Continuous Multiphase Flow Nitration and Cryogenic Flow Formylation: Enabling Process Development and Manufacturing of Pharmaceutical Intermediates

Manufacturing API and pharmaceutical intermediates requires the development of scalable, safe, and environmentally friendly processes. Reactions with high exothermicity or otherwise hazardous in nature, as well as reactions involving the formation of unstable intermediates, can benefit from continuous processing. This technology has been broadly adopted across the pharmaceutical industry due to its intrinsic ability to operate at low reaction volumes, facilitate improved temperature control, and safely accommodate higher pressures. Two such industrially relevant examples are aromatic nitration and regioselective aryl ring metalation, followed by trapping with an electrophile. Both reaction classes commonly face scale-up challenges when performed in batch processing. The nitration reaction usually features a multiphase, mixing-sensitive reaction associated with a large exotherm that can lead to the formation of potentially hazardous overnitrated byproducts. Similarly, metalation reactions of aryl rings often require cryogenic conditions, which are challenging to achieve on scale. In this study, a mixing-limited solid–liquid–liquid (S–L–L) nitration reaction was evaluated to understand the transport phenomena. The determination of the Hatta number and impact of the impeller power on the kinetics enabled the design of a safe, scalable, high-yielding, and robust continuous stirred tank (CSTR) flow process. A study of critical formylation reaction parameters led to a first-generation tubular flow reactor design to process >10 kg of a substrate in the pilot plant. A more practical CSTR reactor system in series was developed to support a resupply delivery. This reactor configuration enabled superior temperature control, alleviated the risks associated with salt formation, and increased the throughput and yield.