【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% |
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 |