Efficient Industrial Synthesis of the MDM2 Antagonist Idasanutlin via a Cu(I)-catalyzed [3+2] Asymmetric
Dan Fishlock1, Ralph Diodone2, Stefan Hildbrand2
1Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel;,
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.
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