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Design and development of an efficient convergent synthetic strategy for novel β-lactam enhancer zidebactam (WCK 5107)

Satish Bhavsar, Sanjeev Joshi, Vikas Deshmukh, Shivaji Pawar, Bharat Dond, Amit Mishra, Abhijeet K. Kayastha, Ravindra Yeole, Prasad Deshpande, Sachin Bhagwat, and Mahesh Patel

Wockhardt Research Centre, Aurangabad, India

 

E-mail: sbhavsar@wockhardt.com

Received: 1 June 2023  Accepted: 14 October 2023

Abstract:

Zidebactam (WCK 5107) is a novel β-lactam enhancer (BLE), developed by Wockhardt, exhibiting standalone antimicrobial activities against panel of gram-negative pathogens. Zidebactam is referred as β-lactam ‘enhancer’, because in combination with a partner β-lactam drug, zidebactam not only inhibits the β-lactamases, but also targets PBP2 and enhances the potency of partner drug. The manuscript details the stereoselective synthesis of Zidebactam, as well as the technique/process for preparing the stable sodium salt of (2S,5R)-6-benzyloxy-7-oxo-1,6-diaza-bicyclo[3.2.1]-octane-2-carboxylic acid and the chirally pure side chain, N-Boc-(R)-(-)-ethyl nipecotate hydrazide via chiral resolution. The convergent synthesis of zidebactam has achieved by coupling between sodium salt of DBO carboxylic acid and Boc-(R)-(-)-ethyl nipecotate hydrazide followed by requisite chemical transformations. Single crystal X-ray analysis established the stereochemistry of zidebactam with empirical formula, C13H21N5O7S.2H2O. Currently, two drug combination products zidebactam with cefepime (WCK 5222) and zidebactam with ertapenem (WCK 6777) awarded qualified infectious disease product (QIDP) status by U.S. Food and Drug Administration (USFDA). WCK 5222 has completed phase I clinical trial studies in the USA and is currently undergoing global phase III clinical studies, WCK 6777 is progressing through phase I clinical studies.

Graphical Abstract

Keywords: Ethyl nipecotate; Chiral resolution; Zidebactam; WCK 5107; Enhancer; DBO sodium salt; Process impurities

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-03176-6

 

Chemical Papers 78 (3) 1493–1504 (2024)

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