典化學(xué)反應(yīng)操作藥明酰胺合成

目錄1.前 2.羧酸與胺的縮合?；?2.1活性酯 應(yīng)用氯甲酸乙酯或異丁酯活性酯法合成酰胺示 應(yīng)用氯甲酸乙酯或異丁酯活性酯法合成伯酰胺示目錄1.前 2.羧酸與胺的縮合?；?2.1活性酯 應(yīng)用氯甲酸乙酯或異丁酯活性酯法合成酰胺示 應(yīng)用氯甲酸乙酯或異丁酯活性酯法合成伯酰胺示 應(yīng)用羰基二咪唑合成Weinreb酰胺示 應(yīng)用的磺酰氯合成酰胺示 應(yīng)用Boc酸酐合成伯酰胺示 2.2碳二亞胺類縮合劑 應(yīng)用DCC縮合法合成酰胺示 應(yīng)用DIC縮合法合成酰胺示 2.2.3應(yīng)用EDC縮合法合成酰胺示例一（二氯甲烷為溶劑 2.2.4應(yīng)用EDC縮合法合成酰胺示例二（DMF為溶劑 鎓鹽類的縮合劑 應(yīng)用HATU/TBTU為縮合劑合成酰胺示 應(yīng)用BOP為縮合劑合成酰胺示 應(yīng)用PyBOP（常規(guī) 應(yīng)用PyBOP為縮合劑合成酰胺示例二（用于合成伯酰胺 有機(jī)磷類縮合 應(yīng)用DPP-Cl為縮合劑合成酰胺示 應(yīng)用DPPA為縮合劑合成酰胺示 應(yīng)用BOP-Cl為縮合劑合成酰胺示 應(yīng)用三苯基磷應(yīng)用DPPA為縮合劑合成酰胺示 應(yīng)用BOP-Cl為縮合劑合成酰胺示 應(yīng)用三苯基磷-多鹵代甲烷合成酰胺示 應(yīng)用三苯基磷-六氯丙酮合成酰胺示 應(yīng)用三苯基磷-NBS合成酰胺示 3.氨或胺與酰鹵的?；?3.1酰鹵的制備示 3.5.1應(yīng)用二氯亞砜合成酰氯示 3.5.2用草酰氯合成酰氯示 3.5.3用三氯均三嗪合成酰氯示 3.5.4用三氟均三嗪合成酰氟示 3.1應(yīng)用酰鹵的合成酰 3.5.1應(yīng)用酰氯合成酰胺示例（有機(jī)堿 3.5.2應(yīng)用酰氯合成酰胺示例（無機(jī)堿 3.5.3應(yīng)用酰氟合成酰胺示 4.氨或胺與酸酐的?；?4.2酸酐合成酰胺示 5.其他縮合方 1.R1OOORRXRX=Activating2.羧酸與胺的縮合酰化羥基乙?；S胺190℃共熱，并蒸出生成的水及過量的芐胺，則生成1.R1OOORRXRX=Activating2.羧酸與胺的縮合酰化羥基乙?；S胺190℃共熱，并蒸出生成的水及過量的芐胺，則生成O+HOCHCNHCH222.1ClCOOEt,NH3rt,CHCl3,-20~5oC,OONNONNOO NCH2Cl2,0oC,OTetrahedron1994,50,OOOOTfOMe(2NNNN NNN-NCH3NO2,2Chem.Pharma.Bull.1982,30,另一類常用的方法是羧酸和磺酰氯生成羧酸-磺酸的混合酸酐，其與胺反應(yīng)得到相（Cl（l和對硝基苯磺酰氯（l）,對硝基苯磺酰氯由于其吸電子性，其與酸反應(yīng)生成活性更高的混合酸酐，一般二級胺和三級胺，甚至位阻很大的胺都能順利反應(yīng)3OO NMsCl,SONreflux,ONNONNOO NCH2Cl2,0oC,OTetrahedron1994,50,OOOOTfOMe(2NNNN NNN-NCH3NO2,2Chem.Pharma.Bull.1982,30,另一類常用的方法是羧酸和磺酰氯生成羧酸-磺酸的混合酸酐，其與胺反應(yīng)得到相（Cl（l和對硝基苯磺酰氯（l）,對硝基苯磺酰氯由于其吸電子性，其與酸反應(yīng)生成活性更高的混合酸酐，一般二級胺和三級胺，甚至位阻很大的胺都能順利反應(yīng)3OO NMsCl,SONreflux,10CH3CN,50oC,15Synthesis1989,OOOOOSNCO2Et3N,DMAP,OOOOO2TetrahedronLett.1995,36, rt,40rt, 應(yīng)用氯甲酸乙酯或異丁酯活性酯法合成酰胺示OOOOH H H NMM, CH5 OOOOO12J.Med.Chem.2004,47,2110-J.Med.Chem.2002,45, 應(yīng)用氯甲酸乙酯或異丁酯活性酯法合成酰胺示OOOOH H H NMM, CH5 OOOOO12J.Med.Chem.2004,47,2110-J.Med.Chem.2002,45,713-Asolutionofacid1and4-methylmorpholine(NMM,0.54mL,4.92mmol)inDMF(10wastreatedatroomtemperaturewithisobutylchloroformate(0.64mL,4.92Aftermin,pentylamine(0.57mL,4.92mmol)wasThereactionmixturewasstirredforThesolventwasevaporated,andtheresiduewaspartitionedbetweenethylacetate(25andwater(25Theethylacetatelayerwaswashedwith5%NaHCO3(10mL)and(20mL),driedoverNa2SO4,andTheresiduewaschromatographedonsilicaelutingwithhexaneandethylacetate(2:1)togive0.33g(33%)oftert-aminoamide應(yīng)用氯甲酸乙酯或異丁酯活性酯法合成伯酰胺ClCOOC2H5,TEA,THF,thenNH3OOOO-20'Cto34Synth.Commun.,Vol.34,No.1,pp.159-170,Toacooled(-20℃)solutionofcompound3(4.8g,18mmol)inanhydrousTHF(50mL)addedEt3N(2.5mL,18mmol)during20After10minethylchloroformate(1.718mmol)wasaddedatthesametemperatureduring10minandstirredforanadditionalTheresultingmixturewassaturatedwithNH3gasandkeptatr.t.mixturewasconcentratedatreducedpressure,theresiduewasdilutedwithH2O(10mL)extractedwithEtOAc(4*