實(shí)驗(yàn)十苯妥英鈉的制備

實(shí)驗(yàn)十苯妥英鈉的制備Experiment10.PreparationofPhenytoinSodium10.1目的要求Purpose（1）掌握抗癲癇藥苯妥英鈉的合成方法。（2）通過了解苯妥英鈉合成路線中各步化學(xué)反應(yīng)的原理，深入理解反應(yīng)的操作過程。（3）熟練進(jìn)行回流、水浴加熱、抽濾、重結(jié)晶、測(cè)熔點(diǎn)等實(shí)驗(yàn)操作。（4）掌握測(cè)定化合物水溶液pH值的方法。（5）本實(shí)驗(yàn)分4次，共22學(xué)時(shí)。10.2背景介紹BackgroundInformation癲癇是一種由大腦神經(jīng)元異常放電引起的短暫神經(jīng)功能失常為特征的慢性腦部疾病，具有突然發(fā)生、反復(fù)發(fā)作的特點(diǎn)。苯妥英鈉（phenytoinsodium）作為抗癲癇藥，主要適用于治療復(fù)雜部分性發(fā)作、單純部分性發(fā)作、全身強(qiáng)直陣攣性發(fā)作和癲癇持續(xù)狀態(tài)。苯妥英鈉還可用于抗心律失常等。PhenytoinSodium苯妥英鈉的化學(xué)名為：5,5-二苯基-2,4-咪唑啉二酮鈉鹽（5,5-diphenyl-2,4-imidazolidinedionesodiumsalt）。苯妥英鈉別名大倫丁鈉，二苯乙內(nèi)酰脲鈉。為白色粉末，無臭，味苦，微有引濕性。在水中易溶，在乙醇中溶解，在三氯甲烷或乙醚中幾乎不溶。苯妥英鈉在空氣中漸漸吸收二氧化碳，分解成苯妥英；水溶液顯堿性反應(yīng)，常因部分水解而發(fā)生混濁[1]。10.3實(shí)驗(yàn)原理ImportantReactions本實(shí)驗(yàn)以苯甲醛為原料，經(jīng)過四步化學(xué)反應(yīng)制備苯妥英鈉。第一步反應(yīng)是安息香(benzoin,2-羥基-1,2-二苯乙二酮)縮合反應(yīng)：在維生素B1催化下2分子苯甲醛縮合生成安息香。第二步反應(yīng)是安息香通過六水合三氯化鐵氧化生成1,2-二苯乙二酮(benzil)。第三步反應(yīng)中，1,2-二苯乙二酮在堿性條件下和尿素縮合并發(fā)生重排，酸化后生成苯妥英。第四步反應(yīng)是苯妥英和氫氧化鈉成鹽，得到苯妥英鈉。具體合成路線如下：BenzaldehydeBenzoinBenzilPhenytoinPhenytoinsodium在本實(shí)驗(yàn)的第一步，即安息香縮合反應(yīng)中，除了以維生素B1催化的方法之外，還可以用氰化鉀[2]做催化劑。因?yàn)榍杌浭莿《酒?，現(xiàn)已采用維生素B1代替氰化鉀制備安息香。在第二步氧化反應(yīng)中，通常采用濃硝酸氧化。為了更適于學(xué)生實(shí)驗(yàn)的需要，用六水合三氯化鐵作為氧化劑，操作更為簡(jiǎn)單，且減少了實(shí)驗(yàn)室的污染。10.4實(shí)驗(yàn)操作ExperimentalProcedures10.4.12-羥基-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?10.4.45,5-二苯基乙內(nèi)酰脲鈉鹽(苯妥英鈉)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苯妥英鈉溶液pH值的測(cè)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實(shí)驗(yàn)報(bào)告要求ImportantInformationAboutTheReportOnecompletereportshouldbewrittenintheformatofAppendix2.Inpartofintroductionandpurpose,thebackgroundoftheexperiment,thechemicalreactionsshouldbeincluded.Studentsshouldfindthemechanismsofreactionsof10.4.1and10.4.3byreferencereading.Inexperimentalpart,theprocessandphen