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目的:建立高效液相色谱-线性离子阱质谱法分离鉴定瑞舒伐他汀药物中间体N-[5-腈基-4-(4-氟苯基)-6异丙基嘧啶-2-]-N-甲基甲磺酰胺中的有关杂质,并探讨这些杂质的质谱裂解规律。方法:采用Cortecs C18色谱柱(100 mm×2.1 mm,2.7μm),以乙腈-0.1%甲酸溶液为流动相,进行梯度洗脱,流速为0.25 m L·min-1,柱温35℃,检测波长为242 nm,电喷雾离子化正负2种离子模式扫描。结果:中间体与各已知杂质均分离良好,根据一级和多级质谱信息,共鉴定出7种杂质,包括对甲基苯磺酸、4-(4-氟苯基)-2-羟基-6-异丙基-5-氰基-嘧啶、4-(4-氟苯基)-2-氨基-6-异丙基-5-氰基-嘧啶、5-氰基-6-(4-氟苯基)-4-异丙基-2-N-甲磺酰胺嘧啶-1-N-氧化物、4-(4-氟苯基)-2-甲氨基-6-异丙基-5-氰基-嘧啶、中间体的氯代产物和5-甲酸内酯化产物。杂质类型主要为氧化、降解产物及合成副产物。结论:本法分析结果为有关杂质确证提供分析方法,为瑞舒伐他汀合成中的质量控制提供指导。
OBJECTIVE: To establish a HPLC method for the separation and identification of rosuvastatin intermediate N- [5-nitrile-4- (4-fluorophenyl) -6 isopropylpyrimidine-2 -] - N-methyl methanesulfonamide, and to explore the mass spectrometry cleavage of these impurities. Methods: The mobile phase consisted of Cortecs C18 column (100 mm × 2.1 mm, 2.7 μm) with acetonitrile-0.1% formic acid as mobile phase at a flow rate of 0.25 m L · min-1 at 35 ℃. Wavelength of 242 nm, electrospray ionization plus or minus 2 ion mode scanning. Results: The intermediates were well separated from all known impurities. Seven kinds of impurities were identified based on the first- and multi-stage MS information, including p-toluenesulfonic acid, 4- (4-fluorophenyl) (4-fluorophenyl) -2-amino-6-isopropyl-5-cyano-pyrimidine, -fluorophenyl) -4-isopropyl-2-N-methanesulfonamide pyrimidine- 1-N-oxide, 4- (4- fluorophenyl) -cyano-pyrimidine, the chloro product of the intermediate and the 5-formate esterification product. The main types of impurities are oxidation, degradation products and byproducts. Conclusion: The results of this method provide an analytical method for the confirmation of impurities and provide guidance for the quality control of rosuvastatin synthesis.