3 -hydroxypyrazine hydrolysis

PIPERAZINES AND PYRAZINES The classical synthetic method for constructing 2-aminopyrazines is illustrated by the synthesis of ampifzine (117), a CNS stimulant. Condensation of aminomalonamide and glyoxal leads to pyrazine 114. Hydrolysis to the acid and decarboxylation gives 2-hydroxypyrazine (115). Reaction with PCl produces chloride 116, and heating with dimethylamine completes... 

Palamidessi and Bernardi have obtained 2-chloropyrazine 1-oxide by mild treatment of pyrazine 1,4-dioxide with phosphoryl chloride. The structure of the 1-oxide was confirmed by hydrolysis to 2-hydroxy-pyrazine 1-oxide, which was also prepared by direct synthesis from glyoxal and glycine hydroxamic acid.398 This synthesis is illustrative of a general method for preparing 2-hydroxypyrazine 1-oxides by condensation of a,/3-dicarbonyl compounds with a-aminohydroxamic acids. An analogous synthesis of 2-aminopyrazine 1-oxides has already... 

Many such hydroxypyrazines have been made by primary synthesis (see Chapters 1 and 2), some by C- or N-hydroxyalkylation procedures (see Sections 3.1.1.1 and 3.2.2.1), and a few by hydrolysis of extranuclear halogenopyrazines (see Section 4.4). Other preparative routes are illustrated in the following classified examples ... 

Disposition in the Body. Well absorbed after oral administration. Metabolised by hydrolysis to pyrazine-2-carboxylic acid and subsequent hydroxylation to 5-hydroxypyrazine-2-carboxylic acid. In 24 hours, about 30 to 40% of a dose is excreted in the urine as pyrazine-2-carboxylic acid and less than 4% as unchanged drug the 5-hydroxy metabolite is also excreted in the urine. 

The reactivity of 2-fluoropyrazine with aqueous sodium hydroxide to give 2-hydroxypyrazine has been investigated (882, 884). In 1.07N sodium hydroxide at 26° the reaction followed pseudo-first-order kinetics with a half-life of 43 minutes, whereas under the same conditions 2-chloropyrazine had a half-life of 18 days, and 2-iodopyrazine and 2-fluoropyridine remained unchanged (882, 884). Thus, under the above conditions, 2-fluoropyrazine was 640 times more reactive than 2-chloropyrazine (882). Hydrolysis of 2-fluoropyrazine in 61V hydrochloric acid proceeded at a much slower rate with a half-life of 4 days at room temperature (884). Some literature preparations of hydroxypyrazines by hydrolysis of halogenopyrazines (chloropyrazines with aqueous sodium or potassium hydroxide unless otherwise specified) are as follows 2-hydroxy (150°) (818) 2-hydroxy-3-methyl (reflux) (680) 2-hydroxy-3,5-dimethyl (reflux) (978) 3-hydroxy-2,5-dimethyl (reflux) (98, 312, 680, 740) [at 120° (978)] 3-hydroxy-2,5-di- -butyl (powdered potassium... 

Klein et al. (978) first attempted the alkaline hydrolysis of 3-chloropyrazine 1 -oxide to 3-hydroxypyrazine 1 -oxide, and although spectroscopic evidence indicated the formation of the hydroxy compound, good quality homogeneous material could not be isolated. Later work by Berkowitz and Bardos (1034) has shown that 3-chloropyrazine 1-oxide was hydrolyzed by refluxing with two equivalents of aqueous sodium hydroxide, and treatment of the product with trimethylsilyl chloride and triethylamine gave 3-(trimethylsilyl)oxypyrazine 1-oxide. 3,6-Di-s-butyl-2-hydroxypyrazine 1-oxide has been prepared from the chloro analogue (no details given) (982). Hydrolysis of 2-amino-6-chloro-3-cyano-5-methylpyrazine... 

Amino-2prepared from 2-amino-3-cyanopyrazine 1-oxide by reflux with acetic acid-acetic anhydride followed by ready deacetylation by refluxing in methanol (538), and in a similar manner 3-amino-2-ethoxycarbonyl-5-hydroxypyrazine has been prepared from 2-amino-3-ethoxycarbonylpyrazine 1 -oxide through 3-acetamido-2-ethoxycarbonyl-5 ydroxy-pyrazine (538), and 2-amino-3-carbamoyl-6-hydroxy-5-methylpyrazine from 2-amino-3-cyano-5-methylpyrazine 1-oxide (538). The preparation of 24 ydroxy-6-methoxycarbonylpyrazine (10) has been claimed from 3-methoxycarbonylpyrazine 1-oxide with acetic anhydride followed by hydrolysis (1057) [cf. Nov Cek et al. (839), who claim it to be the 5-isomer, and Foks (744)]. 

