Synthetic Process Development of Antitumor Agent KT6587, an Indolocarbazole Alkaloid K252a Derivative

Abstract

A facile and large-scale preparation process of an antitumor agent KT6587 (2), derived from an indolocarbazole alkaloid K252a (1), has been developed. The new synthetic process requires four steps: (i) selective N-silylation of the amide group of 1 with tert-butyldimethylsilyl chloride, (ii) methylation of the hydroxy group, (iii) deprotection under aqueous acidic conditions to afford 3, and (iv) reduction of the methoxycarbonyl group to obtain 2. The key strategic improvement is to obtain fine quality of the intermediate 3 in a reasonable yield with reproducibility. This new process improves the overall yield from 33% to 70% without tedious chromatographic separations and hazardous conditions. Multikilogram quantities of KT6587 (2) for early clinical evaluation have been obtained by this method.