|
【结 构 式】 
|
【分子编号】36677 【品名】ethyl 2-oxobutanoate 【CA登记号】 |
【 分 子 式 】C6H10O3 【 分 子 量 】130.1436 【元素组成】C 55.37% H 7.74% O 36.88% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The condensation of 2-fluorobenzylmagnesium bromide (XII) with 2-oxobutyric acid ethyl ester (XIII) in ethyl ether gives 2-(2-fluorobenzyl)-2-hydroxybutyric acid ethyl ester (XIV), which is cyclized by means of NaH in toluene/DMF yielding he ester (VI). The hydrolysis of (VI) with NaOH affords the acid (VII), which is treated with SOCl2 to give the acyl chloride (XV). Then this compound is cyclized with ethylenediamine (XI) by means of AlMe3 in refluxing toluene. The reaction of 2-fluorobenzaldehyde (XVI) with ethyl 2-bromobutyrate (II) by means of potassium tert-butoxide in dioxane gives the epoxide (XVII), which is opened by hydrogenation with H2 over Pd/C in ethanol to afford the previously reported hydroxybutyric ester (XIV). The condensation of 2-fluorophenyllithium (XVIII) or 2-fluorophenylmagnesium bromide (XIX) with 2-(benzyloxymethyl)-2-ethyloxirane (XX) gives 1-(benzyloxy)-2-ethyl-3-(2-fluorophenyl)-2-propanol (XXI), which is cyclized by means of NaH yielding 2-(benzyloxymethyl)-2-ethyl-2,3-dihydrobenzofuran (XXII). Finally, this compound is debenzylated with H2 over Pd/C and oxidized with CrO3 and sulfuric acid to afford the previously reported carboxylic acid (VII). The alkylation of 2,3-dihydrobenzofuran-2-carboxylic acid (XXIII) with ethyl iodide by means of lithium diisopropylamide gives the previously reported carboxylic acid (VII).
| 【1】 Couture, K.; et al.; A new approach to the synthesis of efaroxan. Bioorg Med Chem Lett 1999, 9, 20, 3023. |
| 【2】 Mayer, P.; et al.; A new efficient synthesis of efaroxan. Bioorg Med Chem Lett 1999, 9, 20, 3021. |
| 【3】 Chapleo, C.B.; et al.; alpha-Adrenoceptor reagents. 2. Effects of modification of the 1,4-benzodioxan ring system on alpha-adrenoreceptor activity. J Med Chem 1984, 27, 5, 570-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 36668 | ethyl 2-bromobutanoate | 533-68-6 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 36672 | ethyl 2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylate | C13H16O3 | 详情 | 详情 | |
| (VII) | 36673 | 2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid | C11H12O3 | 详情 | 详情 | |
| (XI) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (XII) | 36688 | bromo(2-fluorobenzyl)magnesium | C7H6BrFMg | 详情 | 详情 | |
| (XIII) | 36677 | ethyl 2-oxobutanoate | C6H10O3 | 详情 | 详情 | |
| (XIV) | 36678 | ethyl 2-(2-fluorobenzyl)-2-hydroxybutanoate | C13H17FO3 | 详情 | 详情 | |
| (XV) | 36682 | 2-ethyl-2,3-dihydro-1-benzofuran-2-carbonyl chloride | C11H11ClO2 | 详情 | 详情 | |
| (XVI) | 36679 | 2-fluorobenzaldehyde | 446-52-6 | C7H5FO | 详情 | 详情 |
| (XVII) | 36680 | ethyl 2-ethyl-3-(2-fluorophenyl)-2-oxiranecarboxylate | C13H15FO3 | 详情 | 详情 | |
| (XVIII) | 36683 | (2-fluorophenyl)lithium | C6H4FLi | 详情 | 详情 | |
| (XIX) | 36684 | bromo(2-fluorophenyl)magnesium | C6H4BrFMg | 详情 | 详情 | |
| (XX) | 36685 | benzyl (2-ethyl-2-oxiranyl)methyl ether; 2-[(benzyloxy)methyl]-2-ethyloxirane | C12H16O2 | 详情 | 详情 | |
| (XXI) | 36686 | 1-(benzyloxy)-2-(2-fluorobenzyl)-2-butanol | C18H21FO2 | 详情 | 详情 | |
| (XXII) | 36687 | 2-[(benzyloxy)methyl]-2-ethyl-2,3-dihydro-1-benzofuran; benzyl (2-ethyl-2,3-dihydro-1-benzofuran-2-yl)methyl ether | C18H20O2 | 详情 | 详情 | |
| (XXIII) | 36681 | 2,3-dihydro-1-benzofuran-2-carboxylic acid | C9H8O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Preparation of the intermediate hydroxy ester (X) has been reported by a different method consisting in the addition of Grignard reagent (XIII), prepared from 2-fluorobenzyl bromide (XII), to ethyl 2-oxobutyrate.
| 【1】 Imbert, T.; Couture, K.; Mayer, P.; Mioskowski, C.; Gouverneur, V. (Pierre Fabre Medicament); Method for preparing 2-disubstd. 2,3-dihydrobenzofuran derivs.. FR 2780967; WO 0002836 . |