DESC: “ONE POT SYNTHESIS OF FAVIPIRAVIR”

FIELD OF THE INVENTION

The present invention relates to a one pot process for the preparation of Favipiravir. The present invention is also relates to an improved, commercially viable, industrially advantageous, easier to handle and environmental friendly process for the preparation of Favipiravir.

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 therapeutical 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'-(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.

ADVANTAGES:

01) Single pot processing is an extremely flexible technology.

02) Direct conversion of 6-bromo-3-hydroxypyrazine-2-carboxamide compound of formula (10) to Favipiravir (I) without isolation of intermediates.

03) The process for the preparation of Favipiravir (I) is carried out in less span of time; hence, the number of required operations are reduced.

04) The advantage of the present invention w.r.t environmental variables, such as humidity, moisture content are eliminated from the manufacturing process.

In view of the foregoing, the present inventors have result of extensive studies, one pot process for the preparation of Favipiravir (I) without isolation of intermediates.

SUMMARY OF THE INVENTION

The present invention relates to a one pot process for the preparation of Favipiravir. The present invention is also relates to an improved, commercially viable, industrially advantageous, easier to handle and environmental friendly process for the preparation of Favipiravir.

In one aspect of the present invention, provides one pot process for the preparation of Favipiravir, comprising the steps of;

a) 6-bromo-3-hydroxypyrazine-2-carboxamide (10) is reacted with chlorinating agent in presence of organic base to obtain in-situly 3,6-dichloropyrazine-2-carbonitrile (11),

b) The compound of formula (11) is reacted with fluorinating agent in presence of PTC to obtain in-situly 3,6-difluoropyrazine-2-carbonitrile (12), which is followed by in-situly converts into 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) in presence of inorganic base and organic solvent,

c) The compound of formula (13) by partial hydrolysis with inorganic base in presence of oxidizing agent to obtain Favipiravir (1).

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 water to obtain pure 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 one pot process for the preparation of Favipiravir. The present invention is also relates to an improved, commercially viable, industrially advantageous, easier to handle and environmental friendly process for the preparation of Favipiravir.

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

a) 6-bromo-3-hydroxypyrazine-2-carboxamide (10) is reacted with chlorinating agent in presence of organic base to obtain in-situly 3,6-dichloropyrazine-2-carbonitrile (11),
b) The compound of formula (11) is reacted with fluorinating agent in presence of PTC to obtain in-situly 3,6-difluoropyrazine-2-carbonitrile (12), which is followed by in-situly converts into 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) in presence of inorganic base and organic solvent,
c) The compound of formula (13) by partial hydrolysis with inorganic base in presence of oxidizing agent to obtain Favipiravir (1).

In an embodiment of the present invention, wherein the compound of formula (10) is reacted with chlorinating agent in presence of organic base and toluene and the reaction is carried out at room temperature to obtain in-situly 3,6-dichloropyrazine-2-carbonitrile (11). The compound of formula (11) is reacted with fluorinating agent in presence of PTC and the reaction is carried out at 50-70ºC stir for 10-15 hrs., preferably 55-60ºC stir for 10-12 hrs to obtain in-situly 3,6-difluoropyrazine-2-carbonitrile (12), which is followed by in-situly converts into 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) in presence of inorganic base and organic solvent 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 . The compound of formula (13) by partial hydrolysis with inorganic base in presence of oxidizing agent 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-chlorosuccinimide.

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 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 organic solvent is selected from, 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 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 water 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

Preparation of 6-fluoro-3-hydroxypyrazine-2-carboxamide (Favipiravir).

Part-A:

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

100 gm of 6-bromo-3-hydroxypyrazine-2-carboxamide added into RBF, add slowly 281 gm of POCl3 into RBF, then cool the reaction mass to below 10ºC temperature add slowly 177.5 g of DIPEA into reaction mass at below 15ºC. Heat the reaction mass to 80-85ºC, stir for 1 hr at same temperature, then heat the reaction mass to 95-100ºC, stir for 6-8 hrs, check the reaction conversion by TLC, if reaction complies cool the reaction mass to 25-30ºC, reaction mass quench into 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 followed by wash with 500 ml of 5% sodium chloride solution. Distilled out toluene completely under vacuum at below 500ºC, Degass the toluene for 2-3 hrs at same temperature, add 200 ml of DMSO into solid for the next reaction.

