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【结 构 式】 
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【药物名称】Dilevalol, Sch-19927, Unicard, Dilevalon, Unicarde, Levadil 【化学名称】[R-(R*,R*)-2-Hydroxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)amino]ethyl]benzamide 【CA登记号】75659-07-3, 75659-08-4 (monoHCl) 【 分 子 式 】C19H24N2O3 【 分 子 量 】328.41473 |
【开发单位】Schering-Plough (Originator), Shionogi (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, beta-Adrenoceptor Antagonists |
合成路线1
The reaction of 5-acetylsalicylamide (I) with benzyl chloride (II) by means of sodium methoxide in hot DMF gives 4-benzyloxy-3-carbamoylacetophenone (III), which by bromination with Br2 in refluxing CHCl3 is converted into 4-benzyloxy-3-carbamoylphenacyl bromide (IV). The condensation of (IV) with N-(4-phenyl-2-butyl)benzylamine (V) (prepared from benzylamine (VI) and 4-phenyl-2-butanone (VII), p-toluenesulfonic acid and NaBH4 in benzene -methanol) by means of K2CO3 in DMF yields 2-benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide (VIII), which is reduced with NaBH4 in ethanol to afford 2-benzyloxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)-N-benzylamino]ethyl]benzamide (IX). Finally, this compound is debenzylated by hydrogenolysis with H2 over Pd/C in ethanol. The separation into its optical isomers is performed by conventional methods.
| 【1】 Gold, E.H.; Chang, W. (Schering Corp.); A phenylalkylaminoethylsalicylamide, its preparation and pharmaceutical compositions containing it. CA 1151211; DD 150457; EP 0009702; JP 55055147; ZA 7904872 . |
| 【2】 Gold, E.H.; Chang, W. (Schering Biotech Corp.); Diastereoisomers of 5-(1-hydroxy-2-(1-methyl-3-phenylpropylamino)ethyl)salicylamide. US 4173583 . |
| 【3】 Serradell, M.N.; Castaner, J.; Weetman, D.F.; Blancafort, P.; Sch-19,927. Drugs Fut 1982, 7, 11, 815. |
| 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) | 32058 | 5-Acetyl-2-hydroxybenzamide; 5-Acetylsalicylamide | 40187-51-7 | C9H9NO3 | 详情 | 详情 |
| (II) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (III) | 32059 | 4-Benzyloxy-3-carbamoylacetophenone; 5-Acetyl-2-(benzyloxy)benzamide | C16H15NO3 | 详情 | 详情 | |
| (IV) | 32060 | 2-(Benzyloxy)-5-(2-bromoacetyl)benzamide; 4-Benzyloxy-3-carbamoylphenacyl bromide; 2-Benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide | C16H14BrNO3 | 详情 | 详情 | |
| (V) | 30353 | N-benzyl-N-(1-methyl-3-phenylpropyl)amine; N-(4-phenyl-2-butyl)benzylamine; N-benzyl-4-phenyl-2-butanamine | C17H21N | 详情 | 详情 | |
| (VI) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VII) | 32061 | 4-phenyl-2-butanone | 2550-26-7 | C10H12O | 详情 | 详情 |
| (VIII) | 32060 | 2-(Benzyloxy)-5-(2-bromoacetyl)benzamide; 4-Benzyloxy-3-carbamoylphenacyl bromide; 2-Benzyloxy-5-[N-benzyl-N-(1-methyl-3-phenylpropyl)glycyl]benzamide | C16H14BrNO3 | 详情 | 详情 | |
| (IX) | 32063 | 5-[2-[Benzyl(1-methyl-3-phenylpropyl)amino]-1-hydroxyethyl]-2-(benzyloxy)benzamide; 2-Benzyloxy-5-[1-hydroxy-2-[(4-phenyl-2-butyl)-N-benzylamino]ethyl]benzamide | C33H36N2O3 | 详情 | 详情 | |
| (X) | 32064 | 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide | 36894-69-6 | C19H24N2O3 | 详情 | 详情 |