Early-Stage Flow Process Development of a Key Intermediate toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate

Abstract

The application of continuous processing can afford certain advantages during development and scale-up, such as enhanced risk mitigation of hazardous compounds and reducing both manufacturing cycle time and solvent waste through telescoping steps and avoiding intermediate isolations. While telescoping is not unique to flow, the operating windows enabled by the process intensification only possible in flow are notable, and they often possess the additional benefit of accessing chemistries not feasible in a batch. In this work, we highlight efforts to translate an early-stage batch route for the AXL-MER inhibitor oncology candidate PF-07265807 into a viable continuous flow process. The route to the key intermediate of interest features two S N Ar reactions, the latter utilizing aqueous hydrazine to enable an intramolecular cascade reaction, followed by a Boc deprotection. Efforts were made to assess and demonstrate the suitability of the process for telescoping steps in flow by finding a solvent/base system that maintained the solubility of all species and led to efficacious reactions. Additional studies were performed to reduce the concentration of aqueous hydrazine solution used as a feed in the continuous process to 5 wt % hydrazine, adding to the various safety advantages not amenable to a traditional batch process. Furthermore, an automated D-optimal design of experiment study was carried out for the aqueous hydrazine step to increase process understanding and screen effects during this early stage of development.