米诺膦酸的合成

Synthesis of minodronic acid

目的:抗骨质疏松症新药米诺膦酸一水合物的合成。方法:以市售化工产品咪唑并[1,2-a]吡啶-3-基甲醇(3)为起始原料,通过溴代反应生成3-溴代甲基-咪唑并[1,2-a]吡啶(4),再与CO2的格式反应得到2-[咪唑并(1,2-α)吡啶-3-基]乙酸盐酸盐(2),与三氯化磷及亚磷酸反应得到米诺膦酸粗品,在稀盐酸中精制析晶,得到米诺膦酸一水合物(1)。结果:米诺膦酸一水合物样品经1H-NMR,ESI-MS和单晶X射线衍射检测确证化学结构正确。纯度经HPLC检测可达99.8%以上。结论:该合成工艺成本低、污染小、操作简单,产物收率高、纯度好,适于工业化大生产。

Objective： To synthesize the anti-osteoporosis drug minodronic acid monohydrate. Methods： The commercial imidazo [ 1,2-a] pyridin-3-yl alcohol （3） was used as a starting material to form 3-bromomethylimidazo [ 1,2-a ] pyridine （4） by bromination reaction. Then, 2-（ imidazo [ 1,2-α] pyridin-3-yl） acetic acid hydrochloride salt （2） was synthesized by the Grignard reaction with CO2, and reacted with phosphorous acid and phosphorus trichloride to produce the crude minodronic acid. The recrystallization was prepared from dilute hydro- chloric acid to yield minodronic acid monohydrate （1）. Results： The chemical structure of minodronic acid monohydrate was confirmed by I H-NMR, ESI-MS and Single crystal diffraction. This compound had a purity of over 99.8% as determined by HPLC. Conclusion： The synthesis process has the advantages of low cost and pollution, simple operation, high product yield and purity, which is more suitable for industrial production.