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【结 构 式】

【分子编号】47138

【品名】4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether

【CA登记号】

【 分 子 式 】C12H17NO

【 分 子 量 】191.27312

【元素组成】C 75.35% H 8.96% N 7.32% O 8.36%

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)

Protected piperidone (I) is condensed with methoxybromobenzene (II) via Grignard reaction by means of Mg and catalytic iodine in refluxing THF, and the resulting alcohol is then dehydrated with refluxing HCl in dioxane to afford compound (III). Hydrogenation of tetrahydropyridine (III) over Pd/C in EtOH yields piperidine derivative (IV), which is then demethylated with aqueous HBr to provide phenol (V). Condensation of (V) with 4-fluorobenzoyl chloride (VI) by means of NaOH in iPrOH/MeOH/H2O furnishes N-benzoylpiperidine derivative (VII), which is converted into the desired product by reaction with ethyl 2-bromo-2-methylpropanoate (VIII) by means of K2CO3 followed by hydrolysis with NaOH in H2O/MeOH/dioxane.

1 Komoto, T.; et al.; Preparation of new fibrates with piperidine ring and the pharmacological activity. 20th Symp Med Chem (Dec 6 2000, Tokyo) 2000, Abst 2P-06.
2 Komoto, T.; et al.; New strong fibrates with piperidine moiety. Chem Pharm Bull 2000, 48, 12, 1978.
3 Komoto, T.; Hirota, H.; Sato, S.; Othsuka, M.; Koya, H.; Mizuno, H.; Kuraishi, T. (SSP Co., Ltd.); Arylamide derivs.. EP 0607536; JP 1995053517; US 5411972 .
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) 15720 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one 3612-20-2 C12H15NO 详情 详情
(II) 35983 m-bromoanisole; 1-Bromo-3-methoxybenzene; 3-Bromoanisole; 3-Bromophenyl methyl ether 2398-37-0 C7H7BrO 详情 详情
(III) 47137 1-benzyl-4-(3-methoxyphenyl)-1,2,3,6-tetrahydropyridine; 3-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)phenyl methyl ether C19H21NO 详情 详情
(IV) 47138 4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether C12H17NO 详情 详情
(V) 47139 3-(4-piperidinyl)phenol C11H15NO 详情 详情
(VI) 17263 4-fluorobenzoyl chloride 403-43-0 C7H4ClFO 详情 详情
(VII) 47140 (4-fluorophenyl)[4-(3-hydroxyphenyl)-1-piperidinyl]methanone C18H18FNO2 详情 详情
(VIII) 39799 ethyl 2-bromo-2-methylpropanoate 600-00-0 C6H11BrO2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

The Hantzsch cyclization of 3-nitrobenzaldehyde (I), methyl acetoacetate (II) and NH4OAc in refluxing ethanol or isopropanol gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (III), which is reduced with H2 over sulfided carbon in ethanol or with Fe/NH4Cl in methanol/water to yield the corresponding amino derivative (IV). The reaction of (IV) with methyl chloroformate and pyridine in acetonitrile/dichloromethane affords the carbamate (V), which is treated with B-chlorocatecholborane in refluxing THF to provide the corresponding isocyanate (VI). Finally, this compound is condensed with 3-[4-(3-methoxyphenyl)piperidin-1-yl]propylamine (VII) in dichloromethane to furnish the target urea. The intermediate 3-[4-(3-methoxyphenyl)piperidin-1-yl]propylamine (VII) is obtained by condensation of 4-(3-methoxyphenyl)piperidine (VIII) with acrylonitrile (IX) in refluxing acetonitrile to give 3-[4-(3-methoxyphenyl)piperidin-1-yl]propionitrile (X), which is reduced with H2 over Raney-Ni in methanol/aq. NH3.

1 Poindexter, G.S.; et al.; Dihydropyridine neuropeptide Y Y1 receptor antagonists. Bioorg Med Chem Lett 2002, 12, 3, 379.
2 Poindexter, G.S.; Bruce, M.; Johnson, G.; leBoulluec, K.; Sloan, C.P. (Bristol-Myers Squibb Co.); Dihydropyridine NPY antagonists: Piperidine derivs.. CA 2177110; EP 0747357; JP 1997003045; US 5668151 .
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) 12646 3-Nitrobenzaldehyde 99-61-6 C7H5NO3 详情 详情
(II) 11791 methyl 3-oxobutanoate; Methyl acetoacetate 105-45-3 C5H8O3 详情 详情
(III) 12667 dimethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate; 2,6-Dimethyl-4-(3-nitro-ph)-1,4-2h-pyridine-3,5-dicarboxylic acid dimethyl ester 21881-77-6 C17H18N2O6 详情 详情
(IV) 55440 dimethyl 4-(3-aminophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate C17H20N2O4 详情 详情
(V) 55441 dimethyl 4-{3-[(methoxycarbonyl)amino]phenyl}-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate C19H22N2O6 详情 详情
(VI) 55442 dimethyl 4-(3-isocyanatophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate C18H18N2O5 详情 详情
(VII) 55443 3-[4-(3-methoxyphenyl)-1-piperidinyl]-1-propanamine; 3-[4-(3-methoxyphenyl)-1-piperidinyl]propylamine C15H24N2O 详情 详情
(VIII) 47138 4-(3-methoxyphenyl)piperidine; methyl 3-(4-piperidinyl)phenyl ether C12H17NO 详情 详情
(IX) 10847 Acrylonitrile 107-13-1 C3H3N 详情 详情
(X) 55444 3-[4-(3-methoxyphenyl)-1-piperidinyl]propanenitrile C15H20N2O 详情 详情
Extended Information