酰化反应ppt课件

1、HNOCOClHNOCONHNH2C6H5C6H5NCOClNNCH3NH2CH3ONCONNCH3NHCH3O+抗抑郁药 罗利普令退热药 烟酰安替比邻贝诺酯氟奋乃静庚酸酯OAcCOONHCOCH3NSNNCH2CH2CH2CH2CH2OCOC6H13CF3NH2NH2SO2NH2NH2(CH3CO)2ONHCOCH3HSO3ClNHCOCH3SO2ClNHCOCH3SO2NH2NH3H2ONH2SO2NH2RCOZRCOSZ=Hal, OCOR, OH, OR, NHRS=RNH, RO, Ar+ SH+ ZHOHCBuOBuLiCONH4ClOBuCOLiOCBuO110110CH3CHO

2、CH3COCH3COCH2CH2R(C6H5CO)2O2RCH=CH2羧酸羧酸酯酸酐酰卤酰胺乙烯酮COOH*COO*RCOOCOCOX*CONH2CONR2CH2=C=O,RCOX (RCO)2O RCOOR, RCOOH RCONH2RCO+HNuCRLNuORNuCO +HLL加成消除(L=OH、OR、OCOR、X、NH2等）RCLORCORO+ HLROH +R-OH + RCOOHRCOOR +H2OR COOHH+R COHOHR COHOHHCH2COOHHOHTsOH/PhH ,HHOOOHOHHOCOOH+ C12H25OHTsOHXylene对 甲 苯 磺 酸OHOHHOCO

3、OC12H25NCOOHH3CCH3OH/C6H6/HCl(gas)O2NCOOHHOCH2CH2N(C2H5)2/ 二甲苯HCl(gas)NCOOC2H5 HClH3CO2NCOOCH2CH2N(C2H5)2H2NCOOCH2CH2N(C2H5)2HClFe/HCl45,2hR COOHAlCl3R COOHAlCl3配位键(增加C的正电性)CH=CH-COOH+ CH3OHBF3/Et2OCH=CH-COOCH3Vesley法10min94%CH3COOH + CH3OH CH3COOCH3R-N=C=N-RCH3-N=C=N-C(CH3)3CH3CH2-N=C=N-(CH2)3-NEt2

4、(CH3)2CH-N=C=N-CH(CH3)2N C NNO(CH2)2NCNCONHNHH2OCSNH2NHNHCS2NCNNH2H2 / cat高温，高压OHH3COCH3COOHHO CHCH3H2C+DCC/Et2OR.T.20minOHH3COCH3COOH酰化能力弱，因为可形成分子内氢键OHH3COCH3COO CHCH3H2COOCH2OHICOOH+DCC/DMAP25OOCH2ICOO96%DMAP：对二甲胺基吡啶RCOOR+ROHRCOOR+ROH沸点低R=CH3 , CH2CH3醇解HNCOOCH2CH3HOCH2CH2N(C2H5)2+C2H5ONaCH3(CH2)3N

5、HCCH2CH2N(C2H5)2OO+C2H5OHCH3(CH2)3CCOOCH2CH3OHN+CH3HOCH3CH2ONaCH3Br60-80,45minCCOOOHNCH3CCOOOHNCH3ch3Br(77%)CCOOCH3OHN+CH3HONaCH3Br110-120CCOOOHNCH3CCOOOHNCH3CH3Br(50-60%)-环 戊 基 -羟 基 苯 乙 酸 甲 酯3-羟 基 -N-甲 基 四 氢 吡 洛N-甲 基 四 氢 吡 洛 酯CROOCORHRCOOCOR+OCRCOOROCROHCROHOHCRCOOR+OCRCOORAlCl3CROOCROAlCl3+CH3OH+

