Advanced Real‐Time Process Analytics for Multistep Synthesis in Continuous Flow**

Abstract

In multistep continuous flowc hemistry,s tudying complex reaction mixtures in real time is as ignificant challenge,but provides an opportunity to enhance reaction understanding and control. We report the integration of four complementary process analytical technology tools (NMR, UV/Vis,IRand UHPLC) in the multistep synthesis of an active pharmaceutical ingredient, mesalazine.T his synthetic route exploits flow processing for nitration, high temperature hydrolysis and hydrogenation reactions,aswell as three inline separations.A dvanced data analysis models were developed (indirect hard modeling,deep learning and partial least squares regression), to quantify the desired products,intermediates and impurities in real time,a tm ultiple points along the synthetic pathway.T he capabilities of the system have been demonstrated by operating both steady state and dynamic experiments and represents as ignificant step forwardi nd ata-driven continuous flow synthesis.

Sampling and Analysis in Flow: The Keys to Smarter, More Controllable, and Sustainable Fine‐Chemical Manufacturing

“…The stream can be directed post‐IR analysis to a second analytical device for the evaluation of a second set of quality attributes (e.g. Raman or NMR spectroscopic analysis) [49, 50] …”

Harnessing autocatalytic reactions in polymerization and depolymerization

“…Within the last decade, reaction and chemical characterization processes in batch and flow reactors have been optimized using neural networks and automated workflows. Both, single [97] and multi-step [98] reactions, such as those involving nitration, hydrolysis, and hydrogenation have been optimized in flow reactors coupled with in situ chemical characterization via NMR, UV-VIS, and FTIR. Similar works on reactions following first-order kinetics have appeared and extension of such efforts to autocatalysis exhibiting deviations from first-order kinetics are expected in the near future.…”

Renewable dimethyl carbonate for tertiary amine quaternisation: kinetic measurements and process optimisation

“…Similar methods have been applied in other studies. 10,[32][33][34] The kinetic parameters and solvent effects will then be used in a computational model of the flow reactor. This model is employed to extrapolate and optimise the operating conditions to maximise the yield and productivity of the reactor.…”