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【结 构 式】 
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【分子编号】35528 【品名】1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether 【CA登记号】1462-37-9 |
【 分 子 式 】C9H11BrO 【 分 子 量 】215.08974 【元素组成】C 50.26% H 5.15% Br 37.15% O 7.44% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of monolabeled diethyl malonate (I) with 2-benzyloxyethyl bromide (II) by means of NaH in refluxing THF gives the corresponding benzyloxyethyl derivative (III), which is reduced with LiAlH4 in ethyl ether yielding the diol (IV). The protection of (IV) by reaction with 2,2-dimethoxypropane (V) and p-toluenesulfonic acid affords the 1,3-dioxane (VI), which is debenzylated with H2 over Pd/C in THF giving the alcohol (VII). The reaction of (VII) with CBr4 and PPh3 in DMF yields the bromide (VIII), which is condensed with the purine (IX) by means of K2CO3 in DMF affording the expected purin-9-yl derivative (X). The hydrolysis of the 1,3-dioxane group with AcOH /water gives the diol (XI), which is monoacylated with isopropyl chloroformate (XII) by means of cool pyridine yielding the mixture of regioisomers (XIII), (XIV). Finally, this mixture is dechlorinated with ammonium formate over Pd/C in refluxing methanol afffording the target compound also as a mixture of regioisomers.
| 【1】 Kim, D.K.; et al.; Synthesis of carbon-14 labelled 2-amino-9-(3-hydroxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (SK 1875), a potential prodrug of penciclovir. J Label Compd Radiopharm 1999, 42, 6, 597. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII),(VIII) | 10916 | 2-(2,2-Dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (XIII),(XIV) | 35533 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 | |
| (I) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (I) | 45348 | diethyl malonate | C7H12O4 | 详情 | 详情 | |
| (II) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |
| (III) | 35529 | diethyl 2-[2-(benzyloxy)ethyl]malonate | C16H22O5 | 详情 | 详情 | |
| (III) | 45349 | diethyl 2-[2-(benzyloxy)ethyl]malonate | C16H22O5 | 详情 | 详情 | |
| (IV) | 35523 | 2-[2-(benzyloxy)ethyl]-1,3-propanediol | C12H18O3 | 详情 | 详情 | |
| (IV) | 45350 | 2-[2-(benzyloxy)ethyl]-1,3-propanediol | C12H18O3 | 详情 | 详情 | |
| (V) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (VI) | 35530 | 5-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxane; benzyl 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl ether | C15H22O3 | 详情 | 详情 | |
| (VI) | 45351 | 5-[2-(benzyloxy)ethyl]-2,2-dimethyl-1,3-dioxane; benzyl 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl ether | C15H22O3 | 详情 | 详情 | |
| (VII) | 45352 | 2-(2,2-dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (VIII) | 45353 | 2-(2,2-dimethyl-1,3-dioxan-5-yl)-1-ethanol | C8H16O3 | 详情 | 详情 | |
| (IX) | 11644 | 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine | 10310-21-1 | C5H4ClN5 | 详情 | 详情 |
| (X) | 35531 | 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine | C13H18ClN5O2 | 详情 | 详情 | |
| (X) | 45354 | 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-amine; 6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]-9H-purin-2-ylamine | C13H18ClN5O2 | 详情 | 详情 | |
| (XI) | 35532 | 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-propanediol | C10H14ClN5O2 | 详情 | 详情 | |
| (XI) | 45355 | 2-[2-(2-amino-6-chloro-9H-purin-9-yl)ethyl]-1,3-propanediol | C10H14ClN5O2 | 详情 | 详情 | |
| (XII) | 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 |
| (XIII) | 45356 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 | |
| (XIV) | 45357 | 4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)butyl isopropyl carbonate | C14H20ClN5O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The condensation of desoxybenzoin (I) with tetrahydropyranyl ether (II) in aq. 48% NaOH containing TEBAC gives 1,2-diphenyl-4-(tetrahydropyranyloxy)-1-butanone (III), which by a Grignard condensation with 4-methoxyphenylmagnesium bromide (IV) in THF yields the monoprotected triphenylbutanediol (V). The deprotection of (V) with H2SO4 in ethanol/water at room temperature affords the triphenylbutane-1,4-diol (VI), which is cyclized with H2SO4 in hot ethanol/water to provide 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran (VII). The reaction of (VII) with 48% HBr in refluxing acetic acid gives a mixture of (E)- and (Z)-4-(4-hydroxyphenyl)-3,4-diphenyl-1-butanol that is separated by chemical working up to obtain the desired (Z)-isomer (VIII). The condensation of the phenolic OH of (VIII) with benzyl protected 2-bromoethanol (IX) by means of NaOH and tetrabutylammonium bromide in refluxing toluene/water gives the benzyloxyethyl ether (X). The reaction of the aliphatic OH group of (X) with PPh3 and CCl4 in acetonitrile yields the corresponding chloro derivative (XI), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethyl acetate/ethanol.
