259793-96-9

Basic information

• Product Name: Pyrazinecarboxamide, 6-fluoro-3,4-dihydro-3-oxo- (9CI)
• Synonyms: Pyrazinecarboxamide, 6-fluoro-3,4-dihydro-3-oxo- (9CI);PYRAZINECARBOXAMIDE, 6-FLUORO-3,4-DIHYDRO-3-OXO-;6-Fluoro-3-hydroxypyrazine-2-carboxamide;Favipiravir;Unii-ew5gl2X7E0;6-fluoro-3,4-dihydro-3-oxo-Pyrazinecarboxamide;6-fluoro-3,4-dihydro-3-oxo- (9CI);T-705
• CAS NO: 259793-96-9
• Molecular Formula: C₅H₄FN₃O₂
• Molecular Weight: 157.1025632
• EINECS: 1533716-785-6
• Product Categories: AMIDE;HALIDE
• Mol File: 259793-96-9.mol
• Article Data: 24

Chemical Properties

• Boiling Point: 552.6 °C at 760 mmHg
• Flash Point: 288 °C
• Appearance: /
• Density: 1.78 g/cm³
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Soluble in DMSO (30 mg/mL), water (12 mg/mL with warming)
• PKA: 8.77±0.60(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO or water may be stored at -20° for up to 3 months.
• CAS DataBase Reference: Pyrazinecarboxamide, 6-fluoro-3,4-dihydro-3-oxo- (9CI)(CAS DataBase Reference)
• NIST Chemistry Reference: Pyrazinecarboxamide, 6-fluoro-3,4-dihydro-3-oxo- (9CI)(259793-96-9)
• EPA Substance Registry System: Pyrazinecarboxamide, 6-fluoro-3,4-dihydro-3-oxo- (9CI)(259793-96-9)

Safety Data

• Hazardous Substances Data: 259793-96-9(Hazardous Substances Data)

Usage

Description

Favipiravir, 6-fluoro-3-hydroxypyrazine-2-carboxamide, is a new broad-spectrum antiviral drug targeting RNA-dependent RNA polymerase (RdRp) developed by Japan's Toyama Chemical Pharmaceutical Company. It was approved for marketing in Japan in March 2014 for the treatment of new and recurrent influenza. During the outbreak of the new coronavirus, the results of the Phase I clinical study of the drug published in March 2020 showed that the drug may have the effect of speeding up virus clearance to alleviate the progress of new coronavirus pneumonia.

History

Favipiravir was originally developed in the late 1990s by a company that was later purchased by the Japanese firm Fujifilm as part of its transition from the photo business to healthcare. After being tested against a range of viruses, the drug was approved in Japan in 2014 for emergency use against flu epidemics or to treat new strains of influenza.

Uses

Favipiravir is used for the treatment of advanced Ebola virus infection in a small animal model. It suppressed the replication of Zaire Ebola virus and prevented a lethal outcome in 100% of the animals. Based on the studies, Favipiravir can be a candidate for the treatment of Ebola hemorrhagic fever. Favipiravir can be used for antiviral treatment of influenza A and B. Studies have shown that in addition to influenza virus, the drug also exhibits good antiviral activity against a variety of RNA viruses, such as Ebola virus, arena virus, Bunia virus, rabies virus and now COVID-19.

Definition

ChEBI: Favipiravir is a member of the class of pyrazines that is pyrazine substituted by aminocarbonyl, hydroxy and fluoro groups at positions 2, 3 and 6, respectively. It is an anti-viral agent that inhibits RNA-dependent RNA polymerase of several RNA viruses and is approved for the treatment of influenza in Japan. It has a role as an antiviral drug, an anticoronaviral agent and an EC 2.7.7.48 (RNA-directed RNA polymerase) inhibitor. It is a primary carboxamide, a hydroxypyrazine and an organofluorine compound.

Mechanism of action

Favipiravir is an antiviral drug that selectively inhibited the RdRP of influenza virus. It showed specific activity against all three influenza A, B, and C (Furuta et al., 2013). It also inhibited the RV replication in HeLa cells, with an EC50 of 29 μg/mL (Furuta et al., 2002). Analysis showed that the primary mechanism of action of favipiravir against the influenza virus was specific inhibition of vRNA polymerase (Furuta et al., 2005). It is predicted that a similar mechanism might occur with other viruses, such as PV and RV, inhibited by favipiravir, which may account for its broad-spectrum inhibition. Mechanistic studies show that the favipiravir and its form favipiravir-RMP (favipiravir-ribofuranosyl-50-monophosphate) do not inhibit influenza RNA polymerase activity, but it is the phosphoribosylated form, favipiravir-ribofuranosyl-50-triphosphate (RTP) that inhibits the enzyme.

