An efficient and practical protocol for the production of pretomanid (PA-824) via a novel synthetic strategy
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ORIGINAL PAPER
An efficient and practical protocol for the production of pretomanid (PA‑824) via a novel synthetic strategy Guojun Chen1 · Minglin Zhu1 · Yuxiang Chen1 · Xiuqi Miao1 · Ming Guo1 · Nan Jiang1 · Xin Zhai1 Received: 15 February 2020 / Accepted: 18 May 2020 © Institute of Chemistry, Slovak Academy of Sciences 2020
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
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11696-020-01211-4) contains supplementary material, which is available to authorized users. * Xin Zhai [email protected] 1
Key Laboratory of Structure‑Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
Pretomanid (PA-824, Fig. 1), a nitroimidazole-oxazine compound developed by TB Alliance, was first approved in the USA in 2019, which would be used in combination with bedaquiline and linezolid to treat patients with extensively drug-resistant tuberculosis (XDR-TB) and intolerant or non-responsive multidrug-resistant tuberculosis (MDRTB) (Alffenaar et al. 2017; Honeyborne et al. 2019; Lenaerts
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Chemical Papers
as expensive starting materials, long synthetic procedure, low total yield and complex workup procedures. Hence, we describe the successful development of a new practical synthesis of PA-824 in this report.
Results and discussion Fig. 1 Chemical structure of pretomanid (PA-824)
et al. 2015). The mechanism of action of PA-824 on M. tuberculosis is generally considered to be the bioreductive generation of reactive nitrogen species (predominantly nitric oxide), which leads to a decrease in intracellular ATP and anaerobic killing (Singh et al. 2008; Maroz et al. 2010). Many synthetic strategies have been reported for the preparatio
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