芳基硼酸频哪醇酯的氟19标记方法的研究  

19F-Fluorination of arylboron esters

作　　者：朱源 赵雅芝 田晨 陈乐园 宁洪鑫 侯文彬 李祎亮[1] ZHU Yuan;ZHAO Ya-zhi;TIAN Chen;CHEN Le-yuan;NIN Hong-xin;HOU Wen-bin;LI Yi-liang(Institute of Radiation Medicine,Peking Union Medical College&Chinese Academy of Medical Sciences,Tianjin 300192,China;Tianjin University of Traditional Chinese Medicine,Tianjin 300193,China)

机构地区：[1]中国医学科学院北京协和医学院放射医学研究所,天津300192 [2]天津中医药大学,天津300193

出　　处：《现代药物与临床》2021年第6期1097-1103,共7页Drugs & Clinic

基　　金：天津市科技计划项目(18ZXXYSY00110);天津市自然科学基金资助项目(18JCQNJC09500);北京协和医学院中央高校基本科研业务费资助(3332020057)。

摘　　要：目的开发一种高效合成氟标记放射性药物的方法。方法使用4-硝基苯硼酸频哪醇酯为反应底物,探索化合物氟标记的有效方法。考察反应配体、反应溶剂、反应温度和反应时间对4-氟硝基苯收率的影响,并通过1H-NMR、13C-NMR、19F-NMR方法对目标产物的结构进行表征,采用HPLC法对反应条件进行定量评价。结果确定了芳基硼酸频哪醇酯类化合物的氟-19标记的最佳反应条件:以3-溴咪唑并[1,2-b]哒嗪为最优配体,在100℃反应10 min即可得到目标化合物。在自动合成仪上重现了最优条件,并用此方法成功合成了11β-羟化酶显像剂美托咪酯。结论本方法为氟-18标记芳基硼酸频哪醇酯类放射性药物前体提供重要合成依据。Objective To develop an efficient method for synthesis of fluorine-labeled radiopharmaceuticals.Methods 4-Nitrophenylboronic acid pinacol ester was employed as the substrates to develop a convenient and efficient method for the synthesis of 4-fluoronitrobenzene.The effects of reaction ligands,solvents,temperature,and time on the yield of the product were systematically investigated.The structures of all compounds were confirmed by 1H-NMR,13C-NMR,and 19F-NMR methods,and the yield of 4-fluoronitrobenzene was obtained by HPLC method.Results The optimum conditions for fluorine-19 labeling were determined.The target compound was obtained by reaction at 100℃for 10 min with 3-bromine[1,2-b]pyridazine as the optimal ligand.Meanwhile,the method was reproduced on an automatic synthesizer,and the 11β-hydroxylase imaging agent medetomide was successfully labeled with this method.Conclusion This method provided an important guidance for further fluorine-18 label aryl boronic acid pinacol ester radiopharmaceutical precursors.

关 键 词：芳基硼酸频哪醇酯 氟-19标记 芳香亲核取代反应 合成 美托咪酯 

分 类 号：R914[医药卫生—药物化学]