Nibentan, HE-11
N-[5-(二乙胺)-1-苯基戊基]-4-硝基苯甲酰盐酸盐Chemical Name: (?-N-[5-(Diethylamino)-1-phenylpentyl]-4-nitrobenzamide hydrochloride
CAS No. 150491-98-8, 150492-05-0 ((-)-enantiomer), 150492-02-7 ((-)-enantiomer, free base), 150492-04-9 ((+)-enantiomer), 150492-03-8 ((+)-enantiomer, free base), 150491-97-7 (free base), 157832-56-9 (undefined stereoch.), 157832-55-8 (undefined stereoch., free b
项目整合开发状态: Phase II
项目研究机构: Center for Chemistry of Drugs (Originator), Russian Academy of Medical Sciences (Originator)
合成路线:Nibentan is obtained as illustrated in Scheme 22645801a:Phenylacetonitrile (I) is condensed with diethyl carbonate by means of sodium ethylate in toluene to give sodium (ethoxycarbonyl)cyanophenylmethanate (II).Subsequent alkylation of (II) with 1,4-dibromobutane provides 5-bromo-1-(ethoxycarbonyl)-1-cyano-1-phenylpentane (III).Treatment of (III) with diethylamine gives 1-(ethoxycarbonyl)-1-cyano-5-(diethylamino)-1-phenylpentane (IV),which is decarboxylated with aqueous KOH in the presence of triethylbenzylammonium chloride to 1-cyano-5-(diethylamino)-1-phenylpentane (V).The reaction of (V) with H2O2 in dimethylsulfoxide gives 1-carbamoyl-5-(diethylamino)-1-phenylpentane (VI),which is rearranged to 1-(methoxycarbonylamino)-5-(diethylamino)-1-phenylpentane (VII) according to Hoffman reaction by means of bromine and sodium methylate in methanol.Hydrolysis of (VII) with NaOH in ethanol provides amine (VIII).Subsequent coupling of (VIII) with 4-nitrobenzoyl chloride in acetonitrile yields nibentan.
📌 参考资料/链接：
参考文献标题:The method of preparation of hydrochloride 1-phenyl-1-p-nitrobenzoylamino-5-N,N-diethylaminopentane and 1-phenyl-1-amino-5-N,N-diethylaminopentane
文献作者:Glushkov,R.G.; Lvov,A.I.; Davidova,N.K.; Sizova,O.S.; Sanzarova,G.M.; Polakova,M.J.; Skachilova,S.J.; Zeltuchin,N.K.; Cherkasova,E.M.
参考来源:SU 2059612
📄 详细内容
合成路线:Nibentan is obtained as illustrated in Scheme 22645801a:Phenylacetonitrile (I) is condensed with diethyl carbonate by means of sodium ethylate in toluene to give sodium (ethoxycarbonyl)cyanophenylmethanate (II).Subsequent alkylation of (II) with 1,4-dibromobutane provides 5-bromo-1-(ethoxycarbonyl)-1-cyano-1-phenylpentane (III).Treatment of (III) with diethylamine gives 1-(ethoxycarbonyl)-1-cyano-5-(diethylamino)-1-phenylpentane (IV),which is decarboxylated with aqueous KOH in the presence of triethylbenzylammonium chloride to 1-cyano-5-(diethylamino)-1-phenylpentane (V).The reaction of (V) with H2O2 in dimethylsulfoxide gives 1-carbamoyl-5-(diethylamino)-1-phenylpentane (VI),which is rearranged to 1-(methoxycarbonylamino)-5-(diethylamino)-1-phenylpentane (VII) according to Hoffman reaction by means of bromine and sodium methylate in methanol.Hydrolysis of (VII) with NaOH in ethanol provides amine (VIII).Subsequent coupling of (VIII) with 4-nitrobenzoyl chloride in acetonitrile yields nibentan.
参考文献标题:Nibentan
文献作者:Glushkov,R.G,Mashkovski,M.C.; Yuzhakov,S.D.
参考来源:Drugs Fut 1997,22(1),30
合成路线:Nibentan is obtained as illustrated in Scheme 22645801a:Phenylacetonitrile (I) is condensed with diethyl carbonate by means of sodium ethylate in toluene to give sodium (ethoxycarbonyl)cyanophenylmethanate (II).Subsequent alkylation of (II) with 1,4-dibromobutane provides 5-bromo-1-(ethoxycarbonyl)-1-cyano-1-phenylpentane (III).Treatment of (III) with diethylamine gives 1-(ethoxycarbonyl)-1-cyano-5-(diethylamino)-1-phenylpentane (IV),which is decarboxylated with aqueous KOH in the presence of triethylbenzylammonium chloride to 1-cyano-5-(diethylamino)-1-phenylpentane (V).The reaction of (V) with H2O2 in dimethylsulfoxide gives 1-carbamoyl-5-(diethylamino)-1-phenylpentane (VI),which is rearranged to 1-(methoxycarbonylamino)-5-(diethylamino)-1-phenylpentane (VII) according to Hoffman reaction by means of bromine and sodium methylate in methanol.Hydrolysis of (VII) with NaOH in ethanol provides amine (VIII).Subsequent coupling of (VIII) with 4-nitrobenzoyl chloride in acetonitrile yields nibentan.
合成路线:The condensation of 4-nitrophenylacetonitrile (I) with diethyl carbonate by means of sodium ethylate in toluene gave the intermediate arylcyanoacetate sodium salt (II) that was further alkylated with 1,4-dibromobutane (III) to yield the bromobutyl derivative (IV).Subsequent treatment of bromide (IV) with diethylamine provided amine (V).Decarbethoxylation of the cyanoester group of (V) to give (VI) was carried out using aqueous KOH in the presence of benzyltriethylammonium chloride.Partial hydrolysis of the nitrile group of (VI) by means of potassium hydroperoxide in DMSO afforded amide (VII).This was subjected to Hoffman rearrangement by means of Br2 and NaOEt to produce carbamate (VIII),which was subsequently hydrolyzed to amine (IX) with KOH.This was finally coupled with benzoyl chloride to furnish the title benzamide.
参考文献标题:Synthesis and antifibrillatory activity of nibentan and its analogues
文献作者:Mashkovskiy,M.D.; Yurhakov,S.D.; Davydova,N.K.; Sizova,O.S.; Vinogradova,S.M.; L'vov,A.I.; Glushov,R.G.; Yuzhakov,S.D.; Mashkovskiy MD.
参考来源:Eur J Med Chem 2000,35(2),205
产品链接: CAS No. 150491-98-8››