实验十苯妥英钠的制备

实验十苯妥英钠的制备Experiment10.PreparationofPhenytoinSodium10.1目的要求Purpose（1）掌握抗癫痫药苯妥英钠的合成方法。（2）通过了解苯妥英钠合成路线中各步化学反应的原理，深入理解反应的操作过程。（3）熟练进行回流、水浴加热、抽滤、重结晶、测熔点等实验操作。（4）掌握测定化合物水溶液pH值的方法。（5）本实验分4次，共22学时。10.2背景介绍BackgroundInformation癫痫是一种由大脑神经元异常放电引起的短暂神经功能失常为特征的慢性脑部疾病，具有突然发生、反复发作的特点。苯妥英钠（phenytoinsodium）作为抗癫痫药，主要适用于治疗复杂部分性发作、单纯部分性发作、全身强直阵挛性发作和癫痫持续状态。苯妥英钠还可用于抗心律失常等。PhenytoinSodium苯妥英钠的化学名为：5,5-二苯基-2,4-咪唑啉二酮钠盐（5,5-diphenyl-2,4-imidazolidinedionesodiumsalt）。苯妥英钠别名大伦丁钠，二苯乙内酰脲钠。为白色粉末，无臭，味苦，微有引湿性。在水中易溶，在乙醇中溶解，在三氯甲烷或乙醚中几乎不溶。苯妥英钠在空气中渐渐吸收二氧化碳，分解成苯妥英；水溶液显碱性反应，常因部分水解而发生混浊[1]。10.3实验原理ImportantReactions本实验以苯甲醛为原料，经过四步化学反应制备苯妥英钠。第一步反应是安息香(benzoin,2-羟基-1,2-二苯乙二酮)缩合反应：在维生素B1催化下2分子苯甲醛缩合生成安息香。第二步反应是安息香通过六水合三氯化铁氧化生成1,2-二苯乙二酮(benzil)。第三步反应中，1,2-二苯乙二酮在碱性条件下和尿素缩合并发生重排，酸化后生成苯妥英。第四步反应是苯妥英和氢氧化钠成盐，得到苯妥英钠。具体合成路线如下：BenzaldehydeBenzoinBenzilPhenytoinPhenytoinsodium在本实验的第一步，即安息香缩合反应中，除了以维生素B1催化的方法之外，还可以用氰化钾[2]做催化剂。因为氰化钾是剧毒品，现已采用维生素B1代替氰化钾制备安息香。在第二步氧化反应中，通常采用浓硝酸氧化。为了更适于学生实验的需要，用六水合三氯化铁作为氧化剂，操作更为简单，且减少了实验室的污染。10.4实验操作ExperimentalProcedures10.4.12-羟基-1,2-二苯乙二酮(安息香)的合成Synthesisof2-Hydroxy-1,2-diphenylethanone(Benzoin)（4hours）Thiaminehydrochloride(1.75g)isputintoa50-mLErlenmeyerflaskanddistilledwater(4mL)isaddedtodissolvethesolid.Then95%alcohol(15mL)isaddedintothesolution.2mol/Laqueoussolutionofsodiumhydroxide(5mL)isaddeddropwise.Themixtureisstirredatroomtemperaturefor5min.Finallybenzaldehyde(10mL)isaddedandthemixtureisstoodatroomtemperatureforaweek.ThesolidiscollectedonaBuchnerfilterbysuctionfiltration.Thesolidiswashedwithasmallamountofcoldwater.Thenthesolidisdriedandthecrudeproductofbenzoinisobtained.Theyieldiscalculated.Themeltingpointismeasured.Notes:(1)Whatisthecrystalproductwhen1mLofbenzaldehydeand5mLofsaturatedsolutionofsodiumbisulfitearemixedforafewminutesandthenthemixtureiscooledinanicebath?(2)Benzaldehydeusedinthisreactionshouldbenewlydistilled.(3)The2mol/LNaOHaqueoussolutionshouldbepreparedaccurately.Questions:(1)Whatisthemechanismofthisreaction?(2)Whythebenzaldehydeshouldbenewlydistilled?(3)Whatisthecatalyticmechanismofpotassiumcyanide?10.4.21,2-二苯乙二酮的合成Synthesisof1,2-diphenylethanone(Benzil)Benzoin(2.12g),ferricchloridehexahydrate(9.0g),andwater(5mL)areaddedintoa100-mLround-bottomedflask.Thentwopiecesofzeoliteareaddedintothemixture.Thenglacialaceticacid(10mL)isaddedaftertheflaskisfittedwitharefluxingcondenser.Thereactionmixtureisheatedtokeepboilingforabout60minutes.Then50mLofwaterisaddedintotheflask.Andthemixtureisheateduntilthesolutionisboilingagain.Theresidueintheflaskiscooled.Somesolidisprecipitated.ThesolidiscollectedonaBuchnerfilterbysuctionfiltration.Thenthecrudeproductofbenzilisobtained.Thecrudeproduct,apieceofzeolite,and12mLofethanolareputintoapear-shapedflask.Theflaskisfittedwitharefluxingcondenserandisheateduntilthecrudeproductisdissolved.Thenthesolutioniscooledandsomeactivecharcoalisaddedintothesolution.Themixtureisheatedtokeepboilingfor10minutes.ThenthehotmixtureisfiltratedquicklyonaBuchnerfilterbysuctionfiltration.Thefiltrateispouredintoabeakerquickly,cooledfirstatroomtemperatureandtheninanicebath.Whencrystalsofbenzilarefullyprecipitated,collectthesolidonaBuchnerfilterbysuctionfiltration.Thesolidiswashedwithasmallamountofcoldmixtureofethanolandether,driedandweighed.Theyieldofbenziliscalculatedandthemeltingpointismeasured[3].Notes:(1)Inthisreaction,glacialaceticacidshouldbeaddedintotheroundflaskaftertherefluxingcondenserhasbeenattached.(2)Keepthecontentsoftheflaskboilinggentlytoavoidexcessiveevaporationofthesolvent.(3)Duringtherecrystallizationprocess,weshouldfilterthehotsolutionofbenzilcontainingactivatedcharcoalrapidlyundervacuum.Andthefunnelandtheleachingbottleshouldbepreheatedfirst.(4)Thebenzilshouldnotbedriedrapidlybywashingitwithether.Questions:(1)Canconcentratednitricacidbeusedtooxidizebenzoininthisexperiment?