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【结 构 式】 
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【药物名称】CDD-0273, CDD-0273-A 【化学名称】3,3'-Oxybis(ethyleneoxy)bis(ethyleneoxy)bis[4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazole] dihydrochloride 【CA登记号】331468-03-2, 331241-45-3 (free base) 【 分 子 式 】C24H38Cl2N6O5S2 【 分 子 量 】625.64166 |
【开发单位】UCB Pharma (Originator), University of Toledo (Originator) 【药理作用】Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Muscarinic M1 Agonists, Muscarinic M4 Agonists |
合成路线1
The reaction of pyridine-3-carbaldehyde (I) with KCN in HOAc/water gives the cyanohydrine (II), which is treated with NH4Cl and NH3 in water to yield 2-amino-2-(3-pyridyl)acetonitrile (III). The cyclization of (III) with S2Cl2 in DMF affords 3-chloro-4-(3-pyridyl)-1,2,5-thiadiazole (IV), which is condensed with tetraethyleneglycol (V) by means of NaH in THF to provide the disubstituted tetraethyleneglycol (VI). The methylation of the pyridine rings of (VI) with methyl iodide in acetone gives the bis N-methylpyridinium derivative (VII), which is finally selectively reduced with NaBH4 in methanol and treated with HCl in the same solvent to furnish the target bis-tetrahydropyridine compound, isolated as the dihydrochloride salt.
| 【1】 Rajeswaran, W.G.; Cao, Y.; Huang, X.-P.; et al.; Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists. J Med Chem 2001, 44, 26, 4563. |
| 【2】 Cao, Y.; Rajeswaran, W.G.; Messer, W.S. (University of Toledo); Muscarinic receptor agonists. US 6211204 . |
| 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) | 53579 | 2-hydroxy-2-(3-pyridinyl)acetonitrile | n/a | C7H6N2O | 详情 | 详情 |
| (III) | 16175 | 2-amino-2-(3-pyridinyl)acetonitrile | C7H7N3 | 详情 | 详情 | |
| (IV) | 16176 | 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine | C7H4ClN3S | 详情 | 详情 | |
| (V) | 53580 | Tetraethylene glycol; Tetraglycol | 112-60-7 | C8H18O5 | 详情 | 详情 |
| (VI) | 53581 | 3-[4-(2-{2-[2-(2-{[4-(3-pyridinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)ethoxy]ethoxy}ethoxy)-1,2,5-thiadiazol-3-yl]pyridine; 4-(3-pyridinyl)-1,2,5-thiadiazol-3-yl 2-{2-[2-(2-{[4-(3-pyridinyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)ethoxy]ethoxy}ethyl ether | n/a | C22H24N6O5S2 | 详情 | 详情 |
| (VII) | 53582 | 1-methyl-3-[4-(2-{2-[2-(2-{[4-(1-methyl-3-pyridiniumyl)-1,2,5-thiadiazol-3-yl]oxy}ethoxy)ethoxy]ethoxy}ethoxy)-1,2,5-thiadiazol-3-yl]pyridinium diiodide | n/a | C24H30I2N6O5S2 | 详情 | 详情 |