Scale-up Synthesis of Tesirine

Abstract

This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody–drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody–drug conjugates in multiple clinical trials, four of them pivotal.