Identification, synthesis, characterization, and a quality control strategy for high-risk chiral impurities in the antifungal drug substance posaconazole

The four chiral centres in posaconazole (POS) result in as many as 16 chiral isomers. Controlling all the chiral impurities in POS is a challenging task. In this study, three high-risk chiral impurities were identified and synthesized, and the corresponding chemical structures were characterized. Three single crystals were obtained and analyzed to support the absolute configuration elucidation. Based on the origin mechanism of the chiral impurities, the synthetic processes were optimized, and appropriate control strategies and control spaces were established, rationalizing the control of chiral impurities of POS, and making the control method easier and more effective.