羧酸的合成水解法-060114

经典化学合成反应标准操作羧酸的合成——水解法编者：杨纯道药明康德新药开发化学合成部目录前言…………………2酰氯的水解………………………3酸酐的水解………………………4酯的水解…………54.1酯的碱水解…………54.2酯的酸水解…………54.3丙二酸二乙酯合成法………………7酰胺的水解………………………85.1酰胺的直接酸水解………………95.2酰胺的直接碱水解………………95.3亚硝酸钠促进的酰胺酸水解法…………………95.4酰胺的间接水解法…………………9腈的水解…………106.1腈的酸水解…………116.2腈的碱水解…………116.3亚硝酸钠促进的腈的酸水解法…………………12前言利用缩水的方法可以将羧酸转变为各种羧酸的衍生物，如酰氯、酸酐、酯、酰胺和腈等，反过来通过水解反应各种羧酸衍生物也可以转变为羧酸，除酰氯和酸酐外，酯、酰胺和腈的水解一般都可以在酸或碱的催化下进行。羧酸衍生物水解的速度与羰基碳原子的正电性有关，一般来说正电性越大，水解速度越快。酰氯的水解把羧酸制成酰氯，再通过酰氯去进行各种反应是有机合成中常用的方法，较少有用酰氯来制备羧酸的例子，但在有些条件下利用酰氯来制羧酸也是较为有效的。例如芳环通过佛克反应与草酰氯反应得到相应的酰氯。一般来讲脂肪酰氯的水解是相当快的，不用加任何催化剂即可反应。但芳香酰氯的反应要相对慢了很多，有时为了促进其水解需要加入碱和酸。2.1酰氯的水解示例Aluminumchloride(160g,1.2mol)wasaddedtoastirredsolutionofthe4-n-pentylbiphenyl(224g,1mol)inmethylenechloride(1000mL)atapproximately-20°C.ThenOxalylchloride(96mL)wasaddedtothesolutionatatemperaturebelow-10°C.Afteraddition,thereactiontemperaturewasallowedtorisetoapproximately0°C.StirringcontinuedatapproximatelyThe4-n-pentylbiphenyl-4’-carboxychloride(142g,0.5mol)wasreactedwithahot,stirredsolutionofsodiumhydroxide(60g,0.75mol)inwater(50mL)andacetone(500mL)foraboutthreehours.Thecoldreactionmixturewasthenacidifiedwithconcentratedhydrochloricacidsolution.Theacidwasfilteredandwashedwithwateruntillthefiltratewasneutralized.Theproductofthereactionwaspurifiedfromethanoltoyield4-n-pentylbiphenyl-4’-carboxylicacid(Reference:US4424371酸酐的水解酸酐也并不常用于制备酸，由于酸酐的活性比酸强，多数情况下直接室温水解就可以转变为羧酸，在有些情况下对反应加加热可以促进反应的进行。3.1酸酐的水解示例Tocitraconicanhydride(22.4g,0.2mol)wasaddedfromapipetexactly4mL(0.22mole)ofdistilledwater.Themixturewasstirredonahotplateuntilahomogeneoussolutionwasformed,thencoveredwithawatchglassandallowedtostandforforty-eighthours.Attheendofthistimethemixturewouldsolidifiedcompletely.Forfurtherpurificationitwasfinelygroundinamortar,washedwith50mLofcoldbenzene,driedintheair,andthendriedfortwenty-fourhoursinavacuumdesiccatoroverphosphoruspentoxidetogivecitraconicacid(24.4g,94%)whichmeltsat92~93°CReference:OrganicSyntheses.Coll.Vol.2,140酯的水解在有机合成中，羧酸和酯可以很方便地相互转换，因此酯化反应是保护羧基的一种常用方法，酯水解也成为水解法制羧酸的重要方法。酯的碱水解水解反应是酯化反应的逆反应，酯化反应要在酸性条件下进行的，因此多数情况下酯的水解在碱性条件下进行是有利的。一般来说非位阻酯的水解主要通过LiOH-MeOH-H2O体系于室温下进行反应，正常条件是氢氧化锂的当量为2-5当量，甲醇与水的比例为5:1~3:1。如果反应仍不能水解，可适当加热直至回流。对于有些位阻大、惰性的酯，需要用更强的反应条件，一般可使用NaOH、KOH的水溶液或水甲醇的混合溶液进行水解，其中最强烈的条件是用KOH的水甲醇的混合溶液回流水解，KOH的浓度越大、溶剂甲醇的比例越高，水解条件越强，很少有在这种条件下水解不了的酯。对于该类水解反应的后处理一般先浓缩去处醇类溶剂，然后用有机溶剂提取可能未反应完的非酸类副产物，再酸化，许多酸在此时可以析出沉淀，过滤即可得到，若为油则用有机溶剂提取。有时当一个分子同时存在甲酯和叔丁酯时，用以上条件很难较好的选择性的水解甲酯，有时需要控制碱的当量数和反应温度。