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【结 构 式】 
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【药物名称】Xanomeline, Hexyloxy-TZTP, NNC-11-0232, LY-246708, Lumeron, Memcor 【化学名称】3-Hexyloxy-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole 【CA登记号】131986-45-3, 152854-19-8 (monotartrate), 141064-23-5 (oxalate salt) 【 分 子 式 】C14H23N3OS 【 分 子 量 】281.42291 |
【开发单位】Lilly (Originator), Novo Nordisk (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS |
合成路线1
The reaction of pyridine-3-carbaldehyde (I) with KCN in acetic acid, followed by a treatment with NH4Cl in aqueous NH4OH yields 2-amino-2-(3-pyridyl)acetonitrile (II), which is cyclized to 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (III) by a treatment with S2Cl2 in DMF. The reaction of (III) with sodium hexyloxide in hexanol yields 3-(hexyloxy)-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is treated with methyl iodide in acetone to afford the corresponding N-methylpyridinium salt (V). Finally, this compound is hydrogenated with NaBH4 in ethanol and salified with oxalic or L-tartaric acid in acetone or isopropanol.
| 【1】 Graul, A.; Castaner, J.; Xanomeline. Drugs Fut 1996, 21, 9, 911. |
| 【2】 Sauerberg, P.; Olesen, P.H. (Ferrosan A/S); Piperidine cpds. and their preparation and use. EP 0384288; US 5260311; US 5264444; US 5328925 . |
| 【3】 Sauerberg, P.; Olesen, P.H.; Mitch, c.H. (Novo Nordisk A/S); Heterocyclic cpds. and their preparation and use. EP 0687265; JP 1996507298; WO 9420495 . |
| 【4】 Osborne, L.M.; Shipley, L.A.; Treppendahl, S.; Petersen, T.G. (Novo Nordisk A/S); Heterocyclic chemistry. US 5834495; WO 9429303 . |
| 【5】 Sauerberg, P.; Olesen, P.H.; Nielsen, S.; et al.; Novel functional M1selective muscarinic agonists. Synthesis and structure-activity relationships of 3-(1,2,5-thiadiazolyl)-1,2,5,6-tetrahydro-1-methylpyridines. J Med Chem 1992, 35, 12, 2274-83. |
| 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) | 12849 | Nicotinaldehyde; 3-Pyridinecarboxaldehyde | 500-22-1 | C6H5NO | 详情 | 详情 |
| (II) | 16175 | 2-amino-2-(3-pyridinyl)acetonitrile | C7H7N3 | 详情 | 详情 | |
| (III) | 16176 | 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine | C7H4ClN3S | 详情 | 详情 | |
| (IV) | 16177 | 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]pyridine; hexyl 4-(3-pyridinyl)-1,2,5-thiadiazol-3-yl ether | C13H17N3OS | 详情 | 详情 | |
| (V) | 16178 | 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1-methylpyridinium iodide | C14H20IN3OS | 详情 | 详情 |