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

Authors

  • Dan Fishlock Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland. daniel.fishlock@roche.com
  • Ralph Diodone Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
  • Stefan Hildbrand Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
  • Bernd Kuhn Contributions to computational chemistry and modelling Computer-aided Drug Design Group Pharmaceutical Research and Early Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
  • Christian Mössner Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
  • Carsten Peters Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
  • Pankaj D. Rege Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
  • Gösta Rimmler Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
  • Markus Schantz. Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland

DOI:

https://doi.org/10.2533/chimia.2018.492

Keywords:

Asymmetric synthesis, Catalysis, Cycloaddition, Process chemistry

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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Published

2018-08-22

How to Cite

[1]
D. Fishlock, R. Diodone, S. Hildbrand, B. Kuhn, C. Mössner, C. Peters, P. D. Rege, G. Rimmler, M. Schantz., Chimia 2018, 72, 492, DOI: 10.2533/chimia.2018.492.