(583f) Considerations for Biocatalytic Oxidation Development of a Key Intermediate for a Drug Candidate

Biocatalytic oxidation reactions provide benefits in environmental sustainability compared to chemical routes through the simplicity of using water as a reaction solvent and oxygen as a reagent, as well as in enantioselectivity through enzyme specificity to increase product yield and purity. The use of a monoamine oxidase was considered for the synthesis route of a recent drug candidate. A previous process with a similar synthesis had utilized a system pressurized with pure oxygen¹, but due to safety concerns around the use of pure oxygen in a manufacturing setting, other options were explored. Air sparging was proposed as a mechanism for providing oxygen to the system, however, because the reaction involved small cyclic structures as the starting material and product, air sparging introduced concerns with potential volatility as a significant mass balance gap was observed in early experiments. To overcome the difficulty of detecting the product by UPLC due to lack of chromophores, process analytical technology (PAT) was implemented and utilized in experiments conducted to gain reaction understanding, and ultimately to propose and evaluate approaches to closing the mass balance gap. This helped support development of the reaction in a pressurized air system. Overall, this work provides recommendations on how to approach development of oxidation reactions with similar challenges in analytical detection or potential for volatility.

¹ Li, Tao, et al. “Efficient, Chemoenzymatic Process for Manufacture of the Boceprevir Bicyclic [3.1.0]Proline Intermediate Based on Amine Oxidase-Catalyzed Desymmetrization.” Journal of the American Chemical Society, vol. 134, no. 14, Mar. 2012, pp. 6467–72, doi:https://doi.org/10.1021/ja3010495.