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    药物详细合成路线

    Name Doripenem;S-4661
    Chemical Name (1R,5S,6S)-6-[1(R)-Hydroxyethyl]-1-methyl-2-[2(S)-(sulfamoylaminomethyl)pyrrolidin-4(S)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid inner salt
    CAS 148016-81-3
    Related CAS
    Formula C15H24N4O6S2
    Structure
    Formula Weight 420.50973
    Stage 上市-2005
    Company Shionogi (Originator), Peninsula Pharmaceuticals (Licensee)
    Activity/Mechanism Antibiotics, ANTIINFECTIVE THERAPY, Carbapenems
    Syn. Route 3
    Route 1
    the reaction of (1r,6s)-6-[1(r)-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylic acid 4-methoxybenzyl ester (i) with diphenyl chlorophosphate (ii) and ethyl diisopropylamine in acetonitrile gives the corresponding penem diphenylphosphate (iii), which is condensed with 1-(tert-butoxycarbonyl)-2(s)-sulfamoylaminomethyl)pyrrolidine-4(s)-thio l (iv) by means of ethyl diisopropylamine in the same solvent, yielding compound (v), which is finally treated with alcl3 to eliminate the protecting groups to obtain s-4661.
    List of intermediates No.
    tert-butyl 2-[4-[2-(1-methyl-1-phenylethyl)-2h-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate (i)
    2,2,2-trifluoro-n-[(1s)-1-[(2r)oxiranyl]-2-phenylethyl]acetamide (ii)
    tert-butyl 2-[(2s,3s)-2-hydroxy-4-phenyl-3-[(2,2,2-trifluoroacetyl)amino]butyl]-2-[4-[2-(1-methyl-1-phenylethyl)-2h-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate (iii)
    tert-butyl 2-[(2s,3s)-3-amino-2-hydroxy-4-phenylbutyl]-2-[4-[2-(1-methyl-1-phenylethyl)-2h-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate (iv)
    tert-butyl (5s,6s,9s)-6-benzyl-9-(tert-butyl)-5-hydroxy-3-[4-[2-(1-methyl-1-phenylethyl)-2h-1,2,3,4-tetraazol-5-yl]benzyl]-8,11-dioxo-12-oxa-2,3,7,10-tetraazatridecan-1-oate (v)
    Reference 1:
        sendo, y.; kii, m.; nishitani, y.; irie, t.; nishino, y. (shionogi & co., ltd.); a production method for sulfamide. ep 0557122 .
    Reference 2:
        castaner, j.; mealy, n.; rabasseda, x.; s-4661. drugs fut 1995, 20, 4, 367.
    Reference 3:
        nishitani, y.; irie, t.; nishino, y. (shionogi & co. ltd.); a pyrrolidylthiocarbapenem derivative. ep 0528678; jp 1993294970; us 5317016 .

    Route 2
    a new synthesis of s-4661 has been reported:the esterification of trans-4-hydroxy-l-proline (i) with methanol/hcl gives the corresponding methyl ester (ii), which is n-protected as trans-n-(4-methoxybenzyloxycarbonyl)-4-hydroxy-l-proline methyl ester (iii). the mesylation of (iii) with methanesulfonyl chloride and triethylamine in dichloromethane affords the 4-o-mesylate (iv), which is treated with sodium triphenylmethylsulfide giving cis-n-(4-methoxybenzyloxycarbonyl)-4-(triphenylmethylsulfanyl)-l-prolin e methyl ester (v). the reduction of (v) with libh4 in thf yields the corresponding methanol (vi), which is mesylated as before affording (vii). the reaction of (vii) with potassium phthalimide (viii) gives the adduct (ix), which is cleaved with hydrazine yielding (2s,4s)-2-(aminomethyl)-1-(4-methoxybenzyloxycarbonyl)-4-(triphenylmeth ylsulfanyl)pyrrolidine (x). the condensation of (x) with n-(4-methoxybenzyl)sulfamoyl chloride (xi) by means of triethylamine affords the corresponding protected sulfamide (xii). deprotection of the trityl group of (xii) by treatment with silver nitrate and pyridine affords compound (xiii) with a free sh group. the reaction of (xiii) with (1r,5s,6s)-2-(diphenoxyphosphoryloxy)-6-[1(r)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-methoxybenzyl ester (xiv) by means of diisopropylethylamine yields the protected final product (xv), which is finally treated with alcl3 in anisole to eliminate the protecting groups.
    List of intermediates No.
    1,3-dichloro-2-[(dichloromethylene)amino]-5-[(2,2,2-trichloroacetyl)amino]benzene (viii)
    2-[5-(bis(benzoyloxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1h-indol-5-yl]]-lambda(5)-bismuthanyl)-1h-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether (i)
    (2s)-2-[[(benzyloxy)carbonyl]amino]-3-[((2r)-2-[[(benzyloxy)carbonyl]amino]-2-carboxyethyl)disulfanyl]propionic acid (ii)
    tert-butyl 2-[(2s,3s)-2-hydroxy-4-phenyl-3-[(2,2,2-trifluoroacetyl)amino]butyl]-2-[4-[2-(1-methyl-1-phenylethyl)-2h-1,2,3,4-tetraazol-5-yl]benzyl]-1-hydrazinecarboxylate (xiv)
    methyl (1s,4s,5s,10s)-4-benzyl-1,10-di(tert-butyl)-5-hydroxy-2,9,12-trioxo-7-[4-(2h-1,2,3,4-tetraazol-5-yl)benzyl]-13-oxa-3,7,8,11-tetraazatetradec-1-ylcarbamate (iii)
    4-(2-methyl-2h-1,2,3,4-tetraazol-5-yl)benzaldehyde (iv)
    tert-butyl 2-[(z)-[4-(2-methyl-2h-1,2,3,4-tetraazol-5-yl)phenyl]methylidene]-1-hydrazinecarboxylate (v)
    tert-butyl 2-[4-(2-methyl-2h-1,2,3,4-tetraazol-5-yl)benzyl]-1-hydrazinecarboxylate (vi)
    tert-butyl 2-[(2s,3s)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-2-[4-(2-methyl-2h-1,2,3,4-tetraazol-5-yl)benzyl]-1-hydrazinecarboxylate (vii)
    1-(1,3-benzodioxol-5-yl)acetone (ix)
    1,1-diethoxy-2-iodoethane (x)
    3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-2-pentanone (xi)
    (2s,3r)-3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-2-pentanol (xii)
    (1s,2r)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutyl (2r)-2-methoxy-2-phenylethanoate (xiii)
    5-[(1r)-1-[(1r)-1-azidoethyl]-3,3-diethoxypropyl]-1,3-benzodioxole (xv)
    Reference 1:
        iso, y.; motokawa, k.; nishitani, y.; nishino, y.; irie, t.; a novel 1beta-methylcarbapenem antibiotic, s-4661. synthesis and structure-activity relationships of 2-(5-substituted pyrrolidin-3-ylthio)-1beta-methylcarbapenems. j antibiot 1996, 49, 2, 199.

