药物合成反应闻韧-第三版课后翻译

./1、About216–224g.<1.62–1.68moles>ofpowderedanhydrousaluminumchlorideisaddedtoa1Lthree-neckedflask.在1L的三口烧瓶中加入大约216-224g<1.62–1.68moles>的无水三氯化铝。Whilethefree-flowingcatalystisstirred<Note3>,81g.<0.67mole>ofacetophenoneisaddedfromthedroppingfunnelinaslowstreamoveraperiodof20–30minutes.自由流动的催化剂边搅拌边用滴液漏斗缓慢滴加81g苯乙酰。Considerableheatisevolved,and,ifthedropsofketonearenotdispersed,darkeningorcharringoccurs.放热反应,假如滴加的酮不能被分散,就会变黑或是碳化。Whenaboutone-thirdoftheacetophenonehasbeenadded,themixturebecomesaviscousball-likemassthatisdifficulttostir.当三分之一的乙酰苯被滴加,反应混合物变成一个很难搅拌的粘性的球状团块。Turningofthestirrerbyhandormorerapidadditionofketoneisnecessaryatthispoint.在这时,改用手动搅拌或快速滴加酮是非常必要的。Theadditionofketone,however,shouldnotbesorapidastoproduceatemperatureabove180°.然而,速度不能太快,当反应温度超过180℃时。Neartheendoftheaddition,themassbecomesmoltenandcanbestirredeasilywithoutbeingeitherheatedorcooled.Themoltenmass,inwhichtheacetophenoneiscomplexedwithaluminumchloride,rangesincolorfromtantobrown.当快滴加完时,团块开始融化,表明苯乙酰已经和三氯化铝混合完全,颜色也逐渐从黄褐色变为棕色。Bromine<128g.,0.80mole>isaddeddropwisetothewell-stirredmixtureoveraperiodof40minutes<Note4>.在40分钟内在搅拌下把溴缓慢滴加到混合物中。Afterallthebrominehasbeenadded,themoltenmixtureisstirredat80–85°onasteambathfor1hour.溴滴加完后,熔融混合物在80-85℃蒸气浴下搅拌1小时。Thecomplexisaddedinportionstoawell-stirredmixtureof1.3l.ofcrackediceand100ml.ofconcentratedhydrochloricacidina2-l.beaker<Note6>.反应物加入到1.3L碎冰和100ml浓盐酸的混合物中在2L的烧杯中混合均匀。Partofthecoldaqueouslayerisaddedtothereactionflasktodecomposewhateverpartofthereactionmixtureremainsthere,andtheresultingmixtureisaddedtothebeaker.把部分的冰水层加入到烧瓶中洗涤残留物,然后合并到烧杯中。Thedarkoilthatsettlesoutisextractedfromthemixturewithfour150-ml.portionsofether分四次把深色的油从混合物中用150ml萃取出来。Theextractsarecombined,washedconsecutivelywith100ml.ofwaterand100ml.of5%aqueoussodiumbicarbonatesolution,driedwithanhydroussodiumsulfate,andtransferredtoashort-neckeddistillationflask.合并萃取液,用100ml水和100ml5%的小苏打洗涤,用无水硫酸钠干燥。Theetherisremovedbydistillationatatmosphericpressure,andcrude3-bromoacetophenoneisstrippedfromafewgramsofheavydarkresiduebydistillationatreducedpressure.乙醚在常压下蒸馏,微量的溴苯乙酮通过减压蒸馏的方法从大量深色残渣中被分离出来。Thecolorlessdistillateiscarefullyfractionatedtoobtain94–100g.通过分馏,得到无色的流出液94-100g2、反应式：3、2-Methyl-4-ethoxalylcyclopentane-1,3,5-trione.Asolutionofsodiumethoxideispreparedina2-l.three-necked,round-bottomedflaskfittedwithamercury-sealedstirrer,arefluxcondensercarryingadryingtube,andastopperbytheadditionof69.0g.<3moles>ofsodiumto950ml.ofabsoluteethanol.69.0g〔3mol钠和950ml无水乙醇在配有干燥回流冷凝管和汞封搅拌器的2L三口圆底烧瓶中制备乙醇钠。Thesolutioniscooledto0–5°inanicebathandstirred.溶液在0-5℃下冰浴搅拌。Thestopperisreplacedbyadroppingfunnel,andacoldmixture<5–15°>of108g.<1.50moles>offreshlydistilled2-butanoneand482g.<3.30moles>ofdiethyloxalate<Note1>isaddedgraduallyoveraperiodof30minutes.瓶塞用分液漏斗取代,108g〔1.5mol的丁二酮和482g〔3.3mol的乙二酸二乙酯在5-15℃下低温混合,在30分钟内逐步滴加到溶液中。Aftertheadditioniscomplete,thethick,orange-redmixtureisallowedtowarmwithcontinuedstirringtoroomtemperature,heatedunderrefluxfor30minutes,andcooledagainto0°inanicebath.完全加入后,橘红色的粘稠物继续搅拌至室温,加热回流30分钟后在冰浴中冷却至0℃。