16298-03-6

Basic information

• Product Name: Methyl 3-amino-2-pyrazinecarboxylate
• Synonyms: METHYL 2-AMINOPYRAZINE-3-CARBOXYLATE;METHYL 3-AMINO-2-PYRAZINECARBOXYLATE;METHYL 3-AMINOPYRAZINE-2-CARBOXYLATE;BUTTPARK 35\02-15;3-AMINOPYRAZINE-2-CARBOXYLIC ACID METHYL ESTER;AKOS 90402;TIMTEC-BB SBB004048;methyl 3-aminopyrazinecarboxylate
• CAS NO: 16298-03-6
• Molecular Formula: C₆H₇N₃O₂
• Molecular Weight: 153.14
• EINECS: 240-387-5
• Product Categories: Pyrazines;Heterocyclic Compounds;Chemical Amines;Pyrazinecarboxylic Acid & Derivatives;Pyrazine;Amines;Heterocycles;Building Blocks;Heterocyclic Building Blocks;amine| carboxylic ester
• Mol File: 16298-03-6.mol
• Article Data: 21

Chemical Properties

• Melting Point: 169-172 °C(lit.)
• Boiling Point: 300.8 °C at 760 mmHg
• Flash Point: 135.7 °C
• Appearance: Yellow/Crystalline Powder
• Density: 1.319 g/cm³
• Vapor Pressure: 0.0011mmHg at 25°C
• Refractive Index: 1.576
• Storage Temp.: Refrigerator
• Solubility: Chloroform, Methanol
• PKA: -0.30±0.10(Predicted)
• BRN: 127495
• CAS DataBase Reference: Methyl 3-amino-2-pyrazinecarboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: Methyl 3-amino-2-pyrazinecarboxylate(16298-03-6)
• EPA Substance Registry System: Methyl 3-amino-2-pyrazinecarboxylate(16298-03-6)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 22-24/25-37/39-26
• WGK Germany: 3
• HazardClass: IRRITANT
• Hazardous Substances Data: 16298-03-6(Hazardous Substances Data)

Usage

Chemical Properties

yellow crystalline powder

Uses

Methyl 3-amino-2-pyrazinecarboxylate has been used in: synthesis of 2-arylpteridin-4-ones and piperazine-derived 2-furan-2-yl-[1,2,4]triazolo[1,5-a] pyrazinesreactions with isocyanates and aroyl chlorides for conversion to pteridinediones

Purification Methods

The ester forms yellow needles from H2O (100 parts using charcoal). If it contains the free acid (see IR), then dissolve it in CH2Cl2, wash it with saturated aqueous Na2CO3, brine, dry over MgSO4 filter, evaporate and recrystallise the residue. The free acid has m 203-204o (dec) [UV: Brown & Mason J Chem Soc 3443 1956] and pK1 <1 and pK2 3.70. The ammonium salt has m 232o(dec) (from aqueous Me2CO) and the amide has m 239.2o (from H2O) [Ellingson et al. J Am Chem Soc 67 1711 1945]. [Beilstein 25 III/IV 4412.]

InChI:InChI=1/C6H7N3O2/c1-11-6(10)4-5(7)9-3-2-8-4/h2-3H,1H3,(H2,7,9)

Synthetic route

methanol (67-56-1) + 3-aminopyrazinoic acid (5424-01-1) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6)

Conditions	Yield
With chlorosulfonic acid In methanol at 20℃; for 16h;	80%
With sulfuric acid	80%
With sulfuric acid at 20℃; Cooling with ice;	76%

2-Aminopyrazine (5049-61-6) + pyruvic acid methyl ester (600-22-6) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6)

Conditions	Yield
With sulfuric acid; dihydrogen peroxide; iron(II) sulfate 1) -10 deg C, 2) 30 min, 0 deg C, 3) 30 min, room temperature;	72%

3-aminopyrazinoic acid (5424-01-1) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6)

Conditions	Yield
With sodium hydrogencarbonate In methanol; sulfuric acid; water	63%

2,3,4,5-tetrahydro-6-methoxypyridine (5693-62-9) + 3-aminopyrazinoic acid (5424-01-1) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 5,6,7,8-Tetrahydro-1,4,8a,10-tetraaza-anthracen-9-one (35982-77-5)

Conditions	Yield
In N,N-dimethyl-formamide for 2h; Heating; Yields of byproduct given;	A n/a B 12 % Turnov.