Synthesis

Favipiravir was synthesized in only six steps from 3-aminopyrazine-2-carboxylic acid with an overall yield of about 22.3%. Key intermediates 3 and 6 were obtained in excellent purity via recrystallization from optimized solvents, which was beneficial to large-scale production. In the key synthetic reaction, 3,6-dichloropyrazine-2-carbonitrile (6) was reacted sequentially, in one pot, with KF and 30% H2O2 to give (after crystallization from 95% EtOH) favipiravir as colorless crystals, with a 60% yield for this final step of the synthesis. (DOI:10.1007/s11696-017-0208-6)645 grams of sodium hydroxide were dissolved in 9L of water, the temperature was lowered to 5°C, and 1.29 kg of 6-fluoro-3-hydroxy-2-cyanopyrazine was added in batches, stirred, and heated slightly, and the temperature of the reaction system was controlled to -10°C, it takes 3.5 hours to complete the addition, after holding for 1 hour, the temperature is raised to 40°C for 1 hour. Add 100g of activated carbon to the reaction solution, hot filter, cool the mother liquor to 5°C, adjust the pH to 3-4 with concentrated hydrochloric acid, precipitate a large amount of solids, filter and dry to obtain a crude off-white powder, beaten with 2.8 liters of 15% methanol aqueous solution and filter After drying, 1.34 kg of white powder favipiravir was obtained. 1H-NMR (DMSO, 600MHz): δ 13.38 (s, 1H), 8.73 (1s, 1H), 8.51-8.49 (d, J=12, 2H) (yield 91%).

References

1) Furuta?et al.?(2002),?In Vitro and In Vivo Activities of Anti-Influenza Virus Compound T-705; Antimicrob. Agents Chemother.,?46?977 2) Takahashi?et al.?(2003)?In Vitro and In Vivo Activities of T-705 and Oseltamivir Against Influenza Virus; Antivir. Chem. Chemother.,?14?235 3) Sleeman?et al.?(2010)?In Vitro Antiviral Activity of Favipiravir (T-705) against Drug-Resistant Influenza and 2009 A(H1N1) Viruses; Antimicrob. Agents Chemother.,?54?2517 4) Furuta?et al.?(2005)?Mechanism of action of T-705 against influenza virus; Antimicrob. Agents Chemother.,?49?981 5) Furuta?et al.?(2013)?), Favipiravir (T-705), a Novel Viral RNA Polymerase Inhibitor; Antiviral Res.,?100?446 6) Dong?et al.?(2020)?Discovering Drugs to Treat Coronavirus Disease 2019 (COVID-19); Drug Discov. Ther.,?14?58 7) Tu?et al.?(2020)?A Review of SARS-CoV-2 and the Ongoing Clinical Trials; Int. J. Mol. Sci., 21?E2657

Synthetic route

6-fluoro-3-hydroxy-2-cyanopyrazine (356783-31-8) → favipiravir (259793-96-9)

Conditions	Yield
Stage #1: 6-fluoro-3-hydroxy-2-cyanopyrazine With sulfuric acid at 50℃; for 4h; Stage #2: With water at 3 - 10℃; for 0.666667h; Stage #3: With sodium hydroxide In water at 10℃; for 0.75h;	92.3%
With sodium hydroxide In water at 5 - 45℃; for 5.5h; Large scale;	91%
With sulfuric acid at 50℃; for 4h;	68.43%
Stage #1: 6-fluoro-3-hydroxy-2-cyanopyrazine With dihydrogen peroxide; sodium hydroxide at 10 - 20℃; for 1h; Stage #2: With N-ethyl-N,N-diisopropylamine In ethyl acetate at 80℃; for 1h; Reagent/catalyst;

C6H5FN2O3 → favipiravir (259793-96-9)

Conditions	Yield
With ammonium carbonate Reagent/catalyst;	92.3%

3,6-difluoro-2-pyrazinecarboxamide (356783-29-4) → favipiravir (259793-96-9)

Conditions	Yield
With water; sodium hydroxide at 60℃; for 3h;	92.1%
With sodium hydrogencarbonate In 1,4-dioxane; water at 60℃; for 8h;	82%
With water; sodium hydrogencarbonate at 50℃; for 8.5h;	65%

