Synthesis, Chromatographic Purification, and Isolation of Epothilone–Folic Acid Conjugate BMS-753493

We describe the synthesis, chromatographic purification, and isolation of the epothilone–folic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10–30 g) of cGMP quality BMS-753493.