Development and Optimization of a Scalable Enzymatic Cascade-Carbamate Formation Telescope Process for the Synthesis of CDK2 Selective Candidate Tegtociclib (PF-07104091)

PF-07104091 (tegtociclib) is a cyclin-dependent kinase 2 (CDK2) selective inhibitor under investigation as an oncology treatment with breast cancer as the leading indication. In this report, we detail the development and optimization of a selective enzyme cascade-carbamate formation telescoped sequence for the synthesis of PF-07104091. The newly developed process enables exquisite stereochemical control and efficient processing, affording crude active pharmaceutical ingredient (API) in good yield and high purity while demonstrating reduced process mass intensity (PMI) and cycle time. This optimized highly efficient and sustainable process was demonstrated during pilot plant scale production of >450 kg of PF-07104091.