Synthesis 2017; 49(09): 2074-2080
DOI: 10.1055/s-0036-1588700
paper
© Georg Thieme Verlag Stuttgart · New York

Determination of the Absolute Configuration and a Practical Chiral Synthesis of 5-[5-(1-Methylethoxy)pyridin-2-yl]-5-methyl­imidazolidine-2,4-dione as a Novel Liver X Receptor β-Selective Agonist

Minoru Koura
a   Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
,
Hisashi Sumida
a   Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
,
Kimiyuki Shibuya*
a   Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Co., Ltd., 2-17-43, Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
,
Shigeru Ohba
b   Research and Education Center for Natural Sciences, Keio University, Hiyoshi 4-1-1, Kohoku-ku, Yokohama 223-8521, Japan   Email: k-sibuya@kowa.co.jp
› Author Affiliations
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Publication History

Received: 30 November 2016

Accepted after revision: 13 January 2017

Publication Date:
31 January 2017 (online)


Abstract

We determined that the absolute configuration of 5-[5-(1-methylethoxy)pyridin-2-yl]-5-methylimidazolidine-2,4-dione (hydantoin) is the (S)-form for the liver X receptor (LXR) β-selective agonist through X-ray crystal structure analysis of the hydantoin hydrogen bromide salt. Furthermore, we established a practical synthesis of the chiral hydantoin with 99% ee by the optical resolution of racemic methyl 2-amino-2-[5-(1-methylethoxy)pyridin-2-yl]propanoate with d-(–)-mandelic acid on a multi-kilogram scale. Finally, we improved the synthesis method of the LXR β-selective agonist.

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