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【结 构 式】 
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【药物名称】Eliprodil hydrochloride 【化学名称】(±)-1-(4-Chlorophenyl)-2-[4-(4-fluorobenzyl)-1-piperidinyl]ethanol hydrochloride 【CA登记号】136634-88-3, 119431-25-3 (free base), 127293-58-7 (undefined isomer; free base) 【 分 子 式 】C20H24Cl2FNO 【 分 子 量 】384.32478 |
【开发单位】Pfizer (Originator), Sanofi-synthélabo (Originator), Alcon (Not Determined) 【药理作用】Antiglaucoma Agents, Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, OCULAR MEDICATIONS, Ophthalmic Drugs, Stroke, Treatment of, NMDA Antagonists |
合成路线1
The overall synthetic approach to eliprodil hydrochloride is shown in Scheme 21238101a: 1-Acetylpiperidine-4-carboxylic acid (I) is converted into its acid chloride and reacted with fluorobenzene in the presence of aluminum chloride to give the ketone (II). Wolff-Kishner reduction of the ketone (II) affords 4-[(4-fluorophenyl)methyl]piperidine (III), which is purified by distillation and isolated as its hydrochloride salt. Condensation of the piperidine derivate (III) (as the free base) with 2-bromo-1-(4-chlorophenyl)ethanone (IV) in the presence of potassium carbonate yields the aminoketone which is isolated as its hydrochloride salt (V). Reduction of (V) with potassium borohydride and salification of the resulting base with anhydrous hydrogen chloride in ether provides eliprodil hydrochloride (VI), which is purified by recrystallization.
| 【1】 Wick, A.; Frost, J.; Gaudilliere, B.; Bertin, J.; Dupont, R.; Rousseau, J. (Sanofi-Synthelabo ); 1-Phenyl-2-piperidino propanol derivs., their preparation and medicines containing them. EP 0109317 . |
| 【2】 Benavides, J.; Scatton, B.; Carter, C.; George, P.; Frost, J.; Thenot, J.P.; Giroux, C.; Eliprodil Hydrochloride. Drugs Fut 1994, 19, 10, 905. |
| 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) | 16788 | 1-acetyl-4-piperidinecarboxylic acid | 25503-90-6 | C8H13NO3 | 详情 | 详情 |
| (II) | 16789 | 1-[4-(4-fluorobenzoyl)piperidino]-1-ethanone | C14H16FNO2 | 详情 | 详情 | |
| (III) | 16790 | 4-(4-fluorobenzyl)piperidine hydrochloride | 92822-02-1 | C12H17ClFN | 详情 | 详情 |
| (IV) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (V) | 16792 | 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)-1-piperidinyl]-1-ethanone hydrochloride | C20H22Cl2FNO | 详情 | 详情 |
合成路线2
A new synthesis of eliprodil and the asymmetric synthesis of its two enantiomers have been reported: 1) Racemic eliprodil is obtained by condensation of 4-chlorophenacyl bromide (I) with 4-(4-fluorobenzyl)piperidine (II) by means of K2CO3 in refluxing ethanol to give 1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidin-1-yl]ethanone (III), which is then reduced with KBH4 in methanol.
| 【1】 Di Fabio, R.; Thomas, R.J.; Pietra, C.; Ziviani, L.; The asymmetric synthesis of both enantiomers of eliprodil. Bioorg Med Chem Lett 1995, 5, 6, 551. |
合成路线3
2) The (R)- and (S)-enantiomers eliprodil are obtained as follows: The asymmetric dihydroxylation of 4-chlorostyrene (IV) by the Sharpless asymmetric dihydroxylation (AD) procedure (J Org Chem 1992, 57: 2768) methods alpha and beta (AD-alpha and AD-beta) gives both the (S)- and (R)-enantiomers of 1-(4-chlorophenyl)ethane-1,2-diol (Valpha) and (Vbeta), respectively. These compounds, by treatment first with methanesulfonyl chloride and then with K2CO3, yield the corresponding epoxides (VIalpha) and (VIbeta), respectively. Finally, both compounds are condensed with 4-(4-fluorobenzyl)piperidine (II) in refluxing isopropanol.
| 【1】 Di Fabio, R.; Thomas, R.J.; Pietra, C.; Ziviani, L.; The asymmetric synthesis of both enantiomers of eliprodil. Bioorg Med Chem Lett 1995, 5, 6, 551. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 16797 | (1S)-1-(4-chlorophenyl)-1,2-ethanediol | C8H9ClO2 | 详情 | 详情 | |
| (Vb) | 16798 | (1R)-1-(4-chlorophenyl)-1,2-ethanediol | C8H9ClO2 | 详情 | 详情 | |
| (VIa) | 16799 | (2S)-2-(4-chlorophenyl)oxirane | C8H7ClO | 详情 | 详情 | |
| (VIb) | 16800 | (2R)-2-(4-chlorophenyl)oxirane | C8H7ClO | 详情 | 详情 | |
| (S)-isomer | 16801 | (1S)-1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidino]-1-ethanol | C20H23ClFNO | 详情 | 详情 | |
| (R)-isomer | 16802 | (1R)-1-(4-chlorophenyl)-2-[4-(4-fluorobenzyl)piperidino]-1-ethanol | C20H23ClFNO | 详情 | 详情 | |
| (II) | 16794 | 4-(4-fluorobenzyl)piperidine | 92822-02-1 | C12H16FN | 详情 | 详情 |
| (IV) | 16796 | p-chlorostyrene; 1-chloro-4-vinylbenzene | 1073-67-2 | C8H7Cl | 详情 | 详情 |
合成路线4
The enzymatic hydrolysis of (rac)-2-(4-chlorophenyl)oxirane (I) with Solanum tuberosum hydrolase enzyme (St-EH) gives a mixture of unreacted (R)-epoxide (R)-(II) and (R)-diol (R)-(III); this enzyme attacks with marked preference the (S)-epoxide at the more substituted position, with inversion of the configuration. The resulting mixture, without isolation, is treated with Aspergillus niger hydrolase enzyme (At-EH), affording enantiomerically pure (R)-diol (R)-(III); this enzyme attacks with marked preference the (R)-epoxide (R)-(II) at the less-substituted position, consequently with retention of the configuration. The resulting (R)-diol (R)-(III) is converted into (R)-(-)-212381 by known methods.
| 【1】 Manoj, K.M.; Baratti, J.; Archelas, A.; Furstoss, R.; Microbiological transformations. Part 45: A green chemistry preparative scale synthesis of enantiopure building blocks of eliprodil: Elaboration of a high substrate concentration epoxide hydrolase-catalyzed hydrolytic kinetic resolution process. Tetrahedron 2001, 57, 4, 695. |
| 【2】 Di Fabio, R.; Thomas, R.J.; Pietra, C.; Ziviani, L.; The asymmetric synthesis of both enantiomers of eliprodil. Bioorg Med Chem Lett 1995, 5, 6, 551. |