Astemizole, MJD-30, R-43512, Hismanal-药物合成数据库

【药物名称】Astemizole, MJD-30, R-43512, Hismanal

化学结构式(Chemical Structure):

参考文献No.	42729
标题:	N-Heterocyclyl-4-piperidinamines
作者:	Janssens, F.; Stokbroekx, R.; Torremans, J.; Luyckx, M. (Janssen Pharmaceutica NV)
来源:	EP 0005318

合成路线图解说明: 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.

参考文献No.	201778
标题:	Astemizole
作者:	Blancafort, P.; Hillier, K.; Serradell, M.N.; Casta馿r, J.
来源:	Drugs Fut 1982,7(1),10

合成路线图解说明: 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.