A Continuous Manufacturing Line Generating Organozinc Species in Flow: Enhancing the Simmons-Smith Reaction Including Post-Reaction Processing

The cyclopropyl fragment is paramount in the pharmaceutical industry, as a wide range of active pharmaceutical ingredients inhere this versatile molecular structure. Recently, even higher importance has been attributed to the cyclopropane ring since many transition drug candidates utilize this carbon–carbon arrangement’s beneficial features. A reliable way to produce cyclopropanes is via the Simmons-Smith reaction, which utilizes a zinc–copper couple to transfer the methylene group of a dihalomethane to the double bond of a target molecule. The whole process involves a quenching and filtration step and is usually completed by a time-consuming extraction of metal salts and other impurities. This work presents a reliable and reproducible method to perform all unit operations continuously. It includes the synthesis step in a packed-bed reactor filled with a zinc–copper couple, activated in flow, eliminating the need for a filtration unit. It is followed by a two-stage cross-flow extraction for simultaneous quenching and removal of zinc salts from the product solution. Finally, the extraction efficiency is monitored atline by an in-house-developed method using chromophoric reagents in continuous flow.