As remdesivir is the first approved treatment for COVID-19 (SARS-CoV-2), its production is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technology in the manufacturing of highvolume active pharmaceutical ingredients and is considered for use in this synthetic sequence. In particular, the challenging Cglycosylation of a pyrrolotriazinamine via metal-halogen exchange was identified as a transformation with significant potential benefit, as exemplified by calorimetric analysis of each reaction step. Multiple simplifications of this process were attempted in batch but in general were found to be unfruitful. The five-feed process was then transferred to a flow setup, where specific conditions were found to circumvent solid formation and permit stable processing. Detailed optimization of stoichiometries provided an improvement upon batch conditions with a total residence time of <1 min.

• Research Center Pharmaceutical Engineering GmbH (RCPE)
• Karl Franzens University Graz

• API

1. active pharmaceutical ingredient synthesis
2. API
3. exothermic chemistry
4. flow chemistry
5. magnesium-halogen exchange
6. organometallics
7. Research Article