A Two-Step Resolution for Preparing Enantiopure (S)-Ethyl Nipecotate

Abstract:

Enantiopure nipecotic acid or ethyl nipecotate are key precursors for synthesizing a variety of pharmaceutically important compounds. In this work a two-step resolution of racemic ethyl nipecotate was developed to prepare enantiopure (S)-ethyl nipecotate. In the enzymatic resolution step, six lipases were screened for their ability to enantioselectively hydrolyze rac-ethyl nipecotate in t-butanol at 30°C and Novozym 435 was found to be the most effective. Solvent effects on the hydrolysis conversion and enantioselectivity showed that water was the optimum medium. When rac-ethyl nipecotate concentration was kept at 0.5M, the hydrolysis under optimum conditions (lipase loading 5mg/mL, phosphate buffer pH 7.0, reaction temperature 30°C, reaction time 6h) afforded 68.9% ees and 69.5% eep at 49.8% conversion. Novozym 435 preferentially hydrolyzed (R)-ethyl nipecotate over (S)-enantiomer. A parallel reaction model was suggested and found to fit the experimental initial rate data very well. (S)-enriched ethyl nipecotate was further resolved using (D)-tartaric acid and enantiopure (S)-ethyl nipecotate (98.5% ee) was acquired in 84.3% yield. The overall yield of enantiopure (S)-ethyl nipecotate by this two-step resolution was up to 36.0%.

• Periodical: Advanced Materials Research (Volumes 393-395)
• Pages: 559-566
• DOI: https://doi.org/10.4028/www.scientific.net/AMR.393-395.559
• Online since: November 2011
• Authors: Feng Xiang Tang, Yun Bo Li, Chun Meng, Xue Qing Zhao
• Keywords: Enantioselective Hydrolysis, Ethyl Nipecotate, Novozym 435, Resolution

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