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Paper | Regular issue | Vol 89, No. 6, 2014, pp.1413-1426
Published online, 2nd May, 2014
DOI: 10.3987/COM-14-12988
An Efficient Synthesis of (3S,5S)-5-[3,3-Dimethyl-1-(o-tolyl)-6-oxo-2H-pyridin-4-yl]piperidine-3-carboxamide as Potent Renin Inhibitor

Yutaka Mori,* Mitsuhiro Iwamoto, Kazuki Mori, Masao Yoshida, Takeshi Honda, Takahiro Nagayama, and Takahide Nishi

*New Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan

Abstract

We report synthesis and biological evaluation of (3S,5S)-5-[3,3-dimethyl-1-(o-tolyl)-6-oxo-2H-pyridin-4-yl]piperidine-3-carboxamide as renin inhibitor. This effective synthetic route involves a zinc mediated Barbier reaction and an intramolecular Horner-Wadsworth-Emmons reaction of sterically hindered ketone as key reactions. The prepared compound 4 exhibited both potent renin inhibitory activity and significant in vivo efficacy in furosemide pretreated cynomolgus monkeys.