2-Carboxy-6- pyrazine

A successful route to 91 utilizes the property of 2-amino-3-carboxy-pyrazines to smoothly undergo nitrative decarboxylation. Thus, treatment of a concentrated sulfuric acid solution of 85 with nitric acid in sulfuric acid at 10 to 25°C gives 2,6-diamino-3,5-dinitropyrazine (92) in high... 

C-Alkyl- and C-arylpyrazines are most generally prepared by primary syntheses, which have been discussed in Chapter II they may also be prepared by alkylation (or arylation) of pyrazines at nuclear or side chain carbon atoms, and by decarboxylation of alkyl carboxy pyrazines. 

Pyrazine 1-oxide is also conveniently prepared by vacuum distillation of 3-carboxypyrazine 1-oxide at 250° and pyrazine 1,4-dioxide by treating 2-carboxy-pyrazine with hydrogen peroxide in acetic acid (744). 

Amino-3-cyano-5-methylpyrazine 1,4-dioxide (91) refluxed for several minutes with acetic anhydride formed 3-acetamido-2-cyano-5-hydroxy-6-methylpyrazine 1-oxide (92) (24%) (532) and 2-acetoxymethyl-5-methylpyrazine 1,4-dioxide refluxed with acetic anhydride afforded a mixture of2,5-di(acetoxymethyl)pyrazine 1-oxide, with some 2,5-diacetoxymethylpyrazine and a monoxide of 2-acetoxy-methyl-5-methylpyrazine (625). 2-Formylpyrazine hydrate 1,4-dioxide with aqueous sodium hydroxide or bicarbonate at < 37° in an unusual reaction gave 3-carboxy-pyrazine 1-oxide mixed with 5 [Pg.188]

Aminopyrazines may be prepared from carbamoylpyrazines by the Hofmann degradation. Gabriel and Sonn (397) first prepared 2-aminopyrazine from 23-dicarbamoylpyrazine with potassium hypobromite through 2-amino-3-carboxy-pyrazine, which was decarboxylated when heated above its melting point (or in refluxing nitrobenzene) (397, 477). 2,3-Dicarbamoylpyrazine with 2 mol of... 

It is effective in lowering blood sugar and FFA levels in intact, adrenalectomized and hypophysectomized rats. This compound is metabolized to 2-carboxy-pyrazine, which is responsible for its action. 39 This is substantiated by the finding that pyrazinamide does not increase glucose oxidation or inhibit FFA release from adipose tissue in vitro whereas 2-carboxypyrazine exerts both actions. Hypoglycemic activity is attributed to the ability of 2-carboxypyrazine to increase glucose utilization in adipose tissue. 39... 

The presence of a 2-substitutent in 3-phenylazirines (17, R —H in Scheme 21) modifies the mode of reaction with molybdenum carbonyl.47 In contrast to pyrazine formation for (17, R =H see Section V,C,2), the alkenyl azirine (18, Scheme 22) is transformed in excellent yield into 2-phenyl-5-carboxy-methylpyrrole. This product probably arises by intramolecular cyclization within an intermediate dienylnitrene intermediate, and related reactions have been devised to synthesize isoxazoles (see Section IV,E,2) and pyrazoles (see Section IV,D,1).47 The molybdenum carbonyl-promoted formation of 2,5-disubstituted pyrroles47 has analogy in uncatalyzed thermal, but not photochemical decomposition of 3-phenyl-2//-azirine 2-acrylate.49... 

Similarly, when dialkyl acetylenedicarboxylates were condensed with 2,3-diaminopyridine in ethanol, the 2-carboxy-carbonylmethylene-l,2-dihydro-4/f-pyrido[2,3- ]pyrazin-3-ones 33 were obtained. The isomers 34 were formed when acidified ethanolic solution was employed <1995JHC1071>. 

Das Erhitzen von 4,5-Dicarboxy-imidazolen mit Essigsaureanhydrid ist die Methode der Wahl zur selektiven Abspaltung einer Carboxy-Gruppe. Im Fall von 1-unsubstituierten Imidazolen erhalt man durch Kochen mit Essigsaureanhydrid 5,10-Dioxo-5H,10H-532 533 ... 

Berninamycinic acid is also a hydrolysis product from the antibiotic sulfomycin. Another hydrolysis product from this antibiotic is racemic sulfomycimine (523 R absent), anhydro-6-carboxy-5,6,7,8-tetrahydro-5-methyl-8-oxothiazolo[3,4-a]pyrazin-4-ium hydroxide (77TL735). 

Fission and desulfurization of 2,2-dimethyl-5,8-dioxo-2,3,6,7,8,8a-hexahydro-5//-(hiazolo[3,2-a]pyrazine-3-carboxylic acid (140), by treatment with Raney nickel in aqueous ethanolic sodium bicarbonate at 20°C during 12 h, gave 1-(I -carboxy-2-methylpropyl)-3,6-dihydro-2,5( 1 //,4//)-pyrazinedionc (141) in 58%... 

