ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

An efficient and practical protocol for the production of pretomanid (PA-824) via a novel synthetic strategy

Guojun Chen, Minglin Zhu, Yuxiang Chen, Xiuqi Miao, Ming Guo, Nan Jiang, and Xin Zhai

Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China

E-mail: zhaixin_syphu@126.com

Received: 15 February 2020  Accepted: 18 May 2020

Abstract:

Abstract

An improved, practical and efficient protocol for the production of pretomanid (1) is described. Key to this optimization was the design and development of a novel synthetic strategy, which involves the preparation of key intermediate (S)-1-(tert-butyldimethylsilyloxy)-3-(2-chloro-4-nitro-1H-imidazol-1-yl) propan-2-ol (6) from 2-chloro-4-nitroimidazole (2) and (S)-epichlorohydrin (3) through nucleophilic substitution, hydrolysis and silicon etherification reactions, followed by further O-alkylation and intramolecular cyclization to obtain pretomanid with excellent quality and yield. The new route addressed the scalability issues that existed in the reported routes, in which the explosive 2,4-dinitroimidazole, expensive (S)-1-O-(tert-butyldimethylsilyl) glycidol and laborious workups can be avoided. Furthermore, this new synthetic route provides a more efficient method to pretomanid with the characteristics of cheap and easily available raw materials, mild experimental conditions, simple operation, ‘one-pot’ procedure, which is satisfied with the requirement of green chemistry and suitable for industrial production.

Graphic abstract

Keywords: Pretomanid; Solvent-free reaction; Impurity control; ‘One-pot’ procedure; Novel synthetic strategy

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-020-01211-4

Chemical Papers 74 (11) 3937–3945 (2020)