A practical synthesis of the complex payload for an anti-Staphylococcus aureus THIOMAB antibody-antibiotic conjugate (TAC) is described. The route takes advantage of a delicate oxidative condensation, achieved using a semi-continuous flow procedure. It allows for the generation of kilogram quantities of a key intermediate to enable a mild nucleophilic aromatic substitution to the tertiary amine free drug. The linker component is introduced as a benzylic chloride, which allows formation of the quaternary ammonium salt linker-drug. This chemical process surmounts numerous synthetic challenges and navigates deeply colored and unstable compounds to support clinical studies to counter S. aureus bacterial infections.
Targeting Staphylococcus aureus with innovation: As a sophisticated therapeutic construct, an antibody–antibiotic conjugate (AAC) requires a robust chemical process to furnish the linker–drug for conjugation. In our case, continuous flow processing allows for a sensitive oxidative condensation reaction to proceed via a recycle loop method. Further streamlined chemistry allows the deeply colored, quaternary ammonium salt linker–drug to be reproducibly accessed in good yield and purity. This challenging synthesis enables construction of the first AAC to help cut through the fog of antibiotic resistance. More information can be found in the Communication by S. G. Koenig et al. on page 2837.
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