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【结 构 式】 
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【分子编号】32061 【品名】4-phenyl-2-butanone 【CA登记号】2550-26-7 |
【 分 子 式 】C10H12O 【 分 子 量 】148.20468 【元素组成】C 81.04% H 8.16% O 10.8% |
合成路线1
该中间体在本合成路线中的序号：(VII)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 |
合成路线2
该中间体在本合成路线中的序号：(V)Reductocondensation of 5-(N,N-dibenzylglycyl)salicylamide (IV) and benzylace-tone (V) with H2 over Pd-Pt/C in methanol - acetic acid.
| 【1】 Lunts, L.H.; et al.; 1-Phenyl-2-aminoethanol derivatives bronchodilators. DE 1643224; FR 1557677; FR 8010M; GB 1200886; US 3642896; US 3644353; US 3705233 . |
| 【2】 Castaner, J.; Blancafort, P.; Labetalol. Drugs Fut 1976, 1, 3, 125. |
合成路线3
该中间体在本合成路线中的序号：(V)Reaction of methyl 5-(2-amino-1-hydroxyethyl)salicylate hydrochloride (VI) with NH3 to 5-(2-amino-1-hydroxyethyl)salicylamide hydrochloride (VII), m.p. >360 C, which is finally condensed with benzylacetone (V) and reduced with H2 over Pd-Pt/C in methanol.
| 【1】 Lunts, L.H.; et al.; 1-Phenyl-2-aminoethanol derivatives bronchodilators. DE 1643224; FR 1557677; FR 8010M; GB 1200886; US 3642896; US 3644353; US 3705233 . |
| 【2】 Castaner, J.; Blancafort, P.; Labetalol. Drugs Fut 1976, 1, 3, 125. |
合成路线4
该中间体在本合成路线中的序号：(I)The required phosphonate reagent (IV) was prepared by two alternative methods. Bromination of benzylacetone (I) in cold methanol afforded 1-bromo-4-phenyl-2-butanone (II). Subsequent displacement of the bromide ion of (II) with NaI in acetone led to the iodo ketone (III). The desired phosphonate (IV) was then obtained by the Arbuzov reaction of (III) with trimethyl phosphite. Alternatively, alkylation of the dianion of dimethyl 2-oxopropyl phosphonate (V) with benzyl bromide led to phosphonate (IV).
| 【1】 Gutman, A.; Nisnevich, G.; Etinger, M.; Zaltzman, I.; Judovich, L.; Pertsikov, B.; A new process for the preparation of latanoprost. WO 0155101 . |
| 【2】 Resul, B.; et al.; Phenyl-substituted prostaglandins: Potent and selective antiglaucoma agents. J Med Chem 1993, 36, 2, 243. |
| 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) | 32061 | 4-phenyl-2-butanone | 2550-26-7 | C10H12O | 详情 | 详情 |
| (II) | 29211 | 1-bromo-4-phenyl-2-butanone | C10H11BrO | 详情 | 详情 | |
| (III) | 59557 | 1-iodo-4-phenyl-2-butanone | C10H11IO | 详情 | 详情 | |
| (IV) | 59558 | dimethyl 2-oxo-4-phenylbutylphosphonate | C12H17O4P | 详情 | 详情 | |
| (V) | 59559 | Dimethyl acetonylphosphonate; Acetylmethylphosphonic acid dimethyl ester; Dimethyl (2-oxopropyl)phosphonate | 4202-14-6 | C5H11O4P | 详情 | 详情 |