Solid Acid-Enabled N -Boc Deprotection and Acetal Hydrolysis in the Synthesis of Vepdegestrant

Two steps in the batch synthesis of Vepdegestrant, namely, N-Boc deprotection and acetal hydrolysis, utilize homogeneous acids as catalysts. In order to streamline these processes, various types of common commercially available heterogeneous solid acids have been evaluated to develop a packed bed reactor (PBR)-enabled flow process. Zeolite H-BEA and amorphous silica–alumina Siral 40 have been shown to facilitate the N-Boc deprotection at 150 °C, a temperature lower than that for thermolytic de-Boc (200 °C). For acetal hydrolysis, only Brønsted acids catalyze the reaction at 100 °C. Brønsted acid site (BAS) quantification by n-propylamine temperature-programmed desorption (TPD) indicates that reactivity toward acetal hydrolysis has a strong dependence on the acid strength rather than the total acid site density. Tungstated zirconia (WZ) demonstrates the optimal reactivity without forming other impurities despite having the lowest density of BASs compared with other solid acid catalysts. The presence of surface polytungstate WOx has contributed to the different reactivity in WZ catalysts. Higher reactivity is observed on WZ catalysts with lower surface W concentration, 4.8 W atoms/nm2 (WZ-Powder), where polytungstate WOx are the primary surface species, in contrast to 6.9 W atoms/nm2 (WZ-0.7 mm), on which bulk WO3 dominates. Flow evaluation in a PBR over granular WZ-0.7 mm has achieved steady-state operation at full conversion for 140 min at 120 °C with a theoretical mean residence time of 8.4 min. Compared to the batch process, the continuous flow process intensified step unit operations by minimizing the requirement for workups, reducing the step PMI from 33 to 17.