An Improved Synthesis of Ionizable Lipids D‐Lin‐KC2‐DMA and D‐Lin‐MC3‐DMA

Considerable interest exists in ionizable lipids (ILs) for the delivery of nucleic acid therapeutics. While not a component of a yet‐approved medication, lipid KC2 is especially competent for the delivery of plasmid DNA, consequently it is in high demand on the part of research laboratories worldwide. Lipid MC3, a component of Onpattro, is a benchmark against which the efficacy of new ILs is evaluated. A new route to KC2 and MC3 through the double alkylation of TosMIC with linoleyl tosylate is described. The new synthesis avoids problematic reactions, proceeds in higher overall yield relative to the literature one, and in the case of KC2, involves three fewer steps.