柠檬酸恩氯米芬的合成与表征  

Synthesis and characterization of trans-clomiphene citrate

作　　者：邹佳智 汤建拓 夏春华 杨晓章 王春省 ZOU Jia-zhi;TANG Jian-tuo;XIA Chun-hua;YANG Xiao-zhang;WANG Chun-sheng(School of Pharmacy,College of Medicine,Nanchang University,Nanchang 330006,China;Zhejiang Tiantai Pharmaceutical Co.,Ltd.,Taizhou 317200,China)

机构地区：[1]南昌大学医学部药学院,江西南昌330006 [2]浙江天台药业股份有限公司,浙江台州317200

出　　处：《化学工程师》2025年第3期1-6,共6页Chemical Engineer

基　　金：江西省双千计划(jxsq2019201032)。

摘　　要：本文研究了柠檬酸恩氯米芬的合成与表征。以N,N-二乙基乙醇胺、4-氟二苯甲酮为原料,叔丁醇钾、苄基氯化镁四氢呋喃溶液、氯化氢乙醇溶液、N-氯代丁二酰亚胺、联萘酚磷酸甲醇溶液等为反应试剂,经取代、消去、氯代等五步合成反应得到目标产物后,通过1H NMR、13C NMR和ESI-MS表征其化学结构。中间产物(1)的最佳合成条件:叔丁醇钾190mmol,反应温度和时间分别为100℃、10h;中间产物(2)的最佳合成条件:2.0mol·L^(-1)苄基氯化镁四氢呋喃溶液95m L,反应温度和时间分别为20℃、24h;中间产物(3)的最佳合成条件:4.0mol·L^(-1)氯化氢乙醇溶液100m L,反应温度和时间分别为50℃、3h;中间产物(4)的最佳合成条件:N-氯代丁二酰亚胺85mmol,反应温度和时间分别为25℃、24h;随后选择40m L质量分数为40%的联萘酚磷酸甲醇溶液拆分Z/E构型,产物最终收率可达65.2%。经1H NMR、13C NMR和ESI-MS表征,确认最终产物为柠檬酸恩氯米芬。The synthesis and characterization of trans-clomiphene citrate was investigated.The target compound was obtained by five step synthetic reaction that was substitution reaction,elimination reaction,chlorination reaction,and so on,using N,N-diethylethanolamine and 4-fluorobenzophenone as raw materials,potassium tert-butoxide,tetrahydrofuran solution of benzyl magnesium chloride,ethanol solution of hydrogen chloride,N-chlorosuccinimide,methanol solution of binaphthol phosphate as reaction reagent.The structure of the target compound was characterized by 1H NMR,13C NMR and ESI-MS.The optimal reaction conditions of intermediate compound(1)were as follows:the dosage of potassium tert-butoxide was 190mmol,temperature and time of reaction were 100℃and 10h,respectively.The optimal reaction conditions of intermediate compound(2)were as follows:the volume of 2.0mol·L^(-1) tetrahydrofuran solution of benzyl magnesium chloride was 95mL,temperature and time of reaction were 20℃and 24h,respectively.The optimal reaction conditions of intermediate compound(3)were as follows:the volume of 4.0mol·L^(-1) ethanol solution of hydrogen chloride was 100mL,temperature and time of reaction were 50℃and 3h,respectively.The optimal reaction conditions of intermediate compound(4)were as follows:the dosage of N-chlorosuccinimide was 85mmol,temperature and time of reaction were 25℃and 24h,respectively.The 40mL of methanol solution of binaphthol phosphate that mass concentration was 40%was selected for resolution of Z/E,and the ultimate yield was up to 65.2%.The ultimate product was verified by 1H NMR,13C NMR and ESI-MS,which was trans-clomiphene citrate.

关 键 词：柠檬酸恩氯米芬 合成 表征 核磁共振波谱 

分 类 号：TQ463[化学工程—制药化工]