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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 1 条

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
Extended Information