Part-B:

Preparation of 6-fluoro-3-hydroxypyrazine-2-carbonitrile:

Charge 400 ml of DMSO, 160 gm of KF, 36.5 gms of tetrabutylammonium bromide and 400 ml of toluene into RBF under nitrogen atmosphere, heat the reaction mass to 125ºC, distilled out toluene at atmosphere pressure at below 150ºC, cool the reaction mass to 55-60ºC, add slowly above DMSO solution from part-A, stir the reaction mass for 10-12 hrs, check the reaction conversion by HPLC, if reaction mass complies cool the reaction mass to 25-30ºC, add 1500 ml of purified water into reaction mass, Add 300 ml of 10% dil. HCl solution into RBF, charge 500 ml of toluene into the reaction mass, separate the layers, take aq layer charge 500 ml of toluene into the reaction mass, stir for 10 min, separate the layers. Take toluene layer wash with 500 ml of purified water and followed by 500 ml of 5% sodium chloride washing. Take toluene layer into RBF add 400 ml of DMSO and 200 ml of purified water. Add 90 gm of sodium acetate into reaction mass. Heat the reaction mass to 55-60ºC, stir for 3-4 hrs, check the reaction conversion of TLC, if reaction complies cool the reaction mass to 25-30ºC, add slowly 1000 ml of purified water, adjust pH to 2-3 by using 90 ml of dil. HCl solution. Charge 500 ml of ethyl acetate into reaction mass stir for 10 min, separate the layers, extract the material 2* 500 ml of ethyl acetate, and combine total ethyl acetate charge into RBF,

Part-C

Preparation of Favipiravir:

Cool the ethyl acetate layer to below 20ºC, add 400 ml of 5% NaOH solution, stir for 30 min, separate the layers, take aq layer and charge 500 ml of toluene into RBF, stir for 10 min, separate the layers, take aq layer into RBF 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, 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, dry the material in hot air oven at 55-60ºC for 8 hrs.

Single maximum unknown impurity: 0.02, total impurity: 0.07%.

Yield: 40 gms,

purity by HPLC: 99.93%,

Example-2:

Preparation of 6-fluoro-3-hydroxypyrazine-2-carboxamide (Favipiravir).

Part-A:

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

100 gm of 6-bromo-3-hydroxypyrazine-2-carboxamide added into RBF, add slowly 281 gm of POCl3 into RBF, then cool the reaction mass to below 10ºC temperature add slowly 177.5 g of DIPEA into reaction mass at below 15ºC. Heat the reaction mass to 80-85ºC, stir for 1 hr at same temperature, then heat the reaction mass to 95-100ºC, stir for 6-8 hrs, check the reaction conversion by TLC, if reaction complies cool the reaction mass to 25-30ºC, reaction mass quench into 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 followed by wash with 500 ml of 5% sodium chloride solution. Distilled out toluene completely under vacuum at below 500ºC, Degass the toluene for 2-3 hrs at same temperature, add 200 ml of DMSO into solid for the next reaction.
Part-B:

Preparation of 6-fluoro-3-hydroxypyrazine-2-carbonitrile:

Charge 400 ml of DMSO, 160 gm of KF, 36.5 gms of tetrabutylammonium bromide and 400 ml of toluene into RBF under nitrogen atmosphere, heat the reaction mass to 125ºC, distilled out toluene at atmosphere pressure at below 150ºC, cool the reaction mass to 55-60ºC, add slowly above DMSO solution from part-A, stir the reaction mass for 10-12 hrs, check the reaction conversion by HPLC, if reaction mass complies cool the reaction mass to 25-30ºC, Add 400 ml of purified water into reaction mass, add 90 gm of sodium acetate into reaction mass. Heat the reaction mass to 55-60ºC, stir for 3-4 hrs, check the reaction conversion of TLC, if reaction complies cool the reaction mass to 25-30ºC, add slowly 1000 ml of purified water, adjust pH to 2-3 by using 90 ml of dil. HCl solution. Charge 500 ml of ethyl acetate into reaction mass stir for 10 min, separate the layers, extract the material 2* 500 ml of ethyl acetate and combine total ethyl acetate charge into RBF.

