Synthesis of the Kinase Inhibitors Nintedanib, Hesperadin, and Their Analogues Using the Eschenmoser Coupling Reaction

A novel synthetic approach involving
an Eschenmoser coupling reaction
of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile
was used for the synthesis of eight kinase inhibitors including Nintedanib
and Hesperadin in yields exceeding 76%. Starting compounds for the
synthesis are also easily available in good yields. 3-Bromooxindoles
were prepared either from corresponding isatins using a three-step
synthesis in an average overall yield of 65% or by direct bromination
of oxindoles (yield of 65–86%). Starting N-(4-piperidin-1-ylmethyl-phenyl)-thiobenzamide was prepared by thionation
of the corresponding benzanilide in an 86% yield and N-methyl-N-(4-thiobenzoylaminophenyl)-2-(4-methylpiperazin-1-yl)­acetamide
was prepared by thioacylation of the corresponding aniline with methyl
dithiobenzoate in an 86% yield.