γ分泌酶抑制剂ly411575类似物的合成

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1、-o笙石季硕士学位论文的结构确证进行了结构确证。通过本课题的研究，我们对LY411575及其类似物的重要中间体进行化学拆分，可以得到克级以上的化合物7，对LY411575及其类似物的放大合成及进一步研究具有重要的意义。关键词：阿尔茨海默氏病；Y．分泌酶抑制剂；LY411575类似物；合成；结构确证2≯主力季硕士学位论文SynthesisoftheT-SecretaseInhibitorLY41575AnaloguesMajor：PharmaceuticalEngineeringPostgraduate：Jian

2、gtaoDongAdvisor：ProfessorHaoFangAbstractAlzheimer’Sdisease(AD)isaninvariablyfatalneurodegenerativediseaseassociatedwithprogressivedementia，andthedeteriorationofthepatient’Smemoryandpersonality．CurrentADtherapiesonlyCangivetheimprovementofpatient’Scognitivefu

3、nctions，andCannotsupplythemethodtotreatthisdiseasefundamentally．Theexactmechanismofitspathogenesisisstillnotcompletelyknown．AhallmarkofADistheformationofcorticalplaquesconsistingmainlyofA13peptides，anditiswell-knownthattheA13peptidesandtheiroligomersplayanim

4、portantroleinthepathologyofthedisease．InhibitionofY·secretasehasproventobeabettertargetfordrugdiscovery．Oneofthefirstdisclosedy-secretaseinhibitorswithhighactivityanddrug—likepropertiesWasLY41575，acompoundwhichWasdevelopedbyLillycompany，andefficaciouslyinhib

5、itedA13productioninanimalmodelsofADafteroraladministration．Accordingtotheliterature，wechoosethesyntheticrouteusing2-aminobiphenylasstartingmaterialandpreparetheracemiccompound5-methyl-7一amino一5H,1H-dibenzo[b，d]azepin一6一one(Intermediate5)viaacylation，Friedel—

6、Craftscycloalkylation，N·methylation，nitrosylationandreductionreactions．Thekeyintermediate(S)一5-methyl-7一amino-5H,7H-dibenzo[b，d]azepin一6一one(Intermediate7)WaspreparedbythereactionofIntermediate5viaL—mandelicacidandresolutionofcolumnchromatographyandacidhydro

7、lization．The1／-secretaseinhibitorLY41l575analogue(2,2，3，3，3-pentafluoropropyl)一carbamicacid(S)一l-(5-methyl一6-OXO·6，7-dihydro一5H-dibenzo[b，d]azepin-7-ylcarbamoyl)一ethylester(CompoundA)and(3，5一Difluorobenzyl)一carbamicacid(S)一l一(5一methyl一6一OXO一6，7一dihydro一5H-di

8、benzo【b,d]azepin一7·ylcarbamoyl)一ethylester(CompoundB)weresynthesized诵tll(S)-5-methyl-7-amino一5H,7H-dibenzo【b，d]azepin一6-oneviacondensationand3少主力弓硕士学位论文ammoniationreactions．Bothanalogueswereiden