Discovery and Structural Characterization of Impurities in the Synthesis of Darolutamide Intermediate

Abstract

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 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 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.

Keywords

• darolutamide intermediate
• nmr
• drug impurities