Continuous flow synthesis of the ionizable lipid ALC-0315

Abstract

The ionizable lipid ALC-0315 is the major component of the lipid nanoparticles used to encapsulate the mRNA in the Biontech–Pfizer COVID-19 vaccine. In early 2021, difficulties encountered in scaling up the production and purification of this lipid impeded vaccine manufacturing, leading to delays in vaccination campaigns designed to combat the global coronavirus pandemic. Flow chemistry has impacted synthetic capabilities on all scales. This work describes a proof of principle continuous flow process comprised of four telescoped steps for the production of ALC-0315 with an overall yield of 20% and a productivity of 7 mmol per hour.