McIntosh JA,
*,
Fier PS.
*
et al.
Merck & Co., Inc., Rahway, USA
Engineered Ribosyl-1-Kinase Enables Concise Synthesis of Molnupiravir, an Antiviral
for COVID-19.
ACS Cent. Sci. 2021;
7: 1980-1985
DOI:
10.1021/acscentsci.1c00608
Key words
molnupiravir - nucleic acids - COVID-19 - enzyme cascade - hexamethyldisilazane -
dehydration
Significance
Molnupiravir (MK-4482) is an orally available antiviral agent that reduces the risk
of hospitalization or death from COVID-19 by 30% compared with placebo. The highly
innovative enzymatic cascade that converts C to E comprises pyruvate oxidase and acetate kinase for ATP regeneration, MTR kinase (engineered)
for the phosphorylation of C, uridine phosphorylase (engineered) for uracil incorporation, and catalase to decompose
hydrogen peroxide formed by pyruvate oxidase. This cascade can be run at high concentrations
(>80 g/L) of C, forms the product in quantitative yield, and allows for easy isolation of crystalline
E in >99.5 wt% purity.
Comment
The conversion of E to molnupiravir occurs in nearly quantitative yield in neat HMDS. The initial product
of the reaction is the bis-TMS derivative (not shown) that allowed easy removal of
inorganic salts and byproducts via aqueous washes. Molnupiravir itself is highly water-soluble,
and the removal of inorganic salts would be difficult without transient masking of
the alcohols as TMS ethers. The TMS groups were easily cleaved by adjusting the pH, after which the product crystallized. The synthesis depicted was accomplished in
three steps and 69% overall yield from commodity chemicals.
