高血压治疗药物R67555甲磺酸盐的手性合成研究.pdf

高血压治疗药物R67555甲磺酸盐的手性合成研究 以上所有反应合成得到的产物，它们的结构分别得到IR,1HNMR、或MS. 或’3CNMR谱和其它相关图谱的确证。 关键词:两一肾上腺素受体 阻滞剂R67555高血压手性合成 水解动力学拆分 Abstract TheasymmetricsynthesisstudyonantihypertensivedrugofR67555 methanesulfonicacidsalt Yun-XuYