An Alternative Synthesis of 2-Benzyloxy-6-hydroxymethyl-3-isobutyl-5-methoxypyrazine 4-Oxide, a Key Intermediate for Synthesis of OPC-15161
MASAHISA OKA, S. Hashizume, Atsunori Sano · Heterocycles · 1994
&!&ad-2-Benzyloxy-6-hydroxymethyl-3-isobutyl-5-methoxypyrazine 4-oxide 6 e ) , a key intermediate for synthesis of OPC-15161 (1 a) having an inhibitory activity against superoxide anion generation, was prepared from 5-amino-2 -benzyloxy-3 -isobutyl-6-methoxycarbonylpyrazine 4-oxide (5b) by 3-step reaction.Actme oxygen species cause a variety of diseases, such as inflamation, autoimmune disease, diabetes, cardiovascular disease and cancer-iniliation. 1.2 OPC-15161 (la), a major degradation product of naturally occurring OPC-15160, was reported to show an inhibitory activity against superoxide anion generation and hence expected to have possibility to control these diseases.Alter the structure of l a was determined by X-ray crystallographic analysis, three synthetic methods have been reported starting respectively from tryptophan methyl ester.Vol.38.No. 7,1994 acid and ethyl aminocyanoacetate, and 5-cllloro-3-isobutyl-6-melhylpyrazine.However, these methods bear either a low yield in the seleclive methylation at the C-5 hydroxy group of 1 b,4 or tedious many-step reaction to obtain 1 a lrom the lieto oxime (3) via methoxy compou~~d (5e). 2-l1ydmxyimino-4-methylpen(anoic 5The authors were interested in exploring an alternative elficienl synthesis 01 2-benzyloxy-6-I~ydro~metl~yl-3-isobutyl-5-~netl~oxypyrazi~~e 4-oxide (5e) lrom 5-amino-2-benzyloxy-3-isobutyl-6-methoxycarbonylpyrazine 4-oxide (5b), because 5 e serves as a key intermediate not only lor synthesis of l a , but also for a variety of chemical modification of OPC-15161.In this paper, our new 3-step synthesis of 5 e from 5b is described.According to the method reported by 110, 5b was obtained lrom amino ester (5a) by the treatment with benzyl bromide.5a was easdy prepared by the cyclizatlon of amide (4) obtainable from methyl aminocyanoacetate (2) 7 and 2-11ydr0xyi1nin0-4-methylpentan0ic acid (3). 5 Scl~erne Synthetic pathway of pyrazine 4-oxide derivatives (5) NH2 COzMe NI-I, ' COzMe C1 C 0 2 M e O M e COzMe O M e CMzOH C1 CII20THP H C 0 2 M e H CH20H * Yields were assayed by hplc (Wakosil 5C18, MeCN : H z 0 = 4 : 6. Uv 254 nm).