10Thecombinedorganicphasesweredriedfilteredandconcentratedtoaffordawhitesolid.Itwasrecrystallizedfrompetroleumandethylacetatetoaffordpureproduct4aswhitecrystal(3.1g,2.1.3酰胺示例CDI,HN(OMe)Me.OO56Toacid5(4.0g,14.1mmol)inCH2Cl2(70mL)at23℃wasadded1,1’-(3.65g,22.5mmol)inequalportionsover15Afterthefinaladdition,2.1.3酰胺示例CDI,HN(OMe)Me.OO56Toacid5(4.0g,14.1mmol)inCH2Cl2(70mL)at23℃wasadded1,1’-(3.65g,22.5mmol)inequalportionsover15Afterthefinaladdition,stirringcontinuedfor10min,thenN,O-dimethylhydroxylamine?HCl(3.43g,35.16mmol)wasinoneThereactionwasallowedtostirat23℃for3h.Et2Owasadded(50mL)thereactionmixturewasThefiltratewasevaporated,dilutedwithEt2O(125washedwith5%aq.citricacid(2x50mL)andbrine(50mL),anddriedovercrudeproductwaspurifiedbyflashchromatography(3:1hexanes:EtOAc)toafford1HNMRamide6(4.29g,93%yield)asacolorlessRf0.42(2:1MHz,CDCl3):δ5.43(m,1H),4.72(s,1H),4.17-4.11(m,1H),3.71(s,3H),3.22(s,3H),2.24(comp.m,3H),2.03(dd,J=14.6Hz,4.1Hz,1H),1.75-1.71(m,3H),0.86(s,9H),0.11(s,3H),0.09(s,3H). OOOOOOK2CO3,reflux,40O78Amixtureofthebenzoicacid(10mmol),4-methylbenzene-1-sulfonylchloride(10K2CO3(5.52g,40mmol)andTEBAC(0.23g,1mmol)in60mLofbenzeneisstirredatfor40Thenethyl2-aminoacetate(10mmol)isaddedandstirringiscontinuedforminatrefluxTheprecipitateisfilteredoff,andthefiltrateisevaporatedreducedThecarboxamide8thusobtainediscrystallizedfromMeOHtoaffordpureproduct(yield2.1.5應(yīng)用Boc酸酐合成伯酰胺示OOOORCOOH.+O+BuOHR 9Bull.Chem.Soc.Jap.1988,61,TypicalToastirredsolution2.1.5應(yīng)用Boc酸酐合成伯酰胺示OOOORCOOH.+O+BuOHR 9Bull.Chem.Soc.Jap.1988,61,TypicalToastirredsolutionofN-protectedaminoacid9(10mmol),pyridine(0.5ml)andBoc2O(3g,13mmol)inanappropriatesolvent(suchasdioxane,DMFandCH3CN,10-15ml),ammoniumhydrogencarbonate(1g,12.6mmol)wasaddedandthemixturewasstirredfor4-16h.Ethylacetatewasaddedandafterwashingswithwaterand5%H2SO4,thesolutionwasdried,solventwasevaporatedandtheproductwastrituratedwithInanothervariantreactionmixturewasdilutedwithwater(30-40ml),stirreduntilcrystallizationwasaresiduewasthencollectedbyfiltration,washedbywater,driedandrecrystallizedas2.2劑主要有三種：二環(huán)己基碳二亞胺(DCC)、二異丙基碳二亞胺(DIC)和1-(3-二甲胺基基)-3-乙基碳二亞胺(EDCI)NCNCNCN使用該類的縮合劑一般需要加入酰化催化劑或活化劑，如4-N,N二甲基吡啶（DMAP1-羥基苯并三氮唑(HOBt)等等，其主要由于在反應(yīng)的第一階段酸對碳二亞會通過重排成相應(yīng)的穩(wěn)定的脲的副產(chǎn)物(PathORROCNPath3OR3ORNRXRXRROX=O COOR1NHNNOOPathNCRORODMAPOOONNNNNNNORROCNPath3OR3ORNRXRXRROX=O COOR1NHNNOOPathNCRORODMAPOOONNNNNNNNNNDCC、DICEDCIDCCDICDCCDMAPDCC有一個最大的缺點就是反應(yīng)的另一產(chǎn)物二環(huán)己基脲進(jìn)一步處理。