Route Design and Scale-Up of a Topoisomerase I Inhibitor Antibody–Drug Conjugate Payload

AstraZeneca is currently developing an antibody–drug conjugate for the treatment of cancer with a topoisomerase I inhibitor payload. The drug portion of the molecule is an analogue of the natural product camptothecin. We describe the initial scale-up of the synthesis to meet preclinical timelines, including route design work to shorten the route by five steps. We also detail several problems we encountered, most notably a low-yield final step. We developed a second-generation route to address these issues, increasing the overall yield from 3.4% to 7.8% while reducing the process mass intensity by 66%. We discuss the impurities formed throughout the process and highlight our workup and purification strategy to remove them.