ammonium bromide as a catalyst for the reaction, which is thermally unstable. also the product, 3,6-difluoropyrazine-2-carbonitrile is low melting solid and highly volatile and hence the reaction and the work up of this product needs to be carried out very carefully so as to avoid the loss of the product due to the high volatility of the product during workup and to obtain the product, 3,6-difluoropyrazine-2-carbonitrile with high isolated yields and purity.

In the light of the above drawbacks of the prior art, it has become an objective of the present invention to provide an improved process for the synthesis of 3,6-difluoropyrazine-2-carbonitrile.

Summary of the invention:
In line with the above objective, the present invention provides an improved process for the synthesis of 3,6-difluoropyrazine-2-carbonitrile, a key intermediate in the synthesis of Favipiravir, which process comprises;
a) reacting 3,6-dichloropyrazine-2-carbonitrile with potassium fluoride in presence of a solvent selected from N-methyl-2-pyrrolidone or N,N-Dimethylacetamide and 18-crown-6 as a catalyst, at a temperature range of 40-140° c; and
b) isolating 3,6-difluoropyrazine-2-carbonitrile from the reaction mass by extracting into low boiling solvents.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, the present invention provides an improved process for the synthesis of 3,6-difluoropyrazine-2-carbonitrile, a key intermediate in the synthesis of Favipiravir, which process comprises;
a) reacting 3,6-dichloropyrazine-2-carbonitrile with potassium fluoride in presence of a solvent selected from N-methyl-2-pyrrolidone or N,N-Dimethylacetamide and 18-crown-6 as catalyst, at a temperature range of 40-140° c; and
b) isolating 3,6-difluoropyrazine-2-carbonitrile from the reaction mass by extracting into low boiling solvents.

In an embodiment, the invention provides a list of low boiling solvents that can be efficiently used for extraction of the 3,6-difluoropyrazine-2-carbonitrile without losing the product. Accordingly, the low boiling solvents are selected from the group consisting of DCM, hexane, methyl-tert-butyl ether, diethyl ether, isobutyl methyl ether. In a preferred embodiment, methyl-tert-butyl ether is used as low boiling solvent for extraction of the product.

The 18-crown-6 catalyst can be used in an amount of from 0.05 to 0.25 eq, to facilitate the reaction. In a preferred embodiment, 18-crown-6 is used preferably in 0.1 eq of the 3,6-dichloropyrazine-2-carbonitrile.
The solvent viz., N-methyl-2-pyrrolidone (NMP) or N,N-dimethylacetamide can be used from 3 volumes to 15 volumes more preferably 10 volumes with reference to 3,6-dichloropyrazine-2-carbonitrile.

Potassium fluoride can be used in 2 to 6 eq of 3,6-dichloropyrazine-2-carbonitrile. Preferably 4 eq of potassium fluoride is sufficient to carry out the reaction successfully.

Accordingly in one embodiment, 3,6-dichloropyrazine-2-carbonitrile is reacted with potassium fluoride in presence of 18-crown-6 as catalyst in N-methyl-2-pyrrolidone as a solvent. The reaction is carried out at a temperature of 40-140° C; preferably at 60 to 100°C and more preferably the reaction is carried out at 80-90° C for 2 to 10hrs, preferably for 2 to 4hrs. The reaction mass is extracted into methyl-tert-butylether and upon concentration, sufficiently pure 3,6-difluoropyrazine-2-carbonitrile is obtained.

According to another embodiment, 3,6-dichloropyrazine-2-carbonitrile is reacted with potassium fluoride in presence of 18-crown-6 as catalyst in N,N-dimethylacetamide as a solvent. The reaction is carried out at a temperature of 40-140°C; preferably at 60 to 100°C and more preferably the reaction is carried out at 80-90°C for 2 to 10hrs, preferably for 2 to 4hrs. The reaction mass is extracted into methyl-tert-butylether and upon concentration, sufficiently pure 3,6-difluoropyrazine-2-carbonitrile is obtained.

