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【结 构 式】 
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【药物名称】N-0437 【化学名称】2-[N-Propyl-N-[2-(2-thienyl)ethyl]amino]-5-hydroxytetralin hydrochloride 【CA登记号】92206-54-7 (free base) 【 分 子 式 】C19H26ClNOS 【 分 子 量 】351.94217 |
【开发单位】UCB (Originator) 【药理作用】Antiglaucoma Agents, Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, NEUROLOGIC DRUGS, OCULAR MEDICATIONS, Ophthalmic Drugs, Dopamine D2 Agonists |
合成路线1
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
| 【1】 Horn AS.1986.Substituted 2-aminotetralins. US 4,564,628. |
| 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) | 14647 | 5-methoxy-3,4-dihydro-2(1H)-naphthalenone | 32940-15-1 | C11H12O2 | 详情 | 详情 |
| (II) | 67409 | 5-methoxy-N-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine | 102120-95-6 | C17H21NOS | 详情 | 详情 |
| (III) | 67410 | N-(5-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(thiophen-2-yl)ethyl)propionamide | C20H25NO2S | 详情 | 详情 | |
| (IV) | 67411 | 5-methoxy-N-propyl-N-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine | C20H27NOS | 详情 | 详情 |
合成路线3
| 【1】 Hacksell U, Svensson U, Nilsson JLG.1979.N-Alkylated 2-aminotetralins: central dopamine-receptor stimulating activity.J Med Chem, 22: 1469～1475. |
| 【2】 Marquillas Olondriz F, Pomares Marco M.2010.Process for the preparation of optically active (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5-hydroxytetraline compounds. WO 2010/043571 A1. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (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 | |
| (I) | 14647 | 5-methoxy-3,4-dihydro-2(1H)-naphthalenone | 32940-15-1 | C11H12O2 | 详情 | 详情 |
| (II) | 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 | |
| (III) | 67412 | (R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid | C15H11N3O7 | 详情 | 详情 | |
| (IV) | 67413 | C14H21NO.C15H11N3O7 | 详情 | 详情 | ||
| (VI) | 67414 | (R)-5-methoxy-N-propyl-N-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine | C20H27NOS | 详情 | 详情 |