Toward Secure Supply of Remdesivir via a 2-Pot Triazine Synthesis: Supply Centered Synthesis

Dinesh J. Paymode^a, Flavio S. P. Cardoso^a, Joshua D. Sieber^a, John W. Tomlin^a, Daniel W. Cook^b, Justina Burns^b, Rodger W. Stringham^b, B. Frank Gupton^a, David Snead^a, Toolika Agrawal^a

• ^aChemical Development, Medicines for All Institute, 737 N. 5th St., Box 980100, Richmond VA, 23298-0100
• ^bAnalytical Development, Medicines for All Institute, 737 N. 5th St., Box 980100, Richmond VA, 23298-0100

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.

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