Development of a Safe and Scalable Process for the Production of a High-Purity Thiocarbamate-Based Ionizable Lipid as an Excipient in mRNA-Encapsulating Lipid Nanoparticles

Thiocarbamate lipid 2 was prepared on a 25–50 g scale by coupling a carbamoyl chloride with 3-(dimethylamino)-1-propanethiol. Chromatography, activated charcoal treatment, and washing were required to obtain 2 (57%, light yellow oil) in >98% purity. Lipid 2 was successfully prepared on a 1 kg scale by replacing the carbamoyl chloride with an acyl imidazolium intermediate and coupling with the lipophilic amine salt 8 to give 2 in a higher yield (68%) and greater purity (99.8%, colorless oil) using an improved, chromatography-free, purification protocol. In addition, mutagenic impurities in 2 could be controlled well below required specifications.