DIC由于其產(chǎn)生的二異丙基脲在有一般的有機(jī)溶劑中溶解度較好，因此EDCI，其一個主要的特點就是其反應(yīng)后的生2-3N-甲基嗎啡啉或二異丙基乙胺（DIEAHunigbase）,縮合時以二氯甲烷為溶劑，若底物的NRNNONONNOO NCORNROR2.2.1應(yīng)用DCC縮合法合成酰胺RO CO2Bu-OOOOOCO2Bu-R +H2OOHOCOCO2Bu-2NRNNONONNOO NCORNROR2.2.1應(yīng)用DCC縮合法合成酰胺RO CO2Bu-OOOOOCO2Bu-R +H2OOHOCOCO2Bu-22COBu-2RRToaofcompound11g,10mmol)inDMF(150mL)wasaddedhydroxybenzotriazole(HOBt,5.64g,42mmol),followedbydicyclohexylcarbodiimide8.60g,42mmol).Afterstirringforlh,asolutionofdi-tert-butyl4-amino-4-[2-(tert-butoxycarbonyl)ethyl]heptanedioate5(17.34g,41.7mmol)inDMF(60mL)wasaddedthesolutionstirredat25℃for23ThecrystalswerefilteredandwashedonthefilterDMF(25 Thesolventwasdistilledat50℃/1mm,andtheresidualoilwasdissolvedether(600Crystalswerefiltered,theetherealsolutionwaswashedsuccessively10%HCl(2x100mL),saturatedNaHCO3(2x100mL),andbrine(2x50mL),thenTheethersolutionwasfilteredthroughceliteandsolventwasthenremovedvacuotoafford19.0gofcrudeproduct,whichwaspurifiedonasilicacolumnelutingtoluene/EtOAc(1:1)tofurnish(60%)thewhite,non-crystallineester12:14.0g;mp55-NMRδ1.43108H),1.94-2.2864H),5.87(s,NH,4H),6.17CH=CH,2H);13CNMR(DMSO-d6)δ28.3(CH3),29.3(CH2CH2),56.8(CNH),69.0171.1(CO),應(yīng)用DIC縮合法合成酰胺OFmoc-Phe-OH,HOBt,DIC,DMF,NToasolutionofamine132.2.2應(yīng)用DIC縮合法合成酰胺OFmoc-Phe-OH,HOBt,DIC,DMF,NToasolutionofamine13(106mg,0.3mmol),Fmoc-Phe-OH(116mg,0.3mmol),and(44.8mg,0.33mmol)inanhydrousDMF(2mL)wasaddedDIC(56μL,0.36resultingmixturewasstirredatroomtemperatureovernight,andDMFwasthenunderhighTheresiduewasdissolvedinethylacetate(10mL),washedwithsaturatedaqueousNaHCO3andbrine,andthendriedoverNa2SO4.TheevaporationofthesolventgavethecrudeproductthatwasdirectlysubmittedfortheFmocremovalwithoutpurification.ThecrudeproductwasdissolvedinDMF(8mL),piperidine(2.0mL)wasadded,andtheresultingsolutionwasstirredatroomtemperaturefor1h.Followingthesolventevaporation,theresiduewaspurifiedbysilicagelchromatography(50%ethylacetateinhexanesto10%methanolinchloroform)toprovideproduct14(128mg)in85%yieldasamixtureoftwodiastereomers.1HNMR(CDCl3,400MHz)‰8.12-8.00(2H,m),7.90-7.80(2H,m),7.70-7.54(2H,m),7.42(2H,m),7.35-7.20(2H,m),6.97-6.83(3H,m),5.32(1H,m),4.32(1H,m),4.20-4.03(2H,m),3.96-3.80(2H,m),3.60(1H,m),2.98(3H,m),2.88(2H,2.60(1H,s),2.00(1H,m),1.85(2H,m),1.77-1.55(3H,m);MS(ES+)m/z)501.4(M+2.2.3EDC（二氯甲烷為溶劑EDC,HOBt,O+OToasolutionofamine16(0.284mg,1.19mmol)and5-hexenoicacid15(0.136g,1.19inCH2Cl2(12.0ml)at0℃wereaddedHOBt(0.177g,1.31mmol)andEDC(0.251g,Thereactionmixturewasstirredatroomtemperaturefor10h,thenwashedwithaqueousHCl(3×15.0ml),5%aqueousNaHCO3(20.0ml),H2O(20.0ml),andbrineml),anddriedPurificationbyflashchromatography(CH3Cl/MeOH,10%,aqueousHCl(3×15.0ml),5%aqueousNaHCO3(20.0ml),H2O(20.0ml),andbrineml),anddriedPurificationbyflashchromatography(CH3Cl/MeOH,10%,Rf0.43)affordedamidoalkene17in99%yieldasabrown2.2.4EDC縮合法合成酰胺示例二（DMF為溶劑ORNOORNEDC,OO R=OSOSADMFsolution(10mL)containingHOBt(103mg,0.76mmol),EDC(192mg,1.0andBoc-D-Ile(172mg,0.76mmol)wasstirredatroomtemperaturefor20Asolutiontheaminoketal18(0.41g,0.76mmol)and4-methylmorpholine(0.17mL,1.5mmol)in10mLofDMFwasthenaddedtothereactionAfter4hthereactionmixturepartitionedbetweenEtOAcand TheorganiclayerwaswashedwithH2O,dried EtOAc/hexanes)affordedtheBocketal19(0.44g,0.59mmol, O-(7-氮雜苯并三氮唑-1-基)-二（二甲胺基）碳（HTU-（HBTU（HCTU（TBTU（TSTU四氟硼酸鹽（TNTU）等NNNNNNNONNNNNO-NNONONNNNNNNNNNOONNONNOONN-NNNO4NNNNOO歸功于有更好活性的Cl-HOBt中間體。