5-Bromo-3-methoxy-2- pyrazine

Amino-3-Methoxy-Pyrazine 3 grams of 2-amino-3-methoxy-5-bromo-pyrazine are hydrogenated, in methanolic solution at room temperature and at atmospheric pressure, in the presence of 1 gram of palladium over charcoal... 

Amino-3-Methoxy-5-Bromo-Pyrazine 7 grams of 2-amino-3,5-dibromo-pyrazine are boiled for 9 hours in a methanolic solution of sodium methylate (obtained from 0.65 gram of Na and 18.5 ml of methanol). By cooling a crystalline product is obtained, filtered and washed once with methanol and 2 to 3 times with water. The yield is 5.4 grams, melting at 138°C. 

Fluorination of 9-benzyloxy-2-(4-fluorobenzyl)-6-methoxy-3,4-dihy-dro-lH,8H-pyrido[l,2-a]pyrazine-l,8-dione with Selectfluor in the presence of Ce2C03 in MeCN at ambient temperature for 6 h provided 7-fluoro derivative. Reaction of 6-bromo-3,4-dihydro-lH,8H-pyrido[1,2-a]pyra-zine-l,8-diones with phenol cyclohexyl-, and cyclopropylmethanols in the presence of Ce2C03 in DMF in a sealed tube at 25-60 °C for 12-24 h afforded 6-phenoxy, 6-cyclohexyl-, and 6-cyclopropylmethoxy derivatives, respectively (06WOP2006/066414). 

The treatment of N-(2-hydroxyethyl),N-(4-fluorophenyl)-4-benzyloxy-3-methoxypyridine-2-carboxamides with a mixture of polystyryldiphe-nylphosphine, imidazole, and I2 in CH2C12 at ambient temperature overnight yielded 9-methoxy-2-(4-fluorophenyl)-3,4-dihydro-l H,8H-pyrido [l,2-fl]pyrazine-l, 8-diones (06WOP2006/066414). When N-(2-hydro-xyethyl),JV-(4-fluorophenyl)-4-benzyloxy-3-methoxy-6-bromopyridine-2-carboxamides was heated in HBr-AcOH solution (38%) at 100 °C for overnight 6-bromo-9-hydroxy-2-(4-fluorophenyl)-3,4-dihydro-lH,8H-pyrido [l,2- ]pyrazine-l,8-diones were the products. 

Malonsaure (Arnino-brom-methy-len) -methylester-nitril E1S/2, 1653 [ROOC-CH(CN)2 + HBr] Pyrazin-l-oxid 2-Bromo-5-methoxy-E9b/2. 319 (H -. Br)... 

Amino-5-bromo-3-carbamoylpyrazine heated with trifluoroacetamide and sodium ethoxide (or butoxide) gave 6-ethoxy(or butoxy)-4-hydroxy-2-trifluoro-methylpteridine (49) (987) and 2-chloro-3-pyridiniopyrazine chloride with methoxide ion gave 2,3-dimethoxypyrazine (765). 2-Amino-3-bromo-5-phenyl-pyrazine with sodium methoxide in methanol at 134° for 8 hours formed 2-amino-3-methoxy-5-phenylpyrazine (365a) and 3-bromo-2-hydroxy-5-phenylpyrazine similarly treated gave 2-hydroxy-3-methoxy-5-phenylpyrazine (365a). 

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). 

The bromine atom in 2-bromopyrazino[2,3-6]pyrazines may be replaced by the methoxy or methylsulfanyl group under nucleophilic conditions.246 Unexpectedly, 6,7-dimethyl-2,3-bis(methylsulfanyl)pyrazino[2,3-h]pyrazine is formed (with introduction of a second methylsulfanyl group) when 2-bromo-6.7-dimethylpyra7ino[2,3-/>]pyrazine is treated with methanethi-ol in a solution of sodium methoxide in methanol at 201C for 4 hours [yield 19% mp 240-242 °C (cyclohexane)].246... 

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