Two sustainable routes to the synthesis of the antiviral drug nirmatrelvir, the key ingredient in Paxlovid, will be presented, featuring critical amide bond-forming steps that utilize new green technology that completely avoids traditional peptide coupling reagents, as well as epimerization of stereocenters. Likewise, dehydration of a primary amide intermediate to the corresponding nitrile is performed and avoids use of the Burgess reagent and chlorinated solvents. DFT calculations for various conformers of nirmatrelvir predict that two rotamers about the tertiary amide are present with an unusually high rotational barrier. Direct comparisons with the original procedures from Pfizer highlight both the anticipated decrease in cost and environmental footprint associated with these routes, potentially expanding the availability of this important drug worldwide.

In parallel, work that relies on the same thioester intermediates formed in situ has also been done that allows for reductions of carboxylic acids to aldehydes or alcohols, also effected under mild, green conditions. Thus, subsequent treatment with a commercially available and air-stable nickel pre-catalyst and a stoichiometric amount of silane affords aldehydes in moderate to good yields. Alternatively, conversion of acids via their thioester derivatives can be followed by reduction to the alcohol (in the same pot) upon treatment with sodium borohydride. A variety of starting materials ranging from highly functionalized acids to educts from the Merck Informer Library can be transformed using these green reaction conditions.

Juan Caravez

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