TSTUTNTU可以用于含水溶劑的酰胺化反應(yīng)。若將HATU和HBTU的二甲胺基變?yōu)樗臍溥量┗梢缘玫交钚员人鼈兏叩腛-（HAPyUNNNNNNNONNNNNO-NNONONNNNNNNNNNOONNONNOONN-NNNO4NNNNOO歸功于有更好活性的Cl-HOBt中間體。TSTUTNTU可以用于含水溶劑的酰胺化反應(yīng)。若將HATU和HBTU的二甲胺基變?yōu)樗臍溥量┗梢缘玫交钚员人鼈兏叩腛-（HAPyU鹽（PyBOP）所代替。NNNNNNNO--PFNNO-NONN6NNNNPyBOP的是一個較為強(qiáng)的縮合劑，一般其他縮合劑縮合不到相應(yīng)的氨基酰胺5PyAOPNOOOOPyBOP,HOBt,ONNOO性酯，以下以HATU的縮合反應(yīng)為例，說明其反應(yīng)ONRO NRNNNONONONNNR RNNNNN+OOintramoleculargeneralbasecatalysisenhances2.3.1HATU/TBTUO+NRR R212OThegeneralThecarboxylacid(10mmol),amine(10.4mmol)andtriethylamine(20mmol)aredissolvedMeCN(20mL),andHBTUorHATUNOOOOPyBOP,HOBt,ONNOO性酯，以下以HATU的縮合反應(yīng)為例，說明其反應(yīng)ONRO NRNNNONONONNNR RNNNNN+OOintramoleculargeneralbasecatalysisenhances2.3.1HATU/TBTUO+NRR R212OThegeneralThecarboxylacid(10mmol),amine(10.4mmol)andtriethylamine(20mmol)aredissolvedMeCN(20mL),andHBTUorHATU(10.4mmol)isaddedtotheAfter15-thereactionis100-200mLofasaturatedNaClsolutionisthenaddedandproductextractedwithEtOAc(3×50Thecombinedorganicsarewashedwith2NandTheorganicsaredriedfiltered,concentratedinvacuotogivetheamide(90-100%2.3.2BOP為縮合劑合成酰ONH2OBOP,TEA,O+ HOOOOOAsolutionoftert-butyloxycarbonylthreonine20(2.19g,10mmol)andphenylalaninemethylesterhydrochloride21(2.16g,10mmol)in150mLCH3CNisstirredatR.T.whiletheBOP-reagent(4.42g,10mmol)isadded,followedbytheadditionoftriethylamine(2.2g,2.8mL,20mmol).ThereactionisstirredatR.T.for1.5hr.100mLofasaturatedNaClsolutionisaddedandtheproductextractedwith2.3.2BOP為縮合劑合成酰ONH2OBOP,TEA,O+ HOOOOOAsolutionoftert-butyloxycarbonylthreonine20(2.19g,10mmol)andphenylalaninemethylesterhydrochloride21(2.16g,10mmol)in150mLCH3CNisstirredatR.T.whiletheBOP-reagent(4.42g,10mmol)isadded,followedbytheadditionoftriethylamine(2.2g,2.8mL,20mmol).ThereactionisstirredatR.T.for1.5hr.100mLofasaturatedNaClsolutionisaddedandtheproductextractedwithEtOAc.ThecombinedorganicsarewashedwithHCl,H2O,5%NaHCO3,andthenTheorganicsaredriedoverMgSO4,filtered,concentratedinvacuotogivethedipeptide(3.74g,2.3.3為縮合劑合成酰胺示例（常規(guī)ONONNTetrahedron61(2005)Morpholine(0.17mL,0.58mmol)andPyBOP(0.56g,0.32mmol)wereaddedtotheofN-methylmorpholine(0.22mL,0.58mmol)andcarboxylicacid23(0.50g,0.29mmol)dimethylformamide(5Themixturewasstirredatroomtemperaturefor3mixturewasquenchedwithwaterandtheaqueoussolutionwasextractedwithdichloromethane.Theorganiclayerwaswashedwithwater,driedoverNa2SO4andconcentratedinvacuo.Thecrudeproductwaspurifiedbysilicagelcolumnchromatographyelutingwithdichloromethane/ethanol(9/1)togivemorpholide24asawhitesolid(109mg,65%).Mp92–94℃.1HNMRd7.56(s,1H,H9),6.99(s,1H,H7),7.