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【结 构 式】 
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【药物名称】Alvameline tartrate, LU-25-109(free base), LU-25-109T 【化学名称】2-Ethyl-5-(1-methyl-1,2,3,6-tetrahydropyridin-5-yl)-2H-tetrazole L-(+)-tartrate 【CA登记号】159792-14-0, 120241-31-8 (free base), 120241-32-9 (oxalate (1:1)) 【 分 子 式 】C13H21N5O6 【 分 子 量 】343.34222 |
【开发单位】Lundbeck (Originator), Forest (Licensee) 【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, RENAL-UROLOGIC DRUGS, Urinary Incontinence Therapy, Muscarinic M1 Agonists, Muscarinic M2 Antagonists, Muscarinic M3 Antagonists |
合成路线1
The methylation of 3-cyanopyridine (I) with methyl iodide in acetone gives 3-cyano-1-methylpyridinium iodide (II), which is reduced with NaBH4 in methanol/water yielding 1-methyl-1,2,5,6-tetrahydropyridine-3-carbonitrile (III). The reaction of (III) with ethyl chloroformate and K2CO3 in 1,1,1-trichloroethane affords 3-cyano-1,2,5,6-tetrahydropyridine-1-carboxylic acid ethyl ester (IV), which is cyclized with sodium azide by means of AlCl3 in refluxing THF giving tetrazole (V). Alkylation of (V) with ethyl iodide and NaOH in refluxing acetone, followed by column chromatography, yields 3-(2-ethyltetrazol-5-yl)-1,2,5,6-tetrahydropyridine-1-carboxylic acid ethyl ester (VI). The decarboxylation of (VI) with HBr in acetic acid affords 2-ethyl-5-(1,2,5,6-tetrahydropyridin-3-yl)tetrazole (VII), which is methylated with formaldehyde/formic acid or with methyl iodide to give 2-ethyl-5-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)tetrazole (VIII). Finally, this compound is treated with L-(+)-tartaric acid.
| 【1】 Pedersen, H.; Bogeso, K.P.; Moltzen, E.K.; et al.; Bioisosteres of arecoline: 1,2,3,6-Tetrahydro-5-pyridyl-substituted and 3-piperidyl-substituted derivatives of tetrazoles and 1,2,3-triazoles. Synthesis and muscarinic activity. J Med Chem 1994, 37, 24, 4085-99. |
| 【2】 Castañer, J.; Mucke, H.A.M.; LU-25-109T. Drugs Fut 1998, 23, 8, 843-846. |
| 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) | 14062 | Nicotinonitrile; 3-Cyanopyridine | 100-54-9 | C6H4N2 | 详情 | 详情 |
| (II) | 17511 | 3-Cyano-1-methylpyridinium iodide | 1004-16-6 | C7H7IN2 | 详情 | 详情 |
| (III) | 17512 | 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarbonitrile | C7H10N2 | 详情 | 详情 | |
| (IV) | 17513 | ethyl 5-cyano-3,6-dihydro-1(2H)-pyridinecarboxylate | C9H12N2O2 | 详情 | 详情 | |
| (V) | 17514 | ethyl 5-(2H-1,2,3,4-tetraazol-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C9H13N5O2 | 详情 | 详情 | |
| (VI) | 17515 | ethyl 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate | C11H17N5O2 | 详情 | 详情 | |
| (VII) | 17516 | 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-1,2,3,6-tetrahydropyridine | C8H13N5 | 详情 | 详情 | |
| (VIII) | 17517 | 5-(2-ethyl-2H-1,2,3,4-tetraazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine | C9H15N5 | 详情 | 详情 | |
| (IX) | 16695 | (2S,3S)-2,3-dihydroxybutanedioic acid; D-(-)-Tartaric Acid; D-Tartaric Acid; (2S,3S)-2,3-dihydroxysuccinic acid | 147-71-7 | C4H6O6 | 详情 | 详情 |