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【结 构 式】 
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【药物名称】Milameline hydrochloride, Miramelin, CI-979, RU-35926, PD-129409 【化学名称】(E)-1-Methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde O-methyloxime monohydrochloride 【CA登记号】139886-04-7, 139886-32-1 (free base), 114485-39-1 (free base; undefined stereoch.), 114485-44-8 (undefined stereoch.) 【 分 子 式 】C8H15ClN2O 【 分 子 量 】190.67455 |
【开发单位】Aventis Pharma (Originator), Pfizer (Originator) 【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Muscarinic M1 Agonists |
合成路线1
Milameline can be obtained by three related ways: 1) By reaction of 1-methyl-1,2,3,6-tetrahydropyridine-3-carbaldehyde (I) with methoxyamine by means of triethylamine in DMF. 2) The reaction of pyridine-3-carbaldehyde (II) with methoxyamine in refluxing methanol gives the corresponding oxime (III), which is alkylated with methyl iodide in refluxing ethyl acetate yielding 3-(methoxyiminomethyl)-1-methylpyridinium iodide (IV). Finally, this compound is hydrogenated with NaBH4 in methanol/water. 3) The reaction of 1,2,3,6-tetrahydropyridine-3-carbaldehyde (V) with methoxyamine gives the corresponding oxime (VI), which is then alkylated with methyl iodide in DMF.
| 【1】 Souda, S.; Ueda, N.; Miyazawa, S.; Tagami, K.; Nomoto, S.; Okita, M.; Shimomura, N.; Kaneko, T.; Fujimoto, M.; Murakami, M.; Oketani, K.; Fujisaki, H.; Shibata, H.; Wakabayashi, T. (Eisai Co., Ltd.); Pyridine derivs., pharmaceutical compsns. comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventative value, and a process for preparing the same. AU 8781138; EP 0268956; EP 0475456; EP 0654471; EP 0786461; JP 1989006270; JP 1993247035; JP 1995291967; US 5045552; US 5998445 . |
| 【2】 Graul, A.; Castaner, J.; Milameline Hydrochloride. Drugs Fut 1996, 21, 11, 1124. |
| 【3】 Bergmeier, S.C.; Downs, D.A.; Moos, W.H.; Moreland, D.W.; Tecle, H. (Pfizer Inc.); O-Substd. tetrahydropyridine oxime cholinergic agents. AU 8781102; EP 0271798; JP 1988215664; US 4710508 . |
| 【4】 Galliani, G.; Barzaghi, F.; Butti, A.; Bonetti, C.; Toja, E. (Aventis Pharma SA); 1,2,5,6-Tetrahydropyridine-3-carboxaldehyde oxime derivs., process for their preparation, their application as medicaments and compsns. containing them. EP 0239445; JP 1987252767; US 5219872 . |
| 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) | 12848 | 1-Methyl-1,2,5,6-tetrahydro-3-pyridinecarbaldehyde | C7H11NO | 详情 | 详情 | |
| (II) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (III) | 12850 | Nicotinaldehyde O-methyloxime | C7H8N2O | 详情 | 详情 | |
| (IV) | 12851 | 3-[(Methoxyimino)methyl]-1-methylpyridinium iodide | C8H11IN2O | 详情 | 详情 | |
| (V) | 12852 | 1,2,5,6-Tetrahydro-3-pyridinecarbaldehyde | C6H9NO | 详情 | 详情 | |
| (VI) | 12853 | 1,2,5,6-Tetrahydro-3-pyridinecarbaldehyde O-methyloxime | C7H12N2O | 详情 | 详情 |