Two-Step Continuous Synthesis of Cabozantinib in a Microreactor: Mechanism and Kinetics Research of EDCI/HOBt-Mediated Amidation

Cabozantinib (CBT) is a small-molecule pharmaceutical approved for the treatment of medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma. The two-step amidation starting with 1,1-cyclopropanedicarboxylic acid (CBT-1) is a large-scale synthetic route for CBT, but the existing processes suffered from highly toxic reagents, low yields, and long reaction times. In this work, a two-step cascaded flow process was developed to synthesize CBT in a microreactor. In the first amidation step, CDI was determined as the coupling reagent to generate 1-(4-fluorophenylaminoformyl) cyclopropane carboxylic acid (CBT-3) with a yield of 97.5% after optimizing the operating conditions. Then, EDCI/HOBt were screened as the coupling reagents to obtain CBT in the second amidation step, and the possible reaction paths and intrinsic kinetics were revealed in the microreactor. The result indicated that the formation of ion pairs between CBT-3 and EDCI was the rate-determining step in the whole reaction process. In the end, the two amidation reactions were cascaded in a microreactor, and CBT was synthesized with a total reaction yield of 96.1% in 35 min. The scale-up of the developed microchemical system showed that the productivity of CBT can achieve about 5.3 g/h. Compared with the existing processes, milder reagents/conditions were used, and the innovative approach of continuous synthesis can provide an efficient and alternative method for the production of CBT.