3,6-difluoropyrazine-2-carbonitrile (356783-28-3) → favipiravir (259793-96-9)

Conditions	Yield
Stage #1: 3,6-difluoropyrazine-2-carbonitrile With sodium acetate In tetrahydrofuran; water for 20h; Reflux; Stage #2: With dihydrogen peroxide; sodium hydroxide In water; toluene at 0 - 20℃; for 4h;	89.6%
Multi-step reaction with 2 steps 1.1: sodium acetate; water / toluene; dimethyl sulfoxide / 7 h / 50 °C 2.1: sulfuric acid / 4 h / 50 °C 2.2: 0.67 h / 3 - 10 °C 2.3: 0.75 h / 10 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / tetrahydrofuran / 1.5 h / 60 °C 2: sodium hydrogencarbonate / 1,4-dioxane; water / 8 h / 60 °C View Scheme

dicyclohexylamine salt (1137606-74-6) → favipiravir (259793-96-9)

Conditions	Yield
Stage #1: dicyclohexylamine salt With water; sodium hydroxide In toluene at 20℃; for 0.5h; Stage #2: With dihydrogen peroxide In toluene at 15 - 25℃; for 0.5h;	84%
Stage #1: dicyclohexylamine salt With sodium hydroxide In water; toluene at 15 - 25℃; for 0.5h; Stage #2: With water; dihydrogen peroxide at 15 - 30℃; Stage #3: With hydrogenchloride In water

C12H10FN3O2 → favipiravir (259793-96-9)

Conditions	Yield
With ammonia; sodium In tetrahydrofuran at -70 - -65℃;	72%

2-hydroxypyrazine-3-carboxamide (55321-99-8) → favipiravir (259793-96-9)

Conditions	Yield
With 1-fluoro-4-methyl-1,4-diazoniabicyclo<2.2.2>octane ditetrafluoroborate In 1,2-dichloro-ethane; N,N-dimethyl-formamide at 70 - 80℃; for 20h; Reagent/catalyst; Solvent; Temperature;	71.3%
With fluorine In water
Multi-step reaction with 5 steps 1.1: bromine / acetonitrile / 6 h / 0 - 40 °C 2.1: trichlorophosphate / chlorobenzene / 0.5 h / 60 °C 2.2: 2.67 h / 90 - 100 °C 3.1: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 2.5 h / 60 °C 4.1: sodium acetate; water / toluene; dimethyl sulfoxide / 7 h / 50 °C 5.1: sulfuric acid / 4 h / 50 °C 5.2: 0.67 h / 3 - 10 °C 5.3: 0.75 h / 10 °C View Scheme
Multi-step reaction with 4 steps 1.1: pyridine; N-chloro-succinimide / acetonitrile / 4 h / 80 - 85 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; phosphorus(V) oxybromide / chlorobenzene / 4 h / 0 °C / Reflux 3.1: potassium fluoride / N,N-dimethyl-formamide / 20 h / 80 - 85 °C 4.1: sodium acetate / tetrahydrofuran; water / 20 h / Reflux 4.2: 4 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate; tetra-(n-butyl)ammonium iodide / acetonitrile / 55 - 60 °C 2.1: formic acid / 5 - 10 °C 2.2: 5 - 8 °C 3.1: ammonia; sodium / tetrahydrofuran / -70 - -65 °C View Scheme

3-hydroxy-6-bromopyrazine-2-carboxamide → favipiravir (259793-96-9)

Conditions	Yield
With potassium fluoride; 18-crown-6 ether In toluene at 100℃; for 20h;	15.96%
Multi-step reaction with 4 steps 1.1: trichlorophosphate / chlorobenzene / 0.5 h / 60 °C 1.2: 2.67 h / 90 - 100 °C 2.1: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 2.5 h / 60 °C 3.1: sodium acetate; water / toluene; dimethyl sulfoxide / 7 h / 50 °C 4.1: sulfuric acid / 4 h / 50 °C 4.2: 0.67 h / 3 - 10 °C 4.3: 0.75 h / 10 °C View Scheme
Multi-step reaction with 4 steps 1: trichlorophosphate; N-ethyl-N,N-diisopropylamine / water / 8 h / 60 - 100 °C 2: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 3 h / 55 °C 3: dihydrogen peroxide / toluene; dimethyl sulfoxide / 2 h / 27 °C / Cooling with ice 4: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 0.25 h / 70 °C 1.2: 6 h / 20 - 100 °C 1.3: 1 h 2.1: potassium fluoride dihydrate; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 50 °C 3.1: potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide; water / 1.5 h / 25 °C 4.1: sodium hydrogencarbonate; water / dimethyl sulfoxide / 8 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: diethylamino-sulfur trifluoride / dichloromethane / 5 h / 0 °C 2: 18-crown-6 ether; potassium fluoride / toluene / 20 h / 110 °C 3: methanol; sodium hydrogencarbonate; water / 8 h / 50 °C View Scheme

6-fluoro-3-methoxy-2-pyrazinecarboxamide → favipiravir (259793-96-9)

Conditions	Yield
With chloro-trimethyl-silane; sodium chloride; sodium thiosulfate In chloroform; water; acetonitrile
With chloro-trimethyl-silane; sodium iodide; sodium chloride; sodium thiosulfate In chloroform; water; acetonitrile

methyl 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate (356783-27-2) → favipiravir (259793-96-9)

Conditions	Yield
With sodium bicarbonate; sodium chloride; ammonia In methanol; water; ethyl acetate

6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile (356783-31-8) → favipiravir (259793-96-9)

Conditions	Yield
With sodium hydroxide; sulfuric acid; dihydrogen peroxide In water

3-amino-6-fluoro-2-pyrazinecarboxamide (356783-42-1) → favipiravir (259793-96-9)

Conditions	Yield
With sodium bicarbonate; sodium chloride; sulfuric acid; sodium nitrite In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; di-isopropyl ether; water; ethyl acetate

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 2.5 h / 60 °C 2.1: sodium acetate; water / toluene; dimethyl sulfoxide / 7 h / 50 °C 3.1: sulfuric acid / 4 h / 50 °C 3.2: 0.67 h / 3 - 10 °C 3.3: 0.75 h / 10 °C View Scheme
Multi-step reaction with 3 steps 1: potassium fluoride; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 55 °C / Sealed tube 2: dihydrogen peroxide / 2 h / 27 °C 3: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 3 h / 55 °C 2: dihydrogen peroxide / toluene; dimethyl sulfoxide / 2 h / 27 °C / Cooling with ice 3: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme

C9H8ClN3O3 (1374986-08-9) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium fluoride / dimethyl sulfoxide / 4 h / 90 °C 2.1: sodium hydrogencarbonate; water / 4 h / 100 °C 2.2: 1.17 h / 20 °C 3.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 3.2: 0.5 h / 15 - 25 °C View Scheme

C9H8FN3O3 (1374986-19-2) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate; water / 4 h / 100 °C 1.2: 1.17 h / 20 °C 2.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 2.2: 0.5 h / 15 - 25 °C View Scheme

C9H10N4O6S (1374986-28-3) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium fluoride / dimethyl sulfoxide / 3 h / 80 °C / Inert atmosphere 1.2: 3 h / 80 °C 1.3: 20 °C 2.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 2.2: 0.5 h / 15 - 25 °C View Scheme

C9H12N2O4 (1374986-36-3) → favipiravir (259793-96-9)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: acetyl chloride; isopentyl nitrite / isopropyl alcohol / 1.5 h / 5 - 40 °C / Inert atmosphere 2.1: trichlorophosphate / toluene; N,N-dimethyl-formamide / 7 h / 15 - 70 °C / Inert atmosphere 3.1: potassium fluoride / dimethyl sulfoxide / 4 h / 90 °C 4.1: sodium hydrogencarbonate; water / 4 h / 100 °C 4.2: 1.17 h / 20 °C 5.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 5.2: 0.5 h / 15 - 25 °C View Scheme

C9H11N3O5 (1374986-38-5) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: trichlorophosphate / toluene; N,N-dimethyl-formamide / 7 h / 15 - 70 °C / Inert atmosphere 2.1: potassium fluoride / dimethyl sulfoxide / 4 h / 90 °C 3.1: sodium hydrogencarbonate; water / 4 h / 100 °C 3.2: 1.17 h / 20 °C 4.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 4.2: 0.5 h / 15 - 25 °C View Scheme

C11H15N2O6(1-)*K(1+) → favipiravir (259793-96-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: trifluoroacetic acid; hydroxylamine hydrochloride / methanol / 5 h / 10 °C / Inert atmosphere; Reflux 2.1: toluene-4-sulfonic acid; acetic acid / 2 h / 77 - 80 °C / Industrial scale 3.1: trichlorophosphate; triethylamine hydrochloride / 4 h / 85 °C 4.1: triethylamine / 2 h / 80 °C 5.1: potassium fluoride / dimethyl sulfoxide / 4 h / 90 °C 6.1: sodium hydrogencarbonate; water / 4 h / 100 °C 6.2: 1.17 h / 20 °C 7.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 7.2: 0.5 h / 15 - 25 °C View Scheme

