Synthetic Approach for Discovery and Development of Novel Rice Herbicide, Pyriminobac-methyl

A novel synthesis of methyl 6-acetylsalicylate, a key intermediate directed at 6-substituted pyrimidin-2-yl-salicylate herbicides (PS) and their analogues, was studied. Three synthetic approaches were successful. Among them, a regioselective ortholithiation method was the most promising, and was applied for the synthesis of various 6-acylsalicylates and for the commercial synthetic method of Pyriminobac-methyl as well. Using methyl 6-acylsalicylate, 6-acyl pyrimidin-2-yl-salicylates (6-acyl PS), their acetal analogues and the close related phthalide analogues were synthesized and their herbicidal activities were evaluated. Among them, the compounds such as methyl 2-acetyl-6- [(4, 6- dimethoxypyrimidin-2-yl) oxy] benzoate gave excellent control of barnyard grass, but had unacceptable injury against rice. In order to reduce rice crop injury while keeping herbicidal activity, further extensive synthetic modification of 6-acyl PS was then examined by the introduction of an oximino group. QSAR study was carried out by examining their herbicidal activity against barnyard grass in paddy rice at various growth stages, including pre-emergence. Finally, Pyriminobac-methyl was found to be the most promising candidate and the industrial synthetic scheme was accomplished by modification of the regioselective ortholithiation method. Recently, Pyriminobac-methyl (Prosper®) was developed for the commercial herbicide and launched to the market.