From Waste to Medicine: Flow Engineering for Lignocellulosic-Based API Synthesis

Abstract

The growing demand for active pharmaceutical ingredients (APIs) continues to reinforce global dependence on fossil-derived feedstocks and energy-intensive batch manufacturing, contributing to greenhouse gas emissions and unsustainable carbon flows. In response to climate targets and circular bioeconomy principles, this doctoral thesis develops continuous flow chemistry strategies for converting waste lignocellulosic biomass (LCB) into high-value chemicals and essential medicines. Locally sourced corncob and rice husk collected from agricultural sites in Kazakhstan were employed as renewable feedstocks. A controlled formic acid pretreatment enabled selective extraction of hemicellulosic sugars, which were subsequently converted into furfural (FF) in a continuous flow millireactor using a ZnCl2/NaCl catalytic system in an IPA:H2O solvent mixture. Under optimized conditions (170 °C, 10 min residence time), FF yields reached 44% from corncob and 27% from rice husk, demonstrating efficient valorization of locally available biomass resources. Building upon biomass-derived FF, an integrated multistep continuous-flow route was developed for the synthesis of prazosin. The sequence comprised oxidation of FF to 2-furoic acid (90% yield, 99% conversion under optimal flow conditions), amide coupling to form 1-(2-furoyl)piperazine (71% yield), regioselective amination of the quinazoline intermediate (70% yield), and final C–N bond formation under intensified flow conditions. Optimization of solvent composition, temperature, and residence time enabled prazosin formation in a THF:MeOH system with an isolated yield of 82%, significantly shortening reaction time while maintaining high selectivity and operational stability. In parallel, continuous-flow synthesis of furosemide from 2,4-dichloro-5-sulfamoylbenzoic acid and furfurylamine was systematically optimized. Solvent screening identified THF as the most suitable medium for flow operation, avoiding precipitation and ensuring stable flow. At 180 °C and 30 min residence time with 3 equivalents of furfurylamine, the system achieved a maximum isolated yield of 79% with 87–93% substrate conversion. These results demonstrate improved selectivity and controlled thermal management relative to conventional batch methodologies. Computational investigations using density functional theory (DFT) provided mechanistic insight into key bond-forming steps, rationalizing observed reactivity trends and supporting experimental optimization. Preliminary sustainability evaluation further suggests that coupling renewable feedstocks with continuous manufacturing reduces solvent inventory, enhances energy efficiency, and improves overall process safety.