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【结 构 式】

【分子编号】63436

【品名】1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether

【CA登记号】

【 分 子 式 】C7H7BrO

【 分 子 量 】187.03598

【元素组成】C 44.95% H 3.77% Br 42.72% O 8.55%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(IV)

The intermediate 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) has been obtained by several related ways: 1.- The condensation of 4-bromonitrobenzene (I) with piperazine (II) gives 1-(4-nitrophenyl)piperazine (III), which is condensed with 4-bromoanisole (IV) by means of Pdo to yield 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V). Alternatively, (V) can also be obtained by condensation of (III) with 4-methoxyphenylboronic acid (VI) by means of Cu(OAc)2 in DMSO. The demethylation of (V) with HBr yields 4-[4-(4-nitrophenyl)piperazin-1-yl]phenol (VII), which is finally reduced with H2 over Pd/C to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). 2.- The condensation of piperazine (II) with 4-bromoanisole (IV) by means of Pdo gives 1-(4-methoxyphenyl)piperazine (IX), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in hot DMSO to yield intermediate 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine (V), already reported. 3.- The condensation of piperazine (II) with 4-(benzyloxy)phenyl bromide (X) by means of Pdo gives 1-(4-benzyloxyphenyl)piperazine (XI), which is condensed with 4-bromonitrobenzene (I) by means of K2CO3 and TBAI in hot DMSO to yield 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII). The nitro group of (XII) is reduced by means of H2 (50 psi) over Pd/C in wet THF at 50? C to afford 4-[4-(4-benzyloxyphenyl)piperazin-1-yl]aniline (XIII), which is finally debenzylated with H2 (80 psi) over Pd/C in wet THF at 70? C or other drastic conditions to afford the target 4-[4-(4-aminophenyl)piperazin-1-yl]phenol (VIII) intermediate (see Synthline, scheme no. 22656202a, intermediate (XIV)). Alternatively, 1-(4-benzyloxyphenyl)-4-(4-nitrophenyl)piperazine (XII) can also be reduced directly to the target intermediate (VIII) with H2 over Pd/C under a variety of drastic conditions.

1 Hepperle, M.; Eckert, J.; Gala, D.; Shen, L.; Evans, C.A.; Goodman, A.; Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate. Tetrahedron Lett 2002, 43, 18, 3359.
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) 26628 1-bromo-4-nitrobenzene 99-99-0 C6H4BrNO2 详情 详情
(II) 10355 Diethylenediamine; Piperazine 110-85-0 C4H10N2 详情 详情
(III) 20299 1-(4-nitrophenyl)piperazine 6269-89-2 C10H13N3O2 详情 详情
(IV) 63436 1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether C7H7BrO 详情 详情
(V) 16314 methyl 4-[4-(4-nitrophenyl)piperazino]phenyl ether; 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine C17H19N3O3 详情 详情
(VI) 39246 4-methoxyphenylboronic acid 5720-07-0 C7H9BO3 详情 详情
(VII) 16345 4-[4-(4-nitrophenyl)piperazino]phenol C16H17N3O3 详情 详情
(VIII) 17110 4-[4-(4-aminophenyl)piperazino]phenol; 1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine; 1-(4-Hydroxyphenyl)-4-(4-aminophenyl)piperazine 74853-08-0 C16H19N3O 详情 详情
(IX) 16312 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether 38212-30-5 C11H16N2O 详情 详情
(X) 43156 1-(benzyloxy)-4-bromobenzene; benzyl 4-bromophenyl ether 6793-92-6 C13H11BrO 详情 详情
(XI) 64373 1-[4-(benzyloxy)phenyl]piperazine; benzyl 4-(1-piperazinyl)phenyl ether C17H20N2O 详情 详情
(XII) 64372 benzyl 4-[4-(4-nitrophenyl)-1-piperazinyl]phenyl ether; 1-[4-(benzyloxy)phenyl]-4-(4-nitrophenyl)piperazine C23H23N3O3 详情 详情
(XIII) 64371 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}aniline; 4-{4-[4-(benzyloxy)phenyl]-1-piperazinyl}phenylamine C23H25N3O 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XVII)

Condensation of desoxybenzoin (I) with 2-(tetra-hydropyranyloxy)ethyl bromide (XIV) by means of aqueous NaOH and TEBAC as before gives 1,2-diphenyl-4-(tetrahydropyranyloxy)-1-butanone (XV), which by a Grignard condensation with 4-methoxyphenylmagnesium bromide (XVI) -prepared from 4-bromoanisole (XVII) and Mg in THF- provides the triphenylbutanol derivative (XVIII). Cleavage of the THP-protecting group of compound (XVIII) with H2SO4 in ethanol/water at room temperature affords the butane-1,4-diol derivative (XIX), which is cyclized by means of H2SO4 in hot ethanol/ water to yield 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran (XX). Finally, this compound is treated with 48% HBr in refluxing AcOH to give 4-(4-hydroxyphenyl)-3,4-diphenyl-3-buten-1-ol (X) as a (Z):(E)-isomeric mixture, from which the desired (Z)-isomer is separated by chemical work up.

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 .
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
(X) 52025 4-[(Z)-4-hydroxy-1,2-diphenyl-1-butenyl]phenol C22H20O2 详情 详情
(XIV) 26934 2-bromoethyl tetrahydro-2H-pyran-2-yl ether C7H13BrO2 详情 详情
(XV) 52021 1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanone C21H24O3 详情 详情
(XVI) 37674 Bromo(4-methoxyphenyl)magnesium; 4-Methoxyphenylmagnesium bromide 352-13-6 C7H7BrMgO 详情 详情
(XVII) 63436 1-bromo-4-methoxybenzene; 4-bromophenyl methyl ether C7H7BrO 详情 详情
(XVIII) 52022 1-(4-methoxyphenyl)-1,2-diphenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanol C28H32O4 详情 详情
(XIX) 52023 1-(4-methoxyphenyl)-1,2-diphenyl-1,4-butanediol C23H24O3 详情 详情
(XX) 52024 2-(4-methoxyphenyl)-2,3-diphenyltetrahydrofuran; 4-(2,3-diphenyltetrahydro-2-furanyl)phenyl methyl ether C23H22O2 详情 详情
(XXI) 30343 1-(4-methoxyphenyl)-2-phenyl-1-ethanone C15H14O2 详情 详情
(XXII) 63437 1-(4-methoxyphenyl)-2-phenyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanone C22H26O4 详情 详情
(XXIII) 17616 bromo(phenyl)magnesium; Phenyl Magnesium Bromide 100-58-3 C6H5BrMg 详情 详情
Extended Information