经典合成反应标准操作

经典合成反应标准操作经典合成反应标准操作经典合成反应标准操作资料仅供参考文件编号：2022年4月经典合成反应标准操作版本号：A修改号：1页次：1.0审核：批准:发布日期：经典化学合成反应标准操作药明康德新药开发有限公司化学合成部编写

前言有机合成研究人员在做化学反应经常碰到常规的反应手边没有现成的标准操作步骤而要去查文献，在试同一类反应时，为了寻找各种反应条件方法也得去查资料。为了提高大家的工作效率，因此化学合成部需要一份《经典合成反应标准操作》。在这份材料中，我们精选药物化学中各类经典的合成反应，每类反应有什么方法，并通过实际经验对每类反应的各种条件进行点评，供大家在摸索合成条件时进行比较。同时每种反应的标准操作，均可作为模板套用于书写客户的finalreport，这样可以大大节省研究人员书写finalreport的时间，也相应减少在报告中的文法错误。另外本版是初版，在今后的工作中我们将根据需要修订这份材料。药明康德新药开发有限公司化学合成部2005-6-28

目录胺的合成还原胺化直接烷基化腈的还原酰胺的还原硝基的还原叠氮的还原Hoffman降解羧酸通过Cris重排羧酸衍生物的合成酰胺化的反应酯化反应腈转化为酯和酰胺钯催化的插羰反应酯交换为酰氨羧酸的合成醇氧化酯水解酰胺的水解腈的水解有机金属试剂的羰基化反应芳香甲基的氧化醛酮的合成Weinreb酰胺合成醛酮醇氧化酯的直接还原有机金属试剂对腈加成合成酮脂肪卤代物的合成醇转化为脂肪溴代物通过PBr3转化通过PPh3与CBr4转化HBr直接交换通过相应的氯代物或磺酸酯与LiBr交换、醇转化为脂肪氯代物通过SOCl2转化通过PPh3与CCl4转化HCl直接交换醇转化为脂肪碘代物通过PPh3与I2转化通过相应的氯代物或磺酸酯与NaI交换芳香卤代物的合成Sandermyyer重氮化卤代直接卤代杂环的酚羟基或醚的卤代醇的合成羧酸或酯的还原醛酮的还原卤代烃的水解吡啶的氧化转位酚的合成Sandermayer重氮化反应醚的水解Bayer-vigerlar氧化硼酸的氧化腈的合成磺酸酯或卤代烃的取代酰胺的脱水芳卤代烃的氰基取代硝化反应醚的合成芳香醚的合成酚与烷基卤代烃的直接烷基化Mitsunobu芳香醚化Buckwald芳香醚化脂肪醚的合成醇的醚化脲的合成胺与异腈酸酯的反应用三光气合成脲羰基二咪唑（CDI）合成脲对硝基苯酚碳酰胺合成脲烯烃的合成Wittig反应羟基的消除Wittig-Horner反应合成,-不饱和酯磺酸及磺酰氯的合成氯磺化反应合成磺酰氯从硫醇合成磺酰氯磺化反应氨基酸的合成Streck反应合成手性氨基酸的合成偶联反应SuzukiCouplingBuckwald芳胺化，芳酰胺化、Heck反应Mitsunobu反应醇的反转胺的取代脱羟基反应酮还原为亚甲基氨的保护及脱保护策略用碳酰胺作保护基苄基保护醇的保护及脱保护策略用硅醚进行保护其他醚类保护羧基的保护

Boc脱保护-------------------------------------------------------------------------------------------------------1格氏反应---------------------------------------------------------------------------------------------------------1还原胺化---------------------------------------------------------------------------------------------------------2卤化反应---------------------------------------------------------------------------------------------------------2Suzukicoupling-------------------------------------------------------------------------------------------------2磺化反应---------------------------------------------------------------------------------------------------------3酯化反应---------------------------------------------------------------------------------------------------------3水解反应---------------------------------------------------------------------------------------------------------3硝化反应---------------------------------------------------------------------------------------------------------4n-BuLi------------------------------------------------------------------------------------------------------------4LiAlH4还原-----------------------------------------------------------------------------------------------------4POCl3的杂环氯代----------------------------------------------------------------------------------------------5NaH---------------------------------------------------------------------------------------------------------------5NBS---------------------------------------------------------------------------------------------------------------5氢化反应---------------------------------------------------------------------------------------------------------6m-CPBA----------------------------------------------------------------------------------------------------------6EDC---------------------------------------------------------------------------------------------------------------6用三光气成脲---------------