资源描述：
《journal of Chemical Research， Synopses.pdf》由会员上传分享，免费在线阅读，更多相关内容在学术论文-天天文库。
1、230RESEARCHPAPERAPRIL,230–232JOURNALOFCHEMICALRESEARCH2010TheasymmetricsynthesisofSitagliptin,aselectivedipeptidylpeptidaseIVinhibitorforthetreatmentoftype2diabetesFengLiu*,WanshengYu,WenhuaOu,XiaokeWang,LiboRuan,YimingLi,XijiangPeng,XiaohuTaoandXianhuaPanSchoolofPerfumeandAromaTechnolog
2、y,ShanghaiInstituteofTechnology,120CaobaoRd.Shanghai200235,P.R.ChinaAnefficientasymmetricsynthesisofSitagliptin,anewDPP-IVinhibitorforthetreatmentoftype2diabetesmellitushasbeendeveloped.Thebeta-aminoacidfragmentofSitagliptinwaspreparedbyasymmetricMichaeladditionofthecorrespondingα,β-unsa
3、turatedesterto(R)-(α-methylbenzyl)benzylaminefollowedbyatwo-stepelaborationtoobtainN-bocbeta-aminoester.HydrolysisoftheesterandcouplingwiththetriazolopiperazineaffordedSitagliptinaftercleavageoftheN-bocgroupandsaltformation.Theoverallyieldwas31%overninesteps.Keywords:Sitagliptin,diabetes
4、,Michaeladdition,asymmetricsynthesis,β-aminoacid.Diabetesmellitustype2ortype2diabetes(T2DM)isaglobalof(E)-methyl4-(2,4,5-trifluorophenyl)but-2-enoate4andepidemicthatischaracterisedbyhighbloodglucoseinthe(R)-(α-methylbenzyl)benzylamine5(Scheme1).contextofinsulinresistanceandrelativeinsuli
5、ndeficiency.1Thesynthesisoftheβ-aminoacidester3startedfromtheThenumberofreportedcaseshasdoubledoverthepast15reductionoftheβ-ketoester613(Scheme2).Thereductionwasyears.2IthasbeenfoundthatinhibitorsoftheenzymeDPP-IVcarriedoutusing0.25equiv.ofNaBHinmethanolat0°C,to4werepromisingnewtreatment
6、sforT2DM.3–5Sitagliptin(1)give7in92%yield.TheuseofamorereductivereagentorahasrecentlybeenreportedtobeapotentinhibitorofDPP-IVhighertemperatureresultedintheby-product1,3-diolinsteadandiscurrentlybeingevaluatedinclinicaltrials.6Asthefirstoftheanticipatedproduct7.Acetylationof7followedbytre
7、at-selectiveDPP-IVinhibitoronthemarket,Sitagliptin(1)repre-mentwithtert-BuOKinethyletheratlowtemperatureyieldedsentsanewclassoforalantihyperglycaemicagents.Ithastheeliminationproduct4.beenshowntobeanorallyactiveandsafeagentforthetreat-Theconjugateadditionof(R)-(α-methylbe
