经典合成反应标准操作

1、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、/4 刖百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

2、 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1 .胺的合成a）还原胺化b）直接烷基化c）月青的还原d）酰胺的还原e）硝基的还原f）叠氮的还原g） Hoffman 降解h）竣酸通过Cris重排2 .竣酸衍生物的合成a）酰胺化的反应b）酯化反应c）月青转化为酯和酰胺d）钳催化的插谈反应e）酯交换为酰氨3 .竣酸的合成a）醇氧化b）酯水解c）酰胺的水解d）月青的水解e）有机金属试剂的染基化反应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）有机金属试剂对月青加成合成酮5 .脂

3、肪卤代物的合成a）醇转化为脂肪澳代物通过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SOC12转化通过PPh3与CC14转化HC1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）杂环的酚羟基或醴的卤代7 .醇的合成a）竣酸或酯的还原b）醛酮的还原c）卤代姓:的水解d）叱噬的氧化转位8 .酚的合成a） Sandermayer重氮化反应b）醴的水解c） Bayer-vigerlar 氧化d）硼酸的氧化9. 睛

4、的合成a）磺酸酯或卤代烂的取代b）酰胺的脱水c）芳卤代姓:的匐基取代10. 硝化反应11. 醍的合成a）芳香醴的合成酚与烷基卤代始的直接烷基化Mitsunobu 芳香84化Buckwald 芳香84化b）脂肪醴的合成醇的醴化12. 月尿的合成a）胺与异月青酸酯的反应b）用三光气合成月尿c）跋基二咪唾（CDI）合成月尿d）对硝基苯酚碳酰胺合成月尿13. 烯炫的合成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

5、酸的合成16. 偶联反应a） SuzukiCouplingb） Buckwald芳胺化，芳酰胺化、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）苇基保护21. 醇的保护及脱保护策略a）用硅醴进行保护b）其他醴类保护22. 竣基的保护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-4LiA1H4还原- -4POC13的杂环氯- -5NaH-5NBS-5氢化反应-6m-CPBA-6E

6、DG-6用三光气 成月尿- -7芳 卤 用 n-BuLi 处 理 后 与 Wei nreb 酰 胺 成 酮 -7Boc上保护ToasolutionofA(2.72g,13.9mmol)andtetramethylammoniumhydroxidepentahydrate(5.62g,31.0m mol)inacetonitrile(270mL)wasaddeddi-tert-butyldicarbonate(3.79g;17.4mmol)andtheresult ingsolutionwasallowedtostir18hatrtandconcentrated.atedtoafford2.58

7、g(63percent)Basawhi tefoam.ReturnBoc脱保护Tert-Butyl2-(2-methoxyphenoxy)ethylcarbamate(23.8g,89mmol)indichloromethane(10ml)wasc ooledto0degCandstirredasamixtureoftrifluoroaceticacid:dichloromethane(1:1,40ml)wasadd eddropwise.Themixturewasallowedtowarmtort,stirredfor2hoursandconcentratedinvacuo.Ther esi

8、duewastakenbackupindichloromethane(100ml)andthesolutionwaswashedwithsaturatedaqueo ussodiumhydrogencarbonate(3*20ml)andaqueoussodiumhydroxide(10percent,3*20ml),dried(Na 2SO4),filteredandconcentratedinvacuotoprovide2-(2-methoxyphenoxy)ethylamine(13g,88per centyield)asalightyellowsolid.Return格氏反应Astir

9、redmixtureofmagnesiumturnings(23.6g,0.98mol)andEt2O(200mL)undernitrogenistreated withacrystalofiodineandabout5percentofasolutionofbromoethane(56.3ml,0.75mol)inEt2O(37 5mL).Whenthereactionstarts,theremainderofthebromoethanesolutionisadded,dropwiseatarat esufficienttomaintainagentlereflux.Aftertheaddi

10、tion,stirringiscontinuedfor1hour.Tothi ssolutionofethylmagnesiumbromidewasslowlyaddedasolutionof4-cyanopyridine(39g,0.375mol )inEt2O(750ml).Thereactionmixturewaswarmedatrefluxfor12hours,treatedwithconcentratedH 2SO4(125ml)/H2O(125ml),andthenwashedthreetimeswithEt2O(250ml).Theaqueousportionwasmad eba

