(584d) Use of Reaction Modeling and on-Line Liquid Chromatography at Pilot Plant Scale to Obtain Mechanistic Insights

Welireg (Belzutifan) is prescribed for the treatment of adult patients with certain types of von Hippel Lindau (VHL) disease-associated tumors. The penultimate step in the synthesis process involves a deoxyfluorination reaction. Detailed reaction engineering studies were performed across scales to better understand the reaction behavior and meet the active pharmaceutical ingredient (API) step’s quality requirements. The method used was to generate a scale independent process fingerprint and couple it with targeted experiments to gain mechanistic insights about the reaction.

In this work, we employ custom fabricated on-line liquid chromatography to map reaction conversion. Samples were collected every 30 minutes during reaction operations, diluted to appropriate concentrations for the analytical method, and injected for analysis of chemical composition. This technology was integrated in the pilot plant production environment and used to monitor the conversion and purity profile for the deoxyfluorination reaction at ~15 kg assay basis. By tracking addition of the fluorinating reagent, its exothermic impact on the batch contents, and the reaction conversion profile in real time, we were able to build a kinetic model in Dynochem. The model from this pilot plant trial was combined with laboratory data to obtain a mechanistic understanding of both the deoxyfluorination reaction and the impurity accumulation from competing reactions. These results guided our subsequent reaction engineering strategies to ensure process robustness leading into the API step. We hope this methodology can be used to study similar reactions at scale.