An Efficient Approach to the Key Intermediate of Memantine HCl in Flow, Followed by the Synthesis of API in Batch

A cost-effective, atom-efficient synthetic route to memantine hydrochloride was developed by replacing the traditional bromination-formylation sequence with an acylation strategy. Conventional bromination of 1,3-dimethyladamantane (1,3-DMA) is corrosive, expensive, and difficult to scale up, prompting the development of a new process in which 1,3-DMA reacts with sulfuric acid and acetonitrile to form the N-acetyl memantine intermediate. Although batch acylation is highly exothermic, a novel flow-batch hybrid method enables safe thermal management by conducting the reaction in a flow reactor at 40 °C, followed by a brief batch hold to provide additional residence time. The intermediate is subsequently isolated in a flow-batch hybrid mode, yielding >99% purity and 90% yield. This is the first reported flow-batch hybrid synthesis of N-acetyl memantine, reducing the reaction exothermicity to manageable levels, improving safety, and enabling industrially viable throughput. The process significantly lowers production costs and enhances atom efficiency, offering a scalable, sustainable route to memantine hydrochloride.