356783-16-9

Basic information

• Product Name: 3,6-dichloropyrazine-2-carbonitrile
• Synonyms: ,6-Dichloropyrazine-2-carbonitrile;3,6-dichloropyrazine-2-carbonitrile;2-Pyrazinecarbonitrile, 3,6-dichloro-;3,6-Dichloro-2-pyrazinecarbonitrile
• CAS NO: 356783-16-9
• Molecular Formula: C₅HCl₂N₃
• Molecular Weight: 173.98754
• EINECS: -0
• Mol File: 356783-16-9.mol
• Article Data: 13

Chemical Properties

• Boiling Point: 262.0±35.0℃ (760 Torr)
• Flash Point: 112.3±25.9℃
• Appearance: /
• Density: 1.60±0.1 g/cm3 (20 ºC 760 Torr)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: -7.43±0.10(Predicted)
• CAS DataBase Reference: 3,6-dichloropyrazine-2-carbonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 3,6-dichloropyrazine-2-carbonitrile(356783-16-9)
• EPA Substance Registry System: 3,6-dichloropyrazine-2-carbonitrile(356783-16-9)

Safety Data

• Hazardous Substances Data: 356783-16-9(Hazardous Substances Data)

Usage

Uses

3,6-Dichloro-2-pyrazinecarbonitrile is useful in the production of Favipiravir (F103350) a drug that is used for the treatment of advanced Ebola virus infection in a small animal model.

Synthetic route

3-hydroxy-6-nitropyrazine-2-carboxamide → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
With pyridine; trichlorophosphate at 20 - 80℃; for 8h; Reagent/catalyst;	90%

3-hydroxy-6-bromopyrazine-2-carboxamide → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Stage #1: 6-bromo-3-hydroxypyrazine-2-carboxamide With trichlorophosphate In chlorobenzene at 60℃; for 0.5h; Stage #2: With N-ethyl-N,N-diisopropylamine In chlorobenzene at 90 - 100℃; for 2.66667h; Stage #3: With sodium hydrogencarbonate In water; toluene	83%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate In water at 60 - 100℃; for 8h; Solvent;	70%
Stage #1: 6-bromo-3-hydroxypyrazine-2-carboxamide With trichlorophosphate at 70℃; for 0.25h; Stage #2: With N-ethyl-N,N-diisopropylamine at 20 - 100℃; for 6h; Stage #3: With water for 1h;	70%
Stage #1: 6-bromo-3-hydroxypyrazine-2-carboxamide With trichlorophosphate at 55℃; for 0.5h; Stage #2: With N-ethyl-N,N-diisopropylamine at 110℃; for 5h;	43.7%

3,6-dichloropyrazine-2-carboxamide → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; trichlorophosphate at 75℃; for 1h;	82%

6-chloro-3-aminopyrazine-2-carbonitrile (17231-50-4) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
With tert.-butylnitrite; titanium tetrachloride In dichloromethane at 0 - 20℃; for 3h; Sandmeyer Reaction;	81%

1,4-dioxopyrazinamide (18960-19-5) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Stage #1: 1,4-dioxopyrazinamide With trichlorophosphate In chlorobenzene at 50 - 70℃; for 1.83333h; Stage #2: With pyridine In chlorobenzene at 110℃; for 8h; Temperature; Reagent/catalyst;	52.55%
Stage #1: 1,4-dioxopyrazinamide With trichlorophosphate at 50 - 70℃; for 1.83333h; Stage #2: With triethylamine at 96℃; for 6h;	45.15%

2-hydroxypyrazine-3-carboxamide (55321-99-8) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1.1: bromine; pyridine / N,N-dimethyl-formamide / 2 h / 80 - 85 °C / Inert atmosphere 2.1: trichlorophosphate / 0.5 h / 55 °C 2.2: 5 h / 110 °C View Scheme

2-pyrazine carbonitrile (19847-12-2) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

3-aminopyrazinoic acid (5424-01-1) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 5 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 View Scheme

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme
Multi-step reaction with 4 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 View Scheme

methyl 3-amino-6-bromopyrazine-2-carboxylate (6966-01-4) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Multi-step reaction with 3 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 View Scheme
Multi-step reaction with 3 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 View Scheme