Themixtureisdecomposedbystirringwith165ml.ofsulfuricacid<1:1byvolume>addedinportions.将165ml浓硫酸〔体积比1:1在搅拌加入,分解混合物。Thesodiumsulfateformedisfilteredbysuctionandwashedwithethanol<150–200ml.><Note2>.硫酸钠抽滤后用乙醇〔150–200ml洗涤。Thewashingsandfiltratearecombinedandconcentratedbyevaporation.合并滤液和洗涤液后蒸发浓缩。Theyellowishbrownproductwhichaccumulatesbyslowcrystallizationiscollectedbyfiltration,washedwithsmallquantitiesofice-coldwater,anddriedinair.过滤缓慢析出的棕黄色产品用小剂量的冰水洗涤后在空气中干燥。Thecrudeproductweighs140–150g.粗产品140-150g。Furtherevaporativeconcentrationofthemotherliquorfollowedbycoolingfurnishesanadditional40–50g.oftheketoester,此外将母液用冷冻蒸发浓缩后又得到40-50g的酮酯。bringingthetotalyieldto180–200g.<53–59%>产品总共180-200g〔产率53-59%<Note2>.Thiscrudematerial<m.p.120–130°>isusedinthenextstep.粗品〔熔点120–130℃用于下一步中ApuresamplecanbeobtainedbycrystallizationfromethylacetateaftertreatmentwithNoritactivatedcarbon,m.p.160–162°.纯品是经过活性炭处理后在乙酸乙酯中结晶得到,熔点160–162℃。Theprocedurefor2-pyrrolealdehyde2-吡咯甲醛Ina3-l.three-neckedround-bottomedflask,fittedwithasealedstirrer,adroppingfunnel,andarefluxcondenser,isplaced80g.<1.1moles>ofdimethylformamide<Note1>.在配有封闭搅拌器、滴液漏斗和冷凝回流装置的三口圆底烧瓶中放入80g〔1.1mol的二甲基甲酰胺。Theflaskisimmersedinanicebath,andtheinternaltemperatureismaintainedat10–20°,while169g.<1.1moles>ofphosphorusoxychlorideisaddedthroughthedroppingfunneloveraperiodof15minutes.烧瓶浸入冰浴中,内部温度保持在10-20℃,169g〔1.1mol的磷酰氯通过滴液漏斗在15分钟内滴加。Anexothermicreactionoccurswiththeformationofthephosphorusoxychloride-dimethylformamidecomplex.放热反应生成磷酰氯二甲基甲酰胺化合物。Theicebathisremoved,andthemixtureisstirredfor15minutes<Note2>.移去冰浴,在搅拌15分钟。Theicebathisreplaced,and250ml.ofethylenedichlorideisaddedtothemixture.重新再冰浴下加入250ml的二氯乙烯。Whentheinternaltemperaturehasbeenloweredto5°,asolutionof67g.<1.0mole>offreshlydistilledpyrrolein250ml.ofethylenedichlorideisaddedthroughacleandroppingfunneltothestirred,cooledmixtureoveraperiodof1hour.当内部温度降到5度时,把67g〔1.0mol新蒸馏的吡咯加入到250二氯乙烯中,通过滴液漏斗在1小时内低温下边搅拌边滴加。Aftertheadditioniscomplete,theicebathisreplacedwithaheatingmantle,andthemixtureisstirredattherefluxtemperaturefor15minutes,duringwhichtimethereiscopiousevolutionofhydrogenchloride.滴加完后,用加热装置取代冰浴,搅拌回流15分钟,直到有大量氯化氢产生。Themixtureisthencooledto25–30°,andtoitisaddedthroughthedroppingfunnelasolutionof750g.<5.5moles>ofsodiumacetatetrihydrate<Note3>inaboutofwater,cautiouslyatfirst,thenasrapidlyaspossible.当混合物降温到25-30℃后,通过滴液漏斗加入750g〔5.5mol的三水醋酸钠溶液,开始要小心,然后要尽可能地快。Thereactionmixtureisagainrefluxedfor15minutes,vigorousstirringbeingmaintainedallthewhile<Note4>.反应物在充分搅拌下重新回流15分钟。Thecooledmixtureistransferredtoa3-l.separatoryfunnel,andtheethylenedichloridelayerisremoved.冷却的混合物转移到分液漏斗中,出去二氯乙烯层。Theaqueousphaseisextractedthreetimeswithatotalofabout500ml.ofether.水相用500ml乙醚分三次萃取。Theetherandethylenechloridesolutionsarecombinedandwashedwiththree100-ml.portionsofsaturatedaqueoussodiumcarbonatesolution,whichisaddedcautiouslyatfirsttoavoidtoorapidevolutionofcarbondioxide.合并乙醚和氯乙烯溶液,用100ml饱和碳酸钠溶液分三次洗涤,然后通入二氧化碳,通入时要小心不要太快。Thenon-aqueoussolutionisthendriedoveranhydroussodiumcarbonate,thesolventsaredistilled,andtheremainingliquidistransferredtoaClaisenflaskanddistilledfromanoilbathunderreducedpressure<Note5>.