16–7.12(m,3H,3Har),7.11(d,2H,J=8.5Hz,2H’ar),6.87(d,2H,J=8.5Hz,2H’ar),4.01–3.97(m,2H,H4),3.74(s,3H,3.65–3.61(m,2H,CH2morph.),3.60–3.57(m,2H,CH2morph.),2.96(m,2H,H6),2.88–2.84(m,4H,CH2),2.68–2.66(m,2H,CH2),2.50–2.46(m,2H,MS-ES+(MeOH):2.39(s,6H,CH3),2.16–2.12(m,2H,H5),1.52–1.48(m,4H,581(M+H+,2.3.4應(yīng)用PyBOP為縮合劑合成酰胺示例二（用于合成伯酰胺NNNNOFOFPyBOP,HOBt,OONOOONONOAsolutionof2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)aceticacidmg,0.17mmol)inanhydrousDMF(1.2mL)wastreatedwithPyBOP(125mg,0.24mmol)andHOBtMS-ES+(MeOH):2.39(s,6H,CH3),2.16–2.12(m,2H,H5),1.52–1.48(m,4H,581(M+H+,2.3.4應(yīng)用PyBOP為縮合劑合成酰胺示例二（用于合成伯酰胺NNNNOFOFPyBOP,HOBt,OONOOONONOAsolutionof2-(4-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)phenyl)aceticacidmg,0.17mmol)inanhydrousDMF(1.2mL)wastreatedwithPyBOP(125mg,0.24mmol)andHOBt(32mg,0.24mmol)followedbyDIPEA(60mL,0.35mmol)andNH4Cl(190.35Afterstirringatroomtemperaturefor20min,themixturewasundervacuumandtheresiduepartitionedbetweenEtOAcandsaturatedaq.NaHCO3TheEtOAcphasewaswashedwithbrine,andconcentratedinproductwaspurifiedbyflashcolumnchromatographyonSiO2elutingwith0-8%ofMeOH/CH2Cl2togivethetitlecompound26(40mg,62percent)asanambercoloredoil.1HNMR(DMSO-d6)d8.23(dd,1H,J=10.7,2.5Hz),8.05(d,1H,J=9.2Hz),7.93(d,1H,J=6.1Hz),7.42-7.32(m,2H),7.33-7.25(m,4H),6.92(s,1H),6.25(d,1H,J=5.6Hz),5.64(s,3.36(s,2H);MS(ESI+):m/z383.17有機(jī)磷類縮合Cl、氰代磷酸二乙酯（DECP、疊氮化磷酸二苯酯（DPPA、硫代二甲基磷?；B（MP二（2-氧-3-唑烷基）磷酰氯（BOP-Cl）等OOSPONPOPOOPOOP3BOP-Crystalline,DPP-synth.Commmun.1993,23,在這些磷酸酯和磷酰胺類縮合劑中，DECPBOP-OROOOOONPOOOO+POOORNNORONOBOP-另外，BOP-Cl的溶解性較差，導(dǎo)致反應(yīng)時間較長，有時會長達(dá)四五天，常2.4.1DPP-ClPh2PCl(DPP-DPP-Cl可以得到94%收率OOOPoOEtN,rt,12Et3N,AcOEt,-103Synthesis1980,2.4.2應(yīng)DPPA為縮合劑合OROOOOONPOOOO+POOORNNORONOBOP-另外，BOP-Cl的溶解性較差，導(dǎo)致反應(yīng)時間較長，有時會長達(dá)四五天，常2.4.1DPP-ClPh2PCl(DPP-DPP-Cl可以得到94%收率OOOPoOEtN,rt,12Et3N,AcOEt,-103Synthesis1980,2.4.2應(yīng)DPPA為縮合劑合成OOOPOOHO3OPO +NNOOToofthisamine30(0.270g,0.96DMF(5mL),phthalimidoethoxy)aceticacid29(0.237g,0.96mmol),DPPA(0.25mL,1.15mmol)and(0.29mL,2.11mmol)at0℃whilethereactionwasstirredatR.T.TheicebathwasremovedaftertwohoursEtOAc(70mL)wasaddedandthesolutionextractedsuccessivelywith10%citricacid,H2O,saturatedNaClsolution(20mLeach),dried(anhydrousMgSO4)andfinnalyevaporatedTheoilyresiduewaspurifiedbycolumnchromatographyonsilicagel,eluting7:1CHCl3-MeOHtogivethedesiredproduct31asawhitesolid.Yield:81%(twosteps);123-127 