搜索
第二节氮原子上的酰化反应一、脂肪胺N-酰化反应机理SN2历程RCOX+R1R2NHRCOXNHR1R2-HXRCONR1R2SN1历程RCOXR1R2NH+HXRCONR1R2+XRCO1.羧酸为酰化剂RCOOH+R1R2NHRCOOH2NR1R2.RCOOHNHR1R2RCONR1R2+H2O羧酸与胺的反应是合成酰胺的重要方法，由于平衡反应的特点，采取过量反应物之一或除去生产的H2O。物理方法：共沸蒸馏（C6H6、CH3C6H5）除水方法化学方法：脱水剂（P2O5、POCl3、PCl5、etal.）NSOH2NCOCH2C6H4NO2OCl.HClCHCOOHN3CHCON3NSOHNCOCH2C6H4NO2OClH2/Pd-CCHCONH2NSOHNCOOHCl-内酰胺类抗生素头孢克洛(Cefaclor)的合成临床用于秘尿道、呼吸道、皮肤、软组织、五官感染，疗效较好加入缩合剂提高反应活性（一）缩合剂：DCC、DICRCOOH+CNNCNNHRCOORCOOCNNHHRCOOCHNNH.R1NH2RCONHR1+HNHNCOHNNCOCORRCOO.HNNCOCOR副产物光学活性氨基酸易消旋化缺点：加入缩合剂提高反应活性（二）异氰化物+R2NCROONR2R1NH2RCONHR1+R2HNCOHRCOOH优点：无酰基脲副反应光学活性氨基酸消旋化程度低加入缩合剂提高反应活性（三）活性磷酸酯RCOOHR1NH2++EtOEtOPOONNNEt3N/DMFr.t.20min.RCONHR1活性磷酸酯：活化能力强条件温和不发生消旋2.羧酸酯为酰化剂BAC2机理:碱催化下酰氧键断裂的双分子反应RCOOR1+R2NH2RCOOR1NH2R2RCONHR2+R1ORCOHNHR2OR1+R2NH2RCONHR2OR1+R2NH3OOCO2Et+HNNH3hOOCONNH94%J.Org.Chem.1998,63,10015-10017ROOR1+NHHNNNHORNNClNH2MeOMeONNNNH2MeOMeONOR123345Table1.PreparationofN-AcylalkylenediaminesaThereactionwasconductedbyheatingamixtureofesteranddiamineat110°Cfortheindicatedduration.Nosolventisused.NOOCH3NH2CH2CH2OH.HNO3NONHOHHNO3.HNO3NONHONO2抗心绞痛药尼可地尔(Nicorandol)的合成有选择性扩张冠状动脉，持续增加冠脉流量，抑制冠脉痉挛的作用。用于各种心绞痛活性酯用来合成酰胺（一）：酚酯NCONHCHCH2CH(CH3)2COONO2+HClNH2CH2CO2C2H5Et3N/CHCl30~20oCCbzNCONHCHCH2CH(CH3)2CONHCH2CO2C2H5cbz(whereAct=CHzCNor-P-C6H4N02)Aug.5,1959PEPTIDESYNTHESES@LaAMINOACIDACTIVEESTERS3981ROONOOHNR1HRONHR1+HONOO邻基促进效应、光学活性氨基酸不发生消旋化、收率高活性酯用来合成酰胺（二）：羟胺酯ROONN+R1NH2FeCl3r.t.RCONHR1NNHO+活性酯用来合成酰胺（三）：肟酯1,2,3,4-四氢异喹啉与-内酯在AlCl3催化下，生成-羰基酰胺NH+OOEt3N/AlCl3ClClNO(CH2)4OH89%3.酸酐为酰化剂(RCO)2O+HNR1R2RCOOCORNHR1R2RCOOCORNHR1R2RCONR1R2+RCOOH酸酐酰化可为酸、碱所催化（自催化）COCOO+PhCH2CHCOOHNH2Tol,2hCOCONHCCH2PhCOOH环状酸酐酰化时，低温单酰化,高温或有脱水剂存在时，进一步生成亚酰胺O2NOOOCH3NH2O2NOOOHNHCH3+O2NOONHCH3OH(CH3CO)2OO2NOONCH356%OOO+H2NHCC2H5COOHCH3COOHNOOHCC2H5COOHZnCH3COOHNOHCC2H5COOH抗凝药吲哚布芬(Indobufen)的合成为血小板凝集抑制剂，并有消炎止痛作用混合酸酐法之一（羧酸-磺酸混合酸酐）ROOHTsCl/K2CO3/TEBA40oC,5~60minROOOSOMeR1NH240oC,10minRNHR1O77~95%混合酸酐法之二（羧酸-磷酸混合酸酐）HCNHCbzCOOHph+NSOH2NHHCOCH2COphODEPCr.t.2hHCNHCbzphNSOHNHHCOCH2COphOCOPOEtOEtOCNDEPC=4.