C11H17N3O6 (1374986-03-4) → favipiravir (259793-96-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: toluene-4-sulfonic acid; acetic acid / 2 h / 77 - 80 °C / Industrial scale 2.1: trichlorophosphate; triethylamine hydrochloride / 4 h / 85 °C 3.1: triethylamine / 2 h / 80 °C 4.1: potassium fluoride / dimethyl sulfoxide / 4 h / 90 °C 5.1: sodium hydrogencarbonate; water / 4 h / 100 °C 5.2: 1.17 h / 20 °C 6.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 6.2: 0.5 h / 15 - 25 °C View Scheme

C7H5N3O4 (1374986-04-5) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: trichlorophosphate; triethylamine hydrochloride / 4 h / 85 °C 2.1: triethylamine / 2 h / 80 °C 3.1: potassium fluoride / dimethyl sulfoxide / 4 h / 90 °C 4.1: sodium hydrogencarbonate; water / 4 h / 100 °C 4.2: 1.17 h / 20 °C 5.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 5.2: 0.5 h / 15 - 25 °C View Scheme

methyl-5-chloroisoxazolo[4,5-b]pyrazine-3-carboxylate (1374986-05-6) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / 2 h / 80 °C 2.1: potassium fluoride / dimethyl sulfoxide / 4 h / 90 °C 3.1: sodium hydrogencarbonate; water / 4 h / 100 °C 3.2: 1.17 h / 20 °C 4.1: water; sodium hydroxide / toluene / 0.5 h / 20 °C 4.2: 0.5 h / 15 - 25 °C View Scheme

2-pyrazine carbonitrile (19847-12-2) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetic acid; dihydrogen peroxide / 22 h / -5 - 95 °C 2.1: trichlorophosphate / 1.83 h / 50 - 70 °C 2.2: 6 h / 96 °C 3.1: potassium fluoride; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 55 °C / Sealed tube 4.1: dihydrogen peroxide / 2 h / 27 °C 5.1: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme

1,4-dioxopyrazinamide (18960-19-5) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: trichlorophosphate / 1.83 h / 50 - 70 °C 1.2: 6 h / 96 °C 2.1: potassium fluoride; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 55 °C / Sealed tube 3.1: dihydrogen peroxide / 2 h / 27 °C 4.1: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1.1: trichlorophosphate / chlorobenzene / 1.83 h / 50 - 70 °C 1.2: 8 h / 110 °C 2.1: tetrabutyl ammonium fluoride; tetrabutylammomium bromide / 3 h / 60 °C / Sealed tube 3.1: sodium acetate; water / 1,4-dioxane / 7 h / 55 °C 4.1: sulfuric acid / 4 h / 50 °C View Scheme

3-aminopyrazinoic acid (5424-01-1) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 8 steps 1: sulfuric acid / 20 °C / Cooling with ice 2: N-Bromosuccinimide / acetonitrile / 20 °C 3: sulfuric acid; sodium nitrite / 2 h / -5 - 20 °C 4: ammonium hydroxide / 3 h / 20 °C 5: trichlorophosphate; N-ethyl-N,N-diisopropylamine / water / 8 h / 60 - 100 °C 6: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 3 h / 55 °C 7: dihydrogen peroxide / toluene; dimethyl sulfoxide / 2 h / 27 °C / Cooling with ice 8: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme
Multi-step reaction with 8 steps 1.1: sulfuric acid / 48 h / Cooling with ice 2.1: N-Bromosuccinimide / acetonitrile / 24 h / 20 °C / Inert atmosphere 3.1: sulfuric acid; sodium nitrite / 2 h / -5 - 25 °C 3.2: 1.5 h 4.1: ammonium hydroxide / 3 h / 20 °C 5.1: trichlorophosphate / 0.25 h / 70 °C 5.2: 6 h / 20 - 100 °C 5.3: 1 h 6.1: potassium fluoride dihydrate; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 50 °C 7.1: potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide; water / 1.5 h / 25 °C 8.1: sodium hydrogencarbonate; water / dimethyl sulfoxide / 8 h / 50 °C View Scheme

