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【结 构 式】 
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【药物名称】T-588 【化学名称】(-)-(R)-1-(Benzothiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethanol hydrochloride 【CA登记号】142935-03-3, 131965-06-5 (undefined isomer) 【 分 子 式 】C16H24ClNO2S 【 分 子 量 】329.89218 |
【开发单位】Toyama (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Amyotrophic Lateral Sclerosis, Agents for, Antiglaucoma Agents, Cognition Disorders, Treatment of, Neurodegenerative Diseases, Treatment of, NEUROLOGIC DRUGS, OCULAR MEDICATIONS, Ophthalmic Drugs, Acetylcholine Release Enhancers |
合成路线1
1) The reaction of dimethyl sulfate (I) with dimethyl sulfide (II) by means of sodium methoxide in acetonitrile gives dimethyl (methylene)-lambda4-sulfane (III), which, without isolation, is condensed with benzo[b]thiophene-5-carbaldehyde (IV) in the same solvent to yield 2-(benzo[b]thiophen-5-yl)oxirane (V) (1). The reaction of (V) with 2-(dimethylamino)ethanol (VI) by means of potassium tert-butoxide in hot DMSO (1, 2), or hot DMF (3) affords (±)-1-(benzo[b]thiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethanol (racemic T-588) (VII), which is submitted to optical resolution first by treatment with acetic anhydride in refluxing toluene to give the corresponding acetate (VIII), and then by reaction of (VIII) with D-dibenzoyltartaric acid (IX) in ethyl acetate/acetone/water followed by fractionated crystallization of the resulting salt to yield the D-dibenzoyltartrate salt of the (R)-isomer (X). Finally, (X) is deacetylated with sodium methoxide in methanol and salified with ethanolic hydrochloric acid.
| 【1】 Ono, S.; Yamafuji, T.; Chaki, H.; Todo, Y.; Maekawa, M.; Kitamura, K.; Kimura, T.; Nakada, Y.; Mozumi, K.; Narita, H.; A new cognition-enhancing agent, (R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethanol hydrochloride. Effects on memory impairment in rats generated by cerebral embolization and basal forebrain lesions. Biol Pharm Bull 1995, 18, 12, 1779-83. |
| 【2】 Ono, S.; Yamafuji, T.; Chaki, H.; Morita, H.; Todo, Y.; Okada, N.; Maekawa, M.; Kitamura, K.; Tai, M.; Narita, H.; Studies on cognitive enhancing agents. III. Antiamnestic and antihypoxic activities of a series of 1-bicycloaryl-2-(omega-aminoalkoxy)ethanols. Chem Pharm Bull 1995, 43, 9, 1492-6. |
| 【3】 Martel, A.M.; Prous, J.; Castaner, J.; T-588. Drugs Fut 1997, 22, 4, 386. |
| 【4】 Ono, S.; Yamafuji, T.; Chaki, H.; Maekawa, M.; Todo, Y.; Narita, H. (Toyama Chemical Co., Ltd.); 1,2-Ethanediol deriv. and salt thereof, process for producing the same, and cerebral function-improving agent comprising them. EP 0383281; EP 0587193; EP 0587194; EP 0589484; FR 2643079; JP 1991047158; JP 1991197422; US 5280032; US 5472984; US 5612381; US 5658904 . |
| 【5】 Ono, T.; Yamafuji, T.; Chaki, H.; Maekawa, M.; Fujido, Y.; Narita, H. (Toyama Chemical Co., Ltd.); 1,2-Ethanediol derivs. and their salts. JP 1992095070 . |
| 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) | 16179 | Dimethyl sulfide; (Methylsulfanyl)methane | 75-18-3 | C2H6S | 详情 | 详情 |
| (III) | 16180 | Dimethyl(methylene)-lambda(4)-sulfane; Dimethylsulfonium-methylide | C3H8S | 详情 | 详情 | |
| (IV) | 16181 | 1-benzothiophene-5-carbaldehyde | C9H6OS | 详情 | 详情 | |
| (V) | 16182 | 2-(1-benzothiophen-5-yl)oxirane | C10H8OS | 详情 | 详情 | |
| (VI) | 16183 | Diethylaminoethanol; 2-(diethylamino)-1-ethanol | 100-37-8 | C6H15NO | 详情 | 详情 |
| (VII) | 16184 | 1-(1-benzothiophen-5-yl)-2-[2-(diethylamino)ethoxy]-1-ethanol | C16H23NO2S | 详情 | 详情 | |
| (VIII) | 16185 | 1-(1-benzothiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethyl acetate | C18H25NO3S | 详情 | 详情 | |
| (IX) | 16186 | (2R,3R)-2,3-bis(benzoyloxy)butanedioic acid | C18H14O8 | 详情 | 详情 | |
| (X) | 16187 | (1R)-1-(1-benzothiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethyl acetate | C18H25NO3S | 详情 | 详情 |
合成路线2
2) The condensation of aldehyde (IV) with bromoform by means of LiOH in hot dioxane/water gives (±)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XI), which is submitted to optical resolution by fractional crystallization of its 2(R)-aminobutanol salt in isopropanol and acidification with HCl to yield (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XII). The cyclization of (XII) with acetone and concentrated H2SO4 affords (R)-(-)-5-(benzo[b]thiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one (XIII), which, by treatment with methanol and H2SO4, is converted into (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid methyl ester (XIV). The protection of the OH group of (XIV) with dihydropyran (DHP) and pyridinium p-toluenesulfonate (Pyr·TsOH) affords the corresponding tetrahydropyranyl ether (XV), which is reduced with NaBH4 in ethanol, giving (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)ethanol (XVI). Finally, this compound is condensed with 2-(diethylamino)ethyl chloride (XVII) by means of NaOH and tetrabutylammonium hydrogensulfate in toluene/water, followed by acidification with HCl. 3) The (R)-dioxolane (XIII) can also be obtained as follows: The racemic hydroxyacetic acid (XI) is cyclized with acetone and H2SO4 as before, giving the racemic dioxolane (XVIII). This compound is dissolved in hot (50 C) tert-amyl alcohol along with 1,8-diazabicyclo[5.4.0]-7-undecene (DCU); this solution is then seeded with a suspension of the (R)-(-)-isomer (XIII) in the same solvent and is slowly cooled at 25 C; a 81% yield of pure crystals of (R)-(-)-isomer (XIII) is obtained. This procedure allows for improving the yields by recovering the unused (S)-(+)-isomer.
| 【1】 Martel, A.M.; Prous, J.; Castaner, J.; T-588. Drugs Fut 1997, 22, 4, 386. |
| 【2】 Nakano, J.; Taya, N.; Chaki, H.; Yamafuji, T.; Momonoi, K. (Toyama Chemical Co., Ltd.); Benzo b thiophen-5-yl deriv. and process for producing the same. EP 0565965 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 48572 | (S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol | 5856-62-2 | C4H11NO | 详情 | 详情 | |
| (IV) | 16181 | 1-benzothiophene-5-carbaldehyde | C9H6OS | 详情 | 详情 | |
| (XI) | 16188 | 2-(1-benzothiophen-5-yl)-2-hydroxyacetic acid | C10H8O3S | 详情 | 详情 | |
| (XII) | 16189 | (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid | C10H8O3S | 详情 | 详情 | |
| (XIII) | 16190 | (5R)-5-(1-benzothiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one | C13H12O3S | 详情 | 详情 | |
| (XIV) | 16191 | methyl (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoate | C11H10O3S | 详情 | 详情 | |
| (XV) | 16192 | methyl (2S)-2-(1-benzothiophen-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propanoate | C17H20O4S | 详情 | 详情 | |
| (XVI) | 16193 | (2R)-2-(1-benzothiophen-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propanol | C16H20O3S | 详情 | 详情 | |
| (XVII) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (XVIII) | 16195 | 5-(1-benzothiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one | C13H12O3S | 详情 | 详情 |