Synthesis And Establishment Of Quality Standard Of Zoledronic Acid

Hypercalcaemia and bone metastases of malignancy are frequently diseases in advanced cancer patients, it threatens patients'life and brings the patients with great pain. Since the eighties of the twentieth century, the human have researched and developed the bisphosphonate, and used successfully these products into the treatment of patients with skeletal complications. Zoledronic acid belongs to the class of heterocyclic ring bisphosphonates by synthesis, which is a member of third-generation bisphosphonates. Up to now, it is the most potent bisphosphonates in clinical trials. Zoledronic acid is an inhibitor of osteoclast-mediated bone resorption. It also effectively reduces serum calcium levels and inhibits tumour growth. Zoledronic acid showed good efficacy in the management of patients with hypercalcaemia of malignancy, in the treatment of advanced cancer patients with bone metastases and in the treatment of patients with Paget's disease. In addition, it might be an effective treatment for osteoporosis.In the article, firstly, the bisphosphonates and the pharmacodynamics, pharma- cokinetics and clinical uses of zoledronic acid are reviewed, then zoledronic acid was synthesized from imidazole, based on the design of the route of synthesis of zoledronic acid. After the synthesis, it's research of quality was carried through. The main research contents and conclusions are illustrated as follows.1. Zoledronic acid was synthesized. The raw material was synthesized from imidazole via N-alkylation with ethyl chloroacetate to give 2-(1H-imidazol-1-yl) ethyl acetate, PEG acted as phase transfer catalyst, followed by hydrolysis, salification to give 2-(1H-imidazol-1-yl)acetic acid hydrochloride, and then reacted with phosphorous acid and phosphorus trichloride to give the target product,the overall yield was 27.9%. The structure of the target product was corroborated by element analysis, infrared spectroscopy, nuclear magnetic resonance and mass spectrometry.2. The quality standard was established. Based on the synthesis of zoledronic acid, the quality research was carried through in detail, including physical chemistry constant, identification, purity and assay. The physical chemistry constant includes appearance, hygroscopicity, solubility, melt point and crystal. The test of identification includes UV, IR, HPLC and identification of phosphate. The test of purity includes related substance, free phosphate, clarity and colour of solvent, acid, loss on drying, heavy metals, arsenic,...