1H-NMR(DMSO-(ppm)=1.10-1.25(m,3H,CH3),1.65-1.95(m,CH2--iGln),3.44-3.60(m,6H,2OCH3),3.68CH2--Glu-NH2),2.23-2.40J=6Hz,CH2O),3.80(t,J=6Hz,NCH2),4.08-4.25(m,2H,2CH),4.64-4.90(m,1H,7.05(s,1H,CONH2),7.35(s,1H,CONH2),7.40-7.80-7.88(m,BOP-Cl為縮合劑合成酰胺示例2.4.3應(yīng)OiPr2NEt,BOP-Cl,OO7.05(s,1H,CONH2),7.35(s,1H,CONH2),7.40-7.80-7.88(m,BOP-Cl為縮合劑合成酰胺示例2.4.3應(yīng)OiPr2NEt,BOP-Cl,OO+OOOOToasolutionoftheacid33indryCH2Cl2(5ml/mmol)wasaddeddiisopropyl(DIEA,1equiv)undernitrogen,andthemixturewasstirredfor10equiv),amine32(1.1equiv)andagainDIPEA(2equiv)wereThen,BOP-ClAfteritwasovernight,mostoftheDCMwasremovedunderreducedpressureandethylacetate(100wasThesolutionwaswashedthreetimeswith5%NaHCO3solutionandconsecutivelywithwater,2MHClsolution,waterandsaturatedbrine(50mlorganiclayerwasdriedoverNa2SO4,andthesolventwasevaporatedtogivethedesired2.5.1應(yīng)用三苯基磷-多鹵代甲烷合成酰OCOPPh,CBr,2 +r.t.,15OOR++RPPh3+Ph3PX2.5.1應(yīng)用三苯基磷-多鹵代甲烷合成酰OCOPPh,CBr,2 +r.t.,15OOR++RPPh3+Ph3PX.R32-OPPh3.2mmolofacarboxylicacid37,2mmolofanamine38,2mmoloftriethylamine,and2ofcarbontetrabromidearedissolvedin5mLofdrymethyleneSolidphosphine(2mmol,554mg)isthenaddedportionwiseover5mintothesolutionstirredroomAfterafurtherperiodof10min.,thesolventisevaporated,andamixtureofhexaneandethylacetateisThesolidtriphenylphosphineoxideisoff,thesolventsareevaporatedandthecrudematerialcanbepurifiedbyconventional應(yīng)用三苯基磷-六氯丙酮合成酰胺OOCCl3COCCl3,PPh3,OH-78'Ctor.Amixtureofbenzoicacid(122mg,1mmol)andhexachloroacetone(132mg,0.5mmol)methylenechloride(2mL)wasstirredunderargonandcooleddownto-Triphenylphosphine(262mg,1mmol)inmethylenechloride(1mL)wasaddeddropwiseandthemixturewasstirredfor20min. Theacylchloridesolutionwasthentreatedwithasolutionofbenzylamine(107mg,1mmol)inmethylenechloride(1mL)dropwise,followedbytriethylamine(101mg,1mmol)inmethylenechloride(1mL)thereactionmixturewasthenallowedtoreachroomtemperatureafterwhichthe solventwasevaporatedunderhighvacuum.Thedryresiduewassuspendedin20%ethylacetateinhexane(4mL)andsilicageladdedinordertoobtainpasta.Thispastawasaddedontothetopofasilicagelcolumnandtheelutionperformedwiththesamesolvent. Thepurefractionsprovidedthetitlecompoundasawhitesolid(187mg,95%):m.p.2.5.3應(yīng)用三苯基磷-合成酰胺示OONOORPh3P--Toastirredsolutionoftriphenylphosphine(2.55mmol,2.5.3應(yīng)用三苯基磷-合成酰胺示OONOORPh3P--Toastirredsolutionoftriphenylphosphine(2.55mmol,0.67g)andhexanoicacid(2.50.29g)inanhydrousdichloromethane(5ml)at0℃wasaddedN-bromosuccinimide(NBS,mmol,0.50g)inoneThereactionmixturecontaining0.25mmolof40wassetasideatroomtemperaturewhileanewsolutionwasbeingprepared:3-Aminophenolmmol,0.28g)andpyridine(3.20mmol,0.26g)wasdissolvedinTHF(5Thewascooledtoabout-25℃(ethanol/granularCO2),andvigorouslystirredwhiletheready-solutionof40wasaddedThecoolingbathwasremovedafterafewminandtemperatureallowedtorisetowardsroomunderreducedpressureandtheproductpurifiedbyMostofthesolventsweresolventgaveN-(3-silicagel60,usingetherasRemovalofhexanamide41(0.52g,98%)asacolourlesssolid,m.p.139-140℃. 1HNMR(200MHz,acetone-d6):δ0.90(m,3H,CH3),1.35(m,4H,CH2),1.65(m,2H,CH2),2.35(t,2H,6.52(m,IH,H~o,~),7.0(m,2H,H~om.),7.42(s,1H,H~o),8.4(s,1H,OH),9.05(s,1H,MS(70eV):m/z(%)207(17,M+),151(6.5),1093.氨或胺與酰鹵的?