Efficient Industrial Synthesis of the MDM2 Antagonist Idasanutlin via a Cu(I)-catalyzed [3+2] Asymmetric Cycloaddition
Dan Fishlock,
Ralph Diodone,
Stefan Hildbrand,
Bernd Kuhn,
Christian Mössner,
Carsten Peters,
Pankaj D. Rege,
Gösta Rimmler,
Markus Schantz.
Affiliations
Dan Fishlock
Process Chemistry and Catalysis Small Molecule Technical Development F. Hoffmann-La Roche, CH-4070 Basel, Switzerland. [email protected]
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
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.
