盐酸兰地洛尔的合成工艺研究  

Study on the Synthesis Process of Landiolol Hydrochloride

作　　者：汪程远[1] 王元忠 谭月晗 张燕 

机构地区：[1]重庆工商大学/催化与功能有机分子重庆市重点实验室/天然药物重庆高校市级重点实验室,重庆400067 [2]重庆利莫里亚生物科技有限公司,重庆400060

出　　处：《中国药房》2015年第13期1773-1775,共3页China Pharmacy

基　　金：重庆高校创新团队建设计划项目(No.KJTD201314)

摘　　要：目的:合成高纯度的盐酸兰地洛尔。方法:以乙二胺为原料,经二碳酸二叔丁酯单边保护得2-氨乙基-叔丁氧基甲酰胺(化合物3),与以吗啡啉与N,N′-羰基二咪唑为原料制成的N,N′-羰基吗啉咪唑(化合物6)反应,脱保护、成盐、游离得N-(2-氨乙基)吗啉甲酰胺(化合物9),再与3-[4-(2S,3-环氧丙氧基)苯基]丙酸(2,2-二甲基-1,3-二氧戊烷-4S)甲基酯(化合物10)开环等得到兰地洛尔,最后成盐得到最终产物。用高效液相色谱法监控反应,并对最终产物进行核磁共振(1H-NMR)和质谱(MS)表征。以兰地洛尔的纯度为指标对化合物9与化合物10的物质的量投料比、反应温度、反应时间进行筛选,以盐酸兰地洛尔的纯度和收率为指标对成盐方式进行筛选。结果:结构表征确定最终产物为目标化合物盐酸兰地洛尔,总收率40%,色谱纯度为99.86%;优化后条件为化合物9与化合物10的物质的量投料比2.0∶1.0、反应温度50℃、反应时间3 h,所得兰地洛尔的纯度为95%;成盐方式为氨解后直接用氯化铵成盐,成盐纯度为98.2%,成盐收率为90%。结论:成功合成盐酸兰地洛尔,且合成条件较温和、收率较高、操作简便,适合工业化生产。OBJECTIVE： To synthesize the landiolol hydrochloride with high purity. METHODS： With the raw material of eth- ylenediamine, 2-aminoethyl - tert-butoxy-carboxarnide （compound 3） obtained from di-tert-butyl-sided protection was reacted with N,N＇-carbonyl morpholino imidazole （compound 6） prepared by morpholine and N,N＇-carbonyldiimidazole. N-（2-aminoethyl） morpholine carboxamide （compound 9） was obtained by deprotection, salt formation and dissociation and then it was open-looped with 3- [4-（2S, 3-epoxypropoxy） phenyl] propionic acid （2, 2-dimethyl-1, 3-dioxolane-4S） methyl ester （compound 10） to obtain landiolol and obtained the final product by salt formation. HPLC was conducted to monitor the reactions and the final products were characterized by nuclear magnetic resonance （1H-NMR） and mass spectrometry （MS）. With the index of the purity of landiolol, the molar inputting ratio, reaction temperature and reaction time of compound 9 and compound 10 were screened; with the index of the purity and yield rate of landiolol hydrochloride, the salt formation way was screened. RESULTS： The final products were landiolol hydrochloride. The total yield was 40% and chromatographic purity was 99.86%. After optimization, the molar inputting ratio of compound 9 and compound 10 was 2.0 ： 1.0 with the reaction temperature of 50 % and reaction time of 3 h, the purity was 95%. The salt formation way was with ammonium chloride after ammonolysis with the salt purity of 98.2%, and salt yield rate of 90%. CONCLUSIONS： Landiolol hydrochloride is successfully synthesized. The synthesis conditions are mild with higher yield rate and simple operation. It is suitable for the industrial production.

关 键 词：盐酸兰地洛尔 合成 工艺 成盐方式 

分 类 号：R943[医药卫生—药剂学] R914.5[医药卫生—药学]