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【结 构 式】 
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【分子编号】67997 【品名】ethyl 4-(2-chloroethyl)piperidine-4-carboxylate hydrochloride 【CA登记号】 |
【 分 子 式 】C10H18ClNO2.HCl 【 分 子 量 】256.172 【元素组成】C 46.87% H 7.47% Cl 27.68% N 5.47% O 12.49% |
合成路线1
该中间体在本合成路线中的序号：(VII)Alkylation of ethyl isonipecotate (I) with 1-bromo-2-chloroethane (II) in the presence of K2CO3 in acetone yields ethyl 1-(2-chloro-ethyl)piperidine-4-carboxylate (III), which by treatment with LDA in THF cyclizes to the quinuclidine derivative (IV) . Alternatively, quinuclidine (IV) can be prepared by alkylation of Boc-protected ethyl nipecotate (V) with 1-bromo-2-chloroethane (II) using LiHMDS in toluene to yield the 4-(2-chloroethyl)piperidine derivative (VI), which is then N-deprotected with HCl in water/dioxane, followed by cyclization of the resulting chloro amine (VII) by means of K2CO3 in refluxing toluene . Addition of phenyl lithium (VIII) to ester (IV) in THF affords 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (IX), which finally undergoes quaternization with benzyl 2-bromoethyl ether (X) in acetonitrile/chloroform .
| 【1】 Lainé, D.I., McCleland, B., Thomas, S. et al. Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists. J Med Chem 2009, 52(8): 2493-505. |
| 【2】 Lainé, D.I., Palovich, M.R., McCleland, B.W., Neipp, C.E., Thomas, S.M.(GlaxoSmithKline plc). Muscarinic acetylcholine receptor antagonists. CA 2564742, CN 102040602, EP 1740177, JP 2007534769, KR 2011010841, US 200785155, US 7498440, US 8183257, US 2012157491, US 8309572, US 2013030015, WO 2005104745. |
| 【3】 Carangio, A., Cheung, I., D’Souza, E.C.F., Leahy, J.H., Strachan, J.B. (GlaxoSmithKline plc). Methods of preparation of muscarinic acetylcholine receptor antagonists. WO 2011029896. |
| 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) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (II) | 24271 | 1-bromo-2-chloroethane | 107-04-0 | C2H4BrCl | 详情 | 详情 |
| (III) | 67994 | ethyl 1-(2-chloroethyl)piperidine-4-carboxylate | C10H18ClNO2 | 详情 | 详情 | |
| (IV) | 67995 | ethyl quinuclidine-4-carboxylate | C10H17NO2 | 详情 | 详情 | |
| (V) | 49847 | 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine | 142851-03-4 | C13H23NO4 | 详情 | 详情 |
| (VI) | 67996 | 1-tert-butyl 4-ethyl 4-(2-chloroethyl)piperidine-1,4-dicarboxylate | C15H26ClNO4 | 详情 | 详情 | |
| (VII) | 67997 | ethyl 4-(2-chloroethyl)piperidine-4-carboxylate hydrochloride | C10H18ClNO2.HCl | 详情 | 详情 | |
| (VIII) | 24014 | Phenyllithium | 591-51-5 | C6H5Li | 详情 | 详情 |
| (IX) | 67998 | diphenyl(quinuclidin-4-yl)methanol;1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol | C20H23NO | 详情 | 详情 | |
| (X) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |