Fast Access to the Nucleobase Unit of the Anti-Covid-19 Drug Remdesivir

Significance 

Remdesivir has attracted global attention for potential use in treating severe coronavirus disease. During the first wave of Covid-19, this phosphoramidate nucleotide analog was approved for emergency and conditional use in different countries, allowing Covid-19 patients to receive remdesivir treatments. Given the global scale of the Covid-19 pandemic and the emergence of more contagious variants, the demand for active pharmaceutical ingredients for producing remdesivir has skyrocketed. Despite the considerable efforts to improve the remdesivir synthetic approach, the current batch synthesis is still complex, costly, lengthy, resource intensive, and is hindered by difficult-to-operate chemistry steps that are characterized by low yields. The traditional batch approach also suffers from typical limitations, like highly exothermic reactions, use of hazardous and unstable chemicals and multiphase reactions, when scaled up for commercialization. For rapid and large-scale production of remdesivir, it is imperative to develop highly effective and scalable remdesivir production protocols.

Through retrosynthetic analysis, remdesivir can be synthesized from three different building blocks: ribolactone unit, phosphoramidate unit and adenine-mimicking nucleobase unit. The synthesis of the nucleobase unit plays a crucial role in the preparation of the target product remdesivir, because its synthesis is still problematic and far from mature, though several synthetic routes have been reported.

Herein, Professor Dang Cheng and Professor Fen-Er Chen from Fudan University together with Yongxing Guo from Wuhan Institute of Technology employed continuous flow technology to overcome the limitations of batch-wise synthesis and developed a five-step fully continuous-flow synthesis of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine from the widely available and inexpensive starting material pyrrole. The use of phosphoryl chloride for the Vilsmeier–Haack reaction was successfully replaced by bis(trichloromethyl) carbonate, thus avoiding the generation of phosphorus-containing wastewater. The relevant side reactions were well restrained in the developed flow process, allowing for the development of a chromatography-free protocol for the synthesis of the target compound. The step-wise separations and purifications were well addressed by the development of micro-scale separation devices including continuous-flow filter, liquid-liquid membrane separator and annular centrifugal extractor, and the incorporation of the workup procedures into the reaction sequences led to a fast and scalable access to 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine with a high atomic economy. Their work is currently published in the journal, Engineering.

The authors obtained 14.1% isolated yield of the target nucleobase unit compound with a throughput of 2.96 g.h-1 and residence time of 79 min under optimal flow conditions. The total residence time obtained via continuous flow processing was significantly shorter than that of batch procedures. In addition, the highly exothermic N-amination and Vilsmeier–Haack reactions involving unstable and hazardous intermediates, strict cryogenic conditions for bromination reaction and oxidative liquid-liquid biphasic transformation were effectively facilitated through the improved protocol.

With the intensification of the mixing and transport processes, the exothermic reactions were well tamed. Additionally, the cryogenic reaction was successfully accommodated and the reaction sequences were fully integrated with the workup procedures by streamlining the continuous-flow system using dedicated separation units and equipment. This formed the salient feature of this synthesis, which played a vital role in improving the overall process efficiency.

In summary, a continuous-flow synthesis of anti-viral drug remdesivir nucleobase unit based on the improved protocol starting from inexpensive and widely available pyrrole was reported. The integration of multiple chemical transformations and the corresponding workup procedures into a single fully streamlined continuous flow process has enabled rapid manufacturing with minimal time, resource consumption and minimal waste generation. As reported, this continuous-flow method represents a greener and more sustainable process to prepare this nucleobase unit with high efficiency and safety.

Fast Access to the Nucleobase Unit of the Anti-Covid-19 Drug Remdesivir - Advances in Engineering

About the author

Dang Cheng is a professor at the Department of Chemistry, Fudan University. He received his PhD degree in Chemical Engineering from the Institute of Process Engineering, Chinese Academy of Sciences in 2014. After that, he did postdoctoral research at the Eindhoven University of Technology and Claude Bernard University Lyon 1 before joining Fudan University in 2017. His research interests include flow chemistry, continuous-flow drug synthesis, the design and development of efficient continuous-flow reactors.

About the author

Fener Chen received his M.S. in Pharmacy and his Ph.D. in Organic chemistry from Sichuan University. He joined Wuhan Institute of Technology in 1988 and was promoted to professor in 1996. In 1998, he moved to Fudan University as a full professor. His current research focuses on the development of new asymmetric catalysts, asymmetric total synthesis of natural products in continuous flow and computer assisted mechanism-based drug design (CADD). Prof. Fener Chen has been a visiting professor at numerous prestigious universities, including Washington University, King’s College London, etc. He is currently a member of Chinese Academy of Engineering.

Reference

Guo, Y., Liu, M., Jiang, M., Tao, Y., Cheng, D., & Chen, F.-E. (2022). Continuous-Flow Synthesis of the Nucleobase Unit of RemdesivirEngineering, 1-9.

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