2- pyrazine with nitrous acid

The imide of 2,3-dicarboxypyrazine (45) with sodium borohydride in tetrahydro-furan gave 2-carbamoyl-3-hydroxymethylpyrazine, and the 2-methylcarbamoyl analogue was prepared similarly (1076). The imide (45) with isopropylamine gave 2-carbamoyl-3-isopropyIcarbamoylpyrazine (1394). 2,5-Dihydrazinocarbonyl-pyrazine with nitrous acid gave 2,5-diazidocarbonylpyrazine (1172). 

The major and recently used preparative routes to azidopyrazines have been covered already by azidolysis of halogenopyrazines (Sections 4.2.6 and 4.4) and by treatment of hydrazinopyrazines with nitrous acid (Section 7.4). In addition, direct C-azidation of pyrazines has been used for example, the lithio intermediate (225), generated in THF by treatment of 2-methoxypyrazine (224) with lithium 2,2,6,6-tetramethylpiperidine, gave 2-azido-3-methoxypyrazine (226) (87%) on subsequent treatment with p-toluenesulfonyl azide.232... 

Diazotization of 2-aminopyrazine with nitrous acid in dilute or concentrated sulfuric acid gave 2 hydroxypyrazine (to 67% yield) (86, 477, 720, 818). Many such conversions have been described, mostly using nitrosylsulfuric acid in concentrated sulfuric acid solution. Preparations of hydroxypyrazines from the aminopyrazines are summarized as follows 2-hydroxy-3-methylpyrazine (sodium nitrite in concentrated sulfuric acid-acetic acid) (681), 2Jiydroxy-3,5-dimethylpyrazine (aqueous nitrous acid, then at 60°) (524), 3-hydroxy-2,5-dimethylpyrazine (477), 2,5-diethyl-3-hydroxypyrazine (aqueous nitrous acid) (478), 2-hydroxy-6-phenyl-pyrazine (365a), 24iydroxy-3,5-diphenylpyrazine (nitrous acid in N hydrochloric acid) (524), 3-hydroxy-2,5-diphenylpyrazine (282), 2-s-butyl-3-hydroxy-5-isobutyl-pyrazine (93), 5TS-butyl-3 hydroxy-2-isobutylpyrazine (92, 536), 2,5-di-s-butyl-3-hydroxypyrazine (89, 720), 3-hydroxy-2-isobutyl-5-isopropylpyrazine (103, 525), 2,3-dihydroxypyrazine (from 2 amino-3-hydroxypyrazine) (757, 1055) and its... 

Pyrazinamide is one of the most powerful drugs available for the inhibition of urate excretion in man, consistently providing a 80-90% reduction in the renal clearance of uric acid (1401, 1403). 2-Morpholinocarbonylpyrazine and its 6-methoxy derivative are claimed to have antidiabetic activity (948, 949, 1351, 1387, 1404), and some 2-(p-ureidosulfonylphenethylcarbamoyl)pyrazines have been shown to have hypoglycemic activity in mice (1405). The effect of 2-amino-3-hydroxy-carbamoylpyrazine on DNA synthesis by Erlich ascites tumor cells in vitro has been investigated (1406) as well as the inhibition by 2-amino-3-hydroxycarbamoylpyrazine on L-histidine carboxylyase (1407) many 2-hydroxyimidazo[4,5-6]pyrazines (prepared from 2-amino-3-hydrazinocarbonylpyrazines with nitrous acid) are potent hypotensive agents in animals (880,891,963,1181). 

Diamino-3-chloro-5-hydrazinocarbonylpyrazine with nitrous acid at 50-55° formed 2,6-diamino-3-azidocarbonyl-5-chloropyrazine, which, refluxed with a solution of guanidine hydrochloride and sodium isopropoxide in propan-2-ol, gave 2,6-diamino-3-chloro-5-guanidinocarbonylpyrazine and many similar preparations were reported (1371). 2-Amino-5-chloro-3-hydrazinocarbonylpyrazine treated with nitrous acid gave 2-amino-3-azidocarbonyl-5-chloropyrazine, which was pyrolyzed to 5-chloro-2-hydroxyimidazo(4,5-Z)]pyrazine (1226). 

The amino group in 8-aminopyrido[2,3-b]pyrazine is hydrolyzed to give the 8-0x0 compound by treatment with sodium hydroxide. Similarly the 6-amino groups in compounds 103 and 104 have been replaced by treatment with nitrous acid." Reaction of 5-alkyl quaternary salts of pyrido[2,3-b]pyrazine with a variety of nucleophiles has been recently described " (see Section IIIl). 

Treatment of the ureide 129 or its 4-methyl derivative with diazomethane results in the formation of the monomethylated, and then the dimethylated spirohydantoin 131. This also demonstrates the ease of cyclization of these ureido derivatives. Similar reactions occur with 1,2-dihydro-2-oxo-3-ureidopyrido[2,3-h]pyrazine. If the methylated hydantoin 131 is treated with nitrous acid, the 1-nitroso compound 132 is formed. On alkaline hydrolysis this yields the 2-methylamino compound 133. The corresponding reactions with the 2-oxo isomer of 131 failed as... 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

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