6、Ac2ODMAP回流例C3H7COHCH3CH3+CCOOOEt3NTEACH3OAcCCOOOOHCCH3C3H7CH3DMAP:对 二 甲 氨 基 吡 啶NNCH3H3COOHOOAc+ Ac2OPyHOCH2OHHOCH2OAcAcOCH2OAcAc2OBF3-Et2OPyAc2O68%62%NOHCH3CH3(C2H5CO)2O/Py/HCl(gas)NOCOC2H5CH3CH3HClOCRCOOF3COHCRCOOF3CCROCF3COOHH+CROOOCF3C(CF3CO)2O+RCOOH+CF3COOH羧酸-三氟乙酸混合酸酐的制备(CF3CO)2OH2NCH2OH+CH3CH2C

7、OOHH2NCH2OCOCH2CH373%COOHCH3CH3COHCH3+(CF3CO)2OCOOBu-tClClClCOClClClClCROOOC+ RCOOHOCRSO2ORRCOOH + RSO2ClCRO+RSO2OHCClOClCClOOEtCEtOOOEtCClOOOCR碳 酸 酯RCOOH其 它 :ClOCRAlCl3CROAlCl4ClOCR+ AlCl3无 机 碱 :去 酸 剂有机碱 ：Py, Et3N, DMAPNN 4-吡 咯 烷 基 吡 啶PPY：NNCH3CH3DMAP：COCl+OHPyRtCH3H3CCH3COCl+Et3-C-OHAgCNHMPT六 甲 基

8、磷 酰 胺COOCH3H3CCH3COOCEt3CRONRRCRONNCRONNCRONNN将氮固定在缺电子环上N的共轭效应使酰胺酯化作用弱NNCNNORCNNOHNNH+RCOOH+CO2CDI碳酰二咪唑Reference 40c-Reference 40cH2CCOOHRH2CCOHORH3C COROCH2=C=O + ROH- HH2COHOH650700(Et3P)CH2=C=O乙 酸 脱 水H2CCH2COCOH2CCH2COCOORHH3C CH2CCOROO2CH2=C=OROH乙 酰 乙 酯 的 工 业 制 法OHCH3OOCOPhCOCH3+PhCOClPyOHp-共轭，羟

9、基氧的亲核性降低，使酚羟基不易被酰化COOHH3CCH3CH3OHH3CCH3COOCH3H3CCH3H3CH3C+(CF3CO)2O立体 位阻 较大的 羧酸H2CH2CCOOHCOOHH2CH2CCOOCOOOH2+POCl3CCNCNH3COH3CCOCH3CH3O乙酰化试剂与反应(专门酰化酚羟基)OH活性部位N-乙酰基-1,5,5-三甲基-乙内酰脲(Ac-TMH)HOCH2OH+Ac-TMHCH3CNAcOCH2OHCCNCNHH3COH3CCH3OCCNCNH3COH3CCOCH3CH3O1,5,5-trimethylhydantoin3-acetyl-l,5,5-trimethylh

10、ydantoin (Ac-TMH)1,5,5-trimethylhydantoin (0.01 mol) in acetic anhydride (9 ml) is refluxed during 1.5 hr; removal of acetic acid and excess anhydride in vacuo followed by crystallization from ethyl acetate-hexane furnishes Ac-TMH (89 % yield), mp 126-127.J. Am. Chem. Soc., 1969, 91 (8), 2162-2163Re

11、ference 47OHHOOHRCOORCOCl / NaOH / Bu4NHSO4 /r.t. 30minOOCH2COOHPhCH2CHCOOHCH2COOC6H4NO2-pPhCH2CHCOOC6H4NO2-p?降糖药米格列奈中间体HOC6H4NO2 -p+(1). 制成酰氯(2). 混合酸酐(如:三氟乙酐, 三氯氧磷)CH2COClPhCH2CHCOClCH2COOHPhCH2CHCOOHCH2COOC6H4NO2-pPhCH2CHCOOC6H4NO2-pSOCl2HOC6H4NO2 -p一一 脂肪氨脂肪氨-N酰化酰化OR-C-L + H2NRNRHCRO+ HLDMF 工 业 生