Methylation of 2-amino-3-hydroxypyrazine (62) with methyl iodide and sodium methoxide afforded 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (63), and when an excess of methyl iodide was used, a mixture of compound (63) and its methio-dide (64) was isolated. Reaction with dimethyl sulfate and alkaU gave compound (63) and l,4-dimethyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine (66) the latter was presumed to be formed by hydrolysis of an intermediate quaternary salt since it was also obtained by treatment of the methiodide (64) with aqueous sodium hydroxide. Reaction of 2-amino-3-hydroxypyrazine with ethereal diazomethane produced a mixture of N- and 0-methyl derivatives, (63) and 2-amino-3-methoxy-pyrazine (65). With methyl toluene-p-sulfonate the quaternary salt 2-amino-3-hydroxy-1-methylpyrazinium toluenesulfonate (67) was obtained on alkaline hydrolysis it gave 3-hydroxy-l-methyl-2-oxo-l,2-dihydropyrazine (68) (832). Pulcherriminic acid with diazomethane gave a dimethyl derivative (99). 

Alkaline hydrolysis of halogenopyrazine A -oxides to hydroxypyrazine 7V-oxides has been described in Section V.7A(2). 

Alkoxypyrazine A -oxides may be hydrolyzed with acid to hydroxypyrazine A -oxides. Some examples are the hydrolysis of 3-ethoxy-2,5-dimethylpyrazine 1-oxide at reflux with 3 A hydrochloric acid to give 3-hydroxy-2,5-dimethylpyrazine 1-oxide (872) 2,5-diethoxy-3,6-dimethylpyrazine 1,4-dioxide with 2N hydrochloric acid at 70° gave 2-ethoxy-5-hydroxy-3,6-dimethylpyrazine 1,4-dioxide and 2,5-dibenzyloxy-3,6-dimethylpyrazine 1,4-dioxide similarly treated but at room temperature gave the 2-benzyloxy analogue (842), but with lOAf hydrochloric acid at room temperature it gave 2,5-dihydroxy-3,6-dimethylpyrazine 1,4-dioxide (842). 

The diazotization of aminopyrazines has been described in earlier sections. Section V.IH records the preparation of 2-fluoropyrazine from 2-aminopyrazine in fluoroboric acid containing copper powder with sodium nitrite (882, 884) and Section V.ll the preparation of iodopyrazines from some aminopyrazines via isodiazotate salts (30) (887). These salts were assigned the isodiazotate structure, on the basis of their inability to couple with 0-naphthol in alkaline solution (887) and they were characterized by hydrolysis in cold 40% aqueous sulfuric acid to the hydroxypyrazine (887). Section V.I K describes the conversion of aminopyrazines to bromopyrazines (798, 800, 807, 890-892) for example, 2-amino-3-methoxy-carbonylpyrazine with hydrobromic acid, bromine, and sodium nitrite in water gave 2-bromo-3-methoxycarbonylpyrazine (798, 890). The diazotization of aminopyrazines to hydroxypyrazines has been described in Section VI. 1C, to alkoxy-pyrazines in Section V1.3C, and to oxopyrazines in Section V1.9A(5). 2-Amino-pyrazine with isopentyl nitrite in benzene gave 2-phenylpyrazine (45%) and some 2-isopentoxypyrazine and 2,2 -dipyrazinyl amino isomers (1211). 

Carboxypyrazine A -oxides have been prepared by hydrolysis of carbamoyl- and alkoxycarbonylpyrazine A(-oxides as follows (reagent and conditions) 2-carbamoyl-pyrazine 1-oxide (10% NaOH/reflux/12h) (838) 3-carbamoylpyrazine 1-oxide (10% NaOH/reflux/30 min) (1266, cf. 838) 3-A(-acetylcarbamoylpyrazine 1-oxide (10% NaOH/heat) (1057) 3-morpholinocarbonylpyrazine 1-oxide (18% HQ/reflux/ 8h) (870) 2-hydroxy-5-methoxycarbonylpyrazine 1-oxide 2.5N NaOH/20-25°/ 20min) (739) 3-hydroxy-5-methoxycarbonylpyrazine 1-oxide (KOH/22 /2h gave 3-carboxy-5-hydroxypyrazine 1-oxide, which interfered with the growth of Streptococcus faecium Escherichia coli at 6 x lO and 4 x 10" M, respectively) (1035) 2-amino-3-benzyloxycarbonyl-5-methyIpyrazine 1-oxide 2N NaOH/reflux/ 30min) (365c) and 2-amino-5-chloro-3-methoxycarbonylpyrazine 1-oxide 2.5N NaOH/heat) (876,1222). 

Acetoxylative deoxygenations are as follows. 3-Methoxycarbonylpyrazine 1-oxide refluxed with acetic anhydride for 30 hours gave 2-acetoxy-6-methoxy-carbonylpyrazine (838), but Novdcek et al. (839) claim that the product (prepared with acetic anhydride at 160°) after hydrolysis with water was 2-hydroxy-5( )-methoxycarbonylpyrazine and 2-amino-3-ethoxycarbonylpyrazine 1-oxide refluxed with acetic acid-acetic anhydride gave 3-acetamido-2-ethoxycarbonyl-5-hydroxypyrazine (538). 

Several reactions of pyrazinecarboxylic esters have been discussed already reduction to N-alkylpiperazines (Section 3.2.2.2), reduction to extranuclear hydroxypyrazines (Section 5.2.1), and hydrolysis to pyrazinecarboxylic acids (Section 8.1.1). Other reactions to be expected of carboxylic or carboximidic esters are typi-hed in the following class lied examples ... 

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