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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

PROCESS, SYNTHESIS Comments Off

Nov 242018

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

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

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

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

Avibactam NMR

spectroscopy, Uncategorized Comments Off

Feb 232018

Avibactam, sodium (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfonate,

Avibactam Sodium Salt (1)

white crystalline solid 1 (395.0 g, 96.2%), mp 259.1–262.4 °C (decomposition);

[α]_D²⁰ = −46.40 (c = 0.79, MeOH/H₂O = 1/1);

1H NMR (500 MHz, D₂O) δ 4.15 (dd, J = 5.8, 2.8 Hz, 1H), 4.01 (d, J = 7.5 Hz, 1H), 3.28 (d, J = 12.2 Hz, 1H), 3.06 (d, J = 12.2 Hz, 1H), 2.23–2.09 (m, 1H), 2.06–1.96 (m, 1H), 1.94–1.82 (m, 1H), 1.81–1.69 (m, 1H).

¹³C NMR (126 MHz, D₂O) δ 174.72 (s), 169.53 (s), 60.43 (s), 59.93 (s), 47.33 (s), 20.03 (s), 18.31 (s). IR (cm^–1): 3459, 1749, 1675, 1361, 1270, 1013, 857, 768. MS (ESI) m/z: 279.0 [M + H]⁺.