A 1-pot synthesis of the SARS-CoV-2 Mpro Inhibitor Nirmatrelvir, the key ingredient in Paxlovid

Caravez, Juan C.; Iyer, Karthik; Kavthe, Rahul D.; Kincaid, Joseph R. A.; Lipshutz, Bruce H.

doi:10.26434/chemrxiv-2022-xz3tv

Cited by 1 publication

(1 citation statement)

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“… This method was optimized for the large-scale production of 7 as an intermediate toward the HCV NS3 protease inhibitor, boceprevir ( 8 ), which features the same bicyclic proline residue as nirmatrelvir. Given the excellent accessibility of imine 3 , we decided to pursue the multicomponent assembly of nirmatrelvir by U-3CR (Scheme ) as a potentially greener alternative to the original route (as well as other, related routes , ) that rely heavily on peptide coupling of the respective protected amino acids (see Supporting Information (SI) Scheme S1 and Table S1 for a direct comparison of our route and the original route).…”

Section: Introductionmentioning

confidence: 99%

Multicomponent Synthesis of the SARS-CoV-2 Main Protease Inhibitor Nirmatrelvir

Preschel,

Otte,

Zhuo

et al. 2023

J. Org. Chem.

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In the wake of the Covid-19 pandemic, it has become clear that global access to efficacious antiviral drugs will be critical to combat future outbreaks of SARS-CoV-2 or related viruses. The orally available SARS-CoV-2 main protease inhibitor nirmatrelvir has proven an effective treatment option for Covid-19, especially in compromised patients. We report a new synthesis of nirmatrelvir featuring a highly enantioselective biocatalytic desymmetrization (>99% ee) and a highly diastereoselective multicomponent reaction (>25:1 dr) as the key steps. Our route avoids the use of transition metals and peptide coupling reagents, resulting in an overall highly efficient and atom-economic process.

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