抗前列腺癌药物恩杂鲁胺有关物质的合成

Synthesis of related substance of anti-prostate cancer drug enzalutamide

目的合成抗前列腺癌药恩杂鲁胺的3个有关物质。方法 2-(3-氟-4-(甲氧甲酰基)苯基氨基)-2-甲基丙酸甲酯与4-氰基-3-三氟甲基苯异硫氰酸酯反应制得中间体3-(4-氰基-3-三氟甲基苯基)-1-(3-氟-4-(甲氧基甲酰)苯基)-5,5-二甲基-2-硫代咪唑啉-4-酮,该中间体与氢氧化钠水溶液发生皂化反应制得杂质4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑烷-1-基)-2-氟苯甲酸(Ⅰ);该中间体与氨水反应制得杂质4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑烷-1-基)-2-氟苯甲酰胺(Ⅱ)。2-(4-(甲氧甲酰基)苯基氨基)-2-甲基丙酸甲酯与4-氰基-3-三氟甲基苯异硫氰酸酯反应制得中间体3-(4-氰基-3-三氟甲基苯基)-1-(4-(甲氧基甲酰)苯基)-5,5-二甲基-2-硫代咪唑啉-4-酮,该中间体与甲胺水溶液反应制得杂质4-(3-(4-氰基-3-(三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑烷-1-基)-N-甲基苯甲酰胺(Ⅲ)。结果与结论合成的3个有关物质的结构经MS、1H-NM R谱确证,HPLC法检测其纯度分别为96.85%、97.61%、99.72%。Ⅰ、Ⅱ、Ⅲ可作为恩杂鲁胺质量控制的杂质对照品。

For the purpose of quality control of enzalutamide,three related substances were synthesized and characterized,the impurities 2-fluoro-4-（ 1,1-dimethylcyanomethyl） amino-benzonic acid（ Ⅰ） and 2-fluoro-4-（ 1,1-dimethylcyanomethyl） aminobenzonamide（ Ⅱ） were synthesized via the same route of enzalutamide but changing the different nucleophilic reagents of sodium hydroxide solution or ammonium hydroxide. The impurity N-methyl-4-（ 1,1-dimethylcyanomethyl） aminobenzonamide（ Ⅲ） was also synthesized by the same route but using different starting materials. The structures of three impurities of enzalutamide were tested by MS and1H-NMR spectra,the purities（ 96. 85%,97. 61%,99. 72%） were determined by HPLC analysis,which also can be used as the reference substances of the related substances in the quality control of enzalutamide.