Imidazol 4(bzw. 5)-Carboxy-l-methyl- E8e, 99 (4-COOH -> 4-H) Pentan 3-Diazo-2,4-dioxo- E14b, 1054 (CH2 - CN2) Pyrazin-l,4-bis-oxid Methyl- E9b/2, 305 (N-Bis-oxidat.)... 

Pyrido 2,3-b pyrazin 7-Carboxy-2-methyl-8-oxo-5-(2-propinyl)-5,8-dihydro- E9c, 243 (NH - N-R) Quinazolin 2-(Cyan-tnethoxycarbo-nyl-methyl)-4-hydroxy- E9h/2, 29 [2-NH2-Ar-COOH/ (NC)2CH-COOR]... 

Pyrido[3,2-b pyrazin 7-Carboxy-3-dimethylamino-5-ethyl-8-oxo-5,8-dihydro- E9c, 248 (SR NR2)... 

H2, 3-Dimethylphenyl)-4-hydroxy-2-oxo-l,2-dihydropteridine with sodium hydroxide in refluxing ethanol gave 2-carboxy-3-(2, 3 -dimethylphenylamino)pyrazine (Laboratories Hermes,... 

Like pyrazinecarboxylic acids, alkylpyrazinecarboxylic acids are decarboxylated on heating to elevated temperatures. For example, 23-dicarboxypyrazine and 2,3-dicarboxy-5,6-dimethylpyrazine are decarboxylated in acetic acid at 180 to pyrazine and 23-dimethylpyrazine, respectively, but on distillation under vacuum they give 2-carboxypyrazine and 5-carboxy-2,3-dimethylpyrazine, respectively (397). 

Normal nucleophilic substitution occurred on treatment of 2-carbamoyl-3-chloropyrazine with alcoholic methylamine at 130° (423, 836) 2-chloro-3-(4 -morpholinocarbonyOpyrazine with morpholine at reflux in benzene (867) 2dimethyl sulfoxide at 65° (857) and cyclohexylamine in benzene at reflux (946) 3-chloro-2-methoxycarbonyl-5-phenylpyrazine with alcoholic methylamine at 140° (375) 2-carboxy-3-chloropyrazine with anhydrous ammonia at 100° for 5 hours (947) 2-carbamoyl-6-chloropyrazine with aqueous methylamine at reflux (940) 2-chloro-6-(4 -morpholinocarbonyl)pyrazine (and other amides) and 2-chloro-6-methoxycarbonylpyrazine with morpholine (and other amines) (870, 948, 949) and 2-chloro-6-methoxycarbonylpyrazine with liquid ammonia at 80° (870). 2-Chloro-3-methoxycarbonylpyrazine fused with guanidine carbonate gave 2-amino4-hydroxypteridine and its 7-methyl-, 7-phenyl, and 6,7-diphenyl analogues were prepared similarly (371,375). 

Replacement of the chloro substituent by methoxide has been observed in the following pyrazines 2-chloro-3-methoxycarbonyl (at <5°) (867) 2-chloro-6-methoxycarbonyl (870) 2-chloro-3-methoxycarbonyl-5,6-diphenyl (371, 837) 2-carboxy-6-chloro (869, 871) 2-carbamoyl-5( )-chloro (839) 2-carbamoyl-6-chloro (805, 839) 2-chloro-6-(4 -morpholinocarbonyl) (870) 2-chloro-3-cyano (810, 811) 5-chloro-3-cyano-2-methoxy (reflux 14h) (881) 2-chloro-5-methoxy-3,6-dimethyl (844) 2-chloro-5-isopropyl-6-methoxy-3-methyl (50, 844) 2-chloro-5-methoxy-3,6-diphenyl (1.1 equivalents of 20% methanolic sodium methoxide at 135° for 20h) (797) 2-benzyloxy-6-chloro(at reflux) (832, cf. 883) 2-chloro-3-pyridinio(pyrazine)chloride (or tosylate) (to give 2,3-dimethoxypyrazine) (765) ... 

The first lithiopyrazine derivative was prepared by Hirschberg et al. (1015) from 3-iodo-2,5-dimethylpyrazine and butyllithium in ether subsequent reaction with (a) carbon dioxide gave 3-carboxy-2,5-dimethylpyrazine, and (b) several aromatic aldehydes gave the carbinols (62, R = H, p-methoxy, m-nitro) (1015). Similar reactions were observed when 2-formylpyridine and 2-acetylpyridine (1016) were used as the carbonyl compounds, but with acetaldehyde attempted reactions were unsuccessful (1015). A patent also describes the preparation of many carbinols from 2,5-disubstituted 3-iodopyrazines (164). The lithio reagent derived from 3-iodo-2,5-dimethylpyrazine (with butyllithium in hexane) with 2-nitrobenzaldehyde gave 2,5-dimethyl-3[ 1 -hydroxy-1 (2"-nitrophenyl)methyl] pyrazine (1017). 

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