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【结 构 式】 
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【药物名称】Eszopiclone, (+)-Zopiclone, (S)-Zopiclone, Estorra 【化学名称】(+)-6-(5-Chloro-2-pyridyl)-7(S)-(4-methylpiperazin-1-ylcarbonyloxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 【CA登记号】138729-47-2, 138680-08-7 ((R)-isomer) 【 分 子 式 】C17H17ClN6O3 【 分 子 量 】388.81644 |
【开发单位】Aventis Pharma (Originator), Sepracor (Licensee) 【药理作用】PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, GABAergic Transmission Enhancers |
合成路线1
| 【1】 Mandava VNBR, Kandala S.et aL 2007. Process for the preparation of eszopiclone from 4-methyl-l-piperazinecarbonyl chloride hyrkochloride. US 200t054914 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 59378 | 4-Methyl-1-piperazinecarboxylic acid 6-[5-chloro-2-pyridinyl]-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester; Zoplicone | 43200-80-2 | C17H17ClN6O3 | 详情 | 详情 |
| (V) | 66362 | C17H17ClN6O3.C20H18O8.H2O | 详情 | 详情 | ||
| (I) | 32796 | 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one | C11H7ClN4O2 | 详情 | 详情 | |
| (II) | 30370 | 4-methyl-1-piperazinecarbonyl chloride | C6H11ClN2O | 详情 | 详情 | |
| (IV) | 66361 | (2R,3R)-2,3-bis((4-methylbenzoyl)oxy)succinic acid hydrate | 71607-32-4 | C20H18O8.H2O | 详情 | 详情 |
合成路线2
The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with vinyl chloroformate (II) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (95% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.
| 【1】 Culy, C.; Castañer, J.; Bayes, M.; Eszopiclone. Drugs Fut 2003, 28, 7, 640. |
| 【2】 Cotrel, C.; Roussel, G. (Aventis Pharma SA); Optically active deriv. of 5H-pyrrolo[3,4-b]pyrazine, its preparation and pharmaceutical compsns. containing it. EP 0495717; EP 0609210; FR 2671800; JP 1994504548; WO 9212980 . |
| 【3】 Gotor, V.; et al.; Enzymic resolution of (±)-6-(5-chloropyridin-2-yl)-7-vinyloxycarbonyloxy-6,7-dihydro[5H] pyrrolo[3,4-b]pyrazin-5-one. Synthesis of (+)-zopiclone. Tetrahedron Asymmetry 1997, 8, 7, 995. |
| 【4】 Bayod Jasanada, M.S.; Brieva Collado, R.; Linares López, F.J.; García Campos, R.; Gotor Santamaría, V. (Asturpharma SA); (+)-6-(5-Chloropyrid-2-yl)-7-oxo-vinylcarbonyloxy-5,6-dihydropyrrolo[3,4b]pyrazine and their use in a process for the preparation of (+)-6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)-carbonyloxy-7-oxo-5,6-dihydropyrrolo[3,4b]pyrazine. ES 2101653 . |
| 【5】 Cotrel, C.; et al. (Aventis Pharma SA); Pyrrolo-[3,4,b]pyrazine derivatives. DE 2300491; GB 1358680; JP 52048687; US 3862149 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(I) | 32796 | 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one | C11H7ClN4O2 | 详情 | 详情 | |
| (S)-(III) | 32797 | 6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl vinyl carbonate | C14H9ClN4O4 | 详情 | 详情 | |
| rac-(III) | 32798 | (5S)-6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl vinyl carbonate | C14H9ClN4O4 | 详情 | 详情 | |
| (II) | 28068 | 1-[(Chlorocarbonyl)oxy]ethylene; Vinyl chloroformate | 5130-24-5 | C3H3ClO2 | 详情 | 详情 |
| (IV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线3
The esterification of (rac)-6-(5-chloro-3-pyridyl)-5-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-7-one rac-(I) with chloromethyl chloroformate (V) in pyridine gives the racemic carbonate rac-(III), which is submitted to an enantioselective hydrolysis with Candida antarctica (SP 435L) lipase in dioxane/benzyl alcohol yielding a mixture of rac-(I), which is recycled, and enantiomerically pure (96% e.e.) (S)-(III). Finally, this compound is condensed with 1-methylpiperazine (IV) in acetone.