    Route 3
    a new synthesis of s-4661 has been reported:the protection of trans-4-hydroxy-l-proline with tert-butoxycarbonyl anhydride gives n-(tert-butoxycarbonyl)-4(r)-hydroxy-l-proline (ii), which is successively treated with ethyl chloroformate, mesylated with mesyl chloride and reduced with nabh4 yielding (2s,4r)-1-(tert-butoxycarbonyl)-2-(hydroxymethyl)-4-(methanesulfonyloxy)pyrrolidine (iii). the reaction of (iii) with potassium thioacetate affords compound (iv), which is condensed with n-(tert-butoxycarbonyl)sulfamide (v) by means of diethyl azodicarboxylate and triphenylphosphine to give the protected pyrrolidinesulfamide (vi). the deacetylation of (vi) with sodium methoxide yields (2s,4s)-1-(tert-butoxycarbonyl)-2-[n-(tert-butoxycarbonyl)-n-sulfamoylaminomethyl]-4-sulfanylpyrrolidine (vii), which is then condensed with (1r,5s,6s)-2-(diphenoxyphosphoryloxy)-6-[1(r)-hydroxyethyl]-1-methyl-1-carba-2-penem-3-carboxylic acid diphenylmethyl ester (viii) by means of diisopropylethylamine to afford the protected final product (ix). finally, this compound is deprotected with alcl3 in anisole.
    List of intermediates No.
    2-[5-(bis(benzoyloxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1h-indol-5-yl]]-lambda(5)-bismuthanyl)-1h-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether (i)
    2-naphthaldehyde (ii)
    (2r,3r)-3-(1,3-benzodioxol-5-yl)-5,5-diethoxy-n-(2-naphthylmethyl)-2-pentanamine (iii)
    dimethyl (2s,3s)-2,3-dimethylbutanedioate (iv)
    1-benzhydryl 4-methyl (2s,3s)-2,3-dimethylbutanedioate (v)
    4-benzhydryl 2,2-diethyl 5-methyl (4s,5r)-1,3-dioxolane-2,2,4,5-tetracarboxylate (vi)
    (4s,5r)-2,2-bis(ethoxycarbonyl)-5-(methoxycarbonyl)-1,3-dioxolane-4-carboxylic acid (vii)
    2,2-diethyl 4-methyl (4r,5s)-5-[[[(1r,2r)-2-(1,3-benzodioxol-5-yl)-4,4-diethoxy-1-methylbutyl](2-naphthylmethyl)amino]carbonyl]-1,3-dioxolane-2,2,4-tricarboxylate (viii)
    2,2-diethyl 4-methyl (4r,5s)-5-[[[(1r,2r)-2-(1,3-benzodioxol-5-yl)-1-methyl-4-oxobutyl](2-naphthylmethyl)amino]carbonyl]-1,3-dioxolane-2,2,4-tricarboxylate (ix)
    Reference 1:
        motokawa, k.; nishitani, y.; iso, y.; kii, m.; irie, t.; sendo, y.; iwaki, t.; synthesis and modification of a novel 1beta-methyl carbapenem antibiotic, s-4661. j antibiot 1996, 49, 5, 478.

    中国竞彩网专家推荐 www.betsyco.net 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多尼培南;英文名Doripenem;S-4661;CAS[148016-81-3]

     
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