唑来膦酸合成工艺改进
Improved Synthetic Process of Zoledronic Acid
王邵峰 1冯中 1吴士忠 1彭壮 1张贵民1
作者信息
- 1. 鲁南制药集团股份有限公司,国家手性制药工程技术研究中心,山东临沂 273400
- 折叠
摘要
对唑来膦酸(1)的合成工艺进行了优化.以经济、易得的咪唑(3)和氯乙酸乙酯(4)为起始物,在叔丁醇钾碱性条件下,通过"一锅法"进行N-烷基化和水解反应,得中间体咪唑-1-乙酸盐酸盐(2盐酸盐).2盐酸盐经三氯化磷膦酸化得1粗品,通过加大甲烷磺酸、三氯化磷的投料量,延长反应时间,收率由46％提至87％;1粗品经水和丙酮精制得1,产品未检出明显杂质(HPLC纯度100.0％),总收率68％(以3计).改进后的工艺生产成本较低,操作安全、简便,收率提高,适合工业化生产.
Abstract
The synthetic process of zoledronic acid(1)was improved.With commercially available imidazole(3)and ethyl chloroacetate(4)as raw materials,the intermediate imidazol-1-acetic acid hydrochloride(2 hydrochloride)was obtained by N-alkylation and hydrolysis reaction through a"one pot method"under the presence of potassium tert-butanol.Crude 1 was then synthesized from 2 hydrochloride,with phosphorus trichloride as the phosphonation reagent.The yield was raised from 46％to 87％by increasing the amounts of methanesulfonic acid and phosphorus trichloride and prolonging the reaction time.After recrystallization from water and acetone,1 was obtained in 68％yield(based on 3)with HPLC purity of 100.0％.The improved process has the characteristics of low production cost,safer and simpler operation and high yield,which makes it amenable for industrial production.
关键词
唑来膦酸/一锅法/膦酸化/合成/工艺改进Key words
zoledronic acid/one-pot process/phosphonation/synthesis/process improvement引用本文复制引用
基金项目
山东省泰山产业领军人才项目(tscx202306086)
出版年
2024
NETL
NSTL
万方数据