经典合成反应标准操作 2.docx

1、经典合成反应标准操作 2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

2、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2005-6-281.胺的合成a)还原胺化b)直接烷基化c)腈的还原d)酰胺的还原e)硝基的还原f)叠氮的还原g)Hoffman降解h)羧酸通过Cris重排2.羧酸衍生物的合成a)酰胺化的反应b)酯化反应c)腈转化为酯和酰胺d)钯催化的插羰反应e)酯交换为酰氨3.羧酸的合成a)醇氧化b)酯水解c)酰胺的水解d)腈的水解e)有机金属试剂的羰基化反应f)芳香甲基的氧化4.醛酮的合成a)Weinreb酰胺合成醛酮b)醇氧化c)酯的直接还原d)有机金属试剂对腈加成合成酮5.脂肪卤代物的合成a)醇转化

3、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、b)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c)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6.芳香卤代物的合成a)Sandermyyer重氮化卤代b)直接卤代c)杂环的酚羟基或醚的卤代7.醇的合成a)羧酸或酯的还原b)醛酮的还原c)卤代烃的水解d)吡啶的氧化转位8.酚的合成a)Sandermayer重氮化反应b)醚的水解c)Bayer-vigerlar氧化d)硼酸的氧化9.腈的合成a)磺酸酯或卤代烃的取代b)酰胺的脱水

4、c)芳卤代烃的氰基取代10.硝化反应11.醚的合成a)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b)脂肪醚的合成醇的醚化12.脲的合成a)胺与异腈酸酯的反应b)用三光气合成脲c)羰基二咪唑（CDI）合成脲d)对硝基苯酚碳酰胺合成脲13.烯烃的合成a)Wittig反应b)羟基的消除c)Wittig-Horner反应合成?,?-不饱和酯14.磺酸及磺酰氯的合成a)氯磺化反应合成磺酰氯b)从硫醇合成磺酰氯c)磺化反应15.氨基酸的合成a)Streck反应合成b)手性氨基酸的合成16.偶联反应a)SuzukiCouplingb)Buckwald芳胺化，芳酰

5、胺化、c)Heck反应17.Mitsunobu反应a)醇的反转b)胺的取代18.脱羟基反应19.酮还原为亚甲基20.氨的保护及脱保护策略a)用碳酰胺作保护基b)苄基保护21.醇的保护及脱保护策略a)用硅醚进行保护b)其他醚类保护22.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Toasolutionof

6、A(2.72g,13.9mmol)andtetramethylammoniumhydroxidepentahydrate(5.62g,31.0mmol)inacetonitrile(270mL)wasaddeddi-tert-butyldicarbonate(3.79g;17.4mmol)andtheresultingsolutionwasallowedtostir18hatrtandconcentrated.atedtoafford2.58g(63percent)Basawhitefoam.ReturnBoc脱保护Tert-Butyl2-(2-methoxyphenoxy)ethylcarb

7、amate(23.8g,89mmol)indichloromethane(10ml)wascooledto0degCandstirredasamixtureoftrifluoroaceticacid:dichloromethane(1:1,40ml)wasaddeddropwise.Themixturewasallowedtowarmtort,stirredfor2hoursandconcentratedinvacuo.Theresiduewastakenbackupindichloromethane(100ml)andthesolutionwaswashedwithsaturatedaque

8、oussodiumhydrogencarbonate(3*20ml)andaqueoussodiumhydroxide(10percent,3*20ml),dried(Na2SO4),filteredandconcentratedinvacuotoprovide2-(2-methoxyphenoxy)ethylamine(13g,88percentyield)asalightyellowsolid.Return格氏反应Astirredmixtureofmagnesiumturnings(23.6g,0.98mol)andEt2O(200mL)undernitrogenistreatedwith

9、acrystalofiodineandabout5percentofasolutionofbromoethane(56.3ml,0.75mol)inEt2O(375mL).Whenthereactionstarts,theremainderofthebromoethanesolutionisadded,dropwiseataratesufficienttomaintainagentlereflux.Aftertheaddition,stirringiscontinuedfor1hour.Tothissolutionofethylmagnesiumbromidewasslowlyaddedaso

10、lutionof4-cyanopyridine(39g,0.375mol)inEt2O(750ml).Thereactionmixturewaswarmedatrefluxfor12hours,treatedwithconcentratedH2SO4(125ml)/H2O(125ml),andthenwashedthreetimeswithEt2O(250ml).Theaqueousportionwasmadebasic(PH9)with15percentNaOHsolutionandextractedfivetimeswith250mlportionsofEt2O.ThecombinedEt

11、2Oextractsweredried(MgSO4),andthesolventwasremovedunderreducedpressuretoaffordabrownoil(48.4g,95percent).Return还原胺化Asolutionof2-amino-4-ethylphenol(1.00g.7.28mmol),2-naphthaldehyde(1.13g,7.28mmol),andp-toluenesulfonicacid(0.05g)inmethanol(50ML)wasstirredatroomtempfor24h.Totheresultantsolution,sodium

12、borohydride(0.82g,22mmol)wasaddedinsmallportions.Afteradditionwascompleted,themixturewasstirredatroomtemperaturefor30minandconcentratedundervacuum.Theresiduewasthensubjectedtocolumnchromatographyonsilicagelelutedwith10percentethylacetateinhexaneandfollowedbyrecrystallization(aqueousmethanol)yielded4