In yet another embodiment, the 3,6-difluoropyrazine-2-carbonitrile thus obtained from the previous stage is converted into 6-fluoro-3-hydroxypyrazine-2-carbonitrile by treating the same in 1,4-dioxane with aq. solution of sodium acetate, at temperature of 50-60°C. After the completion of the reaction, the reaction mixture was diluted with water and acidified using HCl. Product was extracted into toluene and upon concentration of the extract, 6-fluoro-3-hydroxypyrazine-2-carbonitrile, as grey colour solid is obtained.
In a further embodiment, the 6-fluoro-3-hydroxypyrazine-2-carbonitrile in 6% aq. NaOH is treated with 30% hydrogen peroxide at room temperature for 5-6hrs. Finally, the reaction mixture was made acidic with HCl to obtain Favipiravir as crude; which is obtained as pure yellowish solid after re-crystallizing the crude using 95% ethanol.

Accordingly, in a further embodiment, the invention provides a process for synthesis of Favipiravir, which process comprises;
a) reacting 3,6-dichloropyrazine-2-carbonitrile with potassium fluoride in presence of a solvent selected from N-methyl-2-pyrrolidone or N,N-Dimethylacetamide and 18-crown-6 as catalyst, at a temperature range of 40-140°C;
b) isolating 3,6-difluoropyrazine-2-carbonitrile from the reaction mass by extracting into low boiling solvents;
c) reacting the 3,6-difluoropyrazine-2-carbonitrile in 1,4-dioxane with aq. solution of sodium acetate, at temperature of 50-60°C, followed by acidification to obtain 6-fluoro-3-hydroxypyrazine-2-carbonitrile; and
d) treating the 6-fluoro-3-hydroxypyrazine-2-carbonitrile in 6% aq. NaOH with 30% hydrogen peroxide at room temperature, followed by acidification to obtain Favipiravir.

Those of ordinary skilled in the art will appreciate that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments or examples disclosed herein, but is intended to cover modifications within the objectives and scope of the present invention as defined in the specification. The presented examples illustrate the invention, but they should not be considered to limit the scope of the invention in any way.

EXAMPLE 1:
Synthesis of 3,6-difluoropyrazine-2-carbonitrile (2) using NMP: 3,6-dichloropyrazine-2-carbonitrile (3) (100gm, 1 eq.), potassium fluoride (133.6g, 4 eq.), 18-crown-6 ( 15.2 g, 0.1eq.) and N-methyl-2-pyrrolidone (1l) were heated to 80-90° C for 4hrs. Reaction mixture was diluted with water and the product was extracted into methyl-tert-butylether. Upon concentration 69g of product was obtained. 1H NMR (CDCl3): 8.35-8.33 1H(dd)
EXAMPLE 2:
Synthesis of 3,6-difluoropyrazine-2-carbonitrile (2) using N,N-dimethylacetamide: 3,6-dichloropyrazine-2-carbonitrile (3) (100gm, 1 eq.), potassium fluoride (co-distilled over toluene to remove moisture) (133.6gm, 4 eq.), 18-crown-6 ( 15.2 gm, 0.1eq.) and N,N-dimethylacetamide (1l) were heated to 80-90° C for 4hrs. Reaction mixture was diluted with water and the product was extracted into methyl-tert-butylether. Upon concentration 67.3g product was obtained. 1H NMR (CDCl3): 8.35-8.33 1H(dd)
EXAMPLE 3:
Synthesis of 6-fluoro-3-hydroxypyrazine-2-carbonitrile (4): aq. solution of sodium acetate (154gm in 450ml) was added to a solution of 53gm of starting material (2) in 1,4-dioxane (450ml). Reaction mixture was heated overnight at 50-60° C. reaction mixture was diluted with water and acidified using HCl. Product was extracted into toluene. Upon concentration 30gm product was obtained as grey coloured solid. 1H NMR (DMSO-d6): 8.54-8.52 1H(d), 13.81 1H(br).
EXAMPLE 4:
Synthesis of Favipiravir (1): 30% Hydrogen peroxide (30ml) was added to a solution of 30gm of the starting material (4) in 6% aq. NaOH. Reaction mixture was stirred at room temperature for 5-6hrs. Reaction mixture was made acidic using HCl and obtained solid was collected by filtration. 30gm of pure yellowish solid was obtained by re-crystallizing the crude using 95% ethanol. 1H NMR (DMSO-d6): 8.50-8.52 2H(Br d), 8.74 1H(Br s), 13.411H(Br s)