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

By Keutz, Timo von; Williams, Jason D.; Kappe, C. Oliver

Published on CMKC

Abstract

In a rapidly changing environment, such as the current COVID-19 pandemic, continuous flow reactors bear the potential to increase the production of urgently needed active pharmaceutical ingredients (APIs) on demand. 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.

Journal

Organic Process Research & Development. Volume 25, 2021, 1015–1021

DOI

10.1021/acs.oprd.1c00024

Type of publication

Peer-reviewed journal

Affiliations

  • Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE)
  • University of Graz

Article Classification

Research Article

Classification Areas

  • Intermediate
  • API

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