LiOH-MeOH-H2O水解体系的标准操作Toasolutionofester(10mmol)inMeOH-H2O(30mL,MeOH:H2O=3:1~5:1,甲醇浓度越高，水解能力越强)at0°CwasslowlyaddedLiOH.H2O(800mg~2g,20-50mmol).Thereactionmixturewasallowedtowarmtoroomtemperatureovernight(若水解不完全就加热至反应完全).MethanolwasremovedinvacuoandtheresidualaqueoussolutionwaspartitionedwithEt2OorAcOEt(~20mL),thentheorganicphasewasextractedwithH2O(5-10mL,twotimes).ThecombinedaqueousextractswasacidifiedtopH2with1NHCl.TheaqueousphasewasextractedwithCHCl3(threetimes)(注意若有固体析出则过滤得到相应的酸).ThecombinedorganicextractwasdriedoverMgSO4andconcentratedtoaffordthedesiredacid(LiOH-MeOH-H2O体系的选择性水解甲酯和叔丁酯示例Toasolutionofcompound1(14.15g,48.1mmol)inMeOH(250ml)at0°CwasslowlyaddedaqueousLiOH(1M,48ml,48mmol)over15min.ThereactionmixturewasallowedtowarmtoroomtTheorganicsolventwasremovedinvacuoandtheresidualaqueoussolutionwaspartitionedwithEt2O,thentheorganicphasewasextractedwithH2O(twotimes).ThecombinedaqueousextractwasacidifiedtopH2with1NHCl.TheaqueousphasewasextractedwithCHCl3(threetimes).ThecombinedorganicextractwasdriedoverMgSO4andconcentratedtoaffordthedesiredacid(11.4g,85%).Reference:Publ.:US2004/6065A1(2004/01/08);Appl.:US2003-465426(2003/06/19)KOH-H2O体系的水解示例Amixtureofethyl3-methylcoumarilate(70g,0.34mol)and10%aqueouspotassiumhydroxidesolution(500mL)wasrefluxedfor1hour.Theclearyellowishsolutionwasacidifiedwhilehotwithaslightexcessofconcentratedhydrochloricacidtoprecipitate3-methylcoumarilicacid.Thesuspensionwascooledtoroomtemperature,andthecolorlesssolidwasfilteredwithsuction.Thefiltercakewasresuspendedin500mLofcoldwater,stirredvigorouslyforseveralminutes,andfilteredagainwithsuction.ThecolorlesspowderThefiltercakewasdriedinadesiccatorunderreducedpressuretogiveacolorlesspowder(54~57g,90~95%)whichmeltsat192~193°C.Reference:OrganicSyntheses:Coll.Vol.4,590酯的酸水解某些情况下对于一些特定结构的酯需要在酸性条件下进行水解，例如叔丁酯和一些对碱不稳定的酯。有些氨基酸酯在1N盐酸回流条件下水解（一般回流1~2小时即可），蒸干溶剂后可直接以盐的形式进行下面的反应，而无需进一步提纯，此时也可以考虑用酸进行水解。叔丁酯一般比Boc难脱，一般要用50-100%TFA或4NHCl/Dioxane（注意：在用HCl/dioxane来脱除叔丁酯时，千万不能在溶剂处理时中引入甲醇，乙醇或其他小位阻的醇，否则叔丁酯会转变为相应的酯。叔丁酸酯的酸水解示例1-(4-Methoxycarbonyl-2-methylbutanoyl)-L-prolinet-butylester(3.4g,10.8mmol)wasdissolvedintrifluoroaceticacid(25mL)andtheresultingsolutionwaskeptatroomtemperatureforonehour.ThetrifluoroaceticacidwasremovedinvacuoandtheresidueReference:US4154937对碱不稳定的酯的酸水解示例Asolutionofethylα-chlorophenylacetate(119g,0.6mol)inglacialaceticacid(238mL)andconcentratedhydrochloricacid(119mL)washeatedunderrefluxinahoodfor1.5hours.Attheendoftheheatingperiodthesolutionwasconcentratedbyheatinginanoilbathat100°Catreducedpressure(15~20mmHg)untilnofurthermaterialwasdistilled.Theresiduewasallowedtocooltoroomtemperatureandpouredslowlywithstirringinto1Lofice-coldsaturatedsodiumbicarbonatesolution.Solidsodiumbicarbonatewasaddedinsmallportionsuntilthesolutionbecameneutraltouniversalindicatorpaper.Thesolutionwasthenextractedwithtwo200mLportionsofether.Theaqueousphasewasacidifiedcautiouslywithice-cold12NsulfuricaciduntilthemixturewasacidtoCongoredpaper.Theoilysuspensionwasextractedwithtwo200mLportionsofether.Theetherextractswerewashedwithtwo100mLportionsofwateranddriedover45gofanhydroussodiumsulfate.Thedriedetherextractwasconcentratedonasteambathuntiletherwasnolongerdistilled.Totheresiduetherewasadded500mLofwarm(50~60°C)concentratedhydrochloricacid(inahood)andthesuspensionwasallowedtocoolwithoccasionalswirling.Crystallizationwascompletedbychillinginiceandtheproductwascollectedonasintered-glassfunnel.Aftertheproductwasdriedasmuchaspossibleonthefunnelitwasdriedtoconstantweightinavacuumdesiccatoroversolidpotassiumhydroxidetogivethedryacid(82~84g,80~82%)whichmeltsat77.5Reference:OrganicSyntheses.Coll.Vol.4,169丙二酸二乙酯合成法丙二酸二乙酯合成法是把卤代烃转变为多两个碳原子的酸的经典而有效方法，它借助丙二酸二乙酯这一特定试剂，实际包括了α-H的取代、水解和脱羧三步反应。