Translation of a Chemical Reaction from Batch to Continuous Flow via Process Analytical Technology and Chemometrics

Abstract

Current continuous flow reactor (CFR) development and optimization primarily involves the investigation of process parameters such as flow and temperature to optimize a reaction. The advantages of CFRs for stable production - including improved heat transfer, reproducible results, safety and cost considerations, and others - generally result in comparable or improved yield compared to batch chemistry. However, the translation of a reaction from batch to continuous flow may be significantly improved following the thorough investigation of a batch reaction with analytical instrumentation. In this work, the Swern oxidation of S-1-phenylethanol is optimized for continuous flow production via the combination of information discovered in batch and continuous flow validation methods. A model chemistry is investigated with Raman spectroscopy and chemometric modeling in continuous flow, demonstrating the capability of real-time monitoring conversion in a CFR. The Swern oxidation is investigated in batch using Raman spectroscopy, high performance liquid chromatography (HPLC), and gas chromatography tandem mass spectrometry (GC-MS), yielding new information about intermediate kinetics, product formation, and side-product decomposition pathways. A technique for rapidly determining steady state in a CFR is described, using the Swern oxidation as a model chemistry. Finally, the Swern oxidation of S-1-phenylethanol is optimized in a CFR using real-time quantitative Raman monitoring and the mechanistic information uncovered in the batch investigation. This improved CFR development and optimization pathway - a thorough investigation of batch, coupled with optimization of a reaction through understanding of a chemistry - offers significant advantages over the current paradigm, and is applicable to most CFRs.