Kushner, S. published the artcileExperimental chemotherapy of tuberculosis. II. The synthesis of pyrazinamides and related compounds, Application In Synthesis of 4604-72-2, the publication is Journal of the American Chemical Society (1952), 3617-21, database is CAplus.
cf. C.A. 43, 5025b. To 5.0 g. 2-aminothiazole was added slowly a suspension of 3.5 g. freshly prepared pyrazinoyl chloride (I) in 15 cc. EtOAc, the mixture heated 10 min. on a steam bath, the supernatant hot EtOAc decanted, the residue heated again with 15 cc. EtOAc, the procedure repeated, the combined EtOAc-layers were evaporated to dryness, and the solid, yellow residue was washed with cold H2O, filtered, dried, and recrystallized from hot EtOAc to give 3.0 g. (60%) N-(2-thiazolyl)pyrazinamide, m. 187-9°. By the same procedure were prepared the following N-mono- or N,N-disubstituted pyrazinamides (substituent given): Me, m. 105°; Me2, m. 70-2°; Bu 20%, b3 167-70°; C16H33 50%, m. 85-7° (from C6H6-EtOH); PhCH2, m. 116-18°; Ph 55-60%, m. 127-30°; p-ClC6H4 60%, m. 184-5°; o-ClC6H4 60%, m. 135-6°; m-ClC6H4 60%, m. 145-7°; 2-pyridyl, 65%, m. 138-40°; 3-pyridyl 62%, m. 185-6°; 1-piperidyl 80%, m. 68-9° (from Me2CO); 3-quinoxalyl 76%, m. 205-6°; and 2-pyrazinyl 40%, m. 190-2°. Et N-pyrazinoyl-β-alanate (II) (1 g.) in 25 cc. MeOH saturated with NH3 at 0° gave 55% β-(N’-pyrazinoylamino)propionamide, m. 206-8°. Me pyrazinoate (III) (5.0 g.), 7.5 g. HO(CH2)2NHCH2CH2NH2, and 30 cc. absolute EtOH refluxed 60 hrs. gave 84% N-(2-hydroxyethyl)-N’-pyrazinoylethylene-diamine, m. 107-8°. Similarly were prepared from III and iso-BuNH2, N-isobutylpyrazinamide, m. 63-4° (from C6H6-EtOH); and from III and p-MeOC6H4CH2NH2, 50% N-(p-methoxybenzyl)pyrazinamide m. 134-6°. By ammonolysis of the appropriate, substituted pyrazinoates were prepared the following substituted pyrazinamides (substituents given): 6-Me, 83%, m. 204-5° (from EtOH); 3-H2N ,50%, m. 237-9°; 3-amino-6-bromo (IV) 80%, m. 215-17°; 3-HO, m. 265° (decomposition). 2,3-Pyrazinedicarboxamide (V) m. 240°, (decomposition); 2,6-isomer, 90%, m. 300° (decomposition); 6-Me derivative of IV, 80%, m. 215-17°. To 15 g. H2N(CH2)2-CH:CHCO2H and 5.2 g. NaOH in 100 cc. ice-cold H2O were added simultaneously during 30 min. with stirring 9 g. NaOH in 50 cc. H2O and 10 g. I in 50 cc. C6H6, the mixture was stirred 30 min. at room temperature, the C6H6 removed in vacuo, and the resulting aqueous solution acidified with 6N HCl to give 70% 5-pyrazinoylamino-2-pentenoic acid, m. 200-1°. By the same procedure but with NaHCO3 were prepared 70% di-Et N-pyrazinoylaspartate, m. 64-5°, and 50% II, m. 87-9°. Cyanopyrazine (VI), b6-7 86-7°, (21.9 g.) in 125 cc. dry Et2O and 8.4 g. absolute MeOH saturated with HCl at 0° and the mixture let stand 15 hrs. at room temperature gave 25.6 g. Me pyrazinimidate-2HCl, m. above 150° (with darkening and decomposition); this was added to 600 cc. ice-cold 8% alc. NH3, the mixture shaken 1 day at room temperature, filtered, the filtrate evaporated to dryness in vacuo, and the solid residue boiled briefly with 125 cc. Me2CO, filtered, and crystallized from EtOH to give 6 g. pyrazinecarboxamidine-HCl, m. 215-18° (decomposition); picrate, m. 221-4°. VI (15 g.) in 200 cc. saturated, alc. NH3 saturated with H2S and the mixture let stand overnight at room temperature yielded 90% thiocarbamyl-pyrazine, m. 195-6°. To 13.8 g. III and 7 g. NH2OH.HCl in 50 cc. ice-water was added 16 cc. 12.5 N NaOH, and the mixture let stand 15 min. in an ice bath and neutralized with HCl to give 72% pyrazinohydroxamic acid, m. 163-5° (from H2O), gives a wine color with alc. FeCl3. Pyrazinamide (VII) (21 g.), 84 cc. AcOH, and 210 cc. 30% H2O2 heated 34 hrs. at 56° gave 45% pyrazinoic acid 4-oxide, m. 292-3° (decomposition) (from AcOH), also obtained by similar oxidation of VI. VII (10 g.) and 17 g. MeI refluxed 12 hrs. in 100 cc. MeOH yielded 38% 3-carbamyl-1-methylpyrazinium iodide (VIII), m. 192-202° (from H2O). VII (4 g.) refluxed 1.25 hrs. with 20 cc. Ac2O gave 55% N-Ac derivative (IX), of VII, m. 92-7°. VII (15 g.), 18 cc. aqueous CH2O, and 0.2 g. K2CO3 heated on a steam bath until a clear solution was formed yielded 80% N-(hydroxymethyl)pyrazinamide, m. 129-36.5°. 