丙二酸二乙酯合成法示例Toanhydrousbutylalcohol(2.5L)wasaddedclean,brightsodium(115g,5mol)cutinsmallpiecesatonetime.Afterthesodiumwasdissolvedcompletely,thesolutionwasallowedtocoolto70~80°Candthenredistilledethylmalonate(800g,5mol)wasaddedrapidlywithstirring.Afterheatingthereactionsolutionto80~90°C,pureheptylbromide(913g,5.1mol)wasadded.Thebromideshouldbeaddedratherslowlyatfirst,untilprecipitationofsodiumbromidebegan;itmightthenbeaddedatsucharatethatthebutylalcoholrefluxedgently.Usuallyaboutonehourwasrequiredfortheintroductionoftheheptylbromide.ThemixturewasrefluxedgentlyuntilitTotheentiremixture,includingtheprecipitatedsodiumbromide,wasaddedasolutionof90percentpotassiumhydroxide(775g,12.5mol)inanequalweightofwater.Themixturewasheatedcautiously,withoccasionalshaking,untilrefluxingstarted,andrefluxingwascontinueduntilsaponificationwascomplete(aboutfourorfivehours).Theflaskwasfittedatonceforsteamdistillation,andthemixturewasdistilleduntilnomorebutylalcoholpassesover.Totheresiduewasaddedconcentratedhydrochloricacid(1350mL,15.5mol)carefully,withshaking,andthemixturewasrefluxedforaboutonehour.Aftercooling,thewaterlayerwassiphonedoffanddiscarded.Theoilobtainedintheprecedingstepwasheatedunderanair-cooledrefluxcondenserinanoilbathatabout180°C.Whentheevolutionofcarbondioxideceased(abouttwohours),theoilwasdecantedfromasmallamountofsolidmaterial.Thesolidresidueontreatmentwith200~300mLofconcentratedhydrochloricacidgaveanadditionalsmallquantityofoilwhichwaThecrudepelargonicacidwasdistilledinamodifiedClaisenflaskhavingafractionatingsidearm,andthematerialboilingat140~142°C/12mmHg(or188~190°/100mmHg)wascollectedtogiveanoil(525~590g,66~75%ofthetheoreticalamount).Themeltingpointofthepureacidwas12~12.5°Reference:OrganicSynthesesColl.Vol.2,474酰胺的水解酰胺的活性比羧酸差，因此酰胺的水解一般需要强酸或强碱参与并在加热的条件下进行。酰胺水解也有碱水解和酸水解两种情况，在有些情况下，加入亚硝酸钠可以促进酰胺水解。由于酰胺直接水解较为强烈，对于一些复杂的分子无法使用，因此对氮上有活泼氢的酰胺可将其衍生化后水解，一般衍生化的方法是用引入Boc，其反应如下：以上方法也可用于保护氨基的酰胺键，得到相应的Boc保护的胺：酰胺直接酸水解示例Asuspensionof2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionamide(15g,53.7mmol)inamixtureofsulphuricacid(d=1.36,50mL)andwater(60mL)washeatedwithvigorousstirringfor3hoursat110°C.Aftercooling,theproductwhichprecipitatedwasfilteredoffandthenaddedto2Nsodiumhydroxidesolution(55mL).Thealkalinesolution,clarifiedbyfiltration,wasacidifiedbyadding2Nhydrochloricacid(60mL).Theproductwhichprecipitatedwasfilteredoff,driedandthenrecrystallizedfromCCl4(170mL)togive2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten2-yl)propionicacid(7.4g,49.2%)meltingatReference:US3933905酰胺直接碱水解示例Asolutionof4-(1,1-diphenylpropyl)-picolinamide(3.8g,0.012mol)inethanol(50mL)wasadded10%aqueouspotassiumhydroxide(100mL)andtheresultingmixturewasheatedatrefluxovernight。