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(<small>I</small>)-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.

Temozolomide-Acquired Resistance Is Associated with Modulation of the Integrin Repertoire in Glioblastoma, Impact of α5β1 Integrin

“…The discovery of the p53–MDM2 inhibitor Nutlin-3a represented a breakthrough in the development of p53-activators 14 . The more recent development of RG7388 (Idasanutlin), a second-generation MDM2 inhibitor with greater potency, selectivity, bioavailability and effective p53-activating ability leading to the p53-mediated induction of tumour cell apoptosis, is promising for cancers, including GBM [ 18 , 19 ].…”