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4.5-5.0h.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.%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.
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