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【结 构 式】 
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【药物名称】Zanapezil fumarate, TAK-147 【化学名称】8-[3-(1-Benzylpiperidin-4-yl)propanoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine fumarate 【CA登记号】142852-50-4 (free base), 142852-51-5 (fumarate salt (1:1)) 【 分 子 式 】C29H36N2O5 【 分 子 量 】492.62067 |
【开发单位】Takeda (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Acetylcholinesterase Inhibitors |
合成路线1
The Friedel-Crafts condensation of 1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine (I) with 3-(1-acetylpiperidin-4-yl)propionyl chloride (II) by means of AlCl3 in 1,2-dichloroethane gives 3-(1-acetylpiperidin-4-yl)-1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone (III), which is deacetylated in refluxing concentrated aqueous HCl yielding 3-(piperidin-4-yl)-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone (IV). Finally, this compound is benzylated with benzyl bromide (V) and K2CO3 in ethanol affording the final product as free base, which is then treated with fumaric acid in MeOH/CH2Cl2.
| 【1】 Mealy, N.; Rabasseda, X.; Castaner, J.; TAK-147. Drugs Fut 1995, 20, 3, 248. |
| 【2】 Goto, G.; Ishihara, Y.; Miyamoto, M. (Takeda Chemical Industries, Ltd.); Condensed heterocyclic cpds., their production and use. EP 0487071; US 5273974 . |
| 【3】 Ishihara, Y.; Hirai, K.; Miyamoto, M.; Goto, G.; Central cholinergic agents. 6. Synthesis and evaluation of 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanones and their analogs as central selective acetylcholinesterase inhibitors. J Med Chem 1994, 37, 15, 2292-9. |
| 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) | 15970 | 1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-1-ethanone | C12H15NO | 详情 | 详情 | |
| (II) | 15971 | 3-(1-acetyl-4-piperidinyl)propanoyl chloride | C10H16ClNO2 | 详情 | 详情 | |
| (III) | 15972 | 3-(1-acetyl-4-piperidinyl)-1-(1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone | C22H30N2O3 | 详情 | 详情 | |
| (IV) | 15973 | 3-(4-piperidinyl)-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)-1-propanone | C18H26N2O | 详情 | 详情 | |
| (V) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |