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【结 构 式】 
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【分子编号】16183 【品名】Diethylaminoethanol; 2-(diethylamino)-1-ethanol 【CA登记号】100-37-8 |
【 分 子 式 】C6H15NO 【 分 子 量 】117.19124 【元素组成】C 61.49% H 12.9% N 11.95% O 13.65% |
合成路线1
该中间体在本合成路线中的序号：(VI)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
该中间体在本合成路线中的序号：(II)Substitution of 1-chloro-2-methoxy-4-nitrobenzene (I) with 2-(diethylamino)ethanol (II) gives rise to ether (III). Subsequent nitro group reduction in (III) by catalytic hydrogenation affords aniline (IV). Condensation of amine (IV) with triethyl orthoformate, followed by reduction of the resultant formimidate (V) with NaBH4 leads to the N-methyl amine (VI). This is acylated by 4-bromobenzoyl chloride (VII) to furnish the bromobenzamide (VIII). Finally, Suzuki coupling of bromide (VIII) with 4-trifluoromethylphenylboronic acid (IX) produces the title biphenyl compound
| 【1】 Stemp, G.; Johnson, C.N.; Jones, M.; O'Toole, C.A.; Thewlis, K.M.; Witty, D. (GlaxoSmithKline plc); Carboxamide cpds. and their use as antagonists of a human 11CBy receptor. EP 1305304; WO 0210146 . |
| 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) | 60896 | 1-chloro-2-methoxy-4-nitrobenzene; 2-chloro-5-nitrophenyl methyl ether | C7H6ClNO3 | 详情 | 详情 | |
| (II) | 16183 | Diethylaminoethanol; 2-(diethylamino)-1-ethanol | 100-37-8 | C6H15NO | 详情 | 详情 |
| (III) | 60897 | N,N-diethyl-2-(2-methoxy-4-nitrophenoxy)-1-ethanamine; N,N-diethyl-N-[2-(2-methoxy-4-nitrophenoxy)ethyl]amine | C13H20N2O4 | 详情 | 详情 | |
| (IV) | 60898 | N-[2-(4-amino-2-methoxyphenoxy)ethyl]-N,N-diethylamine; 4-[2-(diethylamino)ethoxy]-3-methoxyaniline | C13H22N2O2 | 详情 | 详情 | |
| (V) | 60899 | ethyl 4-[2-(diethylamino)ethoxy]-3-methoxyphenyliminoformate | C16H26N2O3 | 详情 | 详情 | |
| (VI) | 60900 | N-{4-[2-(diethylamino)ethoxy]-3-methoxyphenyl}-N-methylamine; 4-[2-(diethylamino)ethoxy]-3-methoxy-N-methylaniline | C14H24N2O2 | 详情 | 详情 | |
| (VII) | 45960 | 4-bromobenzoyl chloride | 586-75-4 | C7H4BrClO | 详情 | 详情 |
| (VIII) | 60901 | 4-bromo-N-{4-[2-(diethylamino)ethoxy]-3-methoxyphenyl}-N-methylbenzamide | C21H27BrN2O3 | 详情 | 详情 | |
| (IX) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 |