卤代酮的合成-060123

药明康德内部保密资料经典化学合成反应标准操作α-卤代酮的合成编者：齐志奇药明康德新药开发有限公司化学合成部经典合成反应标准操作—α-卤代酮的合成药明康德新药开发有限公司药明康德内部保密资料Page1of2目录1．前言.................................................................................................................22.直接卤化..........................................................................................................23．经重氮酮制备.................................................................................................44．从weinreb酰胺制备....................................................................................65．傅克酰基化合成卤代酮.................................................................................76其他合成α-卤代酮的方法............................................................................9经典合成反应标准操作—α-卤代酮的合成药明康德新药开发有限公司药明康德内部保密资料Page2of21．前言α-卤代酮的合成广泛应用于现代有机合成中，多用于溴的烷基化、合成咪唑及噻唑等杂环类化合物，其合成方法常用直接卤化、经重氮酮制备、经Weinreb酰胺制备、傅克酰基化等方法合成。2.直接卤化酮的α-氢易被取代，可以直接合成α-卤代酮。一般操作是将酮与卤素于醋酸、氯仿、DMF或水中反应。除卤素外，硫酰氯、五卤化磷、过溴化吡啶氢溴酸盐（C5H5NH.Br3）、三卤化三甲基苄基铵盐等也可以做卤化试剂。对称酮或只有一个取代方向的酮卤代时，可以良好产率（80~90%）生成α-卤代酮。不对称酮卤代，往往生成α-及α’-卤代酮的混合物。由于酮卤代的决定步骤是酮的烯醇化，因此，易形成烯醇的方向优先卤代。例2-甲基环己酮与亚硫酰氯作用，多取代的α-氢优先氯代1。OCH3OCH3ClSOCl2,CCl485%若利用双（二甲基乙酰胺基）三溴化氢做溴化剂，可使不对称酮在少取代一边溴代2。OOBr[(Me2NCOCH3)2H]Br3CH3OH,20~45'C84%若将不对称酮首先转变成为一定构型的烯醇盐，继而卤代，是区域定向卤代的新方法3。OH3COH3CCl1.i-Pr2NLi,THF2.p-TsCl,0'CPhCOOEtOCH3PhCOOEtOCH3Br1.NaH,DMSO2.CuBr经典合成反应标准操作—α-卤代酮的合成药明康德新药开发有限公司药明康德内部保密资料Page3of2另外，甲基酮可用甲基格式试剂与相应的Weinreb酰胺来制备，如下例即是先合成甲基酮，后溴化来合成α-溴代酮的4。NBocOHONBocONONBocONBocOBrDCC,DMAP,NHMeOMeMeMgI,etherLDA,TMSCl,thenNBS合成实例一5OOOOOOBrBr2,AcOH2B2AAsuspensionofketone2A(700mg,2.17mmol)inaceticacid(15ml)washeatedto70℃,followedbyadditionofbromine(347mg,2.17mmol).Afterthemixturewasstirredat70℃for3h,thesolventwasevaporatedandtheresiduewaspurifiedbycolumnchromatographytogivethecompound2B(591mg,68%).合成实例二6BrOMeMeOOBrOMeMeOOBrBr2,CHCl32C2DBromine(7.99g,50mmol)inCHCl3(20ml)wasaddedinadropwisemannertoastirredsolutionof2,5-dimethoxy-4-bromoacetophenone2C(12.95g,40mmol)inCHCl3(100ml)at5℃.Aftertheadditionwascompleted,thereactionmixturewasallowedtowarmtoroomtemperatureandstirredforanadditional2h.Themixturewaspouredontocrushedice,theorganicportionwasseparatedandwashedwithwater,saturatedNaHCO3solution,andagainwithwater.ThesolutionwasdriedMgSO4,andevaporatedtodrynessunderreducedpressuretogiveacrudeproduct.TheproductwasrecrystallizedfromMeOHtoyield14.70g(87%)ofthedesiredbromoacetophenone2Dasawhitesolid.