Pyrrolotriazine 1 is an important precursor to Remdesivir, and an efficient synthesis is disclosed. This route features atom economy and reduced derivatization of starting materials, by making use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. A one-pot cascade sequence was developed for direct cyanation of pyrrole. Amination and cyclization with formamidine acetate complete the synthesis. The problematic nature of typically dilute electrophilic aminations was solved with semi-continuous processing. Moreover, development of a continuous platform afforded access to the ideal yet non-commercial aminating reagent, monochloramine. These efforts help to secure the Remdesivir supply chain.
Joshua D. Sieber added to list of authors and email address corrected with figshare.
2020 07 24 Supplemental Information