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【结 构 式】 
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【分子编号】59378 【品名】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 【CA登记号】43200-80-2 |
【 分 子 式 】C17H17ClN6O3 【 分 子 量 】388.81332 【元素组成】C 52.52% H 4.41% Cl 9.12% N 21.61% O 12.34% |
合成路线1
该中间体在本合成路线中的序号：rac-(VI)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. |
合成路线2
该中间体在本合成路线中的序号：(I)The title compound has been obtained from racemic zopliclone (I) by several related procedures. Demethylation of (I) to afford (II) has been achieved by treatment with diethyl azodicarboxylate (DEAD) in boiling toluene, followed by mild hydrolysis with NH4Cl in refluxing EtOH. In a higher yield demethylation procedure, treatment of (I) with chloroethyl chloroformate produced carbamate (III), which was further hydrolyzed to (II) in boiling MeOH. Resolution of racemic N-demethyl zopiclone (II) has been accomplished via formation of the diastereomeric salts with N-Z-L-phenylalanine or, alternatively, by means of semi-preparative chiral HPLC. In a related strategy, racemic zopiclone (I) was first resolved using D-malic acid to provide the (S)-enantiomer (IV). This was then dealkylated by means of either DEAD or employing the chloroethyl chloroformate method.
| 【1】 Hong, Y.; et al.; Synthesis of enantiomerically pure desmethylzopiclone and determination of its absolute configuration. Tetrahedron Asymmetry 2000, 11, 23, 4623. |
| 【2】 Daenens, P.; Mannaert, E.; Semi-preparative chiral resolution of zoplicone and N-desmethylzopiclone. J Pharm Biomed Anal 1996, 14, 8-10, 1367. |
| 【3】 Hong, Y.; Senanayake, C.H.; Jerussi, T.P.; Rubin, P.D.; Bakale, R.A.; Xiang, T.; McConville, F.A. (Sepracor Inc.); Methods of making and using N-desmethylzopiclone. US 6339086; WO 0069442 . |
| 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) | 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 |
| (II) | 59379 | 6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 1-piperazinecarboxylate | C16H15ClN6O3 | 详情 | 详情 | |
| (III) | 59380 | 1-(1-chloroethyl) 4-[6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl] 1,4-piperazinedicarboxylate | C19H18Cl2N6O5 | 详情 | 详情 | |
| (IV) | 59381 | (5S)-6-(5-chloro-2-pyridinyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methyl-1-piperazinecarboxylate | C17H17ClN6O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号： (III)
| 【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 |