2-Carbamoylpyrazine

Pyrazines are known to exhibit a range of physiological activities. For example, 2-carbamoylpyrazine ( pyrazinamide ) is used in the treatment of tuberculosis (138-141). In animals pyrazinamide was at least twice as active as p-aminosalicyclic... 

Methylglyoxal and phenylglyoxal gave exclusively 5-substituted-2-amino-3-carbamoylpyrazines. This reaction was extended to aminoacetamidine by Pitre and Boveri (376), to give a series of 2-aminopyrazines, and to a-(substituted amidino)-a-aminoacetamide monohydrochlorides by Keir et al. (379) to provide 3-(substituted amino)-2-carbamoylpyrazine (57). 

Homolytic amidation of pyrazine to 2-carbamoylpyrazine can be effected in > 80% yield by using concentrated sulfuric acid with carbamoyl radicals ( CONH2) generated from the action of hydrogen peroxide and ferrous sulfate on formamide (611). 

Bis(azidocarbonyl)pyrazine at reflux with ethanol gave 2,5-bis(ethoxy-carbonylamino)pyrazine (1172) 2-carbamoylpyrazine when subjected to the Hofmann degradation gave the sodium salt of 2-carboxyaminopyrazine (which on acidification gave 2-aminopyrazine) (1171). 

Preparations of carbamoylpyrazines and related compounds by primary syntheses have been described in Chapters II.IB (192, 215, 234), II.IJ (298), II.IK (301), II.2 (347, 361, 365a, 369-375, 378-379, 382), II.5 and 11.9 (505), and further data were given in Section VIII.1A(1). Dehydrogenation of 2-carbamoylpiperazine in a current of nitrogen over palladium-charcoal at 290-305° gave 2-carbamoylpyrazine (1391). 

The crystal structure of 2-carbamoylpyrazine has been determined the pyrazine ring is completely planar, with mean C-N = 1.348 and C-C = 1.383 A, and made an angle about 5° to the amide group (C-0 = 1.244 and C-N = I.3I2 A) (1395). Investigations for 2-carbamoylpyrazine have been made of the heat of sublimation (1396), heat of fusion (1397), and solubilities in various solvents (1398) and the results correlated. The pA of 2-carbamoylpyrazine has been determined as — 0.5 (140). 

The antitubercular activity of 2-carbamoylpyrazine and biological activity of pyrazines generally has been mentioned in Section 1.4. Certain pyrimidinyl derivatives of 2-carbamoylpyrazine have been shown to have lower toxicity and rather greater in vitro activity against Mycobacterium tuberculosis than 2-carbamoylpyrazine (1388), and the antitubercular activity of some extranuclear )V-substituted carbamoylpyrazines also showed a higher activity than 2-carbamoylpyrazine (1201). When tested on mice in vivo, 2-carbamoyl-5-methoxypyrazine and 2-hydrazino-carbonylpyrazine had less antitubercular activity than did 2-carbamoylpyrazine (1098) the antitubercular activities in a series of hydrazinocarbonyl-, carbamoyl-, and thiocarbamoylpyrazines have been examined and compared (1399). 

Carbamoylpyrazine in dogs and humans is hydrolyzed to 2-carboxypyrazine and then converted to 2-carboxy-5-hydroxypyrazine (1400) and a combined gas chromatographic-mass spectroscopic technique has been described for the simultaneous determination of 2-carbamoylpyrazine, 2-carboxypyrazine, and 2-carboxy-... 

Carbamoylpyrazines have been hydroxymethylated with formaldehyde and potassium carbonate, and aminomethylated with formaldehyde and amine. In this way the following have been prepared 2-Af-hydroxymethylcarbamoylpyrazine (138) 2W-(diethylaminomethyl)carbamoylpyrazine (1413-1416) 2W-(morpho-linomethyl)carbamoylpyrazine (1414, 1416) and 2-A -[piperidino(pyrrolidino or other amino)methyl]carbamoylpyrazines(1414,1416). 2-7V-(Diethylaminomethyl)-carbamoylpyrazine refluxed with morpholine afforded 2-A -(morpholinomethyl)-carbamoylpyrazine (1415), and 2-carbamoylpyrazine with TV-(morpholinomethyl)-benzenesulfonamide gave 2-7V-(morpholinomethyl)carbamoylpyrazine (1417). 

Carbamoylpyrazine refluxed with acetic anhydride gave 2-)V-acetylcarbamoyl-pyrazine (138,1418) and 2,5-bis-A -acetylcarbamoylpyrazine was prepared similarly (672). 2,3-Dicarbamoylpyrazine heated in a vacuum gave the imide of 2,3-dicarboxy-pyrazine (397). 

