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【结 构 式】 
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【分子编号】36673 【品名】2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C11H12O3 【 分 子 量 】192.21448 【元素组成】C 68.74% H 6.29% O 24.97% |
合成路线1
该中间体在本合成路线中的序号：(VII)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
该中间体在本合成路线中的序号：(VII)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3
该中间体在本合成路线中的序号：(II)Alternatively, the title compound was prepared by an asymmetric synthesis: The known racemic 2-ethyl-2,3-dihydro-2-benzofurancarboxylic acid (II) was resolved by means of (S)-(+)-2-phenylglycinol to furnish the desired (+)-enantiomer (III). After esterification of (III) using MeOH in the presence of SOCl2, the resultant methyl ester (IV) was treated with ammonium hydroxide, yielding amide (V). Subsequent dehydration of amide (V) with P2O5 in refluxing toluene gave nitrile (VI). Treatment of (VI) with EtOH in the presence of a catalytic amount of NaOMe produced an intermediate imidate, which was subsequently treated with ethylenediamine and HCl to generate the title imidazoline.
| 【1】 Imbert, T.; Mayer, P. (Pierre Fabre Medicament); Method for preparing an optically pure benzofuran carboxylic acid and use thereof for preparing efaroxan. FR 2733983; US 5880296; WO 9635682 . |
| 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) | 36673 | 2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid | C11H12O3 | 详情 | 详情 | |
| (III) | 50720 | (2R)-2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid | C11H12O3 | 详情 | 详情 | |
| (IV) | 50721 | methyl (2R)-2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylate | C12H14O3 | 详情 | 详情 | |
| (V) | 50722 | (2R)-2-ethyl-2,3-dihydro-1-benzofuran-2-carboxamide | C11H13NO2 | 详情 | 详情 | |
| (VI) | 50723 | (2R)-2-ethyl-2,3-dihydro-1-benzofuran-2-carbonitrile | C11H11NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Several alternative procedures have been further reported for the synthesis of the intermediate acid (II). The Darzens condensation of 2-fluorobenzaldehyde (VII) with ethyl 2-bromobutyrate (VIII) furnished epoxide (IX). Catalytic hydrogenation of epoxide (IX) gave rise to the hydroxy ester (X), which was hydrolyzed to acid (XI) under basic conditions. Cyclization of (XI) using NaH in hot DMF provided the racemic benzofurancarboxylic acid (II), which was then resolved with 2-phenylglycinol as above.
| 【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 . |
| 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) | 36673 | 2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid | C11H12O3 | 详情 | 详情 | |
| (VII) | 36679 | 2-fluorobenzaldehyde | 446-52-6 | C7H5FO | 详情 | 详情 |
| (VIII) | 36668 | ethyl 2-bromobutanoate | 533-68-6 | C6H11BrO2 | 详情 | 详情 |
| (IX) | 36680 | ethyl 2-ethyl-3-(2-fluorophenyl)-2-oxiranecarboxylate | C13H15FO3 | 详情 | 详情 | |
| (X) | 36678 | ethyl 2-(2-fluorobenzyl)-2-hydroxybutanoate | C13H17FO3 | 详情 | 详情 | |
| (XI) | 50724 | 2-(2-fluorobenzyl)-2-hydroxybutyric acid | C11H13FO3 | 详情 | 详情 |