DESC:F O R M 2

THE PATENTS ACT, 1970 (SECTION 39 of 1970)

COMPLETE SPECIFICATION

(Section 10)

“SYNTHESIS OF FAVIPIRAVIR”

OPTIMUS DRUGS PVT LTD

2nd Floor, Sy No. 37/A & 37/P, Plot No. 6P, Signature Towers, Kothaguda, Kondapur, Hyderabad-500084, Telangana, India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed
“SYNTHESIS OF FAVIPIRAVIR”

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Favipiravir. The present invention is also relates to an improved and commercially viable process of Favipiravir by using 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.

BACKGROUND OF THE INVENTION

Favipiravir (Favipiravir, T-705), chemical entitled 6-fluoro-3-hydroxypyrazine-2-methan amide, is new RNA polymerase (RdRp) the inhibitor class broad-spectrum antiviral drug that RNA relies on, itself does not have antiviral activity, is existed by metabolism Favipiravir ribonucleoside triphosphote form can be rapidly converted in vivo, by simulating guanosine triphosphate (GTP) (GTP) competitive inhibition virus The RNA polymerase that RNA relies on, suppression viral genome replicates and transcribes and play antivirus action, Favipiravir nucleoside three phosphorus Sour form also can penetrate into viral gene, plays antivirus action by inducing fatefulue mutation. Favipiravir is to A type influenza (including bird flu and influenza A H1N1 infection), virus had preferable therapeutically effect moreover it is possible to suppress the transcription of other viruses, such as Arenaviruss, yellow fever virus, west Nile viruses, Bunya virus and hand-foot-mouth disease virus etc., nearest document report it can be effective for treatment of COVID-19. Its structural formula is as follows:

Favipiravir

Favipiravir is reported in US 6787544 by Toyama chemical. The synthetic process for Favipiravir is reported in US ‘544, which comprises, methyl 6-bromo-3-amino-2-pyrazine carboxylate of formula (2) is reacted with methanol in presence of H2SO4 / NaNO2 to obtain methyl 6-bromo-3-methoxy- 2-pyrazinecarboxylate (3). The compound of formula (3) converts into methyl 6-amino-3-methoxy-2-pyrazinecarboxylate (4) in presence of (S)-(-)-2,2'-bis (di phenylphosphino)-1,1'-binaphthyl / benzophenone-imine and Pd2(dba)3 to obtain 6-amino-3-methoxy-2-pyrazinecarboxamide (5). The compound of formula (5) is reacted with pyridine hydrofluoride in presence of NaNO2 / water and chloroform to obtain 6-fluoro-3-methoxy-2- pyrazine carboxamide (6). The compound of formula (6) converts into Favipiravir (1) in presence of NaI and TMSCl.

The above process is schematically shown as below:

total recovery only 0.44%. Amino replacement used catalyst three (dibenzalacetone) two palladium [Pd2(dba)3] and in method (S)-(-)-2,2'-bis(diphenyl phosphine)-1,1'-dinaphthalene costly, and final step reaction is difficult to control, yield only has 4.3%, is unfavourable for suitability for industrialized production.

Chinese Journal of Pharmaceuticals 2013,44 (9) discloses a process for the preparation of Favipiravir (1), which comprises the compound of formula (10) is reacted with POCl3 in presence of DIPEA to obtain the compound of formula (11). The compound of formula (11) is reacted with KF in presence of DMSO to obtain the compound of formula (12). The compound of formula (12) converts into the compound of formula (13) in presence of CH3COONa. The compound of formula (13) converts into Favipiravir (1) in presence of H2SO4 and water.

The above process is schematically shown as below:

Total recovery is 21.8%. This reaction scheme step is longer, and yield is lower, and cost is higher. Be unfavourable for suitability for industrialized production.

US 6800629 of Toyama Chemical discloses a process for the preparation of Favipiravir (1), which comprises 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) converts into pure Favipiravir (1).