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 7 steps 1: N-Bromosuccinimide / acetonitrile / 20 °C 2: sulfuric acid; sodium nitrite / 2 h / -5 - 20 °C 3: ammonium hydroxide / 3 h / 20 °C 4: trichlorophosphate; N-ethyl-N,N-diisopropylamine / water / 8 h / 60 - 100 °C 5: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 3 h / 55 °C 6: dihydrogen peroxide / toluene; dimethyl sulfoxide / 2 h / 27 °C / Cooling with ice 7: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme
Multi-step reaction with 7 steps 1.1: N-Bromosuccinimide / acetonitrile / 24 h / 20 °C / Inert atmosphere 2.1: sulfuric acid; sodium nitrite / 2 h / -5 - 25 °C 2.2: 1.5 h 3.1: ammonium hydroxide / 3 h / 20 °C 4.1: trichlorophosphate / 0.25 h / 70 °C 4.2: 6 h / 20 - 100 °C 4.3: 1 h 5.1: potassium fluoride dihydrate; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 50 °C 6.1: potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide; water / 1.5 h / 25 °C 7.1: sodium hydrogencarbonate; water / dimethyl sulfoxide / 8 h / 50 °C View Scheme

methyl 3-amino-6-bromopyrazine-2-carboxylate (6966-01-4) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 6 steps 1: sulfuric acid; sodium nitrite / 2 h / -5 - 20 °C 2: ammonium hydroxide / 3 h / 20 °C 3: trichlorophosphate; N-ethyl-N,N-diisopropylamine / water / 8 h / 60 - 100 °C 4: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 3 h / 55 °C 5: dihydrogen peroxide / toluene; dimethyl sulfoxide / 2 h / 27 °C / Cooling with ice 6: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid; sodium nitrite / 2 h / -5 - 25 °C 1.2: 1.5 h 2.1: ammonium hydroxide / 3 h / 20 °C 3.1: trichlorophosphate / 0.25 h / 70 °C 3.2: 6 h / 20 - 100 °C 3.3: 1 h 4.1: potassium fluoride dihydrate; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 50 °C 5.1: potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide; water / 1.5 h / 25 °C 6.1: sodium hydrogencarbonate; water / dimethyl sulfoxide / 8 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1: sulfuric acid; sodium nitrite / 0.5 h / 0 - 60 °C 2: bromine; potassium carbonate / tetrahydrofuran / 12 h / 66 °C 3: tetrabutylammomium bromide; potassium fluoride / dimethyl sulfoxide; toluene / 3 h / 80 °C 4: hydrogen; palladium 10% on activated carbon / methanol / 4 h / 20 - 25 °C 5: ammonium carbonate View Scheme

3-hydroxy-6-bromopyrazine-2-carboxylic acid methyl ester (21874-61-3) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: ammonium hydroxide / 3 h / 20 °C 2: trichlorophosphate; N-ethyl-N,N-diisopropylamine / water / 8 h / 60 - 100 °C 3: potassium fluoride; tetrabutylammomium bromide / toluene; dimethyl sulfoxide / 3 h / 55 °C 4: dihydrogen peroxide / toluene; dimethyl sulfoxide / 2 h / 27 °C / Cooling with ice 5: sodium hydrogencarbonate; water / 8.5 h / 50 °C View Scheme
Multi-step reaction with 5 steps 1.1: ammonium hydroxide / 3 h / 20 °C 2.1: trichlorophosphate / 0.25 h / 70 °C 2.2: 6 h / 20 - 100 °C 2.3: 1 h 3.1: potassium fluoride dihydrate; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 50 °C 4.1: potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide; water / 1.5 h / 25 °C 5.1: sodium hydrogencarbonate; water / dimethyl sulfoxide / 8 h / 50 °C View Scheme
Multi-step reaction with 4 steps 1: bromine; potassium carbonate / tetrahydrofuran / 12 h / 66 °C 2: tetrabutylammomium bromide; potassium fluoride / dimethyl sulfoxide; toluene / 3 h / 80 °C 3: hydrogen; palladium 10% on activated carbon / methanol / 4 h / 20 - 25 °C 4: ammonium carbonate View Scheme

3-amino-6-bromo-pyrazine-2-carboxylic acid (486424-37-7) → favipiravir (259793-96-9)

