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【结 构 式】 
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【药物名称】BMS-193885 【化学名称】4-[3-[3-[3-[4-(3-Methoxyphenyl)piperidin-1-yl]propyl]ureido]phenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 【CA登记号】 【 分 子 式 】C33H42N4O6 【 分 子 量 】590.72589 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Anorexigenics, Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders, Neuropeptide Y1 (NPY Y1) Antagonists |
合成路线1
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 |