O-methylcaprolactim (2525-16-8) + 3-aminopyrazinoic acid (5424-01-1) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 7,8,9,10-Tetrahydro-6H-1,4,5,10a-tetraaza-cyclohepta[b]naphthalen-11-one (36120-38-4)

Conditions	Yield
In N,N-dimethyl-formamide for 2h; Heating; Yields of byproduct given;	A n/a B 17 % Turnov.

methyl chloroformate (79-22-1) + 1,1,1-triphenyl-N-(pyrazin-2-yl)-λ5-phosphanimine (69982-02-1) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6)

Conditions	Yield
With hydrogenchloride; triethylamine 1.) benzene, 80 deg C, 20 min, 2.) ethanol, water, 78 deg C, 6 h; Yield given. Multistep reaction;

3-Azidocarbonyl-pyrazine-2-carboxylic acid methyl ester (1027511-72-3) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6)

Conditions	Yield
In benzene for 24h; Heating;	99.0 g

3-(chlorocarbonyl)pyrazinecarboxylic acid, methyl ester (175231-47-7) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaN3 / H2O; acetone / 18 h / 0 °C 2: 99.0 g / benzene / 24 h / Heating View Scheme

3-[(methyloxy)carbonyl]-2-pyrazinecarboxylic acid (73763-86-7) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOCl2 / CHCl3; dimethylformamide / 4 h / Heating 2: NaN3 / H2O; acetone / 18 h / 0 °C 3: 99.0 g / benzene / 24 h / Heating View Scheme

3-aminopyrazinoic acid (5424-01-1) + diazomethyl-trimethyl-silane (18107-18-1) → Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6)

Conditions	Yield
In methanol; toluene at 0℃; for 0.5h;

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → methyl 3-amino-6-bromopyrazine-2-carboxylate (6966-01-4)

Conditions	Yield
With N-Bromosuccinimide In acetonitrile for 2h; Heating / reflux;	100%
With bromine; acetic acid In water	94%
Stage #1: Methyl 3-amino-2-pyrazinecarboxylate With bromine; acetic acid at 45℃; for 0.833333h; Stage #2: With water at 20℃; for 0.5h;	94%

propylamine (107-10-8) + Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → 3-Amino-pyrazine-2-carboxylic acid propylamide (211228-82-9)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene Ambient temperature;	100%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + SEC-BUTYLAMINE (33966-50-6) → 3-Amino-pyrazine-2-carboxylic acid sec-butylamide (211228-64-7)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene Ambient temperature;	100%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 1-amino-2-propene (107-11-9) → N-Allyl-3-aminopyrazine-2-carboxamide (211228-75-0)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene for 4h; Ambient temperature;	100%
With 1,8-diazabicyclo[5.4.0]undec-7-ene for 4h; Ambient temperature; Yield given;

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + triphenylphosphine (603-35-0) → Methyl 2-(triphenylphosphoranylidene)aminopyrazine-3-carboxylate (157731-12-9)

Conditions	Yield
With hexachloroethane; triethylamine In benzene for 3h; Heating;	99%
With hexachloroethane; triethylamine In benzene for 5h; Heating;	96%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → 3-amino-6-chloropyrazine-2-carboxylic acid methyl ester (1458-03-3)

Conditions	Yield
With N-chloro-succinimide In N,N-dimethyl-formamide at 80℃; for 24h;	98.1%
With N-chloro-succinimide In acetonitrile at 82℃; for 12h;	92%
With N-chloro-succinimide In N,N-dimethyl-formamide at 20 - 80℃;	92%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → 3-amino-pyrazine-2-carbohydrazide (6761-52-0)