Conditions	Yield
Multi-step reaction with 6 steps 1: sulfuric acid / 48 h / 0 - 40 °C 2: sulfuric acid; sodium nitrite / 0.5 h / 0 - 60 °C 3: bromine; potassium carbonate / tetrahydrofuran / 12 h / 66 °C 4: tetrabutylammomium bromide; potassium fluoride / dimethyl sulfoxide; toluene / 3 h / 80 °C 5: hydrogen; palladium 10% on activated carbon / methanol / 4 h / 20 - 25 °C 6: ammonium carbonate View Scheme

tetraethyl {[(2-hydroxypropane-1,3-diyl)bis(oxy)]bis(ethylene)}bis(phosphonate) + favipiravir (259793-96-9) → tetraethyl 5-((3-carbamoyl-5-fluoropyrazin-2-yl)oxy)-3,7-dioxanonane-1,9-diphosphonate

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 60 - 65℃; for 0.166667h; Mitsunobu Displacement; Inert atmosphere;	90%

diethyl 2-((2-cyanoethyl)(2-hydroxyethyl)amino)ethylphosphonate (1383381-61-0) + favipiravir (259793-96-9) → diethyl 3-(2-(3-carbamoyl-5-fluoro-2-oxopyrazin-1-yl)ethyl)-5-cyano-3-azapentanephosphonate + diethyl 3-(2-((3-carbamoyl-5-fluoropyrazin-2-yl)oxy)ethyl)-5-cyano-3-azapentanephosphonate

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 60 - 65℃; for 0.166667h; Mitsunobu Displacement; Inert atmosphere; Overall yield = 93 %;	A 23% B 70%

tetraethyl 2,2'-(2-hydroxyethylazanediyl)bis(ethane-2,1-diyl)diphosphonate (1332338-67-6) + favipiravir (259793-96-9) → tetraethyl 3-(2-(3-carbamoyl-5-fluoro-2-oxopyrazin-1-yl)ethyl)-3-azapentane-1,5-diphosphonate + tetraethyl 3-(2-((3-carbamoyl-5-fluoropyrazin-2-yl)oxy)ethyl)-3-azapentane-1,5-diphosphonate

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 60 - 65℃; for 0.166667h; Solvent; Temperature; Time; Mitsunobu Displacement; Inert atmosphere; Overall yield = 94 %;	A 39% B 55%

diethyl [2-(2-hydroxyethoxy)ethyl]phosphonate + favipiravir (259793-96-9) → diethyl 5-((3-carbamoyl-5-fluoropyrazin-2-yl)oxy)-3-oxapentanephosphonate

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 60 - 65℃; for 0.166667h; Mitsunobu Displacement; Inert atmosphere;	51%

diethyl 2-((2-hydroxyethyl)(2-(trityloxy)ethyl)amino)ethylphosphonate (1383381-63-2) + favipiravir (259793-96-9) → diethyl 3-(2-((3-carbamoyl-5-fluoropyrazin-2-yl)oxy)ethyl)-5-trityloxy-3-azapentanephosphonate + diethyl 3-(2-(3-carbamoyl-5-fluoro-2-oxopyrazin-1-yl)ethyl)-5-trityloxy-3-azapentanephosphonate

Conditions	Yield
With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 60 - 65℃; for 0.166667h; Mitsunobu Displacement; Inert atmosphere; Overall yield = 73 %;	A 49% B 24%

dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate (990-91-0) + favipiravir (259793-96-9) → dibenzyl (3-carbamoyl-5-fluoropyrazin-2-yl) phosphate

Conditions	Yield
Stage #1: favipiravir With sodium hydride In N,N-dimethyl-formamide for 1h; Inert atmosphere; Stage #2: dibenzyl [[bis(benzyloxy)phosphoryl]oxy]phosphonate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;	36%

[2-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,3-oxathiolan-5-yl] acetate (139757-72-5) + favipiravir (259793-96-9) → trans-4-(2'-(tert-butyl-diphenylsilyloxy)methyl-1',3'-oxathiolan-5'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide + cis-4-(2'-(tert-butyl-diphenylsilyloxy)methyl-1',3'-oxathiolan-5'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide

Conditions	Yield
Stage #1: favipiravir With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile at 20℃; for 1.5h; Inert atmosphere; Cooling with ice; Stage #2: [2-[[tert-butyl(diphenyl)silyl]oxymethyl]-1,3-oxathiolan-5-yl] acetate With tin(IV) chloride In acetonitrile at 20℃; for 0.333333h; Inert atmosphere; Cooling with ice;	A 30.8% B 11.8%

