Carmofur, a prodrug derivative of 5-fluorouracil (5-FU), is an inhibitor of acid ceramidase and initially developed as an antineoplastic agent against colorectal cancer. Recently through drug repurposing efforts, it has also been identified as a covalent inhibitor of the SARS-CoV-2 main protease (Mpro), making it a promising compound to optimize as a potent antiviral to combat COVID-19. One method of synthesizing carmofur is by treating 5-FU with n-hexyl isocyanate in pyridine. In industry, isocyanates are of interest as they are highly reactive towards alcohols to form polyurethanes. The behavior of isocyanates is highly debated beyond alcoholysis, especially when determining solvent and catalysis kinetic effects when treated in combination with other nucleophiles such as water and amines. We aim to probe the mechanism of isocyanates with varying alkyl and aryl group substituents reacting with 5-FU in order to propose a synthetic workflow to develop more effective carbomylated derivatives. However, due to the insolubility of 5-FU and its related compounds, its synthesis is unamenable being tracked by conventional methods such as thin-layer chromatography or mass spectroscopy. Serendipitously, carmofur’s 5-FU head serves as a spectroscopic handle for benchtop 19F nuclear magnetic resonance spectroscopy (NMR). Recent advances in benchtop NMR has facilitated real-time monitoring, characterization, and quantification of chemical entities without the use of financially prohibitive deuterated solvents, and provides the opportunity to rapidly and quantitatively optimize reaction conditions that conventional reaction tracking methods cannot produce. Here, we implement benchtop 19F NMR as a practical analytical tool to track the reaction kinetics of 5-FU with various isocyanates, optimize reaction conditions, and determine mechanistic differences in the reactivity of alkyl and aryl isocyanates.

Benchtop 19F nuclear magnetic resonance spectroscopy enabled kinetic monitoring and mechanistic studies of the synthesis of carmofur and related 5-fluorouracil analogs

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