赵金龙,程宣,郑枫,尹璐,贾娴,季锡平
ZHAO Jin-long1,CHENG Xuan1,ZHENG Feng2,YIN Lu1,JIA Xian3,JI Xi-ping1(1.JARI Pharmaceutical Company

• 1:连云港杰瑞药业有限公司研发部
• 2:中国药科大学药物分析教研室
• 3:沈阳药科大学制药工程学院

摘要(Abstract)：

目的制备磷酸氟达拉滨的3个特定杂质,以加强磷酸氟达拉滨原料药和制剂产品的质量控制。方法首次以9-β-D-阿拉伯呋喃糖-2-氟腺嘌呤-5'-磷酸酯(磷酸氟达拉滨)为起始原料,分别合成9-β-D-阿拉伯呋喃糖-2-羟基腺嘌呤-5'-磷酸酯(杂质A)和9-β-D-阿拉伯呋喃糖-2-乙氧基腺嘌呤-5'-磷酸酯(杂质F);以9-β-D-阿拉伯呋喃糖-2-氟腺嘌呤(氟达拉滨)为起始原料,经磷酰化、水解反应合成9-β-D阿拉伯呋喃糖-2-氟腺嘌呤-3',5'-二磷酸酯(杂质C)。采用制备色谱对以上3个杂质进行纯化。结果制备了磷酸氟达拉滨3个特定杂质,并通过高分辨质谱、核磁共振等方法进行了结构鉴定。结论制备的化合物可作为磷酸氟达拉滨原料药和制剂产品质量控制的杂质对照品,可对特定杂质进行准确的定性定量控制。
Objective To synthesize three specified impurities as reference substances for strengthening quality control of fludarabine phosphate.Methods 6-Amino-9-(5-O-phosphono-β-D-arabinofuranosyl)-9H-purin-2-ol(impurity A)and 2-ethoxy-9-(5-O-phosphono-β-D-arabinofuranosyl)-9H-purin-6-amine(impurity F)were synthesized from 9-(5-O-phosphono-β-D-arabinofuranosyl)-2-fluoro-9H-purin-6-amine(fludarabine phosphate)through substitution reaction,and 9-(3,5-di-O-phosphono-β-D-arabinofuranosyl)-2-fluoro-9H-purin-6-amine(impurity C)was synthesized from 9-β-D-arabinofuranosyl-2-fluoro-9H-purin-6-amine(impurity E)through phosphorylation and hydrolysis.Reversed-phase HPLC was used to purify the impurities.Results Three specified impurities of fludarabine phosphate were obtained,and their structures were identified by HR-MS and NMR.Conclusions The obtained compounds can be used as reference substances for the qualitative and quantitative analysis of fludarabine phosphate related substances.

关键词(KeyWords)： 磷酸氟达拉滨;有关物质;合成;纯化;结构鉴定
fludarabine phosphate;related substance;synthesis;purification;structure identification

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 赵金龙,程宣,郑枫,尹璐,贾娴,季锡平
ZHAO Jin-long1,CHENG Xuan1,ZHENG Feng2,YIN Lu1,JIA Xian3,JI Xi-ping1(1.JARI Pharmaceutical Company

DOI: 10.14066/j.cnki.cn21-1349/r.2012.01.015

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