3-hydroxy-6-bromopyrazine-2-carboxylic acid methyl ester (21874-61-3) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium hydroxide / 3 h / 20 °C 2: trichlorophosphate; N-ethyl-N,N-diisopropylamine / water / 8 h / 60 - 100 °C View Scheme
Multi-step reaction with 2 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 View Scheme

pyrazinamide (98-96-4) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: acetic acid; 3-chloro-benzenecarboperoxoic acid / ethyl acetate / 24 h / 0 - 20 °C 2.1: trichlorophosphate / chlorobenzene / 1.83 h / 50 - 70 °C 2.2: 8 h / 110 °C View Scheme

2-hydroxy-5-bromopyrazine (374063-92-0) + formamide (77287-34-4, 77287-35-5, 60100-09-6) → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

Conditions	Yield
Stage #1: 2-hydroxy-5-bromopyrazine With trichlorophosphate at 60℃; for 2h; Stage #2: formamide With dipotassium peroxodisulfate; iron In water at 80 - 85℃; Further stages;	320 g

Reaxys ID: 36640215 → 3,6-dichloropyrazine-2-carbonitrile (356783-16-9)

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → 3,6-difluoropyrazine-2-carbonitrile (356783-28-3)

Conditions	Yield
With potassium fluoride; tetrabutylammomium bromide In dimethyl sulfoxide; toluene at 60℃; for 2.5h;	92.3%
With potassium fluoride In dimethyl sulfoxide at 60 - 90℃; Large scale;	85%
With tetrabutyl ammonium fluoride; tetrabutylammomium bromide at 60℃; for 3h; Reagent/catalyst; Temperature; Solvent; Sealed tube;	62.37%

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → 6-chloro-3-hydroxylpyrazine-2-carbonitrile (1374986-27-2)

Conditions	Yield
With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 20℃; for 3h;	85%

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) + 4-methoxy-phenol (150-76-5) → 6-chloro-3-(4-methoxyphenoxy)-2-pyrazinecarbonitrile (356783-22-7)

Conditions	Yield
With potassium carbonate In N-methyl-acetamide; water; ethyl acetate

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) + thiophenol (108-98-5) → 6-chloro-3-(phenylsulfanyl)-2-pyrazinecarbonitrile (356783-25-0)

Conditions	Yield
With sodium chloride; potassium carbonate In water; ethyl acetate; N,N-dimethyl-formamide

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) + 4-Benzyloxyphenol (103-16-2) → 3-[(4-(benzyloxy)phenoxy)]-6-chloro-2-pyrazinecarbonitrile (356783-23-8)

Conditions	Yield
With potassium carbonate In N-methyl-acetamide; di-isopropyl ether; water; ethyl acetate

2-Methylcyclopentane-1,3-dione (765-69-5) + 3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → 6-fluoro-3-[(2-methyl-3-oxo-1-cyclopenten-1-yl)oxy]-2pyrazinecarbonitrile (356783-61-4)

Conditions	Yield
With potassium fluoride; triethylamine In water; dimethyl sulfoxide; 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

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → 3,6-difluoro-2-pyrazinecarboxamide (356783-29-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium fluoride; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 55 °C / Sealed tube 2: dihydrogen peroxide / 2 h / 27 °C View Scheme
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1: potassium fluoride dihydrate; tetrabutylammomium bromide / dimethyl sulfoxide / 3 h / 50 °C 2: potassium carbonate; dihydrogen peroxide / dimethyl sulfoxide; water / 1.5 h / 25 °C View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → 6-fluoro-3-hydroxy-2-cyanopyrazine (356783-31-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrabutyl ammonium fluoride; tetrabutylammomium bromide / 3 h / 60 °C / Sealed tube 2: sodium acetate; water / 1,4-dioxane / 7 h / 55 °C View Scheme
Multi-step reaction with 2 steps 1: potassium fluoride / dimethyl sulfoxide / 60 - 90 °C / Large scale 2: sodium acetate; water / dimethyl sulfoxide / 4 h / 5 - 45 °C / Large scale View Scheme
Stage #1: 3,6-dichloropyrazine-2-carbonitrile With potassium fluoride In N,N-dimethyl-formamide at 105 - 112℃; Stage #2: With acetic acid; triethylamine In N,N-dimethyl-formamide at 0 - 15℃; for 1h;

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → ethyl (S)-2-(2-(3-amino-1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-(tert-butoxy)acetate

