3- Hydroxy-5-methoxycarbonylpyrazine

Many derivatives of carboxy chloropyrazines have been prepared by the action of phosphoryl chloride on the corresponding hydroxypyrazine. In this way were prepared 2-chloro-3-methoxycarbonylpyrazine (371, 423, 836), 2-chloro-3-methoxycarbonyl-5,6-diphenylpyrazine (but the corresponding hydroxy compound did not react with phosphorus tribromide) (837), and 3-chloro-2-methoxycarbonyl-... 

Amino-3-hydroxypyrazine with phosphoryl bromide at 140-150° for 20 minutes gave 2-amino-3-bromopyrazine (807) and 2-hydroxy-6-methoxycarbonyl-pyrazine with phosphoryl bromide at 125° for 10 minutes gave 2-bromo-6-methoxycarbonylpyrazine (867). 

Bromo-3-methoxycarbonylpyrazine with 2,3-dimethylaniline in refluxing toluene gave 2-(2, 3 -dimethylphenyl)amino-3-methoxycarbonylpyrazine (950) [hydrolysis of this product with sodium hydroxide in ethanol gave 2-carboxy-3-(2, 3 -dimethylphenyl)aminopyrazine, which was also obtained by treatment of l-(2, 3 -dimethylphenyl)lumazine with sodium hydroxide in refluxing ethanol (950)]. 3-Bromo-2-hydroxy-5-phenylpyrazine with ammonium hydroxide and copper at 150° gave 3-amino-2-hydroxy-5-phenylpyrazine (365a). Replacement of the iodo substituent from 2-amino-5-iodo-3,6-dimethylpyrazine has been effected with ammonium hydroxide (887). 

Hydrolysis of 2,6-diacetoxy-3,5-diphenylpyrazine (9) (from 2-hydroxy-3,5-diphenylpyrazine 1 -oxide by refluxing with acetic acid-acetic anhydride) with potassium hydrogen carbonate in methanol gave 2,6-dihydroxy-3,5-diphenylpyrazine (873), and 2-acetoxy-6-methoxycarbonylpyrazine (from 3-methoxycarbonyl-pyrazine 1-oxide with acetic anhydride) with methanolic hydrogen chloride gave 2-hydroxy-6 -methoxycarbonylpyrazine (838). 

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)]. 

Methoxypyrazines (31) have been prepared by diazomethane methylation of 2-hydroxy-3-isobutylpyrazine (60, 311, 367), 2-hydroxy-3-isopropylpyrazine (59, 367), 2-hydroxy-3-propyl(ethyl or hexyl)pyrazine (367), 3-hydroxy-2-isobutyl-5(and 6)methylpyrazine and 2-hydroxy-3-isobutyl-5,6-dimethylpyrazine (368), 2,3-dihydroxypyrazine (832), 2-hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenyl-pyrazine (832), 2-hydroxy-6-methoxy(and benzyloxy)pyrazine (832), 2,6-dihydroxy-3,5-diphenylpyrazine (873), 2,3,5-trifluoro-6-hydroxypyrazine (851), 2-chloro-6-hydroxy-3,5-diphenylpyrazine (873), 2-chloro-6-hydroxy-5-methyl-3-phenylpyrazine (873), 2-chloro-6-hydroxy-3-methyl-5-phenylpyrazine (873), 5,6-dichloro-1 -cyclohexyl-34iydroxy-2-oxo-l, 2-dihydropyrazine (853), 2-chloro-5-hydroxy-3-methoxy-6-methoxycarbonylpyrazine (881), 2-(4 -amino-3, 5 -dibromo-phenylsulfonamido)-3Tiydroxy-6-methoxypyrazine (881), 2-amino-3-hydroxy-... 

Dimethoxy-2-methoxycarbonylpyrazine boiled with phosphoryl chloride and phosphorus pentachloride gave the acid chloride, which, treated with aqueous hydrazine, gave 2-hydrazinocarbonyl-3,5-dimethoxypyrazine (881). 2-Methoxy-3-methoxycarbonyl-5-methylpyrazine with methylmagnesium iodide in ether gave 3-(l -hydroxy-r-methylethyl)-2-methoxy-5-methylpyrazine (39) (844). Thebromi-nation of 2-amino-5-bromo-3-methoxycarbonylpyrazine in 30% hydrobromic acid to 2-amino-3,5-dibromopyrazine has been described in Section V.IB (2) (807). 

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). 

Carbamoylpyrazine A-oxides are also prepared from the corresponding esters. 3-Methoxycarbonylpyrazine 1-oxide with ammonium hydroxide at reflux gave 3-carbamoylpyrazine 1-oxide (1266) and similarly with hydroxylamine gave 3-N-hydroxy carbamoylpyrazine 1-oxide (1266). 2-Amino-5-chloro-3-methoxycarbonyl-pyrazine 1-oxide with methylamine gave 2-amino-5-chloro-3-A-methylcarbamoyl-pyrazine 1-oxide (876). 

For the pyrazine A -oxides, there is a table for each substituent type, and compounds are listed (once only) at the first opportunity. For example, 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide is listed in Table A.31 (aminopyrazine A -oxides) and 2-hydroxy-5-methoxycarbonylpyrazine 1-oxide in Table A.32 (carboxypyrazine A -oxides). 

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