非水溶液用无水碳酸钠干燥,蒸馏溶剂,余下的溶液移入克氏烧瓶在油浴中减压蒸馏。Thealdehydeboilsat78°at2mm.;thereisverylittlefore-runandverylittleresidue.醛沸点78度在2mm；很少有预留无和残渣。Theyieldofcrude2-pyrrolealdehydeis85–90g.<89–95%>,asanalmostwater-whiteliquidwhichsooncrystallizes.当几乎透明的液体会马上结晶,粗品产量85-90g〔89-95%。Asampledriedonaclayplatemeltsat35–40°.样品在素烧瓷板上干燥,熔点35-40度。Thecrudeproductispurifiedbydissolvinginboilingpetroleumether<b.p.40–60°>,intheratioof1g.ofcrude2-pyrrolealdehydeto25ml.ofsolvent,andcoolingthesolutionslowlytoroomtemperature,followedbyrefrigerationforafewhours.粗品溶解在沸腾的石油醚中〔沸点40-60度,一克粗品2-甲基吡啶加入25ml溶剂,在室温下冷却,这后再冷冻数小时。Thepurealdehydeisobtainedfromthecrudeinapproximately85%recovery.纯品醛是从粗品中得到,收率85%。Theover-allyieldfrompyrroleis78–79%ofpure2-pyrrolealdehyde,m.p.44–45°.总得率为78-79%熔点44-45度。〔1反应式4、<1>Ina3L.round-bottomedflask<Note1>fittedwitharefluxcondenserareplaced625cc.of95percentalcohol<Note2>,500cc.ofwater,500g.<476cc.,4.7moles>ofpurebenzaldehyde<Note3>,and50g.ofsodiumcyanide<96–98percent>.在配有回流冷凝器的3L圆底烧瓶中加入625ml的95%酒精、500ml水、500g〔476ml,4,7mol的苯甲醛和50g96-98%的氰化钠。Themixtureisthenheatedandkeptboilingforone-halfhour<Note4>.混合物加热并保持沸腾1.5小时。Inthecourseofabouttwentyminutes,crystalsbegintoseparatefromthehotsolution.在20分钟后晶体开始从热溶液中析出。Attheendofthethirtyminutes,thesolutioniscooled,filteredwithsuction,andwashedwithalittlewater.在最后的30分钟,冷却溶液,抽滤并用少量水洗涤Theyieldofdrycrudebenzoin,whichiswhiteorlightyellow,is450–460g.有450-460g白色或亮黄色的干燥的安息香。<90–92percentofthetheoreticalamount>.理论产率90-92%。Inordertoobtainitcompletelypure,thecrudesubstanceisrecrystallizedfrom95percentalcohol,90g.ofcrudematerialbeingdissolvedinabout700cc.ofboilingalcohol;uponcooling,ayieldof83g.ofwhite,purebenzoinwhichmeltsat129°isobtained.为了得到纯度高的产品,粗产品要在酒精中重结晶,90g粗品溶解在700ml沸腾的酒精中,冷却,得到83g熔点为129摄氏度的白色安息香纯品。<2>Ina1L.three-neckedround-bottomedflaskequippedwithamechanicalstirrer,shortrefluxcondenser,andbentglasstubereachingbelowthesurfaceoftheliquidfortheintroductionofhydrogenchloride,areplaced50g.<0.36mole>ofp-nitrophenol<Note1>,650ml.ofconcentratedhydrochloricacid,5ml.ofconcentratedsulfuricacid<Note2>,and76g.<1mole>ofmethylal<Note3>.在配有机械搅拌,短期冷凝回流器和一个为的是深入液面下通氯化氢气体的弯曲的玻璃管三口圆底烧瓶中加入50g〔0.36mol对硝基苯酚,650ml的浓盐酸,5ml的浓硫酸和76g〔1mol的二甲氧基甲烷。Themixtureisstirredwhilethetemperatureismaintainedat70±2°for4–5hoursbymeansofawaterbath<Note4>.在水浴中保持70±2度搅拌4-5小时。Duringthistimehydrogenchlorideisbubbledintothereactionmixturethroughthebentglasstube,andtheexcessgasiscarriedawaythroughtherefluxcondensertoahoodorgas-absorptiontrap<Note5>.在此期间通过玻璃弯管把氯化氢气体通入反应混合物中,过量的气体被带到回流冷凝器被气体吸收罩吸收。The2-hydroxyl-5-nitrobenzylchloridebeginstoseparateasasolidabout1hourafterthebeginningofthereaction.在反应开始后的一个小时,2-羟基-5-硝基苯氯化物作为固体被分离。Attheendthemixtureiscooledinicefor1hourwherebymorecrystalsseparate,afterwhichtheacidliquorsareeitherfilteredordecantedfromthecrystals<Note6>.最后把混合物在冰中冷却1小时,使更多的晶体析出,之后把酸性液体过滤或倾析得到晶体。The2-hydroxy-5-nitrobenzylchlorideispurifiedbyrecrystallizationfrom125ml.ofhotbenzene2-羟基-5-硝基苯氯化物在热的苯中重结晶纯化。<Note7>.Theyieldis46g.<69%basedonp-nitrophenol>ofawhiteproductmeltingat129–130°.白色产物46g〔对硝基苯酚含69%熔点129-130度5、B.Benzyltrans-1,3-butadiene-1-carbamate.A

