Synthesis of Nirmatrelvir: Development of a Scalable Cobalt-Catalyzed Cyclopropanation for Manufacture of the Bicyclic [3.1.0]Proline-Building Block
Russell F. Algera, Christophe Allais, Aaron F. Baldwin, Torsten Busch, Federica Colombo, Matteo Colombo, Christelle Depretz, Yves Dumond, Andres R. Faria Quintero, Marı́a Luisa Heredia, J. Jung, Amrita Lall, Taegyo Lee, Yizhou Liu, Stefano Mandelli, Marvin Mantel, Ronald Morris, Jason Mustakis, Bao N. Nguyen, Robert Pearson, Jared L. Piper, John A. Ragan, Brigitte Ruffin, Courtney Talicska, Sergei Tcyrulnikov, Christopher Uyeda, R. Matthew Weekly, M. Zeng
Abstract
Nirmatrelvir is a potent, selective, and orally bioavailable inhibitor of SARS-CoV-2 M pro . Herein, we report a scalable cyclopropanation to produce the bicyclic [3.1.0]proline derivative, which is one of the key starting materials for the synthesis of nirmatrelvir. To ensure a robust supply chain for this building block and meet the significant API demand, we needed to develop a synthetic process that was complementary to existing strategies. To achieve this goal, we used widely available and inexpensive raw material trans -(2 S,4 R )-4-hydroxy- l -proline as a starting material and implemented a recently reported cobalt-catalyzed gem -dimethylcyclopropanation at the manufacturing scale. Mechanistic studies led to the identification of potential catalyst decomposition pathways and provided insights into the key reaction parameters. This process was demonstrated to produce >200 kg of the bicyclic [3.1.0]proline derivative per batch and multi-metric ton quantities overall.