Challenges in the Synthesis of Remdesivir

Remdesivir is one of the most widely used drugs againstcoronavirus disease 2019 (COVID-19). This compound issynthesized by Gilead Sciences Company and sold underthe brand called Veklury (1). In addition, remdesivir isa prodrug that acts as a ribonucleotide inhibitor of viralRNA polymerase. It releases GS-441524 monophosphatenucleoside into the cell and then converts it to atriphosphate derivative. GS-441524 triphosphate is a viralRNA-dependent RNA-polymerase (RdRp) inhibitor (2).Considering the helpful performance of this drugagainst Ebola, more than 50 countries have used this drugagainst COVID-19 (3).Siegel et al reported a well-known method for thesynthesis of remdesivir (4). This editorial will survey thechallenges and problems of this method in the chemistrylaboratory.The main challenge of this method is its many syntheticsteps. Given that each step requires separation andpurification of the product, the high number of syntheticsteps reduces the product yields, and it is also a timeconsumingprocess.The first challenge starts from the first step, wherecompound 1 must react with phenyl dichlorophosphateat -78 °C. The reaction at this temperature is uneasy. Theobtained product from this step is a racemic mixture thatmay be separated by diastereoselective crystallization.This separation reduces 50% of the product.