12、产HCOOCH3+ (CH3)2NHHCON(CH3)2甲 酸 酯 氨 解消炎痛酰卤的氨解ClCOCl+NHH3COCH2COOHCH3NH3COCH2COOHCH3ClCORCOOH + H2NRRCONHR + H2ORCOHONCNRCOOCNHN+RNH2RCNHROOCHNHN+N,N-二环己基碳酰亚胺，DCC(CH3)2CHN=C=NCH(CH3)2NNNOPEtOEtOOBDPDICNCNDCCRC ORORC NHRO+ H2NR+HORCH2NH2+OOOCH2NH COCH2CH2OHOH2NCH2NORRCCOOEtCOOEt+H2NO2SOCH3CONO2NO2ONH2

13、CH2NC2H5+活性酯NHCCCNHCRROOO巴 比 妥 类 通 用 方 法H2NO2SOCH3CONH2CHNC2H5舒比利RC OCROORCHNRO+ H2NRPy Et3N过量H2NRNO2NHCH3NO2NAcCH3例 ：Ac2O +H3CHC COOHNHCOCH3H3CHC CNHCOCH3O COOOEtH3CHC CNHCOCH3HNHCOCOOHClCOOEtCHNH2COOH羧酸中加入三氟乙酐或氯甲酸酯生成混合酸酐活性酰化剂3 3 酸酐为酰化剂酸酐为酰化剂COCOOCOCOOHHNCHCH2PhCOOHCOCONCHCH2PhCOOHPhCH2CHCOOHNH2如用环

14、状酸酐酰化时，在低温下常生成单酰化产物，高温加热那么可得双酰化亚胺RCOOHSCH3OOOCORRCONHRRCOORTsCl/K2CO3/TEBA40oC, 560min40oC, 10minReflux, 5120minRNH2ROH7795%8088%EtOPOEtOOCORRCOOHEtOPOEtOCN氰代磷酸二乙酯，DEPCHCNHCbzCOOHPhSNOCCH2COPhONH2SNOCCH2COPhONH2COHCPhNHCbz+DEPCr.t. 2hRC ClORCHNRO+H2NR+HCl(加 去 酸 剂 ： 有 机 碱 Py, Et3N)4 4 酰氯为酰化剂酰氯为酰化剂CH

15、CONH2SNHOOCCH3HNOHCCOClNH2HClSNMe3SiOOCCH3H2NO+Et3NCH3CN,-25HNOSOCl2COOHCONOCOOHCONO抗抗真真菌菌药药阿阿莫莫罗罗芬芬中中间间体体? ?噻唑烷酸抗癌药中间体NHSCOOHNSCOOHCOCH3?(CH3CO)2OCH3COClNH2+Ac2ONHAcCOOEtCOOEtNH2ClCONHCONHClCl+ 2Na脂 肪 胺 芳 胺NH2Rp-共 轭因 为NH2ClONHCOOEtClONHCOClONNCOOEt+ClCOOEtPyHNN COOEtCH3ONHCOCH3CH3ONH2Ac2OCH3COClNH2

16、NHCOCH3-芳胺较难酰化芳胺较难酰化AcHNCH2NH2H2NCH2NH2H2NCH2NHAcAc2OpH 4.15pH 11.25Ac2OCHCOOHNH2CHCOOHNHCOOCH2C6H5+ C6H5CH2OCOClNaOH, H2O1 : 1pH89, 0 氨苄西林中间体CH3CH3NHCOCHBrCH3CH3CH3NH2+ CH3CHBrCOClPhHreflux1 : 1.2抗心律失常药妥卡尼等中间体SCH2COOHNH2CH3SCH2CONHCH3BOP-Cl / Et3Nr.t. 1h+NOOPClOONOBOP-ClNH2BrBrBrNHCOCH3BrBrBrAc2O/H

17、2SO4NHCH3NO2NNO2COCH3CH3Ac2O/H2SO4COClNH2COClNHCOCH2Cl地西泮等中间体2-氯乙酰氨基-5-氯二苯酮? ?ClCH2COClClCH2COClCH3COClCl2hvCH3COOHPCl5OCOCH3COOHOHCOOHCH3COClSOCl2OCOCH3COClHONH2(CH3CO)2OHONHCOCH3OHCOOHHONH2ONHCOCH3OCOCH3CO例扑热息痛例扑热息痛(对羟基乙酰苯胺对羟基乙酰苯胺)的合成的合成(一种解热镇痛一种解热镇痛药药), 其制备经过乙酰基化反响其制备经过乙酰基化反响ClNO21). NaOH,H2O2).