酰卤为酰化剂酰卤为活泼的酰化剂，与胺反应强烈快速。为获得良好的收率需除去反应生成的HX以防止其与胺成盐影响反应中和卤化氢有机碱：Py,N(C2H5)3无机碱：NaOH,Na2CO3,NaOAcCOCl+CON(CH3)2NH(CH3)289%+HClCH2SCCH3CH3COOHSOCl2CH2SCCH3CH3COClH2NCHCOOHCH2SCH2CH2SCCH3CH3CONHCHCH2OOHCH2SCH2Na,NH3HSCCH3CH3CONHCHCH2OOHCH2SH慢性关节风湿病的治疗药物布西拉明（Bucillamine)的合成降压药特拉唑嗪（Terazosin)的合成用于肾性、原发性轻、中度高血压和由细胞瘤引起的高血压OCOOHSOCl2OCOClNHHNONCONHH2,RhONCONHH3COH3CONNNH2Cl+N(C2H5)3H3COH3CONNNH2NNCOOHClC2H5OH,H2OH3COH3CONNNH2NNCOOHCl2H2OClOHNNOBrCH2CH2NH2.HBr+ClCOClNaOH,H2OClCONHCH2CH2BrHNO吗氯贝胺(Moclobemide)的合成新一代抗抑郁药，也可用于治疗儿童注意力缺乏多动症二、芳香胺N-酰化芳胺的N-酰化常用酸酐、酰氯等为酰化剂，伯、仲芳胺反应后可得到取代酰胺。H3CONH2+(CH3CO)2OH3CONHCOCH390%NH2+CH3COClCH3COONaNHCOCH3活性酯及活性酰胺在芳胺的酰化中的应用COOH+NNNOONNNCOPyr.t.1hONNNCOPhHONH2r.t.1hOHCONHPhOHNH2+NNNNOCOCH3THFOHNHCOCH395%PhCH2OC-ZO+HNR1R2PhCH2OCONR1R2Z=Cl,CN,OPhCH2OC-O,NN,etal.HNR1R2Pt/CH21.苄氧羰基化(Cbz)三、氨基的保护烷氧羰基化酸、肼解、稳定CCH3CH3H3COCOZ+HNR1R2CCH3CH3H3COCONR1R2Z=-Cl,-F,-N3,-O-C-O-Bu-t,etal.OH+HNR1R22.叔丁氧羰基化(Boc)氢解、肼解、碱分解稳定OHOHOOHONH2OHOONH2HNOOHNH2OOHNHH3COHCH3药物异帕米星（Isepamiin)的合成美国先令公司开发的氨基糖苷类抗生素OHOHOOHONH2HOONH2NH2OOHNHH3COHCH3NOOOCOOCCH3CH3CH3(AcO)2CuOHOHOOHONHHOOHNNH2OOHNHH3COHCH3OCOOCCH3CH3CH3OCOOCCH3CH3CH3NOOCOCHOHH2CHNCOOH2COHOHOOHONHHOOHNHNOOHNHH3COHCH3OCOOCCH3CH3CH3OCOOCCH3CH3CH3COCHOHH2CHNCOOH2C1.H2,Pd/C2.CH3COOHOHOHOOHONH2HOONH2HNOOHNHH3COHCH3COCHOHH2CNH2AcHNHOOHHSOCl2ClCH2CH2ClAcHNHOClHOHCOOCH2PhAcHNHOOCOOHH[H]H2NHOOCOOHH抗溃疡药西曲酸酯（Cetraxate)的合成酰化NHNH3CONHSO2CH3H2NH3CONO2RCOClRCOHNH3CONO2FeRCOHNH3CONH2CH3SO2ClRCOHNH3CONHSO2CH3H2O,H+H2NH3CONHSO2CH3NCl吖啶类抗癌药物安吖啶（Amsacrine)的合成OOOOH2CRORONHRORHNHOOORNHRNHRRHN产物1产物2反应bOOOOH2CHOHONH2OH2NHOOOHNH2NH2H2NDMAP苄基磺酰氯其中R=SO2CH2Ph反应eOOHOHOH2CNH2OH2NHOOOHNH2NH2H2N产物5OOHOHOH2CNHRORHNHOOORNHRNHRRHN产物4液氨金属钠OOHOHOH2CNHBocOBocHNHOOOHNHBocNHBocBocHNOOH2CHOHONH2OH2NHOOOHNH2NH2HOHOH2N原料1产物1反应aBoc酸酐HOHO反应eOOOOH2CNHBocOBocHNHOOOHNHBocNHBocBocHN产物4OOHOHOH2CNH2OH2NHOOOHNH2NH2H2N产物5乙酸80%三氟乙酸作业：掌握氨基的其它保护方法