11、sic(PH9)with15percentNaOHsolutionandextractedfivetimeswith250mlportionsofEt2O.Thec ombinedEt2Oextractsweredried(MgSO4),andthesolventwasremovedunderreducedpressuretoaffo rdabrownoil(48.4g,95percent).Return还原胺化Asolutionof2-amino-4-ethylphenol(1.00g.7.28mmol),2-naphthaldehyde(1.13g,7.28mmol),and p-tolu

12、enesulfonicacid(0.05g)inmethanol(50ML)wasstirredatr00mtempfor24h.Totheresultant solution,sodiumborohydride(0.82g,22mmol)wasaddedinsmallportions.Afteradditionwascompl eted,themixturewasstirredatr00mtemperaturefor30minandconcentratedundervacuum.Theresid uewasthensubjectedtocolumnchromatographyonsilica

13、gelelutedwith10percentethylacetateinh exaneandfollowedbyrecrystallization(aqueousmethanol)yielded450mg(22percent)ofanalytic allypureproduct.Return卤化反应Toastirredsolutionof8-methyl-1-nitro-naphthalene(10.6g,56.32mmol)andiron(III)chloride (0.45g,2.77mmo)inCCl4(150ml) heatedto600 Cwasaddeddropwise(3.0ml

14、,58.23mmol)ofbromine.A fteronehour,thereactionmixturewaspouredintosaturatedNaHCO3solution,andthelayerswerese parated.Theaqueouslayerwasre-extractedwithCH2cl2.Thecombinedorganiclayersweredried(Mg SO4)andthesolventwasremovedunderreducedpressure.Thecruderesiduewasrecrystallizedfrome thanolandthemotherl

15、iquorswereconcentratedandthenflashchromatographedonsilica,eludingh exanes:ethylacetate(12:1).SuzukicouplingToamixtureof4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole(2g,8.2mnmo l)and3-bromobenzene(0.87ml,8.3mmol)inTHF(28ml)wereaddedpalladiumcatalystPd(PPh3)4(284 mg,0.25mmol)andthefreshlypr

16、eparedsodiumhydroxidesolution(984mgin9mlofwater).Thesystem wasdegassedandthenchargedwithnitrogenforthreetimes.Themixturewasstirredundernitrogena t700 Coilbathfor6hours.Thereactionsolutionwascooledtor00mtemperature,dilutedwithethyl acetateandseparatedfromwaterlayer.Theethylacetatesolutionwaswashedbyb

17、rine,driedoverNa 2SO4andconcentrated.Theresiduewaspurifiedonasilicagelcolumneludingwithhexanes:EtOAc9: 1togive1.38g(78%yield)of4-phenyl-1H-indoleasacolorlessliquid.Return磺化反应Chlorosulfonicacid(4.66g,40mmol)isaddeddropwisetoacold(0 °C)solutionof2,3-dihydro-2-trifluoroacetyl-1H-Benzdeisoquinoline

18、(2.9g,8mmol)inchloroform(800ml).Theresultingsol utionisstirredat0 0 Cfor30minutes.Thecoldbathisthenremovedandthesolutionisstirredatroomtemperaturefor1hourthencauti ouslypouredintoicewater.Theorganiclayerisseparated,driedovermagnesiumsulfateandconcen tratedtoaffordthetitlecompound.Thecrudeproductispu

19、rifiedbycolumnchromatographyelutedwith10%aceticetherinpetroleu mether(2.36g,81%yield).Return酯化反应Amixtureof4-hydroxymethylnaphthoicacid(10g,50mmol),methanol(300ml),andconcentrateH2SO 4(2ml)wasrefluxedovernight.Theinsolubleswerefilteredoffandthefiltratewasconcentrated.Theresiduewastakenupinethylacetat

