PRACTICAL SYNTHESIS OF THE HIGH-QUALITY ANTITUMOR AGENT KW-2189 FROM DUOCARMYCIN B2 USING A FACILE ONE-POT SYNTHESIS OF AN INTERMEDIATE

A facile and large-scale preparation process of a potent antitumor age nt 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-Meer wein 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 goad quality hydroxy com pound 4 in a reasonable yield without isolation of the unstable keto i ntermediate 3a, During commercial-scale production at a scale of about 50 g, this strategy provided high-quality KW-2189 (2) in a 55% overal l yield from 1. Potential degradation compounds 7-9 were also synthesi zed and shown to be absent in the KW-2189 (2) prepared.