；从玫臒o機(jī)堿有Na2CO3, K2CO3,NaOH,KOH等。在研究中我們發(fā)現(xiàn)，許多3.1示3.5.1應(yīng)用二氯亞砜合成酰氯示例OOFita100mLtwo-neckedflaskwithadroppingfunnelandarefluxcondenserconnectedatthetoptoagasabsorptiontrap.Place36g(21.5mL,0.3mol)ofredistilledthionylchlorideintheflaskand22g(23mL,0.25mol)ofbutyricacidintheseparatoryfunnel.Heattheflaskgentlyonawaterbath,andaddthebutyricacidduringthecourseof30-40minutes.Whentheacidhasbeenintroduced,heatwasonawaterbathfor30Rearrangeapparatusanddistillation:collectthecrudeacidchlorideboilingbetween70and110Finally,restilfromaflaskprovidedwithashortfractionatingcolumnandcollectthechlorideat100-101Theyieldis23g(86Note:Wrapapieceofabsorbentcottonwoolaroundthestemoftherefluxcondenserabovejointofthereactionflasktoprevent3.5.2用草酰氯合成酰氯示例chlorideat100-101Theyieldis23g(86Note:Wrapapieceofabsorbentcottonwoolaroundthestemoftherefluxcondenserabovejointofthereactionflasktoprevent3.5.2用草酰氯合成酰氯示例OOOxalylOOCompound42(4.19g,13.94mmol)wasdissolvedin20mLCH2Cl2,oxalylchloride(4.2548.40mmol)wasaddedatroomtemperature,theresultantmixturewasstirredatroomtemperaturefor30minandthenthemixturewasgentlywarmedunderrefluxfor30min.Afterthemixturewasconcentratedinvacuo,theresiduewasdissolvedinTHF,andthesolutionagainconcentratedinvacuotoofferquantitativelythecrudechloride3.5.3 NN+ ONOToamixtureofP-nitrobenzoicacid(1.67g,0.01mol)and2,4,6-Trichloro-[1,3,5]triazine(1.84g,0.01mol)inacetone(20mL)wasaddedTEA(1.01,0.01mol)andthemixturewasstirredfor3hr,filtratedtoremovetheseparateddichlorohydroxy-s-triazinederivative,andfiltrateconcentratedunderreducedTheresiduewasextractedandsolventremovedtogivethedesiredacidchloride46(yield58inCCl4wasfoundtobetheunreactedcarboxylic(Note:theresidue3.5.4FRR+NN +FNFNProt=ProtectingTetrahedronlett.Typicalexperimentaldetail:equimolecularamountoftheaminoacid,pyridineandfluoridearemixedandstirredfor3~4hoursindichloromethaneatroomAttime,3.5.4FRR+NN +FNFNProt=ProtectingTetrahedronlett.Typicalexperimentaldetail:equimolecularamountoftheaminoacid,pyridineandfluoridearemixedandstirredfor3~4hoursindichloromethaneatroomAttime,ice-waterisaddedtothereactionmixtureandtheprecipitatedcanuricacidisfilteredtheorganicphaseisdriedandevaporatedtodryness,whichgenerallyleavesthepureaminoacidfluorideincrystallineform.3.13.5.1應(yīng)用酰氯合成酰胺示例（有機(jī)堿O+ONNOOToasolutionof47(1.09g,3.00mmol)wasaddedpyridine(1.50g,18.96mmol),followedbydropwiseadditionofphenylacetylchloride(0.93g,6.00mmol)inCH2Cl2(20mL).Thesolutionwasstirredfor2h.at25°C,thenitwaswashedsuccessivelywith10%HCl,10%NaHCO3andwater,dried(MgSO4),filteredandthesolventwasthenevaporatedtogivetheimpureamidewhichwasrecrystallizedfromethanoltogiveN-(α-carboethoxy-βphenylethyl)-3-phenylacetylamino-4-styryl-2-azetidinone48,3.86g,80%)3.5.2應(yīng)用酰氯合成酰胺示例（無機(jī)堿OOO+OAmixturecontaining8.21gofphenylalanine,5.565gofNa2CO3in40mLofwaterandmLoftetrahydrofuranAmixturecontaining8.21gofphenylalanine,5.565gofNa2CO3in40mLofwaterandmLoftetrahydrofuran(THF)wasstirredatroombenzoylchloride(7.73dissolvedin20mLofanhydrousTHF,wasaddedgraduallyoveraperiodof45minuteswithcontinuedstirringatroomtemperature.Stirringwasallowedtocontinueforanadditionalhour,atwhichtimethereactionmixturewastransferredtoarotaryevaporatorat30℃toremovetheTHF.AnexcessofwaterwasthenaddedandthereactionmixtureextractedtimeswithethylTheaqueousphasewasthentitratedtoPH2with3NAcrystallineprecipitateformedwhichwasrecoveredbyfiltration,washedthreetimeswithcolddiluteHClandthreetimeswithcoldwater,anddriedinavacuumovenoverP2O5at Theproductwasrecrystallizedfromaqueousethanol,yielding8.37g,m.p.184℃.,whichmigratedasasinglecompoundonthinlayerchromatographyinfivesolvent InthisreactionsequencetheracemateisIfaNaOHsolutionisusedinplaceoftheNa2CO3inthisexampleandtheproceduresetinCarter,H.E.etal,J.Biol.Chem.138,627(1941)issubstantiallyfollowed,opticalisThus,ifL-PheorD-Pheisthestartingmaterial,N-alpha-benzoyl-L-phe,oralpha-benzoyl-D-hydroxysuccinimideesterisusedinplaceofbenzoylchlorideinthisexampleandtheprocedureisfollowed,theopticalactivityofD-PheorD-PheismaintainedintheN-alpha-benzoylderivative.CHCOCl,NO2OwassuspendedwithNaHCO3(5g),andacetylchloride(720mg)wasaddeddropwisevigorousAftertheaddition,thereactionwasstirredfor1themixturewasandthefiltratewasconcentratedinvacuo,andthenpurifiedviaflashchlomatographyon(EtOAc:hexanes=3:1to4:1)togivethetitlecompound.MS(ESI,pos.ion)m/z:233(M+3.5.3O RTheN-protectedamino3.5.3O RTheN-protectedaminoacidfluoride(1mmol)isreactedwiththechlorhydrateofanda-aminoester(1.1mmol)andN-methylmorpholine(2.2mmol)inacetonitrile(10ml)untiletheacylfluorideisconsumed(approximately4hat25℃).Thereactionisthenworkedupasusual.MethodAsolutionoftheacylfluoride(1.2mmol)inCH2Cl2(5ml)anda10%NaHCO3aqueoussolution(10ml)areaddedsimultaneouslytoastirredsolutionoftheester(1mmol)inCH2Cl2(5ml)atroomtemperature.Aftercompletionofthereaction(generally1to2hours),themixtureisworkedupas4.氨或胺與酸酐的?；碞OOOO+低OOOOOO+O低OOO4.2酸酐合成酰胺示例ONNNNOOONEt3,O+FNOOFNOOOOOOO+低OOOOOO+O低OOO4.2酸酐合成酰胺示例ONNNNOOONEt3,O+FNOOFNOOOToasolutionofamine53(0.05ml)in（5mL）wasaddedtriethylamine(0.5followedbyAc2O(0.5mL). Thereactionwasstirredatroomtemperaturefor2handevaporatedtodrynessinvacuo. TheresiduewastakenupinDCMandwashedwithsaturatedNaHCO3. TheorganiclayerwasdriedoverNa2SO4andthesolventwasremoved.Theproduct54waspurifiedbycolumnmatographywith10%MeOH/DCMand15mgamide54wasisolatedasawhitesolid(yield5他縮合5.1?；B氮5.1.1?；B氮合成酰胺示例ON+NONNOBoc-Try-ToasolutionofBoc-Tyr-N3(0.65mmol)inDMF(6mL)wereadded7.3NHCl/dioxanemmol)andisopentylnititeON+NONNOBoc-Try-ToasolutionofBoc-Tyr-N3(0.65mmol)inDMF(6mL)wereadded7.3NHCl/dioxanemmol)andisopentylnitite(0.78mmol)underco