Conditions	Yield
Multi-step reaction with 3 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → ethyl (S)-2-(2-(3-bromo-1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-(tert-butoxy)acetate

Conditions	Yield
Multi-step reaction with 4 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C 4: copper(I) bromide; tert.-butylnitrite / acetonitrile / 3 h / 0 - 20 °C View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → tert-butyl (S)-4-(5-(6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-1-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3,6-dihydropyridine-1(2H)carboxylate

Conditions

Yield

Multi-step reaction with 5 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C 4: copper(I) bromide; tert.-butylnitrite / acetonitrile / 3 h / 0 - 20 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 5 h / 80 - 100 °C / Inert atmosphere View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → tert-butyl (S)-4-(5-(6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-1-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)piperidine-1-carboxylate

Conditions

Yield

Multi-step reaction with 6 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C 4: copper(I) bromide; tert.-butylnitrite / acetonitrile / 3 h / 0 - 20 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 5 h / 80 - 100 °C / Inert atmosphere 6: hydrogen; Rh/Al2O3 / ethanol / 8 h View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → tert-butyl (S)-3-(4-(5-(6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-1-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)piperidin-1-yl)azetidine-1-carboxylate

Conditions

Yield

Multi-step reaction with 8 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C 4: copper(I) bromide; tert.-butylnitrite / acetonitrile / 3 h / 0 - 20 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 5 h / 80 - 100 °C / Inert atmosphere 6: hydrogen; Rh/Al2O3 / ethanol / 8 h 7: hydrogenchloride / isopropyl alcohol / 48 h / 20 °C 8: acetic acid; sodium cyanoborohydride / ethanol / 3 h View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → ethyl (S)-2-(2-(3-(1-(azetidin-3-yl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-(tert-butoxy)acetate

Conditions

Yield

Multi-step reaction with 9 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C 4: copper(I) bromide; tert.-butylnitrite / acetonitrile / 3 h / 0 - 20 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 5 h / 80 - 100 °C / Inert atmosphere 6: hydrogen; Rh/Al2O3 / ethanol / 8 h 7: hydrogenchloride / isopropyl alcohol / 48 h / 20 °C 8: acetic acid; sodium cyanoborohydride / ethanol / 3 h 9: hydrogenchloride / isopropyl alcohol View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → methyl (S)-3-(4-(5-(6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-1-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)piperidin-1-yl)azetidine-1-carboxylate

Conditions

Yield

Multi-step reaction with 10 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C 4: copper(I) bromide; tert.-butylnitrite / acetonitrile / 3 h / 0 - 20 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 5 h / 80 - 100 °C / Inert atmosphere 6: hydrogen; Rh/Al2O3 / ethanol / 8 h 7: hydrogenchloride / isopropyl alcohol / 48 h / 20 °C 8: acetic acid; sodium cyanoborohydride / ethanol / 3 h 9: hydrogenchloride / isopropyl alcohol 10: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → (S)-2-(tert-butoxy)-2-(7-(4-chlorophenyl)-2-(3-(1-(1-(methoxycarbonyl)azetidin-3-yl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetic acid

Conditions

Yield

Multi-step reaction with 11 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C 4: copper(I) bromide; tert.-butylnitrite / acetonitrile / 3 h / 0 - 20 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 5 h / 80 - 100 °C / Inert atmosphere 6: hydrogen; Rh/Al2O3 / ethanol / 8 h 7: hydrogenchloride / isopropyl alcohol / 48 h / 20 °C 8: acetic acid; sodium cyanoborohydride / ethanol / 3 h 9: hydrogenchloride / isopropyl alcohol 10: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h 11: methanol; sodium hydroxide / tetrahydrofuran / 2.5 h / 60 °C View Scheme

3,6-dichloropyrazine-2-carbonitrile (356783-16-9) → ethyl (S)-2-(2-(3-(1-(1-acetylazetidin-3-yl)piperidin-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-(tert-butoxy)acetate

