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【结 构 式】 
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【药物名称】Rotigotine hydrochloride, SPM-962(patch), (-)-N-0437, N-0437(undefined isomer), N-0923, Rotigotine CDS 【化学名称】(-)-(S)-2-[N-Propyl-N-[2-(2-thienyl)ethyl]amino]-5-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride 【CA登记号】125572-93-2, 125572-92-1 ((R)-isomer), 112835-48-0 ((R)-isomer;free base), 99755-59-6 (free base), 113349-24-9 (racemic;free bas 【 分 子 式 】C19H26ClNOS 【 分 子 量 】351.94217 |
【开发单位】Aderis (Originator), Mitsubishi Pharma (Licensee), Otsuka (Licensee), Schwarz (Licensee) 【药理作用】Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, Myoclonus, Treatment of, NEUROLOGIC DRUGS, Restless Legs Syndrome, Treatment of, Dopamine D2 Agonists, Dopamine D3 Agonists |
合成路线1
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 |