Safety-Enhanced Multistep Flow Synthesis of Oxolinic Acid with Process Intensification

Safety is paramount in pharmaceutical synthesis. Multistep flow synthesis enhances safety by exploiting microscale channels for precise control and enabling in-situ generation and consumption of reactive intermediates, minimizing hazards from isolation and exposure. Challenges such as reactor clogging and step-to-step incompatibility can be addressed by combining molecular reactivity modulation with advanced flow engineering, creating safer, efficient, and generalizable manufacturing platforms. Here, oxolinic acid, a target involving strong acids, high temperatures, flammable gases, and exothermic reactions, was synthesized via a continuous flow strategy. Ultrasonication was applied to disperse solid particles and prevent agglomeration in tubing, enabling kilogram-per-day water-based nitration. A micro packed-bed reactor reduced hydrogen-handling risks while telescoping nitro reduction and reductive amination. A solvent-free approach facilitated the coupling–cyclization–hydrolysis sequence, improving step compatibility and reducing hazards. Overall, a six-step continuous synthesis of oxolinic acid was achieved without intermediate purification with 65% yield, demonstrating a synergistic improvement in safety, efficiency, and green chemistry.