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【结 构 式】 
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【药物名称】(+)-Efaroxan, Dexefaroxan 【化学名称】(R)-(+)-2-(2-Ethyl-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole 【CA登记号】143249-88-1, 219144-51-1 (HBr salt), 143249-89-2 (monoHCl) 【 分 子 式 】C13H16N2O 【 分 子 量 】216.28527 |
【开发单位】Reckitt & Colman (Originator), Pierre Fabre (Licensee) 【药理作用】Alzheimer's Dementia, Treatment of , Antiparkinsonian Drugs, Cognition Disorders, Treatment of, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, alpha2-Adrenoceptor Antagonists |
合成路线1
The title enantiomer was obtained by resolution of the racemic efaroxan (I) with (+)-dibenzoyl-D-tartaric acid to produce, after two recrystallizations from MeOH/Et2O, the desired pure diastereomeric salt, which was then liberated by treatment with K2CO3.
| 【1】 Chapleo, C.B.; Doxey, J.C.; Stillings, M.R. (Reckitt & Colman Pharmaceuticals); Imidazoline derivs.. WO 9205171 . |
| 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) | 50719 | Efaroxan | C13H16N2O | 详情 | 详情 |
合成路线2
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3
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 |
合成路线4
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 . |
合成路线5
Addition of the in situ-generated Grignard reagent from 2-fluorobromobenzene (XV) to the chiral epoxide (XVI) furnished hydroxy ester (XVII). This was cyclized to the benzofuran derivative (XVIII) by using NaH in hot DMF. Hydrogenolysis of the benzyl ether (XVIII) provided the primary alcohol (XIX), which was then oxidized to the target carboxylic acid (III) employing the Jones reagent in acetone.
| 【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 |
|---|---|---|---|---|---|---|
| (III) | 50720 | (2R)-2-ethyl-2,3-dihydro-1-benzofuran-2-carboxylic acid | C11H12O3 | 详情 | 详情 | |
| (XV) | 50725 | 1-Bromo-2-fluorobenzene; o-Bromofluorobenzene; o-Fluorobromobenzene; 2-Fluorobromobenzene; 2-Bromofluorobenzene | 1072-85-1 | C6H4BrF | 详情 | 详情 |
| (XVI) | 50726 | (2R)-2-[(benzyloxy)methyl]-2-ethyloxirane; benzyl [(2R)-2-ethyloxiranyl]methyl ether | C12H16O2 | 详情 | 详情 | |
| (XVII) | 50727 | (2R)-1-(benzyloxy)-2-(2-fluorobenzyl)-2-butanol | C18H21FO2 | 详情 | 详情 | |
| (XVIII) | 50728 | (2R)-2-[(benzyloxy)methyl]-2-ethyl-2,3-dihydro-1-benzofuran; benzyl [(2R)-2-ethyl-2,3-dihydro-1-benzofuran-2-yl]methyl ether | C18H20O2 | 详情 | 详情 | |
| (XIX) | 50729 | [(2R)-2-ethyl-2,3-dihydro-1-benzofuran-2-yl]methanol | C11H14O2 | 详情 | 详情 |