Darolutamide is an important drug for the treatment of prostate cancer.When studying its synthesis process, three impurities A, B, and C were discovered and purified in the first step of Suzuki coupling and the second step of hydrolysis deprotection reactions.Impurities A and B came from the first-step reaction, and impurity C came from the Peeler second-step reaction.
The structures of impurities A and B were further determined through high-resolution mass spectrometry (HRMS), 1H nuclear magnetic resonance (NMR), and 13C NMR methods.It was discovered that impurities A and B were the deborated pinacol ester product of ARNICA MASSAGE OIL compound 2 and the double coupling product of compound 1, respectively.The accurate structures of compound 3 and impurity C were determined using HRMS, 1H NMR, 13C NMR, 1H-1H COSY (correlation spectroscopy), 1H-13C HSQC (heteronuclear singular quantum correlation), 1H-13C HMBC (heteronuclear multiple bond correlation) and 1H-1H NOESY (nuclear overhauser effect spectroscopy).
The formation mechanisms and avoidance methods of these impurities were also discussed.