(725c) Transport-Kinetic Modeling of a Double N-Debenzylation in the Production of an Active Pharmaceutical Ingredient

Protection of heteroatoms by benzyl groups is a common and effective strategy in organic synthesis. Subsequent deprotection is commonly performed by catalytic hydrogenolysis. Published literature focuses primarily on O-debenzylations; however, N-debenzylations are also reported.¹ Whereas O-debenzylations are commonly reported to be fast, many reports of N-debenzylations show slower kinetics. This is attributed to the relative differences in bond polarity.² The system under investigation involves hydrogenolysis of an N,N-dibenzyl amine on a Pd/C catalyst.

During the synthesis of an intermediate compound, it was observed that the reaction completion time in lab-scale experiments and manufacturing was highly variable at nominally identical conditions. At nominally identical conditions, the reaction was sometimes observed to complete in a matter of hours, and sometimes as long as several days. To diagnose the issue, a thorough exploration and characterization of the reaction space was performed, and a process model was developed.

Since hydrogenation is a multiphase reaction, the initial process development efforts were focused on assessing the gas-liquid mass transfer across the scales. To better understand these effects, pressure-drop experiments were performed in multiple reactors across lab and manufacturing scales. The overall mass transfer coefficients were regressed based on the dynamics of the reactor headspace pressure decrease. To improve the correlation and mapping, CFD simulations were also performed to generate estimates of the mass transfer coefficients.

As direct measurement of hydrogen composition is nontrivial, we next aimed to improve our estimation of the hydrogen partial pressure and thermodynamic solubility. The NIST-modified UNIFAC activity coefficient model³ was employed to improve the calculation of the vapor pressure contributions from liquid-phase species. As there was also some uncertainty of the effects the reaction species may have on hydrogen solubility, we performed a comprehensive survey of the literature for published data. The compiled data spanned the key functional groups present in our system. Using this, molecular hydrogen was treated as a new group, and corresponding UNIFAC parameters were regressed.

An additional challenge presented itself after a substantial amount of kinetic data had been collected. In experiments where the reaction completed quickly, subsequent overreaction of the debenzylated product was frequently observed. Interestingly, these impurities were not observed to grow in experiments that were slower to complete, even when held for long after the completion of the reaction. A detailed reaction kinetic model is developed by taking into account the complex competitive adsorption and variation in molecular sizes based on extended LeVan-Vermeulen adsorption isotherms⁴. A combination of kinetic model, CFD simulations, and mass transfer analysis were used to assess the sensitivity of reaction time across lab and manufacturing scales and to provide a robust scale up strategy.

References

1. David, A., & Vannice, M. (2006). Control of catalytic debenzylation and dehalogenation reactions during liquid-phase reduction by H2. Journal of Catalysis, 237(2), 349–358. https://doi.org/10.1016/j.jcat.2005.11.017
2. Smith, G. V., & Notheisz, F. (1999). Chapter 4 - Hydrogenolysis. In Heterogeneous Catalysis in Organic Chemistry (pp. 119–218). Academic Press.
3. Kang, J. W., Diky, V., & Frenkel, M. (2015). New modified UNIFAC parameters using critically evaluated phase equilibrium data. Fluid Phase Equilibria, 388, 128–141. https://doi.org/10.1016/j.fluid.2014.12.042
4. Frey, D. D., & Rodrigues, A. E. (1994). Explicit calculation of multicomponent equilibria for ideal adsorbed solutions. AIChE Journal, 40(1), 182–186. https://doi.org/10.1002/aic.690400121