华法林钠羟酮缩合杂质的合成研究  

Synthesis study of acetal impurities in warfarin sodium

作　　者：江云兵 周伟 朱阳[1] JIANG Yunbing;ZHOU Wei;ZHU Yang(the Central Research Institute of Shanghai Pharmaceutical Group Co.,Ltd.,Shanghai 201203,China)

机构地区：[1]上海医药集团股份有限公司中央研究院,上海201203

出　　处：《上海医药》2024年第7期71-75,共5页Shanghai Medical & Pharmaceutical Journal

摘　　要：目的:合成华法林钠生产工艺中产生的杂质WF-Z1~WF-Z6;方法:以2’-羟基苯乙酮(SM-1)为起始原料与碳酸二甲酯(SM-2)进行缩合反应生成4-羟基-1-苯并吡喃-2-酮(WF-1),然后与4-苯基-3-丁烯-2-酮(SM-3)进行迈克尔加成反应得到3-(α-丙酮基苄基)-4-羟基香豆素(WF),最后在酸性条件下与甲醇,乙醇或异丙醇进行缩酮反应得到相应的目标杂质WF-Z1~WF-Z6。结果:目标杂质采用液相联用质谱(LCMS),核磁共振氢谱(1H NMR),核磁共振碳谱(13CNMR)等检测手段鉴定了其化学结构。结论:合成的杂质可以作为华法林钠工艺杂质的杂质对照品,且本工艺路线起始原料廉价易得,有望用于工业化生产。Objective:To synthesize the impurities WF-Z1-WF-Z6 produced in the production process of warfarin sodium.Methods:Using 2′-hydroxyacetophenone(SM-1)as a starting material,4-hydroxy-chromen-2-one(WF-1)was synthesized by condensation reaction with dimethyl carbonate(SM-2).Subsequently,Michael addition reaction with 4-phenyl-3-buten-2-one(SM-3)was carried out to obtain 3-(α-acetoneylbenzyl)-4-hydroxycoumarin(WF),and finally the corresponding target impurities WF-Z1-WF-Z6 were synthesized by reaction with methanol,ethanol or isopropanol under acidic conditions.Results:The chemical structure of these impurities were identified by LCMS,1H NMR,13C NMR.Conclusion:The synthesized impurities can be used as a reference material for the quality control of warfarin sodium and moreover,the starting materials used in this synthetic route are cheap and easy to obtain and it is expected to be used in industrial production.

关 键 词：华法林 华法林钠 工艺杂质 合成 

分 类 号：O626.3[理学—有机化学]