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【结 构 式】 
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【分子编号】22959 【品名】2-(2-thienyl)acetic acid 【CA登记号】1918-77-0 |
【 分 子 式 】C6H6O2S 【 分 子 量 】142.17844 【元素组成】C 50.69% H 4.25% O 22.51% S 22.55% |
合成路线1
该中间体在本合成路线中的序号：(VI)The methylation of 1,6-naphthalenediol (I) with dimethyl sulfate gives 1,6-dimethoxynaphthalene (II), which by reaction with sodium-ethanol is converted to 5-methoxy-2-tetralone (III). The condensation of (III) with propylamine - p-toluenesulfonic acid and subsequent hydrogenation with H2 over Pt affords 5-methoxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (IV). which is demethylated with HBr to 5-hydroxy-N-propyl-1,2,3,4-tetrahydronaphthalen-2-amine (V). Finally, this compound is reductively alkytated with 2-thienylacetic acid (VI) using boranetrimethylamine complex to yield N-0437.
| 【1】 Seeman, P.; Horn, A.S.; Grigoriadis, D.; Watanabe, M.; van der Weide, J.; Tepper, P.; Synthesis and radioreceptor binding of N-0437, a n. Pharm Weekbl - Sci Ed 1984, 7, 208. |
| 【2】 Horn, A.S.; N-0437. Drugs Fut 1987, 12, 3, 220. |
| 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) | 22954 | 7,8-dihydro-1,6-naphthalenediol | C10H10O2 | 详情 | 详情 | |
| (II) | 22955 | 5-methoxy-3,4-dihydro-2-naphthalenyl methyl ether; 3,8-dimethoxy-1,2-dihydronaphthalene | C12H14O2 | 详情 | 详情 | |
| (III) | 14647 | 5-methoxy-3,4-dihydro-2(1H)-naphthalenone | 32940-15-1 | C11H12O2 | 详情 | 详情 |
| (IV) | 14648 | N-(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-propylamine; 5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine | C14H21NO | 详情 | 详情 | |
| (V) | 22958 | 6-(propylamino)-5,6,7,8-tetrahydro-1-naphthalenol | C13H19NO | 详情 | 详情 | |
| (VI) | 22959 | 2-(2-thienyl)acetic acid | 1918-77-0 | C6H6O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The reaction of 2,6-dimethylphenol (I) with hexamethylenetetramine (HMT) and sulfuric acid in ethyleneglycol at 130 C gives 4-hydroxy-3,5-dimethylbenzaldehyde (II), which is finally condensed with 2-(2-thienyl)acetic acid (III) by means of piperidine in dichloromethane at 130 C.
| 【1】 Lazer, E.S.; Farina, P.R.; Gundel, R.H.; Wegner, C.D.; 2,6-Disubstituted-4-(2-arylethenyl)phenol 5-lipoxygenase inhibitors: Development and profile of BI-L-239. Drugs Fut 1991, 16, 7, 641. |
合成路线3
该中间体在本合成路线中的序号：The overall synthetic approach to N-0923 is described: Methylation of 1,6-dihydroxynaphthalene (I) with dimethyl sulfate provides 1,6-dimethoxynaphthalene (II), which is converted to 5-methoxy-2-tetralone (III) by reduction with sodium in ethanol. Reductive amination of (III) with propylamine results in the racemic 5-methoxy-2-N-propylaminotetralin (IV), from which the (-)-enantiomer (V) is obtained by fractional crystallization of the dibenzoyl-L-tartaric acid (L-DBTA) salt. Demethylation with aqueous hydrobromic acid affords (-)-(S)-5-hydroxy-2-N-propylaminotetralin (VI), which is reductively alkylated with thienylacetic acid in the presence of trimethylaminoborane to (-)-(S)-5-hydroxy-2-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin (VII). Treatment with anhydrous hydrogen chloride in ether provides N-0923.
| 【1】 Evans, D.; Grey, T.F.; Richards, K.E.; Ames, D.E.; Islip, P.J.; Synthesis of alkoxy-1,2,3,4-tetrahydronaphthalene derivatives. J Chem Soc 1965, 2636-41. |
| 【2】 Wynberg, H.; Ten Hoeve, W.; Ten Hoeve, W., Wynberg, H. The design of resolving agents. Chiral phosphoric acids. J Org Chem 1985, 50, 4508-14. |
| 【3】 Manimaran, T.; Impastato, F.J. (Ethyl Corporation); Resolution of racemic mixtures. US 4968837 . |
| 【4】 Cusack, N.J.; Peck, J.V.; N-0923. Drugs Fut 1993, 18, 11, 1005. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 22959 | 2-(2-thienyl)acetic acid | 1918-77-0 | C6H6O2S | 详情 | 详情 | |
| (I) | 14645 | 1,6-naphthalenediol; 1,6-Dihydroxynaphthalene | 575-44-0 | C10H8O2 | 详情 | 详情 |
| (II) | 14646 | 5-methoxy-2-naphthyl methyl ether; 1,6-dimethoxynaphthalene | 3900-49-0 | C12H12O2 | 详情 | 详情 |
| (III) | 14647 | 5-methoxy-3,4-dihydro-2(1H)-naphthalenone | 32940-15-1 | C11H12O2 | 详情 | 详情 |
| (IV) | 14648 | N-(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-propylamine; 5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine | C14H21NO | 详情 | 详情 | |
| (V) | 14649 | (2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine | C14H21NO | 详情 | 详情 | |
| (VI) | 14650 | (6S)-6-(propylamino)-5,6,7,8-tetrahydro-1-naphthalenol | C13H19NO | 详情 | 详情 | |
| (VII) | 14651 | (6S)-6-[propyl[2-(2-thienyl)ethyl]amino]-5,6,7,8-tetrahydro-1-naphthalenol | C19H25NOS | 详情 | 详情 |