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药物详细合成路线

Name Eszopiclone;(+)-Zopiclone;(S)-Zopiclone;Estorra
Chemical Name (+)-6-(5-Chloro-2-pyridyl)-7(S)-(4-methylpiperazin-1-ylcarbonyloxy)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-one
      (+)-4-Methylpiperazine-1-carboxylic acid 6-(5-chloro-2-pyridyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5(S)-yl ester
CAS 138729-47-2
Related CAS 138680-08-7 ((R)-isomer)
Formula C17H17ClN6O3
Structure
Formula Weight 388.81644
Stage 上市-2005
Company Aventis Pharma (Originator), Sepracor (Licensee)
Activity/Mechanism PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, GABAergic Transmission Enhancers
Syn. Route 3
Route 1
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.
List of intermediates No.
5-(hydroxymethyl)-2-nitrophenol (iv)
(1s)-3-iodo-1-(2-thienyl)propyl 1-naphthyl ether; 2-[(1s)-3-iodo-1-(1-naphthyloxy)propyl]thiophene (ii)
benzyl (2s)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate (rac-i)
benzyl (2s)-2-amino-3-methylbutanoate (s-iii)
benzyl (2s)-3-methyl-2-([[2-(1-trityl-1h-1,2,3,4-tetraazol-5-yl)[1,1-biphenyl]-4-yl]methyl]amino)butanoate (rac-iii)
Reference 1:
    culy, c.; casta?er, j.; bayes, m.; eszopiclone. drugs fut 2003, 28, 7, 640.
Reference 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 .
Reference 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.
Reference 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 .
Reference 5:
    cotrel, c.; et al. (aventis pharma sa); pyrrolo-[3,4,b]pyrazine derivatives. de 2300491; gb 1358680; jp 52048687; us 3862149 .

Route 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 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.
List of intermediates No.
5-(hydroxymethyl)-2-nitrophenol (iv)
1-methyl-2-oxo-5-indolinesulfonyl chloride (v)
benzyl (2s)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoate (rac-i)
Reference 1:
    culy, c.; casta?er, j.; bayes, m.; eszopiclone. drugs fut 2003, 28, 7, 640.
Reference 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.
Reference 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.
Reference 4:
    cotrel, c.; et al. (aventis pharma sa); pyrrolo-[3,4,b]pyrazine derivatives. de 2300491; gb 1358680; jp 52048687; us 3862149 .

Route 3
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.
List of intermediates No.
Reference 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.
Reference 2:
    culy, c.; casta?er, j.; bayes, m.; eszopiclone. drugs fut 2003, 28, 7, 640.
Reference 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.
Reference 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 .
Reference 5:
    daenens, p.; mannaert, e.; semi-preparative chiral resolution of zoplicone and n-desmethylzopiclone. j pharm biomed anal 1996, 14, 8-10, 1367.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名右佐匹克隆;英文名Eszopiclone;(+)-Zopiclone;(S)-Zopiclone;Estorra;CAS[138729-47-2]

 
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