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

Peter Sagmeister, René Lebl, Ismael Castillo, Jakob Rehrl, Julia Kruisz, Martin Sipek, Martin Horn, Stephan Sacher, David Cantillo, Jason D. Williams*, C. Oliver Kappe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


In multistep continuous flow chemistry, studying complex reaction mixtures in real time is a significant 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, IR and UHPLC) in the multistep synthesis of an active pharmaceutical ingredient, mesalazine. This synthetic route exploits flow processing for nitration, high temperature hydrolysis and hydrogenation reactions, as well as three inline separations. Advanced 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, at multiple points along the synthetic pathway. The capabilities of the system have been demonstrated by operating both steady state and dynamic experiments and represents a significant step forward in data-driven continuous flow synthesis.

Original languageEnglish
Pages (from-to)8139-8148
Number of pages10
JournalAngewandte Chemie - International Edition
Issue number15
Publication statusPublished - 6 Apr 2021


  • flow chemistry
  • multistep synthesis
  • process analytical technologies
  • process control
  • real-time analysis

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry


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