Optimized continuous flow Vorbrüggen coupling for synthesis of environmentally improved fluoroquinolones

To address the environmental persistence of fluoroquinolone antibiotics and their contribution to antimicrobial resistance, new benign-by-design fluoroquinolone derivatives, incorporating cleavable linkers, have been developed to enable degradation into products with reduced antimicrobial activity. The synthesis of these compounds, however, is limited by a key Vorbrüggen C–N coupling step that shows poor reproducibility, limited scalability, and safety concerns under conventional batch conditions employing stoichiometric amounts of SnCl₄. Herein, we report the development of a continuous-flow Vorbrüggen C–N coupling within the Cip-hemi synthesis platform. Screening of alternative Lewis acids identified Cu(OTf)₂ as an effective catalyst, providing high conversions under catalytic conditions. Process optimisation revealed that temperature, residence time, tube diameter and especially reaction concentration were critical to suppress precipitation-induced reactor clogging. The residence time could be reduced to 1 min without loss of performance and the reaction was successfully translated to 5 g scale, achieving a space–time yield of up to 1498 g L⁻¹ h⁻¹. This work demonstrates that continuous-flow processing provides a robust and more readily scalable solution to a critical transformation in the synthesis of environmentally improved fluoroquinolone derivatives.

Equipment used in this paper: SF-10 Laboratory Pump

• Raeymackers N
• Coquyt J
• Heugebaert T
• Stevens C

•   Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Campus Coupure, Coupure Links 653, 9000 Ghent, Belgium

• Request a Brochure
• Request more Info
• Request a Quote