Synthesis of Non-Steroidal Anti-Inflammatory Drugs Pelubiprofen, Loxoprofen, and Carprofen Through Batch and Continuous-Flow Photo-Favorskii Rearrangement

Novel and efficient total syntheses of the nonsteroidal anti-inflammatory drugs Pelubiprofen and Loxoprofen via a photo-Favorskii rearrangement are reported herein. The key photochemical transformation was optimized under both batch and continuous-flow conditions using a suitably functionalized chloro-phenylpropan-1-one derivative, affording the target 2-arylpropionic acid in excellent yield. Implementation under continuous-flow conditions increased process productivity and enabled gram-scale operation. Aerobic oxidation of the benzylic position to the corresponding aldehyde, followed by Claisen–Schmidt condensation with cyclohexanone, afforded Pelubiprofen in 35% overall yield. Alternatively, condensation with cyclopentanone afforded the corresponding α,β-unsaturated enone intermediate, whose selective reduction under flow conditions enabled access to Loxoprofen in 28% overall yield. The versatility of the methodology was further demonstrated through the synthesis of Carprofen, highlighting the broader applicability of the photo-Favorskii rearrangement to the synthesis of APIs through previously unreported synthetic routes.