| 【1】 Toivola, R.J.; Karjalainen, A.J.; Kurkela, K.O.A.; Soderwall, M.-L.; Kangas, L.V.M.; Blanco, G.L.; Sundquist, H.K. (Orion Corporation); Tri-phenyl alkene derivs. and their oestrogenic, anti-oestrogenic and progestanic uses. US 4996225; US 5491173 . |
| 【2】 Härkönen, P.; Miettinen, T.; Mäntylä, E.; Kangas, L.; DeGregorio, M. (Orion Corporation); Serum cholesterol lowering agent. WO 9732574 . |
| 【3】 Laine, A.; Degregorio, M.; Harkonen, P.; Wiebe, V.; Vaananen, K.; Kangas, L.V.M. (Orion Corporation); Triphenylethylenes for the prevention and treatment of osteoporosis. WO 9607402 . |
| 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) | 41003 | 1,2-diphenyl-1-ethanone; Deoxybenzoin-2-phenylacetophenone; Dexybenzoin | 451-40-1 | C14H12O | 详情 | 详情 |
| (II) | 26934 | 2-bromoethyl tetrahydro-2H-pyran-2-yl ether | C7H13BrO2 | 详情 | 详情 | |
| (III) | 52021 | 1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanone | C21H24O3 | 详情 | 详情 | |
| (IV) | 37674 | Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide | 352-13-6 | C7H7BrMgO | 详情 | 详情 |
| (V) | 52022 | 1-(4-methoxyphenyl)-1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanol | C28H32O4 | 详情 | 详情 | |
| (VI) | 52023 | 1-(4-methoxyphenyl)-1,2-diphenyl-1,4-butanediol | C23H24O3 | 详情 | 详情 | |
| (VII) | 52024 | 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran; 4-(2,3-diphenyltetrahydro-2-furanyl)phenyl methyl ether | C23H22O2 | 详情 | 详情 | |
| (VIII) | 52025 | 4-[(Z)-4-hydroxy-1,2-diphenyl-1-butenyl]phenol | C22H20O2 | 详情 | 详情 | |
| (IX) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |
| (X) | 52026 | (Z)-4-[4-[2-(benzyloxy)ethoxy]phenyl]-3,4-diphenyl-3-buten-1-ol | C31H30O3 | 详情 | 详情 | |
| (XI) | 52027 | 1-[2-(benzyloxy)ethoxy]-4-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]benzene; benzyl 2-[4-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy]ethyl ether | C31H29ClO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of desoxybenzoin (I) with 2-(benzyloxy)ethyl bromide (II) by means of aqueous 48% NaOH containing triethylbenzylammonium chloride (TEBAC) gives 4-(benzyloxy)-1,2-diphenyl-1-butanone (III), which by reaction with the Grignard reagent (IV) - prepared from 4-(tetrahydropyranyloxy)phenyl bromide (V) and Mg in THF - yields the triphenylbutanol derivative (VI). Elimination of the THP-protecting group of compound (VI) by means of H2SO4 in ethanol/water at room temperature affords the triphenylbutanol derivative (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the butane-1,4-diol derivative (VIII). Cyclization of the butane-1,4-diol (VIII) by means of H2SO4 in hot ethanol/water gives 2-(4-hydroxyphenyl)-2,3-diphenyltetrahydrofuran (IX), which is treated with 48% HBr in refluxing AcOH to yield a mixture of (E)- and (Z)-4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (X), which is separated by chemical work up. The phenolic OH group of the desired (Z)-isomer (X) is condensed with 2-(benzyloxy)ethyl bromide (II) by means of NaOH and tetrabutylammonium bromide in refluxing toluene/ water to afford the benzyloxyethyl ether (XII). Reaction of the aliphatic OH group of ether (XII) with PPh3 and CCl4 in acetonitrile provides the corresponding chloro derivative (XIII), which is finally debenzylated with H2 over Pd/C in ethyl acetate/ethanol.
