Table 1 Comparisons between this work and Pfizer’s route15 to nirmatrelvir (1).

From: A sustainable synthesis of the SARS-CoV-2 Mpro inhibitor nirmatrelvir, the active ingredient in Paxlovid

Reaction parameter

Pfizer

This work

Amide bond formations

Uses HATU, EDCI, non-recyclable solvents: DMF, MEK

Uses DPDTC, recyclable solvent: EtOAc

Amide dehydration

Burgess reagent, solvent: CH2CI2

cat. Pd, FCH2CN, medium: H2O/CH3CN

N-Boc deprotection

Solvent: CH2CI2

Solvents: CH3CN, dioxane

E Factor (all waste)

214

120a

E Factor (excluding aq. waste)

108

54a

Overall yield

48%

70%

  1. aArtificially elevated due to scale; the actual E Factor of this sequence would likely be much lower on scale, as dilution of the reaction medium would not be necessary. Also the academic scale at which this route was developed necessitated dilution of the reaction medium with EtOAc prior to aqueous extraction. This accounts for the EtOAc being concentrated following aqueous washes, and then being freshly added to bring the concentration to the desired level for use in the following step. Such handling would not be involved on scale up.
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