厄洛替尼及其中間體的合成工藝研究.pdf

1、天津大學(xué)碩士學(xué)位論文厄洛替尼及其中間體的合成工藝研究姓名：鄭志剛申請學(xué)位級別：碩士專業(yè)：制藥工程指導(dǎo)教師：李艷妮黃漢忠20090501ABSTRACTErlotinibisanepidermalgrowthfactorreceptorinhibitor(EGFRTKI)whichwasdevelopedbyOSI，GenetechandRocheItisusedforthetreatmentofNonSmallCellLungCance

2、rfNSCLC)andPancreaticCancerinclinicThethesisdeterminedasixsteproutetosynthesizeErlotinibbythemethodsofliterature0alkylationbetweenethyl3，4dihydroxybenzoateand1Chloro2methoxyethanegavedEthyl3，4bis(2methoxyethoxy)benzoate(

3、1)Ethyl2amino4，5bis(2methoxyethoxy)benzoatehydrochlbride(3)wasobtainedfrom(1)vianitration，reductionandsaltformationCyclizationbetweenO)andformamidegaved6，7Bis(2methoxyethoxy)quinazolin4(3H)one(4)(4)ischloro—substitutedby

4、POCl3andN，NdimethylanilineasthecatalyzerAtlast，thehydrochloridesaltofErlotninbcanbeobtainedfrom(5)and3ethynylphenylamineviaNalkylationBytheway，3ethynylphenylaminewassynthesizedviaKnoevenagelcondensation，bromineaddition，d

5、ebrominationdecarboxylation，eliminationandreductionfromm—nitrobelazaldehydeandmalonateThemainimprovementsofthemethodare：reactiontimeisshortenedandfeedcapacityofhalohydrocarbonisreducedbecauseofthereinforceofalkalinityofa

6、cidbindingandincreasethetemperature；theconversionrateof(2)isincreasedbythehigherreactiontemperature；raisingtheyieldandreducingthecostofthesynthesisofcompound(3)duetochangingthereactionsystem；Determinethebestreactiontimea

7、ndthewayofpurificationduringthesynthesisofcompound(5)TheoverallyieldofErlotinibsynthesizedbythemethodis448％onthebasisofethyl3，4一dihydroxybenzoateThestructureofEdotinibwasconfirmedbyIR，1HNMR，MSTheresultindicatesthatthemet