18、H2O,H+HONO2HONH2HONHC-CH3H2,Ni(CH3CO)2OOCCHO-CH=CH-CH-RCOZCRO+Lewis(Z= -X,-OCOR,-OH,OR)RCClORCClOAlCl3R-COALCL4R-COALCL4+AlCl3+机理：CO的位为叔碳时发生烃化反应H3CCCCH3ClOH3CH3CC CCH3ClOH3CAlCl3H3CCCH3CH3AlCl4CCH3CH3CH3AlCl3+CO +COC(CH3)3COC(CH3)3COCl+ (CH3)3CMgBrr.t.,不饱和酰化剂,分子内酯化CH3OCH3CH3OCH3COCH=CHCH3CH3OCH3CH3O

19、OH3COCH3AlCl3有脱去-OCH3中小分子-CH3的能力主次CH3CH=CHCOCl / AlCl3+COClOAlCl3 / CS2(CH2)nCOCl(CH2)nCOSS(CH2)nO/ AlCl3n=2, 90%n=3, 91%n=4, 50%AlCl3COCH3+ (CH3CO)2OAlCl31 : 2.2HCl, H2O83%90 61%COCH3+ CH3COClAlCl31 : 1.2HCl, H2O50 用用酸酸酐酐作作酰酰化化剂剂，可可制制取取芳芳酰酰脂脂肪肪酸酸，并并可可进进一一步步环环合合得得芳芳酮酮衍衍生生物物OOOCOOHCOCH3+AlCl390H2SO41

20、00 2hOO81%COOHH2CCH3H2SO4100 2hCH3CH3Zn-HgHCl邻对位电效应等价clemmensen还 原 ， 只 还 原 酮 或 醛 中 的 羰 基CH3OCOClCOPhCH3CH3CF3SO3HAlCl382%26%CH3CH3+CH3+ CH3COOHCF3SO3H25oC, 2hCH3COCH3OSNH呋 喃噻 吩电 荷 高 的 芳 杂 环CH3CHH3CH3C位阻大OCH3CHCHCOClCl EtH3COEtOOCH3OEtAlCl3 / Py71%13%OMeMeOMeOOMeOHMeOMeOOMeOCH3COCl, AlCl364%OMeOMeOOM

21、eOHLewis酸：活性顺序AlBr3AlCl3FeCl3BF3SnCl4ZnCl2PPA ，浓H2SO4（此反应不用溶剂）酰卤，酸酐羧酸五元杂环中质子酸：NO2沸 点 高 不 好 回 收但 收 率 很 高 ， 因 为 使 反 应 在 均 相 中 进 行沸点沸点210.9 CH3OCOCH2CH2COOH哒嗪酮类化合物的中间体CH3OCOCH2CH2COOHCH3OOOO+CH2ClCH2ClAlCl3CO2NOCO2NClOCO2NOHOSOCl2AlCl3, PhHCH3O2NCOOHO2NCrO3CO2NO 对硝基二苯甲酮甲苯咪唑等的中间体OHCOOHHONH2+POCl3DMF?OHC

22、ONH2OHOHCOOHNH2OHCONHOHCOONH2OHABCD柳氨酚NH2ClCOClZnCl2+?NH2ClCO美达西泮等中间体ROOR+RCNHClZnCl2ROORRCO水 解通 式ORROCRNHORROCRO机理： R-CNHClZnCl2RC=NHZnCl3ORROH2OR CNHClCRNHOOHOHCRHNOHOHCROOHOHOHRC=NHH2OO-酰 化 ， 此 时 O比 芳 环 亲 核 能 力 强此时芳环亲核能力强HOOHOHHOOHOHC=NHHClCH3HOOHOHCOCH3+ CH3CNZnCl2HClEt2OH2OOHOHC2H5合合成成：OHOHCOCH

