經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作

經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作資料僅供參考文件編號(hào)：2022年4月經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作版本號(hào)：A修改號(hào)：1頁次：1.0審核：批準(zhǔn):發(fā)布日期：經(jīng)典化學(xué)合成反應(yīng)標(biāo)準(zhǔn)操作藥明康德新藥開發(fā)有限公司化學(xué)合成部編寫

前言有機(jī)合成研究人員在做化學(xué)反應(yīng)經(jīng)常碰到常規(guī)的反應(yīng)手邊沒有現(xiàn)成的標(biāo)準(zhǔn)操作步驟而要去查文獻(xiàn)，在試同一類反應(yīng)時(shí)，為了尋找各種反應(yīng)條件方法也得去查資料。為了提高大家的工作效率，因此化學(xué)合成部需要一份《經(jīng)典合成反應(yīng)標(biāo)準(zhǔn)操作》。在這份材料中，我們精選藥物化學(xué)中各類經(jīng)典的合成反應(yīng)，每類反應(yīng)有什么方法，并通過實(shí)際經(jīng)驗(yàn)對(duì)每類反應(yīng)的各種條件進(jìn)行點(diǎn)評(píng)，供大家在摸索合成條件時(shí)進(jìn)行比較。同時(shí)每種反應(yīng)的標(biāo)準(zhǔn)操作，均可作為模板套用于書寫客戶的finalreport，這樣可以大大節(jié)省研究人員書寫finalreport的時(shí)間，也相應(yīng)減少在報(bào)告中的文法錯(cuò)誤。另外本版是初版，在今后的工作中我們將根據(jù)需要修訂這份材料。藥明康德新藥開發(fā)有限公司化學(xué)合成部2005-6-28

目錄胺的合成還原胺化直接烷基化腈的還原酰胺的還原硝基的還原疊氮的還原Hoffman降解羧酸通過Cris重排羧酸衍生物的合成酰胺化的反應(yīng)酯化反應(yīng)腈轉(zhuǎn)化為酯和酰胺鈀催化的插羰反應(yīng)酯交換為酰氨羧酸的合成醇氧化酯水解酰胺的水解腈的水解有機(jī)金屬試劑的羰基化反應(yīng)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還原有機(jī)金屬試劑對(duì)腈加成合成酮脂肪鹵代物的合成醇轉(zhuǎn)化為脂肪溴代物通過PBr3轉(zhuǎn)化通過PPh3與CBr4轉(zhuǎn)化HBr直接交換通過相應(yīng)的氯代物或磺酸酯與LiBr交換、醇轉(zhuǎn)化為脂肪氯代物通過SOCl2轉(zhuǎn)化通過PPh3與CCl4轉(zhuǎn)化HCl直接交換醇轉(zhuǎn)化為脂肪碘代物通過PPh3與I2轉(zhuǎn)化通過相應(yīng)的氯代物或磺酸酯與NaI交換芳香鹵代物的合成Sandermyyer重氮化鹵代直接鹵代雜環(huán)的酚羥基或醚的鹵代醇的合成羧酸或酯的還原醛酮的還原鹵代烴的水解吡啶的氧化轉(zhuǎn)位酚的合成Sandermayer重氮化反應(yīng)醚的水解Bayer-vigerlar氧化硼酸的氧化腈的合成磺酸酯或鹵代烴的取代酰胺的脫水芳鹵代烴的氰基取代硝化反應(yīng)醚的合成芳香醚的合成酚與烷基鹵代烴的直接烷基化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與異腈酸酯的反應(yīng)用三光氣合成脲羰基二咪唑（CDI）合成脲對(duì)硝基苯酚碳酰胺合成脲烯烴的合成Wittig反應(yīng)羥基的消除Wittig-Horner反應(yīng)合成,-不飽和酯磺酸及磺酰氯的合成氯磺化反應(yīng)合成磺酰氯從硫醇合成磺酰氯磺化反應(yīng)氨基酸的合成Streck反應(yīng)合成手性氨基酸的合成偶聯(lián)反應(yīng)SuzukiCouplingBuckwald芳胺化，芳酰胺化、Heck反應(yīng)Mitsunobu反應(yīng)醇的反轉(zhuǎn)胺的取代脫羥基反應(yīng)酮還原為亞甲基氨的保護(hù)及脫保護(hù)策略用碳酰胺作保護(hù)基芐基保護(hù)醇的保護(hù)及脫保護(hù)策略用硅醚進(jìn)行保護(hù)其他醚類保護(hù)羧基的保護(hù)

Boc脫保護(hù)-------------------------------------------------------------------------------------------------------1格氏反應(yīng)---------------------------------------------------------------------------------------------------------1還原胺化---------------------------------------------------------------------------------------------------------2鹵化反應(yīng)---------------------------------------------------------------------------------------------------------2Suzukicoupling-------------------------------------------------------------------------------------------------2磺化反應(yīng)---------------------------------------------------------------------------------------------------------3酯化反應(yīng)---------------------------------------------------------------------------------------------------------3水解反應(yīng)---------------------------------------------------------------------------------------------------------3硝化反應(yīng)---------------------------------------------------------------------------------------------------------4n-BuLi------------------------------------------------------------------------------------------------------------4LiAlH4還原-----------------------------------------------------------------------------------------------------4POCl3的雜環(huán)氯代----------------------------------------------------------------------------------------------5NaH---------------------------------------------------------------------------------------------------------------5NBS---------------------------------------------------------------------------------------------------------------5氫化反應(yīng)---------------------------------------------------------------------------------------------------------6m-CPBA----------------------------------------------------------------------------------------------------------6EDC---------------------------------------------------------------------------------------------------------------6用三光氣成脲---------------------------------------------------------------------------------------------------7芳鹵用n-BuLi處理后與Weinreb酰胺成酮-----------------------------------------------------------------7Boc上保護(hù)ToasolutionofAg,mmol)andtetramethylammoniumhydroxidepentahydrateg,mmol)inacetonitrile(270mL)wasaddeddi-tert-butyldicarbonateg;mmol)andtheresultingsolutionwasallowedtostir18hatrtandconcentrated.TheresiduewaspartitionedbetweenEt2O/H2O;thephaseswereseparatedandtheaqueousphaseextractedtwicemorewithEt2O.TheaqueousphasewasbroughttopH4withsolidcitricacidandextractedwithCHCl3mL).Theorganicextractswerecombined,dried(Na2SO4)andconcentratedtoaffordg(63percent)Basawhitefoam.ReturnBoc脫保護(hù)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格氏反應(yīng)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還原胺化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鹵化反應(yīng)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磺化反應(yīng)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酯化反應(yīng)Amixtureof4-hydroxymethylnaphthoicacid(10g,50mmol),methanol(300ml),andconcentrateH2SO4(2ml)wasrefluxedovernight.Theinsolubleswerefilteredoffandthefiltratewasconcentrated.TheresiduewastakenupinethylacetateandwashedwithaqueousNaHCO3(2*),brine,driedoverMgSO4,andconcentratedtogiveayellowoil.Silicagelcolumnchromatographyusingethylacetate/hexane(1/3)gavethedesiredproductasayellowoilg,35%yield).Return水解反應(yīng)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硝化反應(yīng)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還原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的雜環(huán)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氫化反應(yīng)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三光氣成脲Toasolutionof2-(tert-butyldimethylsilyloxy)-4-nitroaniline(200mg,mmol)int