Efficient Industrial Synthesis of the MDM2 Antagonist Idasanutlin via a Cu(i)-catalyzed [3+2] Asymmetric Cycloaddition§

Abstract

A concise asymmetric synthesis has been developed to prepare idasanutlin, a small molecule MDM2 antagonist. Idasanutlin is currently being investigated as a potential treatment for various solid tumors and hematologic malignancies. The highly congested pyrrolidine core, containing four contiguous stereocenters, was constructed via a Cu(i)/(R)-BINAP catalyzed [3+2]-cycloaddition reaction. This optimized copper(i)-catalyzed process has been used to produce more than 1500 kg of idasanutlin. The manufacturing process will be described, highlighting the exceptionally selective and consistent cycloaddition/isomerization/hydrolysis sequence. The excellent yields, short cycle times and reduction in waste streams result in a sustainable production process with low environmental impact.