1-Phenylsulfonyl-2-pyrazinoylhydrazine (X) 86% was obtained from PhSO2Cl and pyrazinoic acid hydrazide(XI),m. 169°. Dry X(10g.)and 18g. finely powd. Na2CO3 heated at 150-70° and 35 mm. pressure, and the vapors bubbled through 3% aqueous H2NC(:S)NHNH2 gave 9% pyrazinaldehyde thiosemicarbazone (XII), m. 237-9° (decomposition). XI (2.8 g.) and 3.3 g. p-AcNHC6H4CHO in 100 cc. absolute EtOH refluxed 5 min. yielded 92% pyrazinoic acid (p-acetamidobenzylidene)hydrazide, m. above 250°. To MeMgI (from 50 g. MeI and 9 g. Mg) in 300 cc. dry Et2O was added dropwise over 20 min. 13 g. VI in 150 cc. Et2O, and the mixture poured on ice and acidified to give 77% acetylpyrazine (XIII), m. 76-8° (from Et2O); thiosemicarbazone (XIV), 67%, m. 226-7° (decomposition); oxime, 50%, m. 113-15° (sublimed at 100° and 0.05 mm.). Powd. S (1.5 g.) in 15 cc. concentrated NH4OH saturated with H2S, 3.0 g. XIII, and 12 cc. dioxane heated 24 hrs. in a sealed tube at 170° gave 0.2 g. pyrazinacetamide, m. 108-10° (from EtOH-petr. ether). XIII (12.2 g.), 5.2 g. S, and 15 cc. morpholine refluxed 6 hrs. yielded 80% 4-(2-pyrazinylthioacetyl)morpholine, m. 92-3°. HCl passed through 29.6 g. pyrazinyldiazomethyl ketone (XV) in 600 cc. dry Et2O until the N evolution ceased gave 30% (chloroacetyl)pyrazine, m. 85-6°; thiosemicarbazone, 30%, m. 222-4°. To 30 cc. glacial AcOH was added at 50° in portions 6.4 g. XV, and, after all the N had been evolved, 0.5 g. KOAc, the mixture heated 1 hr. at 100°, and the AcOH distilled off in vacuo to yield 10% (acetoxyacetyl)pyrazine, m. 67-8°. VI (5.1 g.), 3.3 g. NaN3, 10 cc. glacial AcOH and 15 cc. iso-PrOH autoclaved 5 days at 150° gave 30% 5-pyrazinyl-1H-tetrazole, m. 182-4°. Concentrated aqueous solutions of 2-aminopyrazine and KSCN mixed and acidified during 1 hr. with 1 molar equivalent HCl gave 80% 1-pyrazinyl-2-thiourea, m. 128°. PhONa (36 g.) and 36 g. chloropyrazine refluxed 13 hrs. yielded 72% Ph pyrazinyl ether, m. 50-2°. 3-Methyl-2-quinoxalincarboxaldehyde thiosemicarbazone (XVI), m. 251-2° (decomposition) was obtained in 30% yield by refluxing the components 2 hrs. in absolute EtOH. All above mentioned pyrazine derivatives were tested in a standardized mouse test for T. B. activity at the arbitrary level of 0.2% of diet (8 mg./day), with survival as a criterion. VII, m. 189-91°, was highly active, and IX and XII showed a slight activity. All others were inactive; IV, V, VIII, X, XI, XII, and XIV were also toxic. The following addnl. pyrazine derivatives (substituents and m.ps. given) were also tested and found inactive: CO2H, 225-6°; C(OAc):NH.2HCl, 180°; CO2-Me.HCl, 46°; 6,2-Me(HO2C), 138-40°; 2,3-(HO2C)2, 179-82°; 2,3-CONHCO-, m. 245°; and 6,2,3-Me(HO2C)2, 43.4°. XVI, 2-chloro-3-quinoxalinecarboxamide (XVII), m. 207-9°, and its N-PhCH2 derivative did not exhibit T.B. activity in the above test.
Journal of the American Chemical Society published new progress about 4604-72-2. 4604-72-2 belongs to pyrazines, auxiliary class Pyrazine,Amine,Amide, name is Pyrazine-2-carbothioamide, and the molecular formula is C5H5N3S, Application In Synthesis of 4604-72-2.
Referemce:
https://en.wikipedia.org/wiki/Pyrazine,
Pyrazine | C4H4N2 – PubChem