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Paper | Special issue | Vol 95, No. 1, 2017, pp.370-379
Published online, 31st October, 2016
DOI: 10.3987/COM-16-S(S)28
Preparation of (R)-3-Hydroxy-N-methylpiperidine, a Synthetic Key Intermediate of (R)-Mepenzolate, Based on the Lipase-Catalyzed Resolution of the Racemic Form

Yasunobu Yamashita, Kengo Hanaya, Mitsuru Shoji, and Takeshi Sugai*

*Department of Pharmaceutical Science, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan


In this study, a two-step method for the gram-scale synthesis of (R)-3-hydroxy-N-methylpiperidine in 97.8% enantiomeric excess (ee) is reported. The key chiral synthetic intermediate of (R)-mepenzolate was formed in 22% yield over two steps using a commercially available and inexpensive racemic alcohol as the starting material. In the first step, Candida antarctica lipase B-catalyzed kinetic resolution of the racemic alcohol under acetylation conditions was performed to obtain the acetate form of the (R)-enantiomer in 82.1% ee (E 18). The second step involved enantio-enrichment using the same lipase to catalyze deacetylation. The ee of the product (R)-alcohol was further enriched to 97.8%.