|
【结 构 式】 
|
【药物名称】Astemizole, MJD-30, R-43512, Hismanal 【化学名称】1-(4-Fluorobenzyl)-2-[1-(4-methoxyphenethyl)piperidin-4-ylamino]benzimidazole 【CA登记号】68844-77-9 【 分 子 式 】C28H31FN4O 【 分 子 量 】458.58387 |
【开发单位】Janssen (Originator), Mochida (Licensee) 【药理作用】Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Histamine H1 Antagonists |
合成路线1
The reaction of 1-isothiocyanato-2-nitrobenzene (I) with ethyl 4-aminopiperidine-1-carboxylate (II) in ethanol gives N-(2-nitrophenyl)-N'-(1-ethoxycarbonyl-4-piperidyl)thiourea (III), which is reduced with H2 over Pd/C in methanol saturated with NH3 to afford N-(2-aminophenyl)-N'-(1-ethoxycarbonyl-4-piperidyl)thiourea (IV). The cyclization of (IV) with iodomethane in refluxing ethanol yields 2-(1-ethoxycarbonyl-4-piperidylamino)benzimidazole (V), which is then condensed with 4-fluorobenzyl chloride (VI) by means of Na2CO3 in hot DMF to yield 1-(fluorobenzyl)-2-(1-ethoxycarbonyl-4-piperidylamino)benzimidazole (VII). The decarboxylative hydrolysis of (VII) with 48% HBr in refluxing acetic acid gives 1-(p-fluorobenzyl)-2-(4-piperidylamino)benzimidazole (VIII), which is finally condensed with p-methoxyphenylethyl methanesulfonate (IX) by means of Na2CO3 - KI in hot DMF.
| 【1】 Janssens, F.; Stokbroekx, R.; Torremans, J.; Luyckx, M. (Janssen Pharmaceutica NV); N-Heterocyclyl-4-piperidinamines. EP 0005318 . |
| 【2】 Blancafort, P.; Hillier, K.; Serradell, M.N.; Castaner, J.; Astemizole. Drugs Fut 1982, 7, 1, 10. |
| 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) | 37061 | 1-isothiocyanato-2-nitrobenzene; 2-nitrophenyl isothiocyanate | 2719-30-4 | C7H4N2O2S | 详情 | 详情 |
| (II) | 37062 | 4-amino-N-carbethoxypiperidine; ethyl 4-amino-1-piperidinecarboxylate | 58859-46-4 | C8H16N2O2 | 详情 | 详情 |
| (III) | 37063 | ethyl 4-[[(2-nitroanilino)carbothioyl]amino]-1-piperidinecarboxylate | C15H20N4O4S | 详情 | 详情 | |
| (IV) | 37064 | ethyl 4-[[(2-aminoanilino)carbothioyl]amino]-1-piperidinecarboxylate | C15H22N4O2S | 详情 | 详情 | |
| (V) | 37065 | ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate | C15H20N4O2 | 详情 | 详情 | |
| (VI) | 12354 | 4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene | 352-11-4 | C7H6ClF | 详情 | 详情 |
| (VII) | 37066 | ethyl 4-[[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate | C22H25FN4O2 | 详情 | 详情 | |
| (VIII) | 37067 | 1-(4-fluorobenzyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine; N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-N-(4-piperidinyl)amine | C19H21FN4 | 详情 | 详情 | |
| (IX) | 37068 | [(4-methoxyphenethyl)oxy](methyl)dimethylene-lambda(6)-sulfane; methyl 4-(2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)phenyl ether | C12H18O2S | 详情 | 详情 |