Open AccessEfficient Industrial Synthesis of the MDM2 Antagonist Idasanutlin via a Cu(I)-catalyzed [3+2] Asymmetric Cycloaddition
Author(s) -
Dan Fishlock,
Ralph Diodone,
Stefan Hildbrand,
Bernd Kuhn,
Christian Mößner,
Carsten Peters,
Pankaj D. Rege,
Gösta Rimmler,
Markus Schantz
Publication year - 2018
Publication title -
chimia
Language(s) - English
Resource type - Journals
eISSN - 2673-2424
pISSN - 0009-4293
DOI - 10.2533/chimia.2018.492
Subject(s) - cycloaddition , stereocenter , isomerization , pyrrolidine , combinatorial chemistry , chemistry , catalysis , enantioselective synthesis , stereochemistry , organic chemistry
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.