Scalable and Integrated Four-step Continuous-Flow Synthesis of Ibuprofen Using a Zinc-Catalyzed 1,2-Aryl Migration Strategy

Ibuprofen is an essential nonsteroidal anti-inflammatory drug (NSAID) which is still inaccessible to more than 100 million patients worldwide. Although three elegant continuous-flow approaches toward this NSAID have been developed, the major defect of requiring the use of a stoichiometric amount of highly toxic, corrosive, and expensive oxidizing reagents (such as di(acetoxy)phenyl iodide (PhI(OAc)2) and iodine monochloride (ICl)) prevents their application in industrial manufacturing. Herein, a novel and catalytic synthesis of ibuprofen from commercially available isobutylbenzene is performed by a linear continuous-flow sequence involving four chemical transformations without conducting solvent exchanges or intermediate purifications. This newly developed proof-of-principle regime provided access to ibuprofen in a global yield of 80.6% with an average of 94.7% for each step in a total reaction time of 32.5 min, corresponding to a throughput of 15.22 g/h.