13、50mg(22percent)ofanalyticallypureproduct.Return卤化反应Toastirredsolutionof8-methyl-1-nitro-naphthalene(10.6g,56.32mmol)andiron(III)chloride(0.45g,2.77mmo)inCCl4(150ml)heatedto60Cwasaddeddropwise(3.0ml,58.23mmol)ofbromine.Afteronehour,thereactionmixturewaspouredintosaturatedNaHCO3solution,andthelayerswe

14、reseparated.Theaqueouslayerwasre-extractedwithCH2Cl2.Thecombinedorganiclayersweredried(MgSO4)andthesolventwasremovedunderreducedpressure.Thecruderesiduewasrecrystallizedfromethanolandthemotherliquorswereconcentratedandthenflashchromatographedonsilica,eludinghexanes:ethylacetate(12:1).ReturnSuzukicou

15、pling Toamixtureof4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole(2g,8.2mnmol)and3-bromobenzene(0.87ml,8.3mmol)inTHF(28ml)wereaddedpalladiumcatalystPd(PPh3)4(284mg,0.25mmol)andthefreshlypreparedsodiumhydroxidesolution(984mgin9mlofwater).Thesystemwasdegassedandthenchargedwithnitrogenforthree

16、times.Themixturewasstirredundernitrogenat70Coilbathfor6hours.Thereactionsolutionwascooledtoroomtemperature,dilutedwithethylacetateandseparatedfromwaterlayer.Theethylacetatesolutionwaswashedbybrine,driedoverNa2SO4andconcentrated.Theresiduewaspurifiedonasilicagelcolumneludingwithhexanes:EtOAc9:1togive

17、1.38g(78%yield)of4-phenyl-1H-indoleasacolorlessliquid.Return磺化反应Chlorosulfonicacid(4.66g,40mmol)isaddeddropwisetoacold(0C)solutionof2,3-dihydro-2-trifluoroacetyl-1H-Benzdeisoquinoline(2.9g,8mmol)inchloroform(800ml).Theresultingsolutionisstirredat0Cfor30minutes. Thecoldbathisthenremovedandthesolution

18、isstirredatroomtemperaturefor1hourthencautiouslypouredintoicewater.Theorganiclayerisseparated,driedovermagnesiumsulfateandconcentratedtoaffordthetitlecompound. Thecrudeproductispurifiedbycolumnchromatographyelutedwith10%aceticetherinpetroleumether(2.36g,81%yield).Return酯化反应Amixtureof4-hydroxymethyln

19、aphthoicacid(10g,50mmol),methanol(300ml),andconcentrateH2SO4(2ml)wasrefluxedovernight.Theinsolubleswerefilteredoffandthefiltratewasconcentrated.TheresiduewastakenupinethylacetateandwashedwithaqueousNaHCO3(2*),brine,driedoverMgSO4,andconcentratedtogiveayellowoil.Silicagelcolumnchromatographyusingethy

20、lacetate/hexane(1/3)gavethedesiredproductasayellowoil(3.3g,35%yield).Return水解反应Asolutionof1-Methyl-naphthalene-2-carboxylicacidmethylester(7.20g,35mmol)and2Nsodiumhydroxide(35ml)intetrahydrofuran(130ml)wasstirredunderrefluxfor18hours.Themixturewasneutralisedusing2Nhydrochloricacid,andextractedwithdi

21、chloromethane(3x).Thecombinedorganicsolutionsweredried(MgSO4),andevaporatedunderreducedpressure.Thecrudeproductwaspurifiedbycolumnchromatographyonsilicagelusinganelutiongradientofdichloromethane:methanol(100:0to97:3)toaffordthetitlecompoundasasolid(3.11g,47.8%yield).Return硝化反应Toacold(0C)suspensionof

22、1-methylnaphthalene(5g,35.2mmol)inHNO3wasaddedH2SO4(5ml)dropwise.Afterstirringthereactionforonehour,thesolutionwasdilutedwithethylacetateandwashedwithwater(3*),aqueoussaturatedNaHCO3(2*)andbrine,driedoverMgSO4,andconcentrated.Theproductwaspurifiedbysilicagelcolumnchromatographyusingethylacetate:hexa

23、ne(5:95)andrecrystallizedfrommethanoltogiveyellowneedles(0.22g,33%yield).Returnn-BuLiToadrythree-neckedround-bottomedflaskwithanadditionfunnelandat-78CunderinertatmospherewaschargedwithanhydrousTHF(500ml).Asolutionofn-butyllithium(2.5Minhexane,88ml,220mmol)wasaddeddropwisefollowedbyadditionofasoluti

24、onofacetonitrile(10.43ml,200mmol)inanhydrousTHF(100ml).Theinternaltemperaturewasmaintainedbelow-70Cduringtheentireadditionprocess.After2hrat-78CasolutionofTrifluoro-aceticacidethylester(14.2g,100mmol)inanhydrousTHF(30ml)wasaddeddropwiseandthemixturewasstirredfor1.5hr.Tothemixturewasaddedaceticanhydr

25、idetoquenchthereaction.Thereactionmixturewasallowedtowarmuptort.Aprecipitatewasfilteredandthefiltratewasconcentratedtogiveabrownoil,whichwasusedinthenextstepwithoutpurification.ReturnLiAlH4还原Asolutionof2,3-naphthalenedicarboxylicacid(4.6g,0.023mole)indryTHF(135ml,warmedto50tomaintainsolution)isaddeddropwiseover15minutestoa1.15MlithiumaluminumhydridesolutioninTHF(45ml,0.052mole).Thesolutionisstirred3hoursafterwhichTLCindicatedconsumptionofdiacidandformationofanewmajorproduct.ThereactionisquenchedcarefullywithTHF-water,then2Nhydrochlori