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【结 构 式】 
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【药物名称】(+)-N-Desmethylzopiclone, (S)-DMZ, SEP-174559 【化学名称】(+)-6-(5-Chloro-2-pyridyl)-7(S)-(piperazin-1-ylcarbonyloxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one 【CA登记号】151776-26-0, 300701-71-7 (monoHCl) 【 分 子 式 】C16H15ClN6O3 【 分 子 量 】374.78935 |
【开发单位】Aventis Pharma (Originator), Sepracor (Licensee) 【药理作用】Antispastic Drugs, Antispastic Drugs and Drugs for Muscle Spasms, Anxiolytics, Muscle Spasms, Drugs for, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, GABA(A) Receptor Agonists |
合成路线1
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 |