Scaling the Process Chemistry of a COVID-19 Antiviral Pharmaceutical Down for a Multi-Step Synthesis Experiment in the Undergraduate Teaching Laboratory

Molnupiravir is an orally bioavailable direct acting antiviral agent that received emergency use authorization in late 2021 from the FDA for the treatment of patients with mild, moderate, or severe COVID-19. This prodrug is metabolized into a ribonucleoside that that is incorporated into the viral RNA during replication. Its tautomerization between cytidine- and uridine-like forms ultimately causes multiple irreversible errors in the genetic code of the virus, which prevents successful viral replication. There are multiple process chemistry routes for molnupiravir synthesis published in the literature that attempt to maximize synthetic yield while minimizing cost and waste. In this way, the goals of a successful process scale route are similar to those of an implementable educational laboratory experiment for the teaching laboratory. We have developed a multi-week laboratory module for undergraduate students in which students conduct a multi-step synthesis of molnupiravir. Specifically, our Organic Chemistry II Laboratory course section comprised chemistry and biochemistry majors performed the final two steps of molnupiravir synthesis using procedures derived directly from the published process chemistry literature. We utilized this opportunity to introduce students to reading and interpreting these primary experimental sources. Students obtained authentic characterization data via high pressure liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) spectroscopy to assess the conversion and purity of their products at each synthetic step. The relevance of this laboratory experience to the pandemic, which has had a direct effect on their daily lives, motivates the students to a high level of engagement with this experimental module. We report our in-lab activities and student generated data as well as suggestions for how this laboratory experiment could be tailored to meet similar learning objectives in other courses, such as medicinal chemistry or capstone laboratory courses, and as a function of available instrumentation.