Two-Step Continuous\nSynthesis of Cabozantinib in a\nMicroreactor: Mechanism and Kinetics Research of EDCI/HOBt-Mediated\nAmidation

Cabozantinib (<b>CBT</b>) is a small-molecule pharmaceutical\napproved for the treatment of medullary thyroid cancer, advanced renal\ncell carcinoma, and hepatocellular carcinoma. The two-step amidation\nstarting with 1,1-cyclopropanedicarboxylic acid (<b>CBT-1</b>) is a large-scale synthetic route for <b>CBT</b>, but the\nexisting processes suffered from highly toxic reagents, low yields,\nand long reaction times. In this work, a two-step cascaded flow process\nwas developed to synthesize <b>CBT</b> in a microreactor. In\nthe first amidation step, CDI was determined as the coupling reagent\nto generate 1-(4-fluorophenylaminoformyl) cyclopropane carboxylic\nacid (<b>CBT-3</b>) with a yield of 97.5% after optimizing the\noperating conditions. Then, EDCI/HOBt were screened as the coupling\nreagents to obtain <b>CBT</b> in the second amidation step,\nand the possible reaction paths and intrinsic kinetics were revealed\nin the microreactor. The result indicated that the formation of ion\npairs between <b>CBT-3</b> and EDCI was the rate-determining\nstep in the whole reaction process. In the end, the two amidation\nreactions were cascaded in a microreactor, and <b>CBT</b> was\nsynthesized with a total reaction yield of 96.1% in 35 min. The scale-up\nof the developed microchemical system showed that the productivity\nof <b>CBT</b> can achieve about 5.3 g/h. Compared with the existing\nprocesses, milder reagents/conditions were used, and the innovative\napproach of continuous synthesis can provide an efficient and alternative\nmethod for the production of <b>CBT</b>.