How is Remdesivir synthesised?

Synthesis of Remdesivir

Remdesivir is synthesised using ribonolactone as a raw material through reactions in the presence of a pre-drug coupling partner (P-Stereogenic Prodrug Coupling Partner). The specific synthesis steps are as follows:

Step 1: Preparation of Remdesivir P-Stereogenic Prodrug Coupling Partner

To prepare the P-stereogenic prodrug coupling partner (49), 2-ethylbutyl-L-alanine (47) was subjected to phenyl phosphoryldichloridate (OP- (OPh)Cl2) and 4-nitrophenol to yield a diastereomeric mixture of phosphoramidates 48. Diisopropyl ether induced recrystallization and enabled selective isolation of the (S)-P isomer 49 in 39%yield.

Step 2: Preparation of Remdesivir

With the prodrug coupling partner in hand, the nucleoside core was synthesized. Facile metal−halogen exchange of iodide 51 and the addition to ribolactone 50 yielded glycosylation product 52 in 40% yield. Nitrile 53 was then afforded in 85% yield in a >95:5 anomeric ratio after exposure of 52 to TMSCN at cryogenic temperatures. The authors report that triflic acid in this reaction was critical to establishing the high selectivity favoring the desired β-anomer 53. Lewis acid-mediated global benzyl deprotection provided 54 after crystallization in 86% yield. Subsequently, the 2′,3′- hydroxyl moieties of 54 underwent acetonide protection with 2,2-dimethoxypropane to afford 55. The authors report acetonide protection was crucial to the yield of the following coupling reaction; direct coupling of the unprotected nucleoside 54 with prodrug precursor 49 provided 56 in 40% yield, while coupling of protected nucleoside 55 with prodrug precursor 49 afforded 56 in 70% yield. Lastly, acid-mediated deprotection of acetonide 56 generated the prodrug remdesivir in 69% yield.

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