| 【1】 Sorbera, L.A.; Castaner, J.; Bayes, M.; Ospemifene. Drugs Fut 2004, 29, 1, 38. |
| 【2】 Toivola, R.J.; Karjalainen, A.J.; Kurkela, K.O.A.; Soderwall, M.-L.; Kangas, L.V.M.; Blanco, G.L.; Sundquist, H.K. (Orion Corporation); Tri-phenyl alkene derivs. and their oestrogenic, anti-oestrogenic and progestanic uses. US 4996225; US 5491173 . |
| 【3】 Laine, A.; Degregorio, M.; Harkonen, P.; Wiebe, V.; Vaananen, K.; Kangas, L.V.M. (Orion Corporation); Triphenylethylenes for the prevention and treatment of osteoporosis. WO 9607402 . |
| 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) | 41003 | 1,2-diphenyl-1-ethanone; Deoxybenzoin-2-phenylacetophenone; Dexybenzoin | 451-40-1 | C14H12O | 详情 | 详情 |
| (II) | 35528 | 1-[(2-bromoethoxy)methyl]benzene; benzyl 2-bromoethyl ether | 1462-37-9 | C9H11BrO | 详情 | 详情 |
| (III) | 63429 | 4-(benzyloxy)-1,2-diphenyl-1-butanone | C23H22O2 | 详情 | 详情 | |
| (IV) | 31255 | bromo[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]magnesium | C11H13BrMgO2 | 详情 | 详情 | |
| (V) | 63430 | 4-bromophenyl tetrahydro-2H-pyran-2-yl ether; 2-(4-bromophenoxy)tetrahydro-2H-pyran | C11H13BrO2 | 详情 | 详情 | |
| (VI) | 63431 | 4-(benzyloxy)-1,2-diphenyl-1-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-butanol | C34H36O4 | 详情 | 详情 | |
| (VII) | 63432 | 4-[4-(benzyloxy)-1-hydroxy-1,2-diphenylbutyl]phenol | C29H28O3 | 详情 | 详情 | |
| (VIII) | 63433 | 1-(4-hydroxyphenyl)-1,2-diphenyl-1,4-butanediol | C22H22O3 | 详情 | 详情 | |
| (IX) | 63434 | 4-(2,3-diphenyltetrahydro-2-furanyl)phenol | C22H20O2 | 详情 | 详情 | |
| (X) | 52025 | 4-[(Z)-4-hydroxy-1,2-diphenyl-1-butenyl]phenol | C22H20O2 | 详情 | 详情 | |
| (XII) | 52026 | (Z)-4-[4-[2-(benzyloxy)ethoxy]phenyl]-3,4-diphenyl-3-buten-1-ol | C31H30O3 | 详情 | 详情 | |
| (XIII) | 52027 | 1-[2-(benzyloxy)ethoxy]-4-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]benzene; benzyl 2-[4-[(Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy]ethyl ether | C31H29ClO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)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 |