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【结 构 式】 
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【药物名称】Mibefradil hydrochloride, Ro-40-5967/001, Ro-40-5967, Cerate 50, Posicor 【化学名称】Methoxyacetic acid (1S,2S)-2-[2-[N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylamino]ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydro-2-naphthyl ester dihydrochloride 【CA登记号】116666-63-8, 121039-16-5 (deleted CAS), 116644-53-2 (free base) 【 分 子 式 】C29H40Cl2FN3O3 【 分 子 量 】568.56485 |
【开发单位】Roche (Originator), Asta Medica (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, L-Type Calcium Channel Blockers, T-Type Calcium Channel Blockers |
合成路线1
The condensation of 4-(1-benzyloxy-N-methylformamido)butyric acid (I) with o-phenylenediamine (II) and isobutyl chloroformate (III) by means of triethylamine gives N-[3-[N-(2-aminophenyl)carbamoyl]propyl]-N-methylcarbamic acid benzyl ester (IV), which is cyclized by means of p-toluenesulfonic acid in refluxing toluene to the benzimidazole derivative (V). Hydrogenation of (V) with H2 over Pd/C in methanol affords 2-[3-(methylamino)propyl]benzimidazole (VI), which is condensed with the chiral p-toluenesulfonate (VII) by heating at 120 C to give the chiral tetrahydronaphthol (VIII). Finally, this alcohol is esterified with 2-methoxyacetyl chloride and ethyl diisopropylamine in chloroform.
| 【1】 Merlos, M.; Castaner, J.; Casa, A.; Graul, A.; Mibefradil Hydrochloride. Drugs Fut 1997, 22, 10, 1091. |
| 【2】 Branca, Q.; Jaunin, R.; Marki, H.P.; Marti, F.; Ramuz, H. (F. Hoffmann-La Roche AG); Tetrahydronaphthalene derivs. and medicines containing them. EP 0268148; JP 1988139171; US 4808605 . |
| 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) | 13421 | 4-[[(Benzyloxy)carbonyl](methyl)amino]butyric acid | C13H17NO4 | 详情 | 详情 | |
| (II) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (III) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (IV) | 13424 | benzyl 4-(2-aminoanilino)-4-oxobutyl(methyl)carbamate | C19H23N3O3 | 详情 | 详情 | |
| (V) | 13425 | benzyl 3-(1H-benzimidazol-2-yl)propyl(methyl)carbamate | C19H21N3O2 | 详情 | 详情 | |
| (VI) | 13426 | N-[3-(1H-Benzimidazol-2-yl)propyl]-N-methylamine; 3-(1H-Benzimidazol-2-yl)-N-methyl-1-propanamine | C11H15N3 | 详情 | 详情 | |
| (VII) | 13427 | 2-[(1S,2S)-6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-2-naphthalenyl]ethyl 4-methylbenzenesulfonate | C22H27FO4S | 详情 | 详情 | |
| (VIII) | 13428 | (1S,2S)-2-[2-[[3-(1H-Benzimidazol-2-yl)propyl](methyl)amino]ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydro-2-naphthalenol | C26H34FN3O | 详情 | 详情 | |
| (IX) | 13429 | 2-Methoxyacetyl chloride; Methoxyacetyl chloride | 38870-89-2 | C3H5ClO2 | 详情 | 详情 |