Conditions	Yield
With hydrazine hydrate In ethanol at 60℃; for 2h; Inert atmosphere;	97%
With hydrazine hydrate In ethanol at 20 - 60℃; for 2h;	97%
With hydrazine hydrate In ethanol at 20 - 60℃; for 2h; Inert atmosphere;	97%
With hydrazine hydrate In ethanol for 4h; Reflux;	92%
With hydrazine hydrate

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 4-methyl-1-naphthalenecarbonyl chloride (87700-67-2) → methyl 3-{bis[(4-methylnaphthalen-1-yl)carbonyl]amino}pyrazine-2-carboxylate (1416989-76-8)

Conditions	Yield
With pyridine; dmap In chloroform at 50℃; for 20h; Reflux;	97%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 4-methoxy-benzoyl chloride (100-07-2) → 3-[Bis-(4-methoxy-benzoyl)-amino]-pyrazine-2-carboxylic acid methyl ester (155513-75-0)

Conditions	Yield
With pyridine at 50℃; for 8h;	95%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + m-chlorophenyl isocyanate (2909-38-8) → 3-(m-chloro)phenyl-2,4(1H,3H)-pteridinedione

Conditions	Yield
In pyridine for 6h; Heating;	94%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → 3-aminopyrazine-2-carboxamide (32587-10-3)

Conditions	Yield
With ammonia In water at 20℃; for 12h;	92%
With ammonia at 20℃; for 10h;	90.6%
With ammonia In water at 60℃; for 3h;	82%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → methyl 3-amino-6-iodopyrazine-2-carboxylate (1458-16-8)

Conditions	Yield
With N-iodo-succinimide In dimethyl sulfoxide at 70℃; for 48h; Inert atmosphere; regioselective reaction;	92%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 65℃;	88%
With N-iodo-succinimide In N,N-dimethyl-formamide at 20 - 65℃; for 25h;	88%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + phenethylamine (64-04-0) → 3-amino-N-phenethylpyrazine-2-carboxamide

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene at 20 - 25℃; Inert atmosphere;	91%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + isopropylamine (75-31-0) → 3-amino-pyrazine-2-carboxylic acid isopropylamide (211228-86-3)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene Ambient temperature;	90%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 4-fluorobenzoyl chloride (403-43-0) → methyl 3-(4-fluoro-N-(4-fluorobenzoyl)benzamido)pyrazine-2-carboxylate (1123784-16-6)

Conditions	Yield
With pyridine at 70℃; for 2.08h;	90%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + dimethyl sulfoxide (67-68-5) → S,S-dimethyl-N-(3-carbomethoxypyrazin-2-yl)sulfilimine (86536-73-4)

Conditions	Yield
With trifluoroacetic anhydride In dichloromethane at -78 - -55℃; for 3h; Product distribution; Preparation of sulfilimines (iminosulfuranes) with in situ obtained dimethyl sulfide ditriflate;	85%
With trifluoroacetic anhydride In dichloromethane at -78 - -55℃; for 3h;	85%
With trifluoromethanesulfonic acid anhydride 1.) CH2Cl2, -78 deg C; 2.) -78 deg C, 2 h and -55 deg C, 1 h; Yield given. Multistep reaction;

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 4-Methoxyphenyl isocyanate (5416-93-3) → 3-p-anisyl-2,4(1H,3H)-pteridinedione

Conditions	Yield
In pyridine for 3h; Heating;	84%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) → 3-aminopyrazinoic acid (5424-01-1)

Conditions	Yield
With lithium hydroxide In methanol; water for 2h; Reflux;	83%
With water; sodium hydroxide In methanol at 20℃; for 0.833333h; Inert atmosphere;	1.48 g

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + methylhydrazine (60-34-4) → 3-aminopyrazinecarboxylic acid 2-methylhydrazide (22918-45-2)