23、3CH3CNHCl / ZnCl2H2OZn / Hg, HClOHOHC2H5OHOHOHCOCH2ClOH异丙肾上腺素及抗癌药中间体ClCH2CONH2P2O3ClCH2CNOHOHOHCOCH2ClOH+ ClCH2CNZnCl2HClH2O通 式ArH+HCNCNHHCHOHClZnCl2H2O活性：对芳环要求降低，只存在一个供电子基也可以CNRCNH+OHOHCHOZn(CN)2 / HClZn(CN)2 / HCl / AlCl3CH3H3CCH3CH3H3CCH3CHOZn(CN)2 + 2HCl2HCN + ZnCl2NH2NH2OHOHRRHOSAr：HCNCH3CH3OHC

24、ON(DMF)具 有 甲 酰 胺 结 构ClCClOOSClOHCOCClOHCPOCl3 SOCl2在反应中形成SSCHO DMF/POCl3 H2OCHO DMF/POCl3 H2OVilsmeierArOH + NaOH +CHCl3CCl4ArCHOCClClClCClClClHCHCl3OH -Cl -CCl2卡宾NHONHOCHO50%NaOH, CHCl3OHOHCHONaOH / CHCl3 / -CD60, 20min-环环糊糊精精催催化化得得到到单单一一的的对对位位取取代代产产物物50%NaOH, CHCl3NOHNOHCHONOHCHO15.0%21.5%123reflu

25、x+Zn(CN)2 / HCl / AlCl3CH3H3CCH3CH3H3CCH3CHOGattermann-Koch 反应Vilsmelier反应Reimer-Tiemann反应NHONHOCHO50%NaOH, CHCl3Gattermann 反应+ CO + HClAlCl3, CuCl(CH3)2N(CH3)2NCHO+ (CH3)2NCHOPOCl3CHOHNO3 / H2SO4CH3COCl, AlCl3COCH3COCH3NO2CH2CH3CH2CH3NO2COCH3NO2HNO3 / H2SO4airMnAc2NO2COOHNO2CCH(COOEt)2ONO2COHCH(COO

26、Et)2O-NO2CCH(COOH)2ONO2CCH3OCH2(COOEt)2- OH-C2H5ONa/C2H5OHRCHCH2RCClORCHCH2+RCHCHCROAlCl3加成的方向服从马氏规则,酰基优先进攻氢原子较多的碳原子机 理RCClO+AlCl3RCClOAlCl3RCClOAlCl3RCOR-CH=CH2-H+R CHCHCRORHCH2CCROOOBrOAlCl3 / CH2Cl2+RC CHOXYH2CXYRCClO+B:-NO2-COR-SO2R-COOR-CN-SOR-PhH2CXY机 理H3CCH2CCOOEtOB:H3CCHC

27、COOEtORCOClH3CCHCCOOEtOCORH3CCH2COCORH3CCHCCOOHOCORHH2O-CO2脱酯基NH4Cl/NH4OH脱乙酰基H2CCOOEtCORClCOCl+CH3COCH2COOC2H5ClCOCHCOOC2H5COCH3NH4Cl/NH4OH/H2O脱乙酰基ClCO CH2COOC2H5H2SO4/H2OClCO CH3氯 苯 乙 酮(氯 喘 定 的 合 成 中 间 体 )ClCO CH3COCH3COCH3ClCl2Fe or FeCl3CH3COClAlCl3乙酰基是间位定位基ClClCOCH3CH3CNHCl / ZnCl2H2O氯苯不活泼，不能发生Hoesch反应NH2COCH3NH2CH3COClNaNO2 / HClCuClH2OCOCH3Cl苯胺应事先保护氨基ClCO CH3ClCOOHClCOCl(CH3)2CuLiSOCl2COOHClCOOLiClCClOLiOLiCH3CH3Li- CH4H2OCH3LiCClCH3OORCRH2COORCArOCHCCArOORRO+EtONa酯 与 不 含 -H的 酯 的 缩 合HCCRH2COCOEtROORCRH2COEtONa酯自身缩合ORCRH2CO+机 理CH3COOEtCH2COOEtB:CH2COOEtCH3COEtOCH3COOE