Development of a practical synthesis of an antifungal drug posaconazole and the study of a critical process impurity

A practical synthesis method for the large-scale preparation of Posaconazole is developed. The key intermediate 7 was obtained initially with substantial amounts (∼11.70%) of process impurity A when performed the SN2 reaction. Based on the structure elucidation and careful investigation, it was verified that the formation of impurity A was closely related to the presence of oxygen. Hence, the content of A was below 0.1% after displacing the oxygen, which fundamentally avoided the recrystallization of 7. Furthermore, the efficient removal of palladium (less than 10 ppm) was achieved by the low cost and convenient operation of mercapto silica after the debenzylation of 7, which ensured the high quality of Posaconazole. Finally, the optimized process was successfully implemented (15 kg) and provided Posaconazole (>99.90%) with an overall yield of 82%. This work provides a reference for the manufacture of the antibacterial drug Posaconazole.