• 被欧洲国家踢皮球的移民船终靠岸 地中海漂泊一周 2019-03-22
  • 牢记宗旨,不忘初心,奋勇前行,开创中华民族伟大复兴! 2019-03-22
  • 内蒙古蒙牛乳业(集团)股份有限公司获第十二届人民企业社会责任奖年度扶贫奖 2019-02-12
  • 将“最多跑一次”改革进行到底 2019-02-06
  • 图解:12月起央行出台这些新规 转账开始有“后悔药” 2018-11-26
  • 有机化学人才网 | 最新人才 | 最新职位 | 技术交易 | 药物合成 |
       
    全站搜索: |
      您当前位置:网站首页 >> 药物合成路线图解
     

    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]

     
    推荐VIP企业
    无锡景耀生物科技有限公司
    杭州卢普生物科技有限公司
    宁波赛伦化工有限公司
    苏州昊赛生物科技有限公司
    北京嘉盛扬医药科技有限公司
    上海泽涵生物医药科技有限公司
    河北固安三利化工公司
    郑州凯普瑞生物技术有限公司
    上海药谷药业有限公司
    兰州康寓信生物科技有限公司
    湖北朗昕生化药业有限公司
    武汉福鑫化工有限公司
    嘉兴市英南化工有限公司
    苏州迪飞医药科技有限公司
    北京富安凯科技有限公司
    上海盛中医药化工有限公司
    连云港天和化学有限公司
    南京晨瑞医药科技有限公司
    南京苏如化工有限公司
    常州瑞盛化工有限公司
    热门文章
    FDA 批准罗氏肿瘤免疫疗法
    带你认识第一款专门治疗产后抑郁
    润丰股份致力于打造欧盟农化品活
    欧盟批准罗氏血友病药物 Hem
    陕西地区醋酸价格
    山东地区醋酸价格
    华北地区丁二烯市场报盘走高
    PTA止跌在眼前
    华东地区BDO市场商谈整理
    华北地区BDO市场低位整理
    华北地区醋酸价格下跌
    江苏地区顺酐市场行情整理
    华东地区邻苯市场行情维稳
    山东地区二氯甲烷市场价格上调
    浙江地区二氯甲烷价格暂稳
    山东地区醋酸价格
    华北地区醋酸价格
    山东地区辛醇市场走势整理
    华北地区醋酸价格
    华东地区醋酸价格
     友情链接
    有机化学人才网  
    中国竞彩网专家推荐 | 广告服务 | 建站服务 | 关于我们 | 中国竞彩网专家推荐 | 版权声明
  • 被欧洲国家踢皮球的移民船终靠岸 地中海漂泊一周 2019-03-22
  • 牢记宗旨,不忘初心,奋勇前行,开创中华民族伟大复兴! 2019-03-22
  • 内蒙古蒙牛乳业(集团)股份有限公司获第十二届人民企业社会责任奖年度扶贫奖 2019-02-12
  • 将“最多跑一次”改革进行到底 2019-02-06
  • 图解:12月起央行出台这些新规 转账开始有“后悔药” 2018-11-26