Conditions

Yield

Multi-step reaction with 10 steps 1: toluene / 3 h / 0 °C 2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); potassium propionate / 1,4-dioxane / 3 h / 85 °C / Inert atmosphere 3: potassium carbonate / 2 h / 70 °C 4: copper(I) bromide; tert.-butylnitrite / acetonitrile / 3 h / 0 - 20 °C 5: potassium carbonate; tetrakis(triphenylphosphine) palladium(0) / 1,4-dioxane / 5 h / 80 - 100 °C / Inert atmosphere 6: hydrogen; Rh/Al2O3 / ethanol / 8 h 7: hydrogenchloride / isopropyl alcohol / 48 h / 20 °C 8: acetic acid; sodium cyanoborohydride / ethanol / 3 h 9: hydrogenchloride / isopropyl alcohol 10: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h View Scheme

Upstream product

• 55321-99-8 3-hydroxy-2-pyrazinecarboxamide 
• 5424-01-1 3-aminopyrazinoic acid 
• 16298-03-6 Methyl 3-amino-2-pyrazinecarboxylate 
• 6966-01-4 methyl 3-amino-6-bromopyrazine-2-carboxylate 
• 21874-61-3 3-hydroxy-6-bromopyrazine-2-carboxylic acid methyl ester 
• 374063-92-0 2-hydroxy-5-bromopyrazine 
• 77287-34-4 formamide 
• 1023813-21-9 3,6-dichloropyrazine-2-carboxamide 
• 98142-97-3 3,6-dioxopiperazine-2-carboxamide 
• 41394-71-2 2-(chloroacetylamino)propanedioic acid diethyl ester 
• 544-92-3 copper(I) cyanide 
• 873-40-5 2,3,5-trichloropyrazine 
• 17231-50-4 6-chloro-3-aminopyrazine-2-carbonitrile 
• 98-96-4 pyrazinamide 

Downstream Products

• 356783-22-7 6-chloro-3-(4-methoxyphenoxy)-2-pyrazinecarbonitrile 
• 356783-25-0 6-chloro-3-(phenylsulfanyl)-2-pyrazinecarbonitrile 
• 356783-23-8 3-[(4-(benzyloxy)phenoxy)]-6-chloro-2-pyrazinecarbonitrile 
• 259793-96-9 favipiravir 
• 356783-29-4 3,6-difluoropyrazine-2-carboxamide 
• 356783-31-8 6-fluoro-3-hydroxypyrazine-2-carbonitrile 
• 356783-28-3 3,6-difluoropyrazine-2-carbonitrile 

Relevant articles and documents

PROCESS FOR THE PREPARATION OF 3,6-DICHLOROCYANO PYRAZINE, 3,6-DIOXOPIPERAZINE DERIVATIVES AND PRODUCTION OF FAVIPIRAVIR THEREOF

The present invention relates to a method of preparing derivatives of 3,6-dichlorocyano pyrazine, 3,6-dioxopiperizin and the production of favipiravir by cyclization and chlorination mediated by ammonia or amine using POCl3 in the presence of pyridine or PCl5. [Formula] In derivatives of 3,6-dioxopiperazine (III), X represents CN, CONH2 or COOR2', R1, R 2 and R2' are individually selected from H, alkyl C1-C12, COOR3 and SO2R3, R 3 being a linear or branched lower alkyl substituted or unsubstituted.

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.

Favipiravir intermediate and synthesis method of favipiravir

The invention discloses a favipiravir intermediate and a synthesis method of favipiravir. The synthesis method comprises the following steps: taking 2,5-dihalopyrazine as an initial raw material, reacting 2,5-dihalopyrazine with formamide under the action of an oxide and a catalyst to generate 6-halo-3-chloro-2-amide pyrazine; carrying out a reaction on 6-halo-3-chloro-2-amide pyrazine under the action of a dehydration chlorinating agent and an acid-binding agent to generate a favipiravir intermediate 3,6-dichloro-3-cyanopyrazine; carrying out an aromatic ring fluorination reaction on the obtained favipiravir intermediate and potassium fluoride in dimethyl sulfoxide to generate 3,6-difluoro-3-cyanopyrazine; adding the 3,6-difluoro-3-cyanopyrazine into a water solution containing sodium acetate, and carrying out hydrolysis to obtain 6-fluoro-3-hydroxyl-2-cyanopyrazine; and finally, carrying out a cyano hydrolysis reaction to obtain favipiravir. A mixture of 2,5-dichloropyrazine and 2-chloro-5-bromopyrazine are used as raw materials to synthesize the favipiravir intermediate, the raw material cost is remarkably reduced, and the provided synthesis method has the technical advantages of high yield and low cost.