Development of the Cu(I)-catalyzed [3+2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin
Dr. Dan Fishlock
F. Hoffmann-La Roche
Wednesday, October 10, 2018
C2-361 (Reading Room)
Abstract: A concise asymmetric synthesis has been developed to prepare idasanutlin (1), a small molecule MDM2 antagonist 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)/BINAP catalyzed [3+2]-cycloaddition reaction. This optimized copper(I) catalyzed process has been used to produce more than 1500 kg of idasanutlin.
The evolution of this synthetic route from the laboratory to commercial-scale manufacturing 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.