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【结 构 式】 
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【分子编号】16176 【品名】3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine 【CA登记号】 |
【 分 子 式 】C7H4ClN3S 【 分 子 量 】197.64768 【元素组成】C 42.54% H 2.04% Cl 17.94% N 21.26% S 16.22% |
合成路线1
该中间体在本合成路线中的序号：(III)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 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |