Practical Synthesis of the High-Quality Antitumor Agent KW-2189 from Duocarmycin B2 Using a Facile One-Pot Synthesis of an Intermediate

Abstract

A facile and large-scale preparation process of a potent antitumor agent KW-2189 (2), derived from the antitumor antibiotic duocarmycin B2 (1), has been developed. This new synthetic route required three steps: (i) one-pot carbamoylation and subsequent reduction, (ii) Wagner−Meerwein rearrangement of the methoxycarbonyl group for the production of the pyrrole compound 6, and (iii) formation of the hydrobromide salt 2. The key strategic improvement was to obtain good quality hydroxy compound 4 in a reasonable yield without isolation of the unstable keto intermediate 3a. During commercial-scale production at a scale of about 50 g, this strategy provided high-quality KW-2189 (2) in a 55% overall yield from 1. Potential degradation compounds 7−9 were also synthesized and shown to be absent in the KW-2189 (2) prepared.