US 8586741 of Nippon soda discloses a process for the preparation of Favipiravir, which comprises 6-bromo-3-hydroxypyrazine-2-carboxamide (10) is reacted with POCl3 in presence of DIPEA / toluene and monochlorobenzene to obtain 3,6-dichloropyrazine-2-carbonitrile (11). The compound of formula (11) is reacted with KF in presence of TBAB / toluene and DMSO to obtain 3,6-difluoropyrazine-2-carbonitrile (12). The compound of formula (12) converts into 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) in presence of CH3COONa / DMSO and toluene. The compound of formula (13) converts into pure Favipiravir (I) in presence of conc. H2SO4, NaOH and water.

The above process is schematically shown as below:

The main drawback of the prior art is time consuming process for the preparation of Favipiravir. Direct conversion of 6-bromo-3-hydroxypyrazine-2-carboxamide compound of formula (10) to 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) without isolation of compound of formula (12), which is further converts into Favipiravir (I). The process for the preparation of Favipiravir (I) is carried out in less span of time; hence, the number of required operations are reduced. The advantage of the present invention w.r.t environmental variables, such as humidity, moisture content is eliminated from the manufacturing process.

In view of the foregoing, the present inventors have result of extensive studies, process for the preparation of Favipiravir (I) by using 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Favipiravir. The present invention is also relates to an improved and industrially advantageous process of Favipiravir by using 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt

In one aspect of the present invention provides novel salt of 6-fluoro-3-hydroxypyrazine-2-carbonitrile

In another aspect of the present invention provides 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.

In yet another aspect of the present invention provides a process for the preparation of Favipiravir, comprising the steps of;

a) 6-bromo-3-hydroxypyrazine-2-carboxamide is reacted with chlorinating agent in presence of organic base to obtain 3,6-dichloropyrazine-2-carbonitrile,
b) 3,6-dichloropyrazine-2-carbonitrile is reacted with fluorinating agent in presence of phase transfer catalyst (PCT) to obtain in-situly 3,6-difluoropyrazine-2-carbonitrile, further its treated with inorganic base and isolated in presence of ammonia to give 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt, and
c) 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt is hydrolyzed and oxidized to obtain Favipiravir (1).

In yet another aspect of the present invention, provides purification process for the preparation of Favipiravir having 99.97% having HPLC purity.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Favipiravir. The present invention is also relates to an improved and industrially advantageous process of Favipiravir by using 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt

In one embodiment of the present invention provides a process for the preparation of Favipiravir, comprising the steps of;

a) 6-bromo-3-hydroxypyrazine-2-carboxamide is reacted with chlorinating agent in presence of organic base to obtain in-situly 3,6-dichloropyrazine-2-carbonitrile
b) 3,6-dichloropyrazine-2-carbonitrile is reacted with fluorinating agent in presence of phase transfer catalyst (PCT) to obtain in-situly 3,6-difluoropyrazine-2-carbonitrile, further its treated with inorganic base and isolated in presence of ammonia to give 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt, and
c) 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt is hydrolyzed and oxidized to obtain Favipiravir (1).

In an embodiment of the present invention, 6-bromo-3-hydroxypyrazine-2-carboxamide added into RBF, followed by slow addition of POCl3 and then cool to below 10°C, further added DIPEA into reaction mixture at same temperature. The reaction mass was heated to 80-85ºC, stir for 1 hour at same temperature and then allow to heat at 95-100°C and stir for 6-8 hrs. The reaction mass was cooled to 25-30°C, quench with cold water, extract the material into toluene, wash the toluene layer with sodium bicarbonate solution and sodium chloride solution. The resultant toluene layer was distilled under vacuum and kept aside as part-A solution.
Take separate RBF, added KF, tetrabutylammonium bromide, DMSO and toluene. The reaction mixture was heated to 125°C and distilled out toluene at atmosphere pressure at below 150°C. The reaction mixture was cool to 55-60°C, now slowly added above DMSO solution of part-A and stir the reaction mass for 10-12 hrs (check the reaction conversion by HPLC). The reaction mixture was cool to 25-30°C, added purified water and sodium acetate. The reaction mass was heated to 55-60°C and stir for 3-4 hrs. (Check the reaction conversion of TLC). The reaction mass was cool to 25-30°C, added purified water, adjust pH to 2-3 by dil.HCl solution, added ethyl acetate and stir for 10 min to separate the layers. The obtain ethyl acetate layer was washed with purified water, sodium chloride solution and adjust the pH 8-9 by using ammonia gas at 25-30°C. The resultant ethyl acetate layer was allow to cool at 0-5°C, stir for 60 min, the obtain precipitated material was filtered and dried at 45-50°C for 8 hrs to get 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt, further it is treated with inorganic base and oxidizing agent, the reaction is carried out at 50-70ºC stir for 2-5 hrs, adjust pH to 2-5 by using dil. HCl, preferably 55-60ºC stir for 3-4 hrs, adjust pH to 2-3 to obtain Favipiravir (1).

