Abstract
Pyrrolotriazine 1 is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes 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. These efforts help to secure the remdesivir supply chain.
Highlights
Pyrrolotriazine 1 is an important precursor to remdesivir
Waste will be generated in the process of purifying the aldehyde, aldoxime, or other intermediates
A recent paper nicely demonstrated use of DMPU·HCl as a key additive, but in our case, DMF as solvent worked sufficiently well.16c The yield was further improved to >90% assay yield (AY) by activating the oxime formed in situ with acetic anhydride and base
Summary
Amination attempts with the biphasic conditions were unsuccessful, and we did not have access to the degree of engineering required for gaseous chloramine generation; use of solid aminating reagents such as O-(4Nitrobenzoyl)hydroxylamine provided a means to run reactions at 15−20 volumes, greatly increasing product throughput.[22] This reagent has been used at scale;14d neither aminating reagent is available at commodity levels, they are not atom economic, and there are safety concerns with use of these reagents at increasing temperatures and concentrations.[23] Complements to these existing strategies were the focal point of remaining efforts It is worth mentioning the safety hazards of monochloramine production. Effective cycle time for this operation can be achieved because MTBE is removed from reaction solution due to its low boiling point (55 °C), and because the amination of pyrrole is very rapid, occurring in less than 5 min This presents a reasonable path toward manufacturing, and 90% of solvent was recycled.
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