Four-Step Continuous-Flow Total Synthesis of 4-Chloro-6,7-dimethoxyquinoline, a Key Intermediate for Tyrosine Kinase Inhibitors

Tivozanib and cabozantinib are important oral tyrosine kinase inhibitors for the clinical treatment of advanced renal cell carcinoma. In this study, 4-chloro-6,7-dimethoxyquinoline, a common intermediate for two drug syntheses, was designed to be prepared from readily available 1,2-dimethoxybenzene through a sequence of Friedel–Crafts acylation, nitration, hydrogenation, and chlorination. Furthermore, the fully continuous-flow technology was applied to optimize the process and reduce safety risks, achieving the four-step “end-to-end” reaction by concatenating the synthesis, quenching, and phase-separation steps. In the nitration step, the byproduct of 3,4-dimethoxynitrobenzene could isolate by recrystallization. A kinetic model for the nitration reaction was established, indicating that >99% conversion could be achieved at 30 °C with a residence time of 6 min. In the chlorination step, triphosgene (BTC) was used in place of conventional chlorinating reagents (POCl 3, (COCl) 2 ), enabling one-step synthesis of 4-chloro-6,7-dimethoxyquinoline in 73% isolated yield with 99% HPLC purity. Compared with the batch process, the fully continuous-flow synthesis of 4-chloro-6,7-dimethoxyquinoline shortened the total reaction time from 480 to 70 min, increased the overall yield from 46.6% to 53.7%, and reduced PMI by 26%.