达罗他胺中间体合成中杂质的发现和结构表征

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

达罗他胺是治疗前列腺癌的重要药物,在进行其合成工艺研究时,在第一步Suzuki偶联和第二步水解脱保护反应中,发现并纯化得到3个杂质A、B和C,其中杂质A和B来自第一步反应,杂质C来自第二步反应.通过高分辨质谱(HRMS)、核磁共振氢谱(^(1)HNMR)和核磁共振碳谱(^(13)CNMR)表征方法,确定了杂质A和B的结构,分别为初始反应原料化合物2的脱硼酸频哪醇酯产物和初始反应原料化合物1的双偶联产物;借助HRMS、^(1)HNMR、^(13)CNMR、^(1)H-^(1)HCOSY、^(1)H-^(13)CHSQC、^(1)H-^(13)CHMBC和^(1)H-^(1)HNOESY方法确定了中间体化合物3和杂质C的准确结构,对其形成机理和规避方法也进行了讨论分析.

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),^(1)H nuclear magnetic resonance(NMR),and ^(13)C 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,^(1)H NMR,^(13)C NMR,^(1)H-^(1)H COSY(correlation spectroscopy),^(1)H-^(13)C HSQC(heteronuclear singular quantum correlation),^(1)H-^(13)C HMBC(heteronuclear multiple bond correlation)and ^(1)H-^(1)H NOESY(nuclear overhauser effect spectroscopy).The formation mechanisms and avoidance methods of these impurities were also discussed.