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
• PKA: 8.77±0.60(Predicted)
• 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

Mode of Action

Favipiravir inhibits the RNA-dependent RNA polymerase (RdRp) — an enzyme that allows the coronavirus to replicate inside host cells.Inside the cells, favipiravir is converted to favipiravir ribofuranosyl-5′-triphosphate (favipiravir-RTP) by host cells. This molecule then blocks the RdRp enzyme of SARS-CoV-2, the virus that causes Covid-19.According to a statement by Glenmark, favipiravir works only during the earlier stages of the disease, when the viral replication is higher, but the body's immune response has not gone into overdrive. Metabolism of favipiravir to its triphosphate form occurs in an extracellular environment in a concentration-dependent manner. The vRNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide. This favipiravir-RTP is misincorporated in nascent vRNA, or it may act by binding to conserved polymerase domains, preventing incorporation of nucleotides for vRNA replication and transcription (Jin et al., 2013).

History

Favipiravir is a broad-spectrum antiviral drug that was cleared by the Drugs Controller General of India (DCGI) last week for “emergency restricted” use among Covid-19 patients. Glenmark will sell the generic favipiravir under the brand name FabiFlu. 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.

A Potential Antiviral for COVID-19?

Currently, there is not any specific effective antiviral treatment for COVID-19. Although most of the COVID-19 patients have mild or moderate courses, up to 5%–10% can have severe, potentially life threatening course, there is an urgent need for effective drugs. Optimized supportive care remains the mainstay of therapy. There have been more than 300 clinical trials going on, various antiviral and immunomodulating agents are in various stages of evaluation for COVID-19 in those trials and some of them will be published in the next couple of months. Despite the urgent need to find an effective antiviral treatment for COVID-19 through randomized controlled studies, certain agents are being used all over the world based on either in-vitro or extrapolated evidence or observational studies. The most frequently used agents both in Turkey and all over the world including chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir and remdesivir will be reviewed here .Nitazoxanide and ivermectin were also included in this review as they have recently been reported to have an activity against SARS-CoV-2 in vitro and are licensed for the treatment of some other human infections.

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

• 259793-94-7 Pyrazinecarboxamide, 3-hydroxy-, 4-oxide (9CI) 
• 259793-90-3 2-PyrazinecarboxaMide, 6-chloro-3,4-dihydro-3-oxo- 
• 259793-88-9 6-bromo-3-hydroxypyrazine-2-carboxamide 
• 2597-93-5 EMMI 
• 259792-96-6 methyl ({3-nitro-6-[(2-methoxy-2-oxoethyl)sulfanyl]-2-pyridinyl}sulfanyl)acetate 
• 259792-94-4 METHYL 9-[METHYL-4-(TRIFLUOROMETHOXY)ANILINO]-9-OXONONANOATE 
• 259792-69-3 4-BROMO-1H-PYRROLE-2-CARBOHYDRAZIDE 
• 2597-92-4 Ethylmercury 2,3-dihydroxypropylmercaptide 
• 25979-07-1 tert-Butyldichlorophosphine 
• 25979-01-5 5-PENTAFLUOROETHYL-4H-[1,2,4]TRIAZOL-3-YLAMINE 
• 25979-00-4 3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine(SALTDATA: FREE) 
• 259-79-0 BIPHENYLENE 
• 25978-74-9 METHYL 3-CYANO-4-METHOXYBENZOATE 
• 25978-68-1 4-Cyano-3-methylBenzoic acid methyl ester 

Downstream Products

• 259793-97-0 2-PyrazinecarboxaMide, 6-nitro-3,4-dihydro-3-oxo- 
• 259793-98-1 Pyrazinecarboxamide, 3,4-dihydro-5-hydroxy-3-oxo- (9CI) 
• 259794-01-9 Pyrazinecarboxamide, 5-fluoro-3,4-dihydro-3-oxo- (9CI) 
• 25979-40-2 N-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-4-({[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]carbamoyl}amino)benzamide 
• 259794-02-0 1,2,4-Triazine-6-carboxamide,2,5-dihydro-5-oxo-(9CI) 
• 259794-06-4 METHYL 6-BROMO-3-METHOXYPYRAZINE-2-CARBOXYLATE 
• 259794-13-3 2-OXAZOLIDINONE, 5-(HYDROXYMETHYL)-4-(4-METHOXYPHENYL)-, (4S,5S)- 
• 25979-42-4 N-[4-(5-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-4-({[4-(5-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]carbamoyl}amino)benzamide 
• 25979-43-5 N-[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]-4-({[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]carbamoyl}amino)benzamide 
• 259794-53-1 tert-Butyl 3-amino-2,2-dimethylpropanoate 
• 25979-47-9 3,5-bis({[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]carbamoyl}amino)-N-ethylbenzamide 
• 25979-48-0 3,5-bis({[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]carbamoyl}amino)-N-propylbenzamide 
• 259795-03-4 2,7-Naphthalenedisulfonic acid, 5-4-chloro-6-2-2-(ethenylsulfonyl)ethoxyethylamino-1,3,5-triazin-2-ylamino-4-hydroxy-3-(1-sulfo-2-naphthalenyl)azo-, trisodium salt 
• 25979-50-4 N-propyl-3,5-bis({[4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]carbamoyl}amino)benzamide 

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