Conditions	Yield
In 1,4-dioxane; ethanol for 4h; Reflux;	82%
In 1,2-dimethoxyethane for 24h; Heating;	71%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + Ethoxycarbonyl isothiocyanate (16182-04-0) → methyl 3-(3-(ethoxycarbonyl)thioureido)pyrazine-2-carboxylate

Conditions	Yield
In acetonitrile at 20℃; for 18h; Inert atmosphere;	82%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + phenyl isocyanate (103-71-9) → 3-phenyl-2,4(1H,3H)-pteridinedione (25379-87-7)

Conditions	Yield
In pyridine for 2h; Heating;	81%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + di-tert-butyl dicarbonate (24424-99-5) → 3-di-(tert-butoxycarbonyl)amino-pyrazine-2-carboxylic acid methyl ester (908833-92-1)

Conditions	Yield
With dmap In dichloromethane for 4h; Heating / reflux;	81%
With dmap In dichloromethane for 48h; Inert atmosphere;

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 4-chloro-benzoyl chloride (122-01-0) → 3-[Bis-(4-chloro-benzoyl)-amino]-pyrazine-2-carboxylic acid methyl ester (155513-72-7)

Conditions	Yield
With pyridine at 50℃; for 4h;	80%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 4-nitro-benzoyl chloride (122-04-3) → 3-[Bis-(4-nitro-benzoyl)-amino]-pyrazine-2-carboxylic acid methyl ester (155513-76-1)

Conditions	Yield
With pyridine at 50℃; for 2h;	80%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 5-(3-fluoro-4-methoxyphenyl)thianthreniumyl perchlorate → 9-fluoro-8-methoxy-5H-pyrazino[2,3-b]quinolin-10-one

Conditions	Yield
With lithium diisopropyl amide In tetrahydrofuran; n-heptan1ol; ethylbenzene for 3h;	76%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + ethyl chlorocarbonylacetate (36239-09-5) → ethyl 8-hydroxy-6-oxo-5,6-dihydropyrido[2,3-b]pyrazine-7-carboxylate (948915-52-4)

Conditions	Yield
Stage #1: Methyl 3-amino-2-pyrazinecarboxylate; ethyl chlorocarbonylacetate With triethylamine In dichloromethane at 20℃; Stage #2: With sodium ethanolate In ethanol at 20℃; for 2h; Stage #3: With hydrogenchloride In ethanol; water	73%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + ortho-toluoyl chloride (933-88-0) → 3-[Bis-(2-methyl-benzoyl)-amino]-pyrazine-2-carboxylic acid methyl ester (155513-74-9)

Conditions	Yield
With pyridine at 50℃; for 8h;	72%

Methyl 3-amino-2-pyrazinecarboxylate (16298-03-6) + 3-tolyl isocyanate (621-29-4) → 3-m-tolyl-2,4(1H,3H)-pteridinedione

Conditions	Yield
In pyridine for 5h; Heating;	71%

Upstream product

• 67-56-1 methanol 
• 5424-01-1 3-aminopyrazinoic acid 
• 79-22-1 methyl chloroformate 
• 69982-02-1 1,1,1-triphenyl-N-(pyrazin-2-yl)-λ⁵-phosphanimine 
• 18107-18-1 diazomethyl-trimethyl-silane 
• 1027511-72-3 3-Azidocarbonyl-pyrazine-2-carboxylic acid methyl ester 
• 2525-16-8 O-methylcaprolactim 
• 5049-61-6 2-Aminopyrazine 
• 600-22-6 pyruvic acid methyl ester 
• 5693-62-9 2,3,4,5-tetrahydro-6-methoxypyridine 
• 73763-86-7 3-[(methyloxy)carbonyl]-2-pyrazinecarboxylic acid 
• 175231-47-7 3-(chlorocarbonyl)pyrazinecarboxylic acid, methyl ester 

