抗骨质疏松症药物——阿伦膦酸钠的合成研究

Study on the process for preparation of sodium alendronate

阿伦膦酸钠(Sodium Alendronate)为第三代氨基二膦酸盐类骨吸收抑制剂,与骨内羟基磷灰石有强亲和力,通过抑制破骨细胞的活性而发挥抗骨吸收作用,且没有骨矿化抑制作用.将γ-氨基丁酸、三氯化磷和亚磷酸在溶剂中加热,之后中和其反应生成物,合成得这种治疗骨质疏松症的药物阿伦膦酸钠.通过对反应溶剂、物料配比、反应时间、温度等影响产品质量和产率的主要因素的考察,提出了一种较佳的工艺条件:在n(γ-氨基酸)∶n(亚磷酸)∶n(三氯化磷)=1∶1.2∶1.2,以环己烷为溶剂,反应温度80℃,反应时间5 h等条件下,收率较佳,并且解决了由于反应易受温度影响而失控造成冲料报废的难题.

Sodium alendronate has strong appetency with hydroxyapatite in the bone and can inhibits bone resorption via restrain the activity of the osteoclasts without any restrain on bone mineralization. So, it can be used as a therapeutic agent for osteoporosis and osteoarthritis （OA）. Sodium alendronate was synthesized by refluxing γ-aminobutanoic acid, phosphorous chloride and phosphorous acid in cyclohexane and subsequently neutralizing the resulting product. Some main factors such as the solvent, the mole ratio of raw materials, reaction temperature and time, which affect the yield and the purity of the product were investigated. An industrial process for the production of sodium alendronate was presented to solve the problem that the reaction is easy to get out of control to burst because of its high sensitivity to the reaction temperature.