Development of Dual Practical Manufacturing Routes to Cognate Pyrrolobenzodiazepine-Based Linker-Drugs

The synthetic strategies for two distinct but related linker-toxins 1 and 2 were reconfigured in order to devise an efficient and unified supply chain for both compounds. This involved establishing novel chemical routes to crystalline, monomeric building blocks that could be combined in a unique way for each molecular target. This streamlined approach avoided challenging desymmetrization efforts en route to each target molecule as well as a drastically reduced need for multiple chromatographic purifications throughout the syntheses. In the final instance, the shared-building-block concept enabled access to advanced intermediates from which the optimized endgames were implemented, ultimately resulting in robust synthetic processes to both 1 and 2.