How is Remdesivir synthesised?
Dec 21,2023
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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