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Development and Scale-Up of an Asymmetric Synthesis of AZD8186 Using the Fukuyama Modification of the Mitsunobu Reaction

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journal contribution
posted on 2021-07-15, 14:50 authored by Peter R. Moore, James C. Muir, Jerome Dubiez, Kevin W. Leslie, Paula Tomlin, Marc McCormick, Sophie L. Janbon, Philip Cornwall, Per Ryberg, Robert Berg
A large-scale asymmetric synthesis has been developed for the kilo-lab manufacture of AZD8186. The process initially employs a regioselective Heck coupling in water to provide the starting aromatic ketone. This ketone is reduced asymmetrically under ruthenium-catalyzed transfer hydrogenation conditions to provide a chiral alcohol in high enantiomeric purity. The key synthetic step then requires the reaction of this chiral alcohol with the activated derivative of 3,5-difluoroaniline under the Mitsunobu reaction conditions. The common issues associated with the use of the Mitsunobu reaction, such as removal of triphenylphosphine oxide and reduced diisopropyl azodicarboxylate (DIAD) by-products, have been eliminated through crystallization of the relevant intermediates.