骨质疏松症治疗药唑来膦酸的合成工艺改进OACSTPCD

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(POCl3)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(H3PO3)as solvent,with imidazole acetic acid and POCl3 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.