New technology: Flash Chemistry Approach to Organometallic C-Glycosylation for the Synthesis of Remdesivir

Flash Chemistry Approach to Organometallic C-Glycosylation for the Synthesis of Remdesivir

Timo von Keutz,  Jason D. Williams*, and C. Oliver Kappe*

https://doi.org/10.1021/acs.oprd.1c00024

In the synthesis of remdesivir, the organometallic C-glycosylation step was identified as a limitation for the large-scale production, requiring long addition periods and cryogenic temperatures. Previous studies have focused on a Grignard-based protocol, but a flash chemistry approach, using organolithium reagents, has facilitated significant improvements. After gaining further understanding of the C-glycosylation, this step was successfully transferred to a five-stream continuous flow process, achieving 60% yield at a moderate temperature (−30 °C) in a total residence time of just 8 s. Stable processing was demonstrated for 2 h, providing an exceptionally high space–time yield of 10.4 kg L–1 h–1, in a scalable flow reactor system.