An efficient and practical synthetic route to OPC-15161 (1), a novel inhibitor of superoxide anion generation, is described. Intensive survey on pyrazine ring manipulation has led to the development of multi-kilo synthetic pathway, in which beneficial use of a nitrogen protecting group is the key to the problematic cyclization and O-methylation process, both being carried out in one-pot operation. Thus, the synthesis proceeds in 40% overall yield in four steps from tryptophan methyl ester with simple operation and without chromatographic purification, which also opens a general route for the preparation of related 5-alkoxypyrazin-2 (1H) -one 4-oxide such as emeheterone.
