Development of Continuous Flow Processes to Access Pyrrolo[2,1-f][1,2,4]triazin-4-amine: An RSM for the Synthesis of Antiviral Drugs

• Maksim Vasilev^a, Aravind S. Gangu^a, Praveen Gajula^a, Nathaniel D. Kaetzel^a, Vasudevan Natarajan^a, Bimbisar Desai^a, Gopal Sirasani^a, Bo Qu^a, and Chris H. Senanayake^a

• ^aTCG GreenChem, Inc., 701 Charles Ewing Boulevard, Ewing, New Jersey 08628, United States

Pyrrolo[2,1-f][1,2,4]triazines are important scaffolds in a number of active pharmaceutical ingredients with a broad range of biological activities to treat broad-spectrum viral infections. We recently reported the synthesis at the kilogram scale in batch mode with extensive process safety studies, where NaH was applied as the base to deprotonate 2-cyanopyrrole, and then in situ prepared monochloramine solution was utilized for the N-amination, followed by cyclization with formamidine acetate to produce the required pyrrolo[2,1-f][1,2,4]triazine (1) as the regulatory starting material for the antiviral drug Remdesivir. To meet the market demand of Remdesivir for the treatment of the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a high-throughput process is required to supply this key starting material on a large scale in a timely manner. In this Article, we report the second-generation synthesis of pyrrolo[2,1-f][1,2,4]triazine 1 by employing continuous flow chemistry tools. The amination step was adapted to continuous flow by applying in situ monochloramine synthesis and utilizing a process-friendly soluble base KOt-Bu. The new multistage continuous flow approaches, including both chemical steps, extractions and separations, afford a viable process to access this widely employed key starting material 1 for the synthesis of Remdesivir.

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