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CC BY 4.0 · Pharmaceutical Fronts 2023; 05(03): e161-e167
DOI: 10.1055/s-0043-1772252
Original Article

Multistep Synthesis of Paracetamol in Continuous Flow

Jian-Li Chen
1   College of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, People's Republic of China
2   Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education and Key Laboratory of Pharmaceutical Engineering of Zhejiang Province, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, People's Republic of China
,
Jing-Yu Hu
1   College of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, People's Republic of China
,
Qi-Fan Wang
1   College of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, People's Republic of China
,
Peng Ge
1   College of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, People's Republic of China
,
Quan-Hui Wang
1   College of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, People's Republic of China
,
Zi-Shuo Lou
1   College of Advanced Materials Engineering, Jiaxing Nanhu University, Jiaxing, People's Republic of China
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Abstract

p-Aminophenol (AP) is the key intermediate of the traditional synthesis of paracetamol. The method of obtaining AP included a selective reduction reaction of the generation of N-arylhydroxylamine (AHA) using nitrobenzene (NB) as the raw material, followed by a Bamberger rearrangement reaction to transfer AHA to the target product. The generation of AHA is a key step, but due to its structural instability and the incompatibility of the two reaction systems, one-pot synthesis of paracetamol faces great challenges. Considering that using flow reactors in series may avoid the problems faced by batch reactors, the article presents the strategy to obtain paracetamol via a continuous flow technology. In particular, we focus on condition screening in total synthesis experiments, including hydrogenation, Bamberger rearrangement, and amidation in flow. The continuous three-step synthesis process used NB as a raw material to generate AHA, which entered the downstream for timely conversion, achieving in situ on-demand preparation of the unstable intermediate AHA, avoiding cumbersome processing and storage processes. Moreover, each step of the reaction system exhibits excellent compatibility, and the work-up is simple.

Keywords

mutistep synthesis - paracetamol - continuous flow


Publication History

Received: 15 July 2023

Accepted: 21 July 2023

Article published online:
21 August 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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