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Here we describe an efficient and cost-effective chemoenzymatic synthesis of the β-lactamase inhibitor avibactam starting from commercially available ethyl 5-hydroxypicolinate hydrochloride. Avibactam was synthesized in 10 steps with an overall yield of 23.9%. The synthetic route features a novel lipase-catalyzed resolution step during the preparation of (2S,5S)-ethyl 5-hydroxypiperidine-2-carboxylate, a valuable precursor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate. Our synthetic route was used to produce 400 g of avibactam sodium salt.

Use of Lipase Catalytic Resolution in the Preparation of Ethyl (2S,5R)-5-((Benzyloxy)amino)piperidine-2-carboxylate, a Key Intermediate of the β-Lactamase Inhibitor Avibactam

Tao Wang^†§, Liang-Dong Du^‡, Ding-jian Wan^‡, Xiang Li^‡, Xin-Zhi Chen*^§ , and Guo-Feng Wu*^† 

^† Research &Development Center, Zhejiang Medicine Co., Ltd, 59 East Huangcheng Road, Xinchang, Zhejiang 312500, P. R. China

^‡ Shanghai Laiyi Center for Biopharmaceuticals R&D, 5B, Building 8 200 Niudun Road Pudong District, Shanghai 201203, P. R. China

^§ Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Zhejiang University, 38 Zhejiang University Road, Xihu District, Hangzhou 310007, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00173

Publication Date (Web): November 5, 2018

Copyright © 2018 American Chemical Society

*E-mail: xcwuyuanzhang@163.com., *E-mail: xzchen@zju.edu.cn.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00173

///////////lipase, resolution, avibactam

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