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【结 构 式】 
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【药物名称】Nibentan, HE-11 【化学名称】(±)-N-[5-(Diethylamino)-1-phenylpentyl]-4-nitrobenzamide hydrochloride 【CA登记号】150491-98-8, 150492-05-0 ((-)-enantiomer), 150492-02-7 ((-)-enantiomer, free base), 150492-04-9 ((+)-enantiomer), 150492-03-8 (( 【 分 子 式 】C22H30ClN3O3 【 分 子 量 】419.9557 |
【开发单位】Center for Chemistry of Drugs (Originator), Russian Academy of Medical Sciences (Originator) 【药理作用】Antiarrhythmic Drugs, CARDIOVASCULAR DRUGS, Potassium Channel Blockers |
合成路线1
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.
| 【1】 Glushkov, R.G, Mashkovski, M.C.; Yuzhakov, S.D.; Nibentan. Drugs Fut 1997, 22, 1, 30. |
| 【2】 L'vov, A.I.; Davydova, N.K.; Sizova, O.S.; Glushov, R.G.; Mashkovskiy, M.D.; Vinogradova, S.M.; Yurhakov, S.D.; Synthesis and antifibrillatory activity of nibentan and its analogues. Eur J Med Chem 2000, 35, 2, 205. |
| 【3】 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.; The method of preparation of hydrochloride 1-phenyl-1-p-nitrobenzoylamino-5-N,N-diethylaminopentane and 1-phenyl-1-amino-5-N,N-diethylaminopentane. SU 2059612 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 | |
| 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 | |
| (I) | 17046 | Phenylacetonitrile; 2-phenylacetonitrile; Benzyl cyanide | 140-29-4 | C8H7N | 详情 | 详情 |
| (II) | 17047 | ethyl 2-cyano-2-phenylacetate | 4553-07-5 | C11H11NO2 | 详情 | 详情 |
| (III) | 17048 | ethyl 6-bromo-2-cyano-2-phenylhexanoate | C15H18BrNO2 | 详情 | 详情 | |
| (IV) | 17049 | ethyl 2-cyano-6-(diethylamino)-2-phenylhexanoate | C19H28N2O2 | 详情 | 详情 | |
| (V) | 17050 | 6-(diethylamino)-2-phenylhexanenitrile | C16H24N2 | 详情 | 详情 | |
| (VI) | 17051 | 6-(diethylamino)-2-phenylhexanamide | C16H26N2O | 详情 | 详情 | |
| (VII) | 17052 | methyl N-[5-(diethylamino)-1-phenylpentyl]carbamate | C17H28N2O2 | 详情 | 详情 | |
| (VIII) | 17053 | N-(5-amino-5-phenylpentyl)-N,N-diethylamine; N(5),N(5)-diethyl-1-phenyl-1,5-pentanediamine | C15H26N2 | 详情 | 详情 |