Asymmetric Synthesis of Akt Kinase Inhibitor Ipatasertib
2017
Han, Chŏng | Savage, Scott | Al-Sayah, Mohammad | Yajima, Herbert | Remarchuk, Travis | Reents, Reinhard | Wirz, Beat | Iding, Hans | Bachmann, Stephan | Fantasia, Serena M. | Scalone, Michelangelo | Hell, André | Hidber, Pirmin | Gosselin, Francis
A highly efficient asymmetric synthesis of the Akt kinase inhibitor ipatasertib (1) is reported. The bicyclic pyrimidine 2 starting material was prepared via a nitrilase biocatalytic resolution, halogen–metal exchange/anionic cyclization, and a highly diastereoselective biocatalytic ketone reduction as key steps. The route also features a halide activated, Ru-catalyzed asymmetric hydrogenation of a vinylogous carbamic acid to produce α-aryl-β-amino acid 3 in high yield and enantioselectivity. The API was assembled in a convergent manner through a late-stage amidation/deprotection/monohydrochloride salt formation sequence.
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