Synthesis of Nirmatrelvir: Development of a Scalable Cobalt-Catalyzed Cyclopropanation for Manufacture of the Bicyclic [3.1.0]Proline-Building Block

Nirmatrelvir is a potent, selective, and orally bioavailable inhibitor of SARS-CoV-2 Mpro. 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-(2S,4R)-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.