经典合成反应标准操作—α-卤代酮的合成药明康德新药开发有限公司药明康德内部保密资料Page4of2合成实例三7ONNH2NONNH2NBrAcOH,48%aq.HBrandBr2Toasolutionof1-(2-aminopyrimidin-4yl)ethanone(412mg,3mmol)inglacialaceticacid(1mL)and48%aq.HBr(0.3mL),bromine(0.153mL)inaceticacid(0.4mL)wasaddedandtheresultingorangesolutionwasstirredatRTfor1.5hours.Afterdilutingwithethylacetate(15mL),theprecipitatewasfilteredandwashedwithethlacetatethusaffordingthetargetcompoundasawhitishsolid(580mg,65%).合成实例四8OOBnMe3NBr3,CH2Cl2,MeOHSiOOSiBr2E2FBenzyltrimethylammoniumtribromide(4.17g,10.7mmol)wasaddedtoasolutionofCompound2E(4.00g,10.7mmol)inCH2Cl2-MeOH(5:2,25mL).ThemixturewasstirredatRTfor3h.AtthistimethereactionmixturewasconcentratedinvacuoandH2O(15mL)wasadded.Themixturewasextractedwithdiethylether(3×20mL).Thecombinedorganicextractswerewashedwithbrine(15mL),driedoverMgSO4,filteredandconcentratedinvacuo.Theresiduewaspurifiedbysilicagelchromatography(hexanes:EtOAc,3:1)toaffordtoaffordCompound2F(3.97g,8.8mmol,82%)asathickyellowoil.3．经重氮酮制备不对称酮卤代时，有时无法得到单卤代产物。此时，从酰氯或活泼酯经重氮酮合成α-卤代酮可以顺利得到单卤代产物。重氮酮常用重氮甲烷的醚溶液加到相应的酰氯或活波酯中制得，也可以用三甲基硅重氮甲烷处理相应的酰氯制得。重氮酮用相应的卤化氢处理即可高产率得到α-卤代酮。经典合成反应标准操作—α-卤代酮的合成药明康德新药开发有限公司药明康德内部保密资料Page5of2合成实例一COOHCOClOBr(COCl)21.CH2N2/Et2O2.HBr/AcOH3A3BToasolutionofcompound3A(0.7g,4.3mmol)inDCM(15ml,2dropsofDMF)wasaddedoxalylchloride(0.55ml,6.47mmol).ThereactionmixturewasstirredatRTfor10min,atrefluxfor1h.Thenthesolventwasremovedinvacuo.TheresiduewasdissolvedinTHF(8ml),thenthemixturewascooledto0℃.Diazomethaneinether(42ml,21mmol)wasthenaddedslowly,thereactionsolutionwasstirredat0℃for1h,followedby2hatRT.Thereactionmixturewascooledto0℃again,and1.2mlof35%ofHBrinaceticacidwasaddedslowly.ThereactionmixturewasstirredatRTovernight.Thereactionsolutionwaspouredintocooledwater,andextractedwithEtOAc.Theorganiclayerwaswashedwithwater,saturatedammoniumchlorideandbrine,driedoversodiumsulfate.Thesolventwasconcentratedunderreducedpressuretoafford1gofα-bromoketone3B(yield80%).Note:PreparationofdiazomethaneSO2NNO+ROHCH2N2+SO2OR+H2OKOHAreactionanddistillationapparatusisassembledbyconnectinganadditionfunnelandcondensortoa100mllong-neckdistillationflask.Twoinseriesreceivingflasksareconnectedtotheapparatuswiththesecondflaskcontaininganinductiontube.Asolutioncontaining6gpotassiumhydroxidein10mlwater,andasolutioncontaining35mlCarbitol(diethyleneglycolmonoethylether)and10mlofetherareplacedinthedistillationflask.20~30mletherisplacedinthesecondreceivingflaskmakingsuretheinductiontubeisimmersedintotheether.Bothreceivingflasksarecooledto0℃.Asolutioncontainingp-toluenesulfonyl-N-methyl-N-nitosamide(21.5g,0.1mol)in140mletherisplacedintheadditionfunnel.Heatthedistillationflaskto70℃inawa