20、eandwashedwithaqueousNaHCO3(2*),brine,driedoverMgSO4 ,andconcentratedtogiveayellowoil.Silicagelcolumnchromatographyusingethylacetate/hexan e(1/3)gavethedesiredproductasayellowoil(3.3g,35%yield).Return水解反应Asolutionof1-Methyl-naphthalene-2-carboxylicacidmethylester(7.20g,35mmol)and2Nsodiumh ydroxide(3

21、5ml)intetrahydrofuran(130ml)wasstirredunderrefluxfor18hours.Themixturewasne utralisedusing2Nhydrochloricacid,andextractedwithdichloromethane(3x).Thecombinedorgan icsolutionsweredried(MgSO4),andevaporatedunderreducedpressure.Thecrudeproductwaspurifiedbycolumnchromatographyonsilicagelusinganelutiongra

22、dientofdichloromethane:methanol(100:0to97:3)toaffordthetitlecompoundasasolid(3.11g,47.8%yield).Return硝化反应Toacold(0 0 C)suspensionof1-methylnaphthalene(5g,35.2mmol)inHNO3wasaddedH2SO4(5ml)drop wise.Afterstirringthereactionforonehour,thesolutionwasdilutedwithethylacetateandwashe dwithwater(3*),aqueous

23、saturatedNaHCO3(2*)andbrine,driedoverMgSO4,andconcentrated.Thep roductwaspurifiedbysilicagelcolumnchromatographyusingethylacetate:hexane(5:95)andrecr ystallizedfrommethanoltogiveyellowneedles(0.22g,33%yield).Return n-BuLiToadrythree-neckedround-bottomedflaskwithanadditionfunnelandat-78 0 Cunderinert

24、atm ospherewaschargedwithanhydrousTHF(500ml).Asolutionofn-butyllithium(2.5Minhexane,88ml, 220mmol)wasaddeddropwisefollowedbyadditionofasolutionofacetonitrile(10.43ml,200mmol)i nanhydrousTHF(100ml).Theinternaltemperaturewasmaintainedbelow-70 0 Cduringtheentireadd itionprocess.After2hrat-78 0 Casoluti

25、onofTrifluoro-aceticacidethylester(14.2g,100mmol) inanhydrousTHF(30ml)wasaddeddropwiseandthemixturewasstirredfor1.5hr.Tothemixturewasad dedaceticanhydridetoquenchthereaction.Thereactionmixturewasallowedtowarmuptort.Apreci pitatewasfilteredandthefiltratewasconcentratedtogiveabrownoil,whichwasusedinth

26、enextst epwithoutpurification.Return LiAlH4还原Asolutionof2,3-naphthalenedicarboxylicacid(4.6g,0.023mole)indryTHF(135ml,warmedto50°tomaintainsolution)isaddeddropwiseover15minutestoa1.15Mlithiumaluminumhydridesolution inTHF(45ml,0.052mole).Thesolutionisstirred3hoursafterwhichTLCindicatedconsumptio

27、nofdi acidandformationofanewmajorproduct.ThereactionisquenchedcarefullywithTHF-water,then2N hydrochloricacid(40ml)isadded,andtheresultingmixtureisextracted3timeswithether.Thecom binedetherextractsarewashedwithwater(2times),withsaturatedsodiumbicarbonatesolution(1 time),withwater,andaredried(sodiumsu

28、lfate),filtered,andconcentratedtogiveatansolid(3. 67g).Thesolidisrecrystallizedfromethylacetategivingthetitlecompound(2.91g,67.3%yield) asalighttancrystallinematerial. ReturnPOC13的杂环氯代Toasuspensionof2,4-dihydroxy-5,6-dimethy1pyrimidine(6.2g,0.044mo1)inPOC13(25m1)wass1o w1yaddedN,N-dimethy1ani1ine(6.

