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.
The coupling of a modular microreactor platform, real-time inline analysis by IR and NMR, and online UPLC, leads to efficient optimization of a multistep organolithium transformation to a given product without the need for human intervention.
Autonomous flow reactors are becoming increasingly utilized in the synthesis of organic compounds, yet the complexity of the chemical reactions and analytical methods remains limited. The development of a modular platform which uses rapid flow NMR and FTIR measurements, combined with chemometric modeling, is presented for efficient and timely analysis of reaction outcomes. This platform is tested with a four variable single-step reaction (nucleophilic aromatic substitution), to determine the most effective optimization methodology. The self-optimization approach with minimal background knowledge proves to provide the optimal reaction parameters within the shortest operational time. The chosen approach is then applied to a seven variable two-step optimization problem (imine formation and cyclization), for the synthesis of the active pharmaceutical ingredient edaravone. Despite the exponentially increased complexity of this optimization problem, the platform achieves excellent results in a relatively small number of iterations, leading to >95% solution yield of the intermediate and up to 5.42 kg L −1 h −1 space-time yield for this pharmaceutically relevant product.
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