(2)Whydoweuseferricchloridehexahydrateasanoxidantinsteadofconcentratednitricacidinourexperiment?10.4.35,5-二苯基-2,4-咪唑烷二酮（苯妥英）的合成Synthesisof5,5-Diphenyl-2,4-imidazolidinedioneInthisreaction,benziliscondensedwithureainthebasecondition.Thestartingmaterials,includingthebenzilwhichissynthesizedinlastreaction,urea,sodiumhydroxideandalcohol,aremixedintoaroundflaskaccordingtothefollowingscale.Benzil:urea:15%NaOH:alcohol=1g:0.57g:3.1mL:5mL.And2piecesofzeoliteareaddedintotheflask.Theflaskisadaptedwitharefluxingcondenser.Thentheflaskisheatedonawaterbath.Themixtureintheflaskwillbeboilingandkeptfor2hours.Thenstopheating,thereactantiscooledatroomtemperatureandispouredintoabeakercontainingthecalculatedamountofwater(benzil:water=1g:37mL).Themixtureinthebeakerisstirredandstoodatroomtemperatureforabout15minutes.Somesolidprecipitationisfilteredout.Thefiltrateisacidifiedwith15%hydrochlorideaciduntilthepHvalueisabout4~5.Thenthewhitesolidisprecipitated.ThesolidisfiltratedonaBuchnerfilterbysuctionfiltrationandwashedwithasmallamountofcoldwater.Thesolidisdried.Thenthecrudeproductofphenytoinisobtainedandweighed.TheyieldofphenytoiniscalculatedandNotes:(1)Inthisreaction,therearetwofiltrationoperations.Duringthefirstoperation,thefiltrateistakenandthesolidby-productisfilteredout.(2)Duringthereaction,calculatedamountof15%sodiumhydroxideaqueoussolutionshouldbeaddedtothebottomoftheflask,notsticktothebottleneck.Questions:(1)Whatisthemechanismofthereaction?(2)Whatisthestructureoftheby-productofthereaction?10.4.45,5-二苯基乙内酰脲钠盐(苯妥英钠)的合成SynthesisofThephenytoinsynthesizedinthelastreactionisputintoaflask.Thenthecalculatedwater(phenytoin:water=1g:5mL)isadded.Theflaskisheatedto40℃onawaterbath.Then15%sodiumhydroxideaqueoussolutionisaddedslowlyuntilthesolidisalldissolved.Thensomeactivatedcharcoalisaddedintothesolution.Themixtureisheatedto60℃for10minutesandthesolutionisdecolorized.Thenthehotmixtureisfilteredquickly.Thefiltrateisstoodatroomtemperatureforabout20minutesandcooledincoldwater.Solidisprecipitatedandisfiltered,washedwithasmallamountofcoldwaterora1:1mixtureofcoldalcoholandacetylether.Thesolidisdriedinvacuumandthephenytoinsodiumisobtained.TheweightofphenytoinsodiumismeasuredandtheyieldiscalculatedNotes:Inthisreaction,temperatureofthecontentsintheflaskshouldbecontrolledunder60℃Questions:(1)Whythesolidofphenytoinsodiumisdriedundervacuum?(2)Whydoweuseactivatedcharcoaltodecolorizethesolution?10.4.5苯妥英钠溶液pH值的测定ThepHValueMeasurementoftheSolutionofPhenytoinSodium(6hours)ThepHvalueofphenytoinsodiumsolutionismeasuredwiththepHmeter.First,thepHmetershouldbecalibratedby2standardbuffersolutions.Preparationofthestandardbuffersolutionofborax:borax(3.81g)isweighedpreciselyandputintoaflask.Distilledwaterisaddedtodissolveit.Thenthesolutionisdilutedto1000mlLPreparationofthestandardbuffersolutionofcalciumhydroxide:at25℃,preparethesaturatedsolutionofcalciumhydroxidewithdistilledwater.TakethesupernatantofthesolutionasthestandardbufferCalibrationofthepHmeter:CalibratethepHmeterwiththebuffersolutionofborax.Forexample,thepHvalueofboraxbuffershouldbe9.18at25℃.Whentheboraxbuffersolutionisusedasthetestsolution,thepHvalueofpHmetershouldbeadjustedto9.18ThenthestandardbuffersolutionofcalciumhydroxideisusedtocalibratethepHmeter.At25℃,thepHvalueofthestandardbufferofcalciumhydroxideis12.45.ThenmeasurethepHofthebufferandadujustthepHmetertoshowthevalueof12.45MeasurementTake0.35gofphenytoinsodiumintoabeaker,andadd10mLdistilledwatertodissolveit.ThenthepHvalueofthesolutionismeasuredusingthepHmeterfor2timesandtaketheaverage.10.5实验报告要求ImportantInformationAboutTheReportOnecompletereportshouldbewrittenintheformatofAppendix2.Inpartofintroductionandpurpose,thebackgroundoftheexperiment,thechemicalreactionsshouldbeincluded.Studentsshouldfindthemechanismsofreactionsof10.4.1and10.4.3byreferencereading.Inexperimentalpart,theprocessandphen