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.