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【结 构 式】 
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【药物名称】Efaroxan, RX-821037(HCl) 【化学名称】(±)-2-(2-Ethyl-2,3-dihydro-2-benzofuranyl)-2-imidazoline 【CA登记号】89197-32-0, 89197-00-2 (HCl) 【 分 子 式 】C13H16N2O 【 分 子 量 】216.28527 |
【开发单位】Reckitt & Colman (Originator), Pierre Fabre (Licensee) 【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, alpha2-Adrenoceptor Antagonists |
合成路线1
The condensation of 2-hydroxybenzaldehyde (I) with ethyl 2-bromobutyrate (II) by means of K2CO3 and NaI in DMF gives ethyl-2-(2-formylphenoxy) butyrate (III), which is reduced with NaBH4 and NaOEt in ethanol yielding the hydroxymethyl derivative (IV). The reaction of (IV) with SOCl2 affords the corresponding chloromethyl compound (V), which is cyclized by means of NaH in N-methylpyrrolidone to give 2-ethyl-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester (VI). The hydrolysis of the ethyl ester of (VI) with NaOH in methanol yields the expected carboxylic acid (VII), which is treated with SOCl2 and then with NH3 to afford the amide (VIII). This compound can also be obtained directly from ester (VI) by reaction with NH3. The dehydration of (VIII) by means of P2O5 or POCl3 gives the nitrile (IX), which is treated with HCl in ethanol yielding the carboxyimidate (X). Finally, this compound is cyclized with ethylenediamine (XI) in ethanol.
| 【1】 Edwards, C.R.; et al.; A practical synthesis of 2,3-dihydro-2-benzofurancarboxylic acid: A general route to 2,3-dihydrobenzofurans. J Heterocycl Chem 1987, 24, 495. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (I) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (II) | 36668 | ethyl 2-bromobutanoate | 533-68-6 | C6H11BrO2 | 详情 | 详情 |
| (III) | 36669 | ethyl 2-(2-formylphenoxy)butanoate | C13H16O4 | 详情 | 详情 | |
| (IV) | 36670 | ethyl 2-[2-(hydroxymethyl)phenoxy]butanoate | C13H18O4 | 详情 | 详情 | |
| (V) | 36671 | ethyl 2-[2-(chloromethyl)phenoxy]butanoate | C13H17ClO3 | 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 | |
| (VIII) | 36674 | 2-ethyl-2,3-dihydro-1-benzofuran-2-carboxamide | C11H13NO2 | 详情 | 详情 | |
| (IX) | 36675 | 2-ethyl-2,3-dihydro-1-benzofuran-2-carbonitrile | C11H11NO | 详情 | 详情 | |
| (X) | 36676 | ethyl 2-ethyl-2,3-dihydro-1-benzofuran-2-carboximidoate | C13H17NO2 | 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 |
合成路线2
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 |