Part-C:

Preparation of Favipiravir:

Cool the ethyl acetate layer to below 20ºC, add 400 ml of 5% NaOH solution, stir for 30 min, separate the layers, take aq layer and charge 500 ml of toluene into RBF, stir for 10 min, separate the layers, take aq layer into RBF 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, cool the reaction mass to below 10ºC, adjust the reaction mass pH to 2-3 by using 10% dil.HCl solution. Stir for 30-60 min at 10-15ºC, filter the material, suck dry the material, and dry the material in hot air oven at 55-60ºC for 8 hrs.

Single maximum unknown impurity: 0.02%, total impurity: 0.07%.

Yield: 40 gms,

purity by HPLC: 99.93%,

Example-3:

Purification of Favipiravir.

Charge 100 gm of Favipiravir into RBF, Charge 1200 ml of acetone, heat the reaction mass to 40-45ºC, 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 vaccum until remain 200 ml acetone present in the RBF, cool the reaction mass to 0-5ºC, stir for 60 min, filter the material, dried the material at 45-50ºC for 8 hrs.

SMI: 0.02%, Total impurity: 0.03%

Yield: 85 gms,

HPLC Purity: 99.97%,

Example-4:

Purification of Favipiravir:

Charge 100 gm of Favipiravir into RBF, charge 1200 ml of acetone, heat the reaction mass to 40-45ºC, 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 vaccum until no solvent remain in the flask, charge 200 ml of purified water into RBF, cool the reaction mass to 0-5ºC, stir for 60 min, filter the material, dried the material at 45-50ºC for 8 hrs.

SMI: 0.02%, Total impurity: 0.04%

Yield: 90 gms,

HPLC Purity: 99.96%,

Example-5:

Purification of Favipiravir:

Charge 100 gm of Favipiravir into RBF, charge 1200 ml of acetone, heat the reaction mass to 40-45ºC, 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, add 100 ml of dimethylformamide 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, filter the material, dried the material at 55-60ºC for 8 hrs.

SMI: 0.03%, Total impurity: 0.07%.

Yield: 88 gms,

HPLC Purity: 99.93%,
,CLAIMS:WE CLAIM:

1. One pot process for the preparation of favipiravir, comprising the steps of;

a) 6-bromo-3-hydroxypyrazine-2-carboxamide (10) is reacted with chlorinating agent in presence of organic base to obtain in-situly 3,6-dichloropyrazine-2-carbonitrile (11),

b) The compound of formula (11) is reacted with fluorinating agent in presence of PTC to obtain in-situly 3,6-difluoropyrazine-2-carbonitrile (12), which is followed by in-situly converts into 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) in presence of inorganic base and organic solvent,

c) The compound of formula (13) by partial hydrolysis with inorganic base in presence of oxidizing agent to obtain Favipiravir (1).

2. The process as claimed in claim 1, 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.

3. The process as claimed in claim 1, wherein the fluorinating agent is selected from hydrofluoric acid, potassium fluoride, fluorine gas, sodium fluoride, xenon fluoride, lithium fluoride and silver fluoride.

4. The process as claimed in claim 1, 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), 5-diazabicyclo[4.3.0]non-5-ene (DBN).

5. The process as claimed in claim 1, Wherein the suitable inorganic base is selected from, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, sodium acetate, and potassium acetate.

6. The process as claimed in claim 1, wherein the phase transfer catalyst 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 1, 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).

8. The process as claimed in claim 1, wherein the organic solvent is selected from, ethanol, methanol, isopropanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethyl acetate, isopropyl acetate and n-butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, methylene dichloride, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and acetonitrile.

9. A purification process for the preparation of Favipiravir, which comprises the Favipiravir (1) is purified with mixture of acetone and water to obtain pure Favipiravir (1).

10. The process as claimed in claim 8, purification process for the preparation of favipiravir having 99.97% having HPLC purity.