dry,1-l.,three-necked,round-bottomedflaskisequippedwithamagneticstirringbar,athermometer,anda250-ml.,pressure-equalizingdroppingfunnelbearinganitrogeninlet.Theflaskisflushedwithnitrogenandchargedwith

49g.<0.50mole>of

trans-2,4-pentadienoicacid,

80g.<0.62mole>of

N,N-diisopropylethylamine,and

300ml.of

acetone<Note6>.Theresultingsolutionisstirredandcooledto0°inan

ice–saltbath.Asolutionof

55g.<0.51mole>of

ethylchloroformatein

150ml.of

acetoneisaddedover30minuteswhilethetemperatureismaintainedbelow0°<Note7>.Stirringiscontinuedforanadditional30minutesat0°,afterwhichachilledsolutionof

65g.<1.0mole>of

sodiumazide<Note8>in170ml.ofwaterisaddedovera20-minuteinterval,keepingthetemperaturebelow0°.Thecontentsoftheflaskarestirredforanadditional10–15minutesat0°<Note9>andpouredintoa

2-l.separatoryfunnelcontaining500ml.ofice-water.Theacylazideisisolatedbyextractionwithsix

250-ml.portionsof

toluene.Thecombinedtolueneextractsaredriedover

anhydrous

magnesiumsulfatefor20minutesandconcentratedtoavolumeofca.300ml.onarotaryevaporatoratawaterbathtemperatureof40–50°<Note10>.Caution!Theacylazideispotentiallyexplosive.Thesolutionshouldnotbeevaporatedtodryness.Whilethetoluenesolutionisbeingconcentrated,a

dry,2-l.,three-necked,round-bottomedflaskequippedwithamechanicalstirrer,a500-ml.pressure-equalizingdroppingfunnel,asimpledistillationhead,andaheatingmantle

ischargedwith

43g.<0.40mole>ofbenzylalcohol,

250mg.of

4-tert-butylcatechol<Note11>,and

200ml.of

toluene.About30ml.oftouleneisdistilledfromtheflasktoremovetraceamountsofwater,andthedistillationheadisreplacedwithacondenserfittedwithanitrogeninlet.Thetoluenesolutionisstirredandheatedatarapidrefluxunderanitrogenatmosphereasthetoluenesolutionoftheacylazideisaddedover30minutes.ThedisappearanceoftheacylazideandisocyanateisfollowedbyIRanalysis<Note12>.Conversiontothecarbamateiscompletein10–30minutes,afterwhichthesolutioniscooledrapidlytoroomtemperaturebyimmersingtheflaskinan

icebath.Thetolueneisrapidlyremovedonarotaryevaporatorwiththewaterbathat40–50°,producingayellowsolidresidue<Note13>whichisdissolvedin

50ml.of95%

ethanolandallowedtocrystall