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

Abstract

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.