Otimização das rotas sintéticas do molnupiravir e de intermediários do remdesivir no contexto da farmacoterapia anti-Covid-19

Abstract

The Covid-19 viral infection pandemic represented one of the greatest health challenges ever recorded, whose impacts extended beyond the sphere of public health and triggered a global socioeconomic recession. Although population-wide vaccination helped contain the spread of the disease, factors such as the persistence of vulnerable individuals and the risk of emerging variants of SARS-CoV-2, its etiological agent, underscored the need for safe, accessible, and readily available pharmacotherapies to complement immunization strategies. To this end, given the high costs and long timelines associated with developing new bioactive molecules, investigating the clinical efficacy of existing drugs emerged as a viable alternative, culminating in the approval of the antivirals molnupiravir and remdesivir for the emergency treatment of Covid-19 in several countries, including Brazil. In this context, the present work aimed to optimize the synthetic routes to key intermediates of molnupiravir and remdesivir to improve the production of these drugs. We synthesized molnupiravir in 68% overall yield and >99% purity through two reactions (protection + esterification; functionalization + deprotection) starting from uridine. Beginning with 1H-pyrrole, we also obtained pyrrolo[2,1-f][1,2,4]triazin4-amine, the N-heteroaromatic core present in the structure of remdesivir, in 85% overall yield and 98% purity through three reactions (formylation + cyanation, N-amination, and cyclization). We further established alternative strategies to selectively functionalize the C-7 position of this N-heterocycle and improved its coupling to D-ribose in the C-glycosylation step, obtaining a key intermediate in the remdesivir synthetic route in 66% overall yield. Taken together, these results represent strategic contributions toward synthesizing intermediates of molnupiravir and remdesivir in a more efficient, practical, and economical manner.