According to an embodiment of the present invention, wherein the chlorinating agent is selected from phosphorus pentachloride, phosphoryl chloride, phosphorus oxychloride, thionyl chloride, aluminium chloride, methyl sulfonyl chloride, acetyl chloride, chlorine gas, phosgene, diphosgene, triphosgene, sodium hypochlorite, cyanuric chloride and N-chloro succinimide.

According to an embodiment of the present invention, wherein the fluorinating agent is selected from hydrofluoric acid, potassium fluoride, fluorine gas, sodium fluoride, xenon fluoride, lithium fluoride and silver fluoride.

According to an embodiment of the present invention, wherein the organic base is selected from trimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, aniline, N,N-dimethylaniline, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 5-diazabi cyclo[4.3.0]non-5-ene (DBN).
According to an embodiment of the present invention, wherein the suitable inorganic base is selected from, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, sodium acetate, and potassium acetate.

According to an embodiment of the present invention, wherein the phase transfer catalyst (PCT) is selected from, tetrabutyl ammonium bromide, tetraoctylammonium bromide, tetrabutyl ammonium chloride, tetrabutylamine iodide, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, 18 crown 6, 15 crown 5, or cyclodextrin.

According to an embodiment of the present invention, wherein the oxidizing agent is selected from, hydrogen peroxide (H2O2), urea-hydrogen peroxide (UHP), trifluoroacetic acid (TFA) – sulfuric acid (H2SO4), acetic acid- sulfuric acid and H2O2.FeSO4 (Fenton's reagent).

According to an embodiment of the present invention, wherein the reaction is carried out in the presence of solvents such as ethanol, methanol, isopropanol, toluene, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methylene dichloride, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and acetonitrile.

In another embodiment of the present invention provides 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.

In another aspect of the present invention, provides purification process for the preparation of Favipiravir which comprises the Favipiravir (1) is purified with mixture of acetone and dimethyl formamide to obtain pure Favipiravir (1).

In yet another embodiment of the present invention provides purification process for the preparation of Favipiravir having 99.97% having HPLC purity.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1:

6-fluoro-3-Hydroxypyrazine-2-carbonitrile ammonia salt.

Part-A:
Preparation of 3,6-dichloro pyrazine-2-carbonitrile:

100 gm of 6-bromo-3-hydroxypyrazine-2-carboxamide added into RBF, followed by slow addition of 281 gm of POCl3 and then cool to below 10ºC, further added 177.5 g of DIPEA into reaction mixture at same temperature. The reaction mass was heated to 80-85ºC, stir for 1 hr at same temperature and then allow to heat at 95-100ºC and stir for 6-8 hrs. The reaction mass was cooled to 25-30ºC, quench with 1200 ml of cold water, extract the material into 700 ml of toluene, wash the toluene layer with 500 ml of 5% sodium bicarbonate solution and 500 ml of 5% sodium chloride solution. The resultant toluene layer was distilled under vacuum at below 500ºC for 2-3 hrs at same temperature, further added 200 ml of DMSO for the next reaction.

Part-B:
Preparation of 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.