Carbamoylpyrazine was methylated to 3-carbamoyl-l -methylpyrazinium iodide by methyl iodide in methanol at reflux (138) and by methyl iodide in dimethyl sulfoxide at room temperature (666) under the latter conditions the rate of methylation relative to pyrazine was 0.53 (666). 3-Carbamoyl-l-methylpyrazinium iodide reacted with liquid ammonia at — 40° to give 2-amino-5-carbamoyl-l-methyl-1,2-dihydropyrazine (46) (609). With nitromethide ions in liquid ammonia, none of the carbon addition reaction was found (721), but with ethanethiolate ion in liquid ammonia it gave 5-carbamoyl-2-ethylthio-l-methyl-1,2-dihydropyrazine (721). 2-(4 -Morpholino)carbonylpyrazine with methyl iodide gave 3-(4 -morpholino)-carbonyl-1-methylpyrazinium iodide (870). 

Reduction of 2-carbamoylpyrazine in ethanol over palladium-charcoal at atmospheric pressure gave 2-carbamoylpiperazine (870, 1269, 1352), and the 2-carbamoyl-3-carboxy (1269) and 2,3-dicarbamoyl (1269, 1352) analogues were prepared similarly, but 2,3-dicarboxypyrazine imide gave 50% 2,3-dicarboxy-1,4,5,6-tetrahydropyrazine imide (1269). 2-Hydroxy-3-V-phenylcarbamoylpyrazine oxidized with hydrogen peroxide in acetic acid at 50° for 96 hours did not give an 7V-oxide but only a tar and 2,3-dihydroxypyrazine (1055). 

Cyanopyrazine with concentrated aqueous ammonia was converted through 2-[A(-(C-imino-C-pyrazin-2-ylinethyl)amidino]pyrazine (43) to 2-carbamoylpyrazine (985), and 2-chloro-6-cyanopyrazine reacted similarly (985). 2-Ethoxy-6-(C-ethoxy-C-iminomethyl)pyrazine was found to be a by-product of the reaction of 2-chloro-6-cyanopyrazine with concentrated ethanolic ammonia and 2-ethoxy(or methoxy)-6-[C-ethoxy(or methoxy)-C-iminomethyl]pyrazine was obtained from 2-chloro-6-cyanopyrazine by the action of ethanol (or methanol) in the presence of triethylamine (985). 2-Cyanopyrazine treated in water with hydroxylamine hydrochloride and sodium carbonate at 70-75° gave 2-(C-amino-C-hydroxyiminomethyl)-pyrazine (62), and 2aluminum chloride at 140-220° gave 2-(C-anilino-C-iminomethyl)pyrazine (and similar preparations were carried out with other aromatic amines) (1334,1410). 

Cyano-2,3-diphenylpyrazine heated with dry ammonium thiocyanate at ISO gave 5-amidino-2,3-diphenylpyrazine (866). 2-Cyano-5-phenylthiopyrazine heated in acetic acid with hydrogen peroxide for 3 hours gave 2-cyano-5-phenylsulfonyl-pyrazine and some 2-carbamoyl-5-phenylsulfonylpyrazine (840) and 2-cyano-pyrazine with hydrogen peroxide in aqueous alkali at 70° gave 2-carbamoylpyrazine... 

Cyanopyrazine 1-oxide and 3-cyanopyrazine 1-oxide each with alkaline 3% hydrogen peroxide at 55° gave 2-carbamoylpyrazine 1-oxide and 3-carbamoyl-pyrazine 1-oxide, respectively (838). 3-Amino-2-cyanopyrazine 1-oxide refluxed with trifluoroacetic anhydride in triHuoroacetic acid for 5 hours gave 3-amino-2-carbamoylpyrazine 1-oxide (538), and 2-amino-3-cyano-5-methylpyrazine 1-oxide with sulfuric acid (d. 1.8) at 100° gave 2-amino-3-carbamoyl-5-methylpyrazine 1-oxide (1255). 2-Amino-6-chloro-3-cyano-5-methylpyrazine 1-oxide with 0.5N sodium hydroxide at room temperature for 48 hours formed a mixture of 2-amino-3-cyano-6-hydroxy-5-methylpyrazine 1-oxide (56%) and 2-amino-3-carbamoyl-6-chloro-5-methylpyrazine 1-oxide (22%)(533). 3-7V-Acetylcarbamoylpyrazine 1-oxide was hydrolyzed by hot 10% sodium hydroxide to 3-carboxypyrazine 1-oxide (1057). 

Oxidation of 2-carbamoylpyrazine with hydrogen peroxide in acetic acid gave a mbcture containing mainly 3-carbamoylpyrazine 1-oxide (138, 575, 757, 839, 840,... 

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