Development of a Continuous Trickle-Flow Hydrogenation Process for Cbz Deprotection in Dipeptide Synthesis

Abstract The synthesis of enlicitide decanoate (MK-0616), a first-in-class oral PCSK9 inhibitor, requires efficient Cbz deprotection of a proline–threonine dipeptide intermediate, presenting safety and economic challenges for traditional batch hydrogenation. Here, we report the development of a continuous trickle-bed flow reactor with customized components that addresses these manufacturing constraints through systematic process optimization. This paper reports the development of a laboratory-scale trickle-bed flow reactor with customized components on a commercially available system along with catalyst characterization and continuous temperature mapping. The optimized process achieved complete conversion with 3.8% catalyst loading (24% reduction versus batch processing) and maintained a robust performance over extended operations. This comprehensive development establishes a scalable, safer alternative to batch hydrogenation while reducing precious-metal usage, providing a template for pharmaceutical flow chemistry applications requiring heterogeneous catalysis.