29、18m1 ,0.049mo1).Themixturewasthenref1uxedat125 0 Cfor3hou rs.Afterthistime,thestartingmateria1comp1ete1ydisso1vedindicatingthatthereactionwasco mpleted.Thereactionmixturewascoo1edandthenpoureds1ow1yontoicetoquenchthePOC13(cautionexo thermic).Aprecipitateformed,whichwasfi1teredandwashedwithice-co1dwa

30、ter.Theprecipitat ewasdriedunderhighvacuumovernighttoyie1d2,4-dich1oro-5,6-dimethy1-pyrimidine(7.2g,0.0 41mo1,92%yie1d)asaye11owso1id.Return NaHSodiumhydride(50%inminera1oi1,5.5g,0.11mo1)wasaddedportionwiseat0 0 Cunderanitrogenatm ospheretoaso1utionof2-aminobenzenethio1(12m1,0.1mo1)inDMF(120m1).Afte

31、r0.5h,benzy1ch1o ride(11.5m1,0.1mo1)inDMF(80m1)wasaddedin0.5h.Theso1utionwasstirredfor3hwhi1ethetemper aturewasa11owedtorisetort,thenitwaspouredintoice/water(1000g).Theprecipitatewasfi1ter ed,disso1vedinethy1acetateandwashedwithbrine.Theorganic1ayerwasdriedoverNa2SO4andevap orated.Theso1idobtainedwa

32、sgroundinpentane(19.3g,90%yie1d). ReturnNBSAmixtureof2,4-Dich1oro-6-ethy1-5-f1uoro-pyrimidine(27.46g,0.14mo1),AIBN(1.32g)andn-bromosuccinimide(27.02g , 0.152mo1)inCH2C12(170m1)wasref1uxedunderanitrogenatmospherefor36h.Thenwashedbywater,t heaqueouswasextractedbyCH2c12.Thecombinedorganic1ayerwaswashed

33、bysaturatedNa2s2O3andbr ine,driedoverNa2SO4,andevaporatedtogiveawhiteso1idwhichwaspurifiedbyco1umnchromatogra phye1utedwith50%aceticetherinpetro1eumether(34g,88.6%yie1d).Return氢化反应Amixtureofethy13-(N-benzy1amino)-3-methy1butyratehydroch1oride(25g,0.1mo1)and10percen tPd-C(2g)in250m1ofdrieda1coho1wash

34、ydrogenatedunder55psiH2forfourdays.Thereactionmediu mwasthenfilteredandevaporatedunderreducedpressuretoprovideanamberoilwhichgraduallycry sta11izeduponstanding(18g,100%yie1d).m-CPBAAsolutionof85%m-chloroperoxybenzoicacid(19g,94mmol)inCH2Cl2(350ml)wasaddedat -5-0° C toasolutionof2-Benzylsulfanyl

35、-phenylamine(19g,88mmol)inCH2Cl2(400ml).Themixturewasall owedtowarmtortin3h,thenitwaswashedwitha5%Na2s2O3solution,10%NaHCO3solutionandbrine.Th eorganiclayerwasdriedoverNa2SO4,andevaporated.Thesolidwasgroundinpentane(19g,95%yield ).Return EDCToaO° CmixtureofBoc -L-tyrosine(2.04g,7.26mmol)andamyl

36、amine(0.63gl,7.26mmol)inmethylen echloride(30ml)isadded1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC)(1.53g,9.9mmo l ).Thewhitemixtureisstirredat0 0 Cfor5minandatroomtempfor23hrs.Theresultingsolutionisd ilutedwithmethylenechloride(30ml)andwashedsuccessivelywith0.5MHCl(40ml),water(20ml)an dsataqs

37、odiumbicarbonate(25ml).Theorganicphaseisdriedovermagnesiumsulfateandconcentrat edtoafoam(1.84g,72.4%yield),sufficientlypuretocarryintothenextstep.Ananalyticalsample isobtainedbyHPLC.Return三光气成月尿Toasolutionof2-(tert-butyldimethylsilyloxy)-4-nitroaniline(200mg,0.75mmol)intoluene(1 0ml)triethylamine(0.13ml,1.64mmol)andtriphosgene(88.4mg,0.3mmol)wereadded.Thereaction mixturewasstirredat70 0 Cfor2hours,thencooledtoroomtemperature.Thenmore2 -(tert-butyldi methylsilyloxy)-4-nitroaniline