Downstream Products

• 36204-76-9 3-Aminopyrazin-2-(N-methyl)carboxamid 
• 854699-17-5 3-[(N-acetyl-sulfanilyl)-amino]-pyrazine-2-carboxylic acid methyl ester 
• 32587-10-3 3-aminopyrazine-2-carboxamide 
• 51171-02-9 3-bromo-pyrazine-2-carboxylic acid methyl ester 
• 24719-09-3 3-amino-N-hydroxypyrazine-2-carboxamide 
• 6761-52-0 3-amino-pyrazine-2-carbohydrazide 
• 6966-01-4 methyl 3-amino-6-bromopyrazine-2-carboxylate 
• 90361-95-8 (pyrrolyl-1)-3 pyrazinoate de methyle 
• 63012-75-9 2,3-dihydro-5H-thiazolo[2,3-b]pteridin-5-one 
• 173290-17-0 methyl 3-iodopyrazine-2-carboxylate 
• 1458-03-3 3-amino-6-chloropyrazine-2-carboxylic acid methyl ester 
• 33332-29-5 2-amino-5-chloropyrazine 
• 1154614-79-5 3-(2-chloro-5-trifluoromethyl-phenylmethanesulfonylamino)-pyrazine-2-carboxylic acid methyl ester 
• 92044-73-0 3-(4-chloro-benzoylamino)-pyrazine-2-carboxylic acid methyl ester 

Relevant articles and documents

A practical and step-economic route to Favipiravir

A practical and step-economic route to Favipiravir, an antiviral drug, was developed. 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.

Derivatives of 3-Aminopyrazine-2-carboxamides: Synthesis, antimicrobial evaluation, and in vitro cytotoxicity

We report the design, synthesis, and in vitro antimicrobial activity of a series of N-substituted 3-aminopyrazine-2-carboxamides with free amino groups in position 3 on the pyrazine ring. Based on various substituents on the carboxamidic moiety, the series is subdivided into benzyl, alkyl, and phenyl derivatives. The three-dimensional structures of the title compounds were predicted using energy minimization and low mode molecular dynamics under AMBER10:EHT forcefield. Compounds were evaluated for antimycobacterial, antibacterial, and antifungal activities in vitro. The most active compound against Mycobacterium tuberculosis H37Rv (Mtb) was 3-amino-N-(2,4-dimethoxyphenyl)pyrazine-2-carboxamide (17, MIC = 12.5 μg/mL, 46 μM). Antimycobacterial activity against Mtb and M. kansasii along with antibacterial activity increased among the alkyl derivatives with increasing the length of carbon side chain. Antibacterial activity was observed for phenyl and alkyl derivatives, but not for benzyl derivatives. Antifungal activity was observed in all structural subtypes, mainly against Trichophyton interdigitale and Candida albicans. The four most active compounds (compounds 10, 16, 17, 20) were evaluated for their in vitro cytotoxicity in HepG2 cancer cell line; only compound 20 was found to exert some level of cytotoxicity. Compounds belonging to the current series were compared to previously published, structurally related compounds in terms of antimicrobial activity to draw structure activity relationships conclusions.

Method for synthesis of favipiravir

The invention discloses a method for synthesis of favipiravir. The method comprises an esterification reaction of 3-aminopyrazine-2-carboxylic acid and an alcohol, a bromination reaction, a diazotization reaction, an ammonolysis reaction, a chlorination-dehydration reaction, a one-pot series connection aromatic ring fluorination reaction, a cyan-hydrolysis reaction, an aromatic ring hydroxyl substitution reaction, and purification treatment so that favipiravir is obtained. The method utilizes 3-amino-2-carboxypyrazine as a raw material to synthesize favipiravir through 8-step reactions and has a total yield of 26%. The key intermediates 3 and 6 in the method are purified by recrystallization so that column chromatography separation in the literature is avoided. The final three reactions are finished by a one-pot method so that the operation is simplified. The synthesis method improves a yield, realizes a low cost and green economy and is conducive to industrial production.