(18c) Hydrogenation Process Scale up from Lab to Manufacturing

Protection of heteroatoms by certain protecting groups is a common and effective strategy in organic synthesis. Subsequent deprotection is often performed by catalytic hydrogenolysis. The hydrogenation processes involve complex multiphase and multiscale phenomena related to both heat and mass transfer. The system under investigation involves the hydrogenolysis of protected amine-containing molecules on a common catalyst, where the dissolved hydrogen in the reaction medium is kLa-dependent—a phenomenon influenced by the scale of the equipment.

During the synthesis of the target compound, significant variability in reaction completion time was observed between lab-scale experiments and manufacturing under nominally identical conditions. To diagnose and resolve this variability, a comprehensive exploration and characterization of the reaction parameter space was conducted, and a process model was developed.

Given the multiphase nature of hydrogenation, initial development efforts focused on assessing gas-liquid mass transfer across various scales. Pressure-drop experiments were conducted in multiple reactors, ranging from laboratory to manufacturing scales. The overall mass transfer coefficients were determined by analyzing the dynamics of reactor headspace pressure reduction. To refine these correlations and facilitate accurate scale-up predictions, computational fluid dynamics (CFD) simulations were performed to estimate the mass transfer coefficients.

Integrating kinetic modeling, CFD simulations, and mass transfer analyses allowed for evaluating the sensitivity of reaction time variations across laboratory and manufacturing scales. This integrated approach provided a robust scale-up strategy validated through CFD simulations, enabling reliable scaling from laboratory to pilot and multiple manufacturing-scale reactors.