骨质疏松症治疗药唑来膦酸的合成工艺改进  

Improved synthesis of osteoporosis drug zoledronic acid

作　　者：罗君陶 王新仙 卢定强[1,2] LUO Juntao;WANG Xinxian;LU Dingqiang(School of Pharmaceutical Sciences,Nanjing Tech University,Nanjing 211800,China;Jiangsu Provincial Institute of Material Medica,Nanjing 211800,China)

机构地区：[1]南京工业大学药学院,江苏南京211800 [2]江苏省药物研究所有限公司,江苏南京211800

出　　处：《生物加工过程》2024年第1期75-80,共6页Chinese Journal of Bioprocess Engineering

摘　　要：随着我国人口老龄化问题越来越严重,老年人的骨质疏松症问题也越发突显。唑来膦酸可显著抑制破骨细胞的骨吸收作用,用以治疗骨质疏松症所引起的疼痛,是骨修复治疗的首选药物。在经大量文献调研的基础上,优化筛选了一条稳定性高、操作简单且环境友好的唑来膦酸合成路线。以咪唑和氯乙酸乙酯为起始原料,进行了N-烷基化反应,得到咪唑乙酸乙酯;咪唑乙酸乙酯经水解反应得到咪唑乙酸;咪唑乙酸与三氯氧磷进行磷酸化反应,最终生成产物唑来膦酸,并获得了合成中间体咪唑乙酸及产物唑来膦酸的最佳工艺条件,以固体亚磷酸为溶剂,咪唑乙酸和三氯氧磷的投料量为摩尔比1.0∶2.2,反应温度为75℃。总产率为43.55%,HPLC纯度达到99.97%,符合欧洲药典规定的质量标准。With the issue of aging population in our country,osteoporosis is becoming a more and more serious age-related disease.Zoledronic acid,which can significantly inhibit the bone absorption of bone-breaking cells,is the preferred drug for bone repair therapy to treat pain caused by osteoporosis.Herein we described the optimization of a synthetic route towards zoledronic acid,and our new process,with imidazole and ethyl chloroacetate as the two starting materials,proved to be highly reliable and environmentally friendly,along with simple operations.Upon the N-alkylation of imidazole with chloroacetate,the resultant ester was hydrolyzed to give imidazole acetic acid,which subsequently underwent phosphorylation by treatment with phosphorus oxychloride(POCl 3)to afford the desired product zoledronic acid.After a variety of conditions were screened for the two key transformations,N-alkylation and phosphorylation,the final step was conducted at 75℃using solid phosphorous acid(H 3PO 3)as solvent,with imidazole acetic acid and POCl 3 at the ratio of 1.0∶2.2.The overall yield of our new approach was 43.55%,and the HPLC analysis of final product zoledronic acid showed 99.97%purity,which met the quality standards stipulated by the European Pharmacopoeia.

关 键 词：唑来膦酸 合成 路线优化 骨质疏松症 

分 类 号：R914[医药卫生—药物化学] Q954.654[医药卫生—药学]