高效液相色谱-线性离子阱质谱鉴定瑞舒伐他汀中间体中相关杂质  

Identification of impurities in rosuvastatin intermediate by high performance liquid chromatography coupled with linear ion trap mass spectrometry

作　　者：谢思骏 汪航[1] 

机构地区：[1]上海交通大学分析测试中心,上海200240

出　　处：《药物分析杂志》2017年第2期243-251,共9页Chinese Journal of Pharmaceutical Analysis

摘　　要：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 develop a high performance liquid chromatography coupled with linear ion trap mass spectrometric method for the identification of impurities in rosuvastatin intermediate：N-[5-cyano-4-（4-fluorophenyl）-6-isopropylpyrimidin-2-yl]-N-methylmethane sulfonamide.The fragmentations were also discussed.Methods：The analysis was conducted on a Waters Cortecs C18 column（100 mm×2.1 mm,2.7 μm） with a mobile phase of acetonitrile-water（0.1% formate acid） by gradient elution at the flow rate of 0.25 m L·min-1.The column temperature was 35 ℃ and the detection wavelength was 242 nm.MS was scanning in ESI source,positive and negative ions mode.Results：The impurities and intermediate were completely separated from each other;Seven impurities were identified by MS1 and MSn fragments.The impurities were identified as 4-methylbenzenesulfonic acid,4-（4-fluorophenyl）-2-hydroxy-6-isopropylpyrimidine-5-carbonitrile,2-amino-4-（4-fluoro phenyl）-6-isopropylpyrimidine-5-carbonitrile,5-cyano-6-（4-fluorophenyl）-4-isopropyl-2-（N-methylmethylsulfonamido）pyrimidine-1-oxide;N-[8-fluoro-4-isopropyl-5-oxo-5H-chromeno（4,3-d）pyrimidin-2-yl]-N-methylmethanesulfonamide;4-（4-fluorophenyl）-6-isopropyl-2-（methylamino）pyrimidine-5-carbonitrile and N-[4-（chloro-4-fluorophenyl）-5-cyano-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide.The impurities include oxidative products,degradation products and synthesis byproducts.The mass fragmentation patterns and structural assignments of these seven impurities were studied.Conclusion：The established method is suitable for the identification of related substances and provides a tool for the quality control in the synthesis of rosuvastatin.

关 键 词：瑞舒伐他汀 中间体 N-[5-腈基-4-(4-氯苯基)-6异丙基嘧啶-2-]-N-甲基甲磺酰胺 HMG-Co A还原酶抑制剂 有关物质 杂质鉴定 高效液相色谱法 线性离子阱质谱 多级质谱 

分 类 号：R917[医药卫生—药物分析学]