ThesolventwasremovedunderreducedpressureandtheresiduewasaddedwaterthenadjustedtoaboutpH5with10%aqueoushydrochloricacid.Theresultingsolidwasfilteredandrecrystallizedfromethanoltoobtainthedesiredcompoundofthisexample(1.6g,42.0%)meltingat191~193°Reference:US4138488亚硝酸钠促进的酰胺酸水解法示例Toasolutionof4-carbamoyl-3-methoxyisothiazole(7.9g,0.05mole)in90mLof80%sulfuricacidat10~15°Cwasaddedslowlybeneaththesurfaceoftheliquidasolutionofsodiumnitrite(9.5g,0.137mol)inwater(13mL).Whentheadditionwascompletethesolutionwasallowedtocometo25°Candthenwasheatedto60°Cforseveralminutes.Aftercoolingto25°Cthereactionsolutionwaspouredontoicetoafford4-carboxy-3-methoxyisothiazole(Reference:US3957808酰胺的间接水解法示例Toa0.5Msolutionof(R)-N-Methyl-3-phenylbutanamide(194mg,1.09mmol)inmethylenechloridewasaddedtriethylamine(0.15ml,1.09mmol),di-tert-butyldicarbonate(0.5ml,2.18mmol)and4-(dimethylamino)pyridine(150mg,1.11mmol).Thesolutionwasstirredfor8hatroomtemperature.Thevolatileswereremovedandtheresiduewaspurifiedbyflashchromatogramphy(1/20(v/v)EtOAc/hexane)toaffordthedesired(R)-N-Boc-N-Methyl-3-phenylbutanamide(210mg,70%).A0.2Msolutionof(R)-N-Boc-N-Methyl-3-phenylbutanamide(175mg,0.63mmol)inTHF(4ml),underN2atmosphere,wascooledto0°C.Tothissolutionwasadded1Nlithiumhydroxide(2.0ml,2.0mmol).Thereactionmixturewasallowedtostirfor6h.AfterremovalofTHFinvacuo,thebasicresiduewasacidifiedwith5%HClandextractedwithether(3×15ml).ThecombinedetherlayersweredriedoveranhydrousMgSO4,filteredandconcentratedunderreducedpressure.Theresiduewaspurifiedbybulb-to-bulbdistillation(110~120°C/1.2mmHg)togivethedesiredReference:J.Org.Chem.;61;14;1996;4542~4554.腈的水解由于氰基很容易由卤代烃或重氮盐与无机氰化物反应引入，因此腈水解是制备羧酸的很重要的方法。腈水解也有酸水解和碱水解两种情况。腈的酸水解一般都是用浓硫酸在水或水-乙醇的溶剂中进行，若用浓盐酸，经常会停留在酰胺一步。在某些特殊情况下，腈水解也会停留在酰胺这一步，此时为了水解完全，可以加入亚硝酸钠促进水解反应的进行。直接将腈水解为酸的反应条件相当苛刻，因此并不是一个很好的办法，一般来说，是将腈在HCl/MeOH中转化为甲脂，而后再水解，这样条件就要温和了很多。6.1腈的酸水解示例Amixtureofwater(1150mL),commercialsulfuricacid(840mL)andbenzylcyanide(700g,6mol)washeatedunderarefluxcondenserandstirredforthreehours,cooledslightly,andthenpouredinto2Lofcoldwater.Themixtureshouldbestirredsothatasolidcakewasnotformed;thephenylaceticacidwasthenfilteredoff.Thecrudematerialwasmeltedunderwaterandwashedbydecantationseveraltimeswithhotwater.Thesewashings,oncooling,depositedasmallamountofphenylaceticacidwhichwasfilteredoffandaddedtothemainportionofmaterial.Thelastofthehotwaterwaspouredofffromthematerialwhileitwasstillmolten,anditwasthentransferredtoaClaisendistillingflaskanddistilledunderreducedpressure.Asmallamountofwatercameoverfirstandwasrejected;about20mL,containinganappreciableamountofbenzylcyanide,thendistils.Thisfractionwasusedi