Continuous-Flow Synthesis of the Nucleobase Unit of Remdesivir

In this work, the nucleobase unit of the antiviral drug remdesivir, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine, was synthesized through five-step continuous flow. By adapting batch synthetic chemistry, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was successfully produced through sequential flow opera-tions from the widely available and inexpensive starting material pyrrole. Under optimal flow conditions, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was obtained in 14.1% isolated yield in a total residence time of 79 min with a throughput of 2.96 g center dot h-1. The total residence time was significantly shorter than the total time consumed in batch procedures (> 26.5 h). In flow, the highly exothermic Vilsmeier-Haack and N-amination reactions involving hazardous and unstable intermediates, oxidative liquid-liquid biphasic transformation, and a bromination reaction requiring strict cryogenic conditions are favorably facilitated. The salient feature of this synthesis is that the workup procedures are fully integrated into the reaction sequences by deploying dedicated equipment and separation units, thus forming a stream-lined continuous-flow system that maximizes the overall process efficiency. This method represents a greener and more sustainable process to prepare this nucleobase unit with high efficiency and safety. (c) 2022 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

In this study, the nucleobase unit of the antiviral drug remdesivir, 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine, was synthesized through a five-step continuous flow process. The synthesis was carried out from a readily available and inexpensive starting material pyrrole using sequential flow operations. The optimized flow conditions allowed for the production of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine in a significantly shorter time compared to traditional batch procedures, with a high yield and enhanced safety.