Scalable and Sustainable Synthesis of Calcium Dobesilate via Integrated Five-Step Continuous-Flow Chemistry

Calcium dobesilate is a widely prescribed veno-tonic drug in over 60 countries for treating chronic venous disease, diabetic retinopathy, and hemorrhoidal attack symptoms. Although two batchwise manufacturing routes to this treatment have been developed, the drawbacks, such as poor regioselectivity, chemical waste emission, and extensive utilization of organic solvents, still pose challenges for organic chemists regarding advancements in its eco-friendly synthesis. Herein, we present an integrated continuous-flow synthesis of calcium dobesilate from commercially available p-chloronitrobenzene by performing four reaction steps in the water-based, closed-loop recycling of aqueous sulfuric acid to address the environmental concerns of massive waste aqueous acid. In a customized integrated flow platform, calcium dobesilate is obtained in 81% isolated yield with an average value exceeding 95% for each step in a total residence time of 18 min without intermediate purification or reaction solvent switching, corresponding to a productivity of 15.69 g/h (376.56 g/day). Green metrics have been evaluated, and at least seven of the 12 principles of green chemistry, as defined by the American Chemical Society, are implemented in this newly developed continuous-flow regime.