| 【1】 Culy, C.; Castañer, J.; Bayes, M.; Eszopiclone. Drugs Fut 2003, 28, 7, 640. |
| 【2】 Solares, L.F.; Diaz, M.; Brieva, R.; Sanchez, V.M.; Bayod, M.; Gotor, V.; Enzymatic resolution of new carbonate intermediates for the synthesis of (S)-(+)-zopiclone. Tetrahedron Asymmetry 2002, 13, 23, 2577. |
| 【3】 Gotor, V.; et al.; Enzymic resolution of (±)-6-(5-chloropyridin-2-yl)-7-vinyloxycarbonyloxy-6,7-dihydro[5H] pyrrolo[3,4-b]pyrazin-5-one. Synthesis of (+)-zopiclone. Tetrahedron Asymmetry 1997, 8, 7, 995. |
| 【4】 Cotrel, C.; et al. (Aventis Pharma SA); Pyrrolo-[3,4,b]pyrazine derivatives. DE 2300491; GB 1358680; JP 52048687; US 3862149 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(I) | 32796 | 6-(5-chloro-2-pyridinyl)-7-hydroxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one | C11H7ClN4O2 | 详情 | 详情 | |
| rac-(III) | 62951 | chloromethyl 6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl carbonate | C13H8Cl2N4O4 | 详情 | 详情 | |
| (S)-(III) | 62952 | chloromethyl (5S)-6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl carbonate | C13H8Cl2N4O4 | 详情 | 详情 | |
| (IV) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (V) | 19249 | Chloromethyl chloroformate; Chloro[(chlorocarbonyl)oxy]methane | 22128-62-7 | C2H2Cl2O2 | 详情 | 详情 |
合成路线4
Eszopiclone can also be obtained by optical resolution of zopiclone by several different methods: i) crystallization of the D-(+)-O,O'-dibenzoyltartaric acid salt in acetonitrile, followed by treatment with NaOH in dichloromethane/water; ii) crystallization of the (+)-malic acid salt in MeOH/acetone followed by treatment with KHCO3 in MeOH water and extraction with dichloromethane/ethyl acetate; iii) chiral chromatography over a Chiralpak AS column; iv) capillary electrophoresis in the presence of octakis-(2,3,6-tri-O-methyl)-g-cyclodextrin.
| 【1】 Koppenhoefer, B.; Jakob, A.; Zhu, X.; Lin, B.; Separation of enantiomers of drugs by capillary electrophoresis with permethyl-gamma-cyclodextrin as chiral solvating agent. HRC - J High Resolut Chromatogr 2000, 23, 6, 413. |
| 【2】 Culy, C.; Castañer, J.; Bayes, M.; Eszopiclone. Drugs Fut 2003, 28, 7, 640. |
| 【3】 Blaschke, G.; Hempel, G.; Muller, W.E.; Preparative and analytical separation of the zopiclone enantiomers and determination of their affinity to the benzodiazepine receptor binding site. Chirality 1993, 5, 6, 419. |
| 【4】 Cotrel, C.; Roussel, G. (Aventis Pharma SA); Optically active deriv. of 5H-pyrrolo[3,4-b]pyrazine, its preparation and pharmaceutical compsns. containing it. EP 0495717; EP 0609210; FR 2671800; JP 1994504548; WO 9212980 . |
| 【5】 Daenens, P.; Mannaert, E.; Semi-preparative chiral resolution of zoplicone and N-desmethylzopiclone. J Pharm Biomed Anal 1996, 14, 8-10, 1367. |