1药物Macitentan（马西替坦）合成检索总结报告一、Macitentan（马西替坦）简介Macitentan（马西替坦）于2013年10月18日在美国上市。Macitentan（马西替坦）适应于肺动脉高压。Macitentan（马西替坦）不良反应：贫血、鼻咽炎、支气管炎、头痛、感冒和尿道感染。Macitentan（马西替坦）分子结构式如下:英文名称：Macitentan中文名称：马西替坦本文主要对Macitentan（马西替坦）的合成路线、关键中间体的合成方法及实验操作方法进行了文献检索并作出了总结。二、Macitentan（马西替坦）合成路线2三、Macitentan（马西替坦）合成检索总结报告(一)Macitentan（马西替坦）中间体2的合成合成方法实验步骤参考文献操作方法一20mlacetonitrilewasaddedto4-bromophenylaceticacid1(2g,9.3mmol)and1,8-diazabicyclo[5.4.0]undec-2-ene(1.7g,11.2mmol)wasaddedat0°C.Iodomethane(1.98g,14.0mmol)wasslowlydroppedtothemixtureandstirredfor2hoursatroomtemperature.Afterthereactioniscomplete,themixturewasextractedusingwater(100ml×2)anddichloromethane(100ml).Thetitlecompound2(1.7g,75%)wasobtainedbycolumnchromatography(ethylacetate/n-hexane,1/15).US2013/72482;(2013);(A1)English操作方法二Toastirredsolutionof(4-bromophenyl)aceticacid1(1.5g,6.9mmol)inDMF(10mL),potassiumcarbonate(1.92g,14mmol)andmethyliodide(1.46g,10mmol)wasaddedat0°C.inaRBflask.ReactionmixturewaskeptatRTfor2h.ThenthereactionmixturewascooledtoRT,pouredintowaterandextractedwithethylacetate.Thecombinedextractswerewashedwithwaterandbrinesolution.TheorganiclayerwasdriedoveranhydrousNa2SO4andconcentratedinvacuum.Thecrudeproductobtainedwaspurifiedbycolumnchromatographytogetthetitlecompound2asayellowliquid(1g,yield:63.69%).US2016/333004;(2016);(A1)English操作方法三Toasolutionof4-Bromo-phenyl-aceticacid1(8.6g,40mmol)inDMF(80mL)isaddedK2CO3(6.16g,44mmol)followedbymethyliodide(2.8mL,45mmol).Theresultingmixtureisstirredfor2.5hours,thendilutedwithether,washedwithwaterandbrine,driedoverMgSO4andconcentratedtogive9.1gofthetitlecompound2asanoil.US2003/6541505;(2003);(B1)English操作方法四Asolutionof4-bromophenylaceticacid1(10g,47mmol)inmethanol(194ml)andsulfuricacid(2.48ml,46.5mmol)washeatedtorefluxfor16hours.Reactionwasconcentrated,dilutedwithethylacetateandwashedwithsaturatedsodiumbicarbonateandbrine.Organicwasdriedoversodiumsulfate,filteredandconcentratedtogivemethyl2-(4-bromo-phenyl)acetate2(10.63g,100%)asacolorlessoil.WO2010/86820;(2010);(A1)EnglishConcentratedsulfuricacid(30ml)wasaddedtoasolutionof(4-bromophenyl)aceticacid1(101g,468mmol)inmethanol(1000ml)underice-cooling,andthemixturewasstirredat3操作方法五roomtemperaturefor2hours.Thereactionmixturewasconcentratedand,afterethylacetatewasaddedtotheresidue,themixturewassuccessivelywashedwithwater,saturatedaqueoussodiumhydrogencarbonatesolutionandsaturatedaqueousNaClsolution,anddriedoveranhydroussodiumsulfate.Theresidueobtainedbyevaporatingthesolventunderreducedpressurewaspurifiedbysilicagelcolumnchromatography(elutionsolvent:n-hexane/ethylacetate=5/1)toobtainmethyl(4-bromophenyl)acetate2(107g,yield:100%).EP2007/1764075;(2007);(A1)English(二)Macitentan（马西替坦）中间体4的合成合成方法实验步骤参考文献操作方法一15.0g(65.5mmol)ofmethyl(4-bromophenyl)acetate2weredissolvedin300mlofTHF,andsodiumhydrideinmineraloil(60%)wasaddedatRT.ThemixturewasstirredatRTfor1h,afterwhich23.6g(262mmol)ofdimethylcarbonate3wereslowlyaddeddropwise.ThereactionwasthenstirredatRTfor3d.1Nhydrochloricacidwasthenadded,andthereactionmixturewasconcentrated.Theresiduewasdissolvedinethylace...
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