2-tert-butyldiphenylsilyloxymethyl-4-acetyl-1,3-oxathiolane + favipiravir (259793-96-9) → cis-4-(2'-(t-butyl-diphenylsilyloxy)methyl-1',3'-oxathiolan-4'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazine-carboxamide + trans-4-(2'-(t-butyl-diphenylsilyloxy)methyl-1',3'-oxathiolan-4'-yl)-6-fluoro-3,4-dihydro-3-oxo-2-pyrazinecarboxamide

Conditions	Yield
Stage #1: favipiravir With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile at 20℃; for 1.5h; Inert atmosphere; Cooling with ice; Stage #2: 2-tert-butyldiphenylsilyloxymethyl-4-acetyl-1,3-oxathiolane With tin(IV) chloride In acetonitrile at 20℃; for 0.333333h; Inert atmosphere; Cooling with ice;	A 12.7% B 27%

((3-((methylsulfonyl)oxy)cyclobutyl)methyl)benzoate (929911-63-7) + favipiravir (259793-96-9) → C17H16FN3O4

Conditions	Yield
Stage #1: favipiravir With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Stage #2: ((3-((methylsulfonyl)oxy)cyclobutyl)methyl)benzoate In N,N-dimethyl-formamide; mineral oil at 130℃; for 25h;	26%

N,O-bis-(trimethylsilyl)-acetamide (10416-59-8) + favipiravir (259793-96-9) → 6-fluoro-3-((trimethylsilyl)oxy)pyrazine-2-carboxamide

Conditions	Yield
In acetonitrile at 0 - 20℃; for 1.5h;

favipiravir (259793-96-9) → 6-fluoro-3-hydroxy-2-pyrazinecarboxamide monosodium salt (1366418-99-6)

Conditions	Yield
With sodium hydroxide In water pH=7; Reagent/catalyst; Solvent; pH-value; Temperature;

1-deoxy-1-(methylamino)-D-glucitol (6284-40-8) + favipiravir (259793-96-9) → 6-fluoro-3-hydroxy-2-pyrazinecarboxamide meglumine salt (1370365-08-4)

Conditions	Yield
In water Concentration; Temperature;

Upstream product

• 1257072-34-6 6-bromo-3-chloropyrazine-2-carbonitrile 
• 356783-26-1 methyl 3,6-difluoropyrazine-2-carboxylate 
• 1118-02-1 trimethylsilyl isocyanate 
• 1237524-82-1 3-hydroxy-2-carbamoylpyrazine sodium salt 
• 1023813-21-9 3,6-dichloropyrazine-2-carboxamide 
• 17231-50-4 6-chloro-3-aminopyrazine-2-carbonitrile 
• 98-96-4 pyrazinamide 
• 486424-37-7 3-amino-6-bromo-pyrazine-2-carboxylic acid 
• 21874-61-3 3-hydroxy-6-bromopyrazine-2-carboxylic acid methyl ester 
• 6966-01-4 methyl 3-amino-6-bromopyrazine-2-carboxylate 
• 16298-03-6 Methyl 3-amino-2-pyrazinecarboxylate 
• 5424-01-1 3-aminopyrazinoic acid 
• 18960-19-5 1,4-dioxopyrazinamide 

Relevant articles and documents

PROCESS FOR PREPARATION OF FAVIPIRAVIR

The present invention relates to a process for the preparation of favipiravir and salts thereof. The present invention also relates to salts of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile with inorganic base, process for their preparation and conversion thereof to favipiravir. The present invention also relates to salts of 6-bromo-3-hydroxypyrazine-2-carboxamide with organic and inorganic base and their use in the preparation of favipiravir.

Preparation method of fluoropyrazine compound

The invention discloses a preparation method of a fluoropyrazine compound. The preparation method is characterized in that in a catalytic system, a compound A is directly subjected to a fluorination reaction to prepare the fluoropyrazine compound B. The preparation method is high in compatibility and suitable for various reaction substrates, different catalytic systems can be selected according to the activity of the reaction substrates, and the preparation method is flexible and easy and convenient to operate; and a reagent is simple and easily available, a catalytic condition is mild, and catalytic efficiency is high.

Preparation method of 6 -fluoro -3 -hydroxypyrazine -2 - formamide

The invention provides a preparation method of a pyrazine compound represented by the formula (I). To the invention, 6 -fluoro -3 -hydroxypyrazine -2 - methyl cyanide is used as a starting material, dimethyl sulfoxide is added under the conditions of hydrogen peroxide and sodium hydroxide, so that generation of oxygen in the system is avoided, and the production safety is greatly improved. The method provided by the invention is safe and suitable for industrial amplification, and has great help for industrial mass production of laprevir API.