Isolation, synthesis, identification of new process-related impurities in evocalcet

Evocalcet is a calcimimetic for the treatment of secondary hyperparathyroidism. In the preparation of evocalcet, eleven process-related impurities were detected in the reaction solution of the last step at levels of 0.05%− 2.50% by a new HPLC method. Ten impurities were separated from the enriched mother liquor and synthesized directly. These impurities were characterized and identified by HRMS and NMR spectra and then coinjected with commercial products to confirm their retention times in HPLC. The possible formation pathways and synthetic methods of ten process-related impurities ware discussed in detail. [Display omitted] •Eleven process-related impurities in evocalcet were detected by HPLC in the range 0.05%−2.50%.•An HPLC method was developed and validated.•Ten impurities were separated by PLC, synthesized successfully and possible formation pathways were discussed.•Ten impurity structures were determined by HRMS and NMR technologies.•Ten impurities in commercial products were confirmed by co-spiking studies.