2023, Volume 21, Issue 2
Engineering >> 2023, Volume 21, Issue 2 doi: 10.1016/j.eng.2021.07.029
Continuous-Flow Synthesis of the Nucleobase Unit of Remdesivir
a Key Laboratory of Green Chemical Engineering Process of the Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, China
b Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
c Shanghai Engineering and Technology Research Center for Industrial Asymmetric Catalysis of Chiral Drugs, Shanghai 200433, China
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Abstract
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 operations 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·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 streamlined 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.
Keywords
Flow chemistry ; Continuous multistep synthesis ; Microreaction technology ; Reaction–separation integration
SupplementaryMaterials
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