------------------------------------------------------------------------------------7芳卤用n-BuLi处理后与Weinreb酰胺成酮-----------------------------------------------------------------7Boc上保护ToasolutionofAg,mmol)andtetramethylammoniumhydroxidepentahydrateg,mmol)inacetonitrile(270mL)wasaddeddi-tert-butyldicarbonateg;mmol)andtheresultingsolutionwasallowedtostir18hatrtandconcentrated.TheresiduewaspartitionedbetweenEt2O/H2O;thephaseswereseparatedandtheaqueousphaseextractedtwicemorewithEt2O.TheaqueousphasewasbroughttopH4withsolidcitricacidandextractedwithCHCl3mL).Theorganicextractswerecombined,dried(Na2SO4)andconcentratedtoaffordg(63percent)Basawhitefoam.ReturnBoc脱保护Tert-Butyl2-(2-methoxyphenoxy)ethylcarbamateg,89mmol)indichloromethane(10ml)wascooledto0degCandstirredasamixtureoftrifluoroaceticacid:dichloromethane(1:1,40ml)wasaddeddropwise.Themixturewasallowedtowarmtort,stirredfor2hoursandconcentratedinvacuo.Theresiduewastakenbackupindichloromethane(100ml)andthesolutionwaswashedwithsaturatedaqueoussodiumhydrogencarbonate(3*20ml)andaqueoussodiumhydroxide(10percent,3*20ml),dried(Na2SO4),filteredandconcentratedinvacuotoprovide2-(2-methoxyphenoxy)ethylamine(13g,88percentyield)asalightyellowsolid.Return格氏反应Astirredmixtureofmagnesiumturningsg,mol)andEt2O(200mL)undernitrogenistreatedwithacrystalofiodineandabout5percentofasolutionofbromoethaneml,mol)inEt2O(375mL).Whenthereactionstarts,theremainderofthebromoethanesolutionisadded,dropwiseataratesufficienttomaintainagentlereflux.Aftertheaddition,stirringiscontinuedfor1hour.Tothissolutionofethylmagnesiumbromidewasslowlyaddedasolutionof4-cyanopyridine(39g,mol)inEt2O(750ml).Thereactionmixturewaswarmedatrefluxfor12hours,treatedwithconcentratedH2SO4(125ml)/H2O(125ml),andthenwashedthreetimeswithEt2O(250ml).Theaqueousportionwasmadebasic(PH9)with15percentNaOHsolutionandextractedfivetimeswith250mlportionsofEt2O.ThecombinedEt2Oextractsweredried(MgSO4),andthesolventwasremovedunderreducedpressuretoaffordabrownoilg,95percent).Return还原胺化Asolutionof2-amino-4-ethylphenolg.mmol),2-naphthaldehydeg,mmol),andp-toluenesulfonicacidg)inmethanol(50ML)wasstirredatroomtempfor24h.Totheresultantsolution,sodiumborohydrideg,22mmol)wasaddedinsmallportions.Afteradditionwascompleted,themixturewasstirredatroomtemperaturefor30minandconcentratedundervacuum.Theresiduewasthensubjectedtocolumnchromatographyonsilicagelelutedwith10percentethylacetateinhexaneandfollowedbyrecrystallization(aqueousmethanol)yielded450mg(22percent)ofanalyticallypureproduct.Return卤化反应Toastirredsolutionof8-methyl-1-nitro-naphthalene,mmol)andiron(III)chlorideg,mmo)inCCl4(150ml)heatedto60°Cwasaddeddropwiseml,mmol)ofbromine.Afteronehour,thereactionmixturewaspouredintosaturatedNaHCO3solution,andthelayerswereseparated.Theaqueouslayerwasre-extractedwithCH2Cl2.Thecombinedorganiclayersweredried(MgSO4)andthesolventwasremovedunderreducedpressure.Thecruderesiduewasrecrystallizedfromethanolandthemotherliquorswereconcentratedandthenflashchromatographedonsilica,eludinghexanes:ethylacetate(12:1).ReturnSuzukicoupling