Added 160 gm of KF, 36.5 gms of tetrabutylammonium bromide, 400 ml DMSO and 400 ml of Toluene into above resultant mass in part-A. The reaction mixture was heated to 125ºC, and distilled out toluene at atmosphere pressure at below 150ºC. The reaction mixture was cool to 55-60ºC, now slowly added above DMSO solution of part-A and stir the reaction mass for 10-12 hrs (check the reaction conversion by HPLC). The reaction mixture was cool to 25-30ºC, added 400 ml of purified water and 90 gm of sodium acetate. The reaction mass was heated to 55-60ºC and stir for 3-4 hrs. (Check the reaction conversion of TLC). The reaction mass was cool to 25-30ºC, added 1000 ml of purified water, adjust pH to 2-3 by dil.HCl solution, added 500 ml of ethyl acetate and stir for 10 min to separate the layers. The obtain ethyl acetate layer was washed with purified water, 5% sodium chloride solution and adjust the pH 8-9 by using ammonia gas at 25-30ºC. The resultant ethyl acetate layer was allow to cool at 0-5ºC, stir for 60 min, the obtain precipitated material was filtered and dried at 45-50ºC for 8 hrs to get title compound.
Yield: 55 gms
Purity by HPLC: 99.3%,

SMI-0.2%, Total impurity: 0.7%
Example-2:

400 ml of 5% NaOH solution is added to 100 gm of 6-fluoro-3-hydroxypyrazine-2-carbo nitrile ammonia salt and stir for 30 min, cool the reaction mass to 0-5ºC and then slowly added 70 ml of 30% hydrogen peroxide at below 10ºC. The reaction mixture was allow to 25-35ºC stir for 2-3 hrs, if reaction complies, add activated carbon and stir for 30 min. The resultant mass was filter through hyflo bed, obtain filtrate was cool to 10°C, adjust pH 2-3 by using 10% HCl solution and stir for 30-60 min at 10-15°C. The obtain material was filtered and dried, the afford material was charged into 1200 ml of acetone and heat it to 40-45°C, followed by 10 gm of activated charcoal and stir for 30 min at same temperature. The obtain reaction mass was filter through hyflo bed, wash with 100 ml of acetone, take filtrate into RBF, distilled out acetone at below 40ºC under vacuum until remain 200 ml acetone present in the RBF, cool the reaction mass to 0-5ºC, stir for 60 min. The resultant material was filtered and dried at 45-50°C for 8 hrs to get desired compound.

Yield: 75 gms

Purity by HPLC: 99.93

SMI- 0.02, total impurity: 0.07%.

Example-3:

Charge 100 gm of 6-fluoro-3-Hydroxypyrazine-2-carbonitrile ammonia salt into RBF, add 400 ml of 5% NaOH solution, stir for 30 min, cool the reaction mass to 0-5ºC, add slowly 70 ml of 30% hydrogen peroxide into RBF at below 10ºC, heat the reaction mass to 25-35ºC, stir for 2-3 hrs, check the reaction mass conversion by HPLC, if HPLC complies, add activated carbon into RBF, stir for 30 min, filter the reaction mass through hyflo bed, take filterate into RBF, cool the reaction mass to below 10ºC, adjust the reaction mass pH to 2-3 by using 10% HCl solution. Stir for 30-60 min at 10-15ºC, filter the material, suck dry the material, charge wet material into RBF, charge 1200 ml of acetone, heat the reaction mass to 40-45ºC, and stir for 10 min to get a clear solution. charge 10 gm of activated charcoal into reaction mass, stir for 30 min at same temperature, filter the reaction mass through hyflo bed, wash with 100 ml of acetone, take filtrate into RBF, distilled out acetone at below 40ºC under vacuum until no solvent remain in the RBF, add 200 ml of purified water, cool the reaction mass to 0-5ºC, stir for 60 min, filter the material, dried the material at 45-50ºC for 8hrs.

Yield: 75 gms

Purity by HPLC: 99.94

SMI- 0.02, total impurity: 0.06%.

Example-4:

400 ml of 5% NaOH solution is added to 100 gm of 6-fluoro-3-hydroxypyrazine-2-carbo nitrile ammonia salt and stir for 30 min cool the reaction mass to 0-5ºC and then slowly added 70 ml of 30% hydrogen peroxide at below 10ºC. The reaction mixture was allow to 25-35ºC, stir for 2-3 hrs, if reaction complies, add activated carbon and stir for 30 min. The resultant mass was filter through hyflo bed, obtain filterate was cool to 10°C, adjust pH 2-3 by using 10% HCl solution and stir for 30-60 min at 10-15°C. The obtain material was filtered and dried, the afford material was charged into 1200 ml of acetone and heat it to 40-45°C, followed by 10 gm of activated charcoal and stir for 30 min at same temperature. The obtain reaction mass was filter through hyflo bed, wash with 100 ml of acetone, 100 ml of dimethylformamide into RBF take filtrate into RBF, distilled out acetone at below 40°C under vacuum until remain 200 ml acetone present in the RBF, cool the reaction mass to 0-5°C and stir for 60 min. The resultant material was filtered and dried at 45-50°C for 8 hrs to get desired compound.

Yield: 80 gms

Purity by HPLC: 99.95%

SMI- 0.03%, total impurity: 0.05%.
,CLAIMS:WE CLAIM:

1. A compound of 6-Fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.

2. A process for the preparation of Favipiravir, comprising the steps of;

a) 6-bromo-3-hydroxypyrazine-2-carboxamide is reacted with chlorinating agent in presence of organic base to obtain 3,6-dichloropyrazine-2-carbonitrile,
b) 3,6-dichloropyrazine-2-carbonitrile is reacted with fluorinating agent in presence of phase transfer catalyst (PCT) to obtain in-situly 3,6-difluoropyrazine-2-carbonitrile, further its treated with inorganic base and isolated in presence of ammonia to give 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt, and
c) 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt is hydrolyzed and oxidized to obtain Favipiravir (1).

3. A process for the preparation of 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt, comprising the steps of;

a) 6-bromo-3-hydroxypyrazine-2-carboxamide is reacted with chlorinating agent in presence of organic base to obtain 3,6-dichloropyrazine-2-carbonitrile, and
b) 3,6-dichloropyrazine-2-carbonitrile is reacted with fluorinating agent in presence of phase transfer catalyst (PCT) to obtain in-situly 3,6-difluoropyrazine-2-carbonitrile, further its treated with inorganic base and isolated in presence of ammonia to give 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.

4. The process as claimed in claim 2 and 3, wherein the chlorinating agent is selected from phosphorus pentachloride, phosphoryl chloride, phosphorus oxychloride, thionyl chloride, aluminium chloride, methyl sulfonyl chloride, acetyl chloride, chlorine gas, phosgene, diphosgene, triphosgene, sodium hypochlorite, cyanuric chloride and N-chlorosuccinimide.

5. The process as claimed in claim 2 and 3, wherein the fluorinating agent is selected from hydrofluoric acid, potassium fluoride, fluorine gas, sodium fluoride, xenon fluoride, lithium fluoride and silver fluoride.

6. The process as claimed in claim 2 and 3, wherein the phase transfer catalyst (PCT) is selected from tetrabutyl ammonium bromide, tetraoctylammonium bromide, tetrabutyl ammonium chloride, tetrabutylamine iodide, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, 18 crown 6, 15 crown 5, or cyclodextrin.

7. The process as claimed in claim 2 and 3, wherein the organic base is selected from trimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethyl amine, aniline, N,N-dimethylaniline, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 5-diazabicyclo[4.3.0]non-5-ene (DBN).

8. The process as claimed in claim 2, wherein the suitable inorganic base is selected from, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, sodium acetate, and potassium acetate.

9. The process as claimed in claim 2, wherein the oxidizing agent is selected from, hydrogen peroxide (H2O2), urea-hydrogen peroxide (UHP), trifluoroacetic acid (TFA) – sulfuric Acid (H2SO4), acetic acid- sulfuric acid and H2O2.FeSO4 (Fenton's reagent).