高效双膦酸药物唑来膦酸合成工艺改进

对以咪唑和氯乙酸乙酯为原料,经N-烷基化反应、成盐得咪唑乙酸盐酸盐,再与三氯氧磷和磷酸反应后水解合成唑来膦酸的工艺进行了研究。重点探讨了反应溶剂对合成唑来膦酸工艺的影响。结果表明:采用甲苯、体积分数95%乙醇、质量分数85%磷酸为反应溶剂,不仅毒性和成本低,反应过程和前后处理的操作更加合理和简便,总收率43%。对以甲苯为溶剂的N-烷基化反应条件进行了优选,优化结果为反应温度65—70℃,反应时间4.5—5.0 h。得到操作简便、合成周期短、成本低、收率较高,易实现工业化的唑来膦酸合成工艺。

Improved process of highly potent bisphosphonate zoledronic acid

An improved process for preparing bisphosphonate zoledronic acid was studied.The intermediate product 1H-imidazol-1-yl-acetic acid hydrochloride was synthesized with imidazole and ethyl chloroacetate as raw materials via N-alkylation and salification.Then final product zoledronic acid was prepared with 1H-imidazol-1-yl-acetic acid hydrochloride,phosphorus oxychloride and phosphoric acid by hydrolysis.The influence of the solvents on the reaction was mainly discussed.The results show that the toluene,ethanol with volume fraction of 95%,phosphoric acid with mass fraction of 85% are suitable for the zoledronic acid synthesis because of their lower poisonousness,low cost and easy operation as solvents.The overall yield of zoledronic acid is 43%.The optimized conditions for N-alkylation with the toluene as solvent are at 65-70 ℃ for 4.5-5.0 h.The novel process presents simple operation,short reaction time,low cost and is easy for industrial production of bisphosphonate zoledronic acid.