Toamixtureof4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole(2g,mnmol)and3-bromobenzeneml,mmol)inTHF(28ml)wereaddedpalladiumcatalystPd(PPh3)4(284mg,mmol)andthefreshlypreparedsodiumhydroxidesolution(984mgin9mlofwater).Thesystemwasdegassedandthenchargedwithnitrogenforthreetimes.Themixturewasstirredundernitrogenat70°Coilbathfor6hours.Thereactionsolutionwascooledtoroomtemperature,dilutedwithethylacetateandseparatedfromwaterlayer.Theethylacetatesolutionwaswashedbybrine,driedoverNa2SO4andconcentrated.Theresiduewaspurifiedonasilicagelcolumneludingwithhexanes:EtOAc9:1togiveg(78%yield)of4-phenyl-1H-indoleasacolorlessliquid.Return磺化反应Chlorosulfonicacid,40mmol)isaddeddropwisetoacold(0°C)solutionof2,3-dihydro-2-trifluoroacetyl-1H-Benz[de]isoquinoline,8mmol)inchloroform(800ml).Theresultingsolutionisstirredat0°Cfor30minutes. Thecoldbathisthenremovedandthesolutionisstirredatroomtemperaturefor1hourthencautiouslypouredintoicewater.Theorganiclayerisseparated,driedovermagnesiumsulfateandconcentratedtoaffordthetitlecompound. Thecrudeproductispurifiedbycolumnchromatographyelutedwith10%aceticetherinpetroleumetherg,81%yield).Return酯化反应Amixtureof4-hydroxymethylnaphthoicacid(10g,50mmol),methanol(300ml),andconcentrateH2SO4(2ml)wasrefluxedovernight.Theinsolubleswerefilteredoffandthefiltratewasconcentrated.TheresiduewastakenupinethylacetateandwashedwithaqueousNaHCO3(2*),brine,driedoverMgSO4,andconcentratedtogiveayellowoil.Silicagelcolumnchromatographyusingethylacetate/hexane(1/3)gavethedesiredproductasayellowoilg,35%yield).Return水解反应Asolutionof1-Methyl-naphthalene-2-carboxylicacidmethylester,35mmol)and2Nsodiumhydroxide(35ml)intetrahydrofuran(130ml)wasstirredunderrefluxfor18hours.Themixturewasneutralisedusing2Nhydrochloricacid,andextractedwithdichloromethane(3x).Thecombinedorganicsolutionsweredried(MgSO4),andevaporatedunderreducedpressure.Thecrudeproductwaspurifiedbycolumnchromatographyonsilicagelusinganelutiongradientofdichloromethane:methanol(100:0to97:3)toaffordthetitlecompoundasasolid,%yield).Return硝化反应Toacold(0°C)suspensionof1-methylnaphthalene(5g,mmol)inHNO3wasaddedH2SO4(5ml)dropwise.Afterstirringthereactionforonehour,thesolutionwasdilutedwithethylacetateandwashedwithwater(3*),aqueoussaturatedNaHCO3(2*)andbrine,driedoverMgSO4,andconcentrated.Theproductwaspurifiedbysilicagelcolumnchromatographyusingethylacetate:hexane(5:95)andrecrystallizedfrommethanoltogiveyellowneedles,33%yield).Returnn-BuLiToadrythree-neckedround-bottomedflaskwithanadditionfunnelandat-78°CunderinertatmospherewaschargedwithanhydrousTHF(500ml).Asolutionofn-butyllithiumMinhexane,88ml,220mmol)wasaddeddropwisefollowedbyadditionofasolutionofacetonitrileml,200mmol)inanhydrousTHF(100ml).Theinternaltemperaturewasmaintainedbelow-70°Cduringtheentireadditionprocess.After2hrat-78°CasolutionofTrifluoro-aceticacidethylesterg,100mmol)inanhydrousTHF(30ml)wasaddeddropwiseandthemixturewasstirredforhr.Tothemixturewasaddedaceticanhydridetoquenchthereaction.Thereactionmixturewasallowedtowarmuptort.Aprecipitatewasfilteredandthefiltratewasconcentratedtogiveabrownoil,whichwasusedinthenextstepwithoutpurification.ReturnLiAlH4还原Asolutionof2,3-naphthalenedicarboxylicacidg,mole)indryTHF(135ml,warmedto50°tomaintainsolution)isaddeddropwiseover15minutestoaMlithiumaluminumhydridesolutioninTHF(45ml,mole).Thesolutionisstirred3hoursafterwhichTLCindicatedconsumptionofdiacidandformationofanewmajorproduct.ThereactionisquenchedcarefullywithTHF-water,then2Nhydrochloricacid(40ml)isadded,andtheresultingmixtureisextracted3timeswithether.Thecombinedetherextractsarewashedwithwater(2times),withsaturatedsodiumbicarbonatesolution(1time),withwater,andaredried(sodiumsulfate),filtered,andconcentratedtogiveatansolidg).Thesolidisrecrystallizedfromethylacetategivingthetitlecompoundg,%yield)asalighttancrystallinematerial.ReturnPOCl3的杂环氯代Toasuspensionof2,4-dihydroxy-5,6-dimethylpyrimidineg,mol)inPOCl3(25ml)wasslowlyaddedN,N-dimethylanilineml,mol).Themixturewasthenrefluxedat125°Cfor3hours.Afterthistime,thestartingmaterialcompletelydissolvedindicatingthatthereactionwascompleted. ThereactionmixturewascooledandthenpouredslowlyontoicetoquenchthePOCl3(caution[exothermic]).Aprecipitateformed,whichwasfilteredandwashedwithice-coldwater.Theprecipitatewasdriedunderhighvacuumovernighttoyield2,4-dichloro-5,6-dimethyl-pyrimidineg,mol,92%yield)asayellowsolid.ReturnNaHSodiumhydride(50%inmineraloil,g,mol)wasaddedportionwiseat0°Cunderanitrogenatmospheretoasolutionof2-aminobenzenethiol(12ml,mol)inDMF(120ml).Afterh,benzylchlorideml,mol)inDMF(80ml)wasaddedinh.Thesolutionwasstirredfor3hwhilethetemperaturewasallowedtorisetort,thenitwaspouredintoice/water(1000g).Theprecipitatewasfiltered,dissolvedinethylacetateandwashedwithbrine.TheorganiclayerwasdriedoverNa2SO4andevaporated.Thesolidobtainedwasgroundinpentaneg,90%yield).ReturnNBSAmixtureof2,4-Dichloro-6-ethyl-5-fluoro-pyrimidineg，,AIBNg)andn-bromosuccinimideg，inCH2Cl2(170ml)wasrefluxedunderanitrogenatmospherefor36h.Thenwashedbywater,theaqueouswasextractedbyCH2Cl2.ThecombinedorganiclayerwaswashedbysaturatedNa2S2O3andbrine,driedoverNa2SO4,andevaporatedtogiveawhitesolidwhichwaspurifiedbycolumnchromatographyelutedwith50%aceticetherinpetroleumether(34g,%yield).Return氢化反应Amixtureofethyl3-(N-benzylamino)-3-methylbutyratehydrochloride(25g,mol)and10percentPd-C(2g)in250mlofdriedalcoholwashydrogenatedunder55psiH2forfourdays.Thereactionmediumwasthenfilteredandevaporatedunderreducedpressuretoprovideanamberoilwhichgraduallycrystallizeduponstanding(18g,100%yield).Returnm-CPBAAsolutionof85%m-chloroperoxybenzoicacid(19g,94mmol)inCH2Cl2(350ml)wasaddedat–5–0°Ctoasolutionof2-Benzylsulfanyl-phenylamine(19g,88mmol)inCH2Cl2(400ml).Themixturewasallowedtowarmtortin3h,thenitwaswashedwitha5%Na2S2O3solution,10%NaHCO3solutionandbrine.TheorganiclayerwasdriedoverNa2SO4,andevaporated.Thesolidwasgroundinpentane(19g,95%yield).ReturnEDCToa0°CmixtureofBoc-L-tyrosineg,mmol)andamylaminegl,mmol)inmethylenechloride(30ml)isadded1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC)g,mmol).Thewhitemixtureisstirredat0°Cfor5minandatroomtempfor23hrs.Theresultingsolutionisdilutedwithmethylenechloride(30ml)andwashedsuccessivelywithMHCl(40ml),water(20ml)andsataqsodiumbicarbonate(25ml).Theorganicphaseisdriedovermagnesiumsulfateandconcentratedtoafoamg,%yield),sufficientlypuretocarryintothenextstep.AnanalyticalsampleisobtainedbyHPLC.Return三光气成脲Toasolutionof2-(tert-butyldimethylsilyloxy)-4-nitroaniline(200mg,mmol)int