A practical semi-synthesis to the highly complex small molecule intermediate for an anti-Staphyloccocus aureus THIOMAB-antibiotic conjugate (TAC) is described. This synthetic route took advantage of a highly efficient oxidative condensation of fluoride-substituted resorcinol and rifamycin S in a novel, semi-continuous process design. A mild SNAr reaction of piperidine and the fluoride-substituted rifamycin derivative offered an efficient access to the key intermediate. Careful preparation and isolation of linker chloride intermediate enabled an expedient formation of the quaternary ammonium intermediate. Finally, scalable chromatography conditions were developed to deliver the linker-drug in high purity and enable conjugation to support the anti-Staphyloccocus aureus TAC in the clinic.

Development of a practical synthesis of small molecule intermediate for THIOMAB-antibiotic conjugates (TACs)

254th National Meeting (2017)

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