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【结 构 式】 
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【药物名称】Zoledronic acid monohydrate, CGP-42446(anhydrous), ZOL-446, CGP-42446A(disodium salt), CGP-42446B(triNa salt, hydrate), Zometa 【化学名称】1-Hydroxy-2-(1-imidazolyl)ethylene-1,1-diphosphonic acid monohydrate 【CA登记号】165800-06-6, 118072-93-8 (anhydrous), 165800-07-7 (diNa salt), 157432-59-2 (Mg salt), 131654-46-1 (Na salt), 165800-08-8 (triNa 【 分 子 式 】C5H12N2O8P2 【 分 子 量 】290.10759 |
【开发单位】Novartis (Orphan Drug), Novartis (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiarthritic Drugs, Bone Cancer Therapy, Bone Diseases, Treatment of, Bone Resorption Inhibitors, METABOLIC DRUGS, Neuropathic Pain, Treatment of, Oncolytic Drugs, Rheumatoid Arthritis, Treatment of, Treatment of Hypercalcemia, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Osteoporosis, Treatment of Paget's Disease, Angiogenesis Inhibitors, Bisphosphonates |
合成路线1
Zoledronate sodium can be prepared by reaction of 2-(1-imidazolyl)acetic acid hydrochloride (I) with PCl3, with optional presence of phosphoric acid, in refluxing chlorobenzene, followed by hydrolysis with refluxing 9N hydrochloric acid and final formation of the sodium salt by treatment with aqueous NaOH.
| 【1】 Widler, L.; et al.; Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). J Med Chem 2002, 45, 17, 3721. |
| 【2】 Jaeggi, K.A.; Widler, L. (Novartis AG); Substituted alkanediphosphonic acids and pharmaceutical use. AU 8781453; EP 0275821; JP 1988150291; US 4939130 . |
| 【3】 Castaner, J.; Rabasseda, X.; Sorbera, L.A.; Zoledronate Disodium. Drugs Fut 2000, 25, 3, 259. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 33401 | 2-(1H-imidazol-1-yl)acetic acid hydrochloride | C5H6N2O2.HCl | 详情 | 详情 |
合成路线2
| 【1】 Mao JH, Mukherjee S. Zhang Y, et al. 2006. Solid-State NMR, crystallograpbie, and computational investigation of bisphosphonates and fanesyl diphosphate synthase-bisphosphonate-comlexes. J Am Chem Soc, 128 (45):14485--14497 |
合成路线3
| 【1】 Cai W, Zhang YB, Cao YF, et al. 2005. Preparation of zoledronic acid from imidazole. 发明专利申请公开说明书．CN 1693308 |
| 【2】 Yadav RP, Shrukh ZG, Mukarrarn SM, et aL. 2007. Processes for the preparation of pure zoledronic acid. W0 2007069049 |
合成路线4
| 【1】 Widler L, Jaeggi KA, Glatt M, Mueller K, et aL. 2002. Highly potent geminal bisphoaphonates, from pamidronate disodium (Aredia) to zoledmnic acid (Zameta). J Med Chem, 45 (17): 3721～3738 |
合成路线5
| 【1】 Wan R, Wang HB. 2003．Synthesis of zoledroruc acid. 中国医药工业杂志，34 (11): 513～544 |
合成路线6
| 【1】 Kieczykowski GR, Jobson RB, Melillo DG, et aL. 1995. Preparation of (4-amino-l-hydroxybuqdidene) bisphosphonic acicl sodium salt, MK-217 (alendmnate sodium): an improved procedure for the preparation of l-hydroxy-l,l-bisphosphonic acids. J Org Chem, 60 (25): 8310～8312 |
| 【2】 Patel VM, Chitturi TR, Thennati R 2005. A process for the preparation of 2-(imidazol-l-yl)-l-hydroxyethane-l,l-diphosphoruc acid. W0 2005066188 |
| 【3】 Zhu J．Zhou YJ, Lu JG, et al. 2003. Synthesis of zoledroruc acid. 中国新药杂志．12 (1):39～40 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 66984 | benzyl 2-(1H-imidazol-1-yl)acetate | C12H12N2O2 | 详情 | 详情 | |
| (IV) | 66982 | 2-(1H-Imidazol-1-yl)acetic acid | 22884-10-2 | C5H6N2O2 | 详情 | 详情 |