A two-step continuous flow synthesis of multi-tail ionizable lipids

A robust and safe continuous flow synthesis of multi-tail ionizable lipids, key components in LNP formulations for RNA therapeutic delivery, is reported. A nearly quantitative conversion in the epoxidation of long-chain terminal alkenes is safely achieved in continuous flow using the Oxone/acetone system, which prevents the buildup of hazardous dimethyldioxirane. A catalyst-free polyalkylation of amine nucleophiles via high-temperature epoxide ring-opening reduces reaction time dramatically-from several days in batch to just twenty minutes of residence time in continuous flow. Alkylation of the crude epoxidation product enabled the production of representative ionizable lipids with a throughput exceeding 10 g h^-1 in a laboratory setting, demonstrating strong potential for rapid and safe lipid manufacturing at scale.