Safe and Efficient Preparative Approach to Chiral α-Chloroketones Based on In-Flow Generated Diazomethane

α-Chloroketones are valuable semi-products in the organic synthesis and pharmaceutical industry. In particular, they are used as key building blocks for the production of HIV protease inhibitors, such as atazanavir and darunavir. A well-known approach to their synthesis involves the Arndt-Eistert homologation, which relies on the formation of diazoketones followed by their halogenation. However, this process poses significant safety and implementation challenges due to the use of diazomethane (CH2N2). The high toxicity, carcinogenicity, and explosion hazard of CH2N2 limit its large-scale application and require design of specialized laboratory setups to reduce the risks. In this study, we present a new continuous-flow diazomethane generator that integrates the membrane technology with a traditional flow reactor setup for a safe and efficient generation of CH2N2. The flow technology eliminates the need for storage and handling of diazomethane, while facilitating its direct use in multistep synthesis. As a proof-of-concept, we demonstrate its application in the three-step synthesis of chiral α-chloroketones from N-protected amino acids. The approach newly developed offers a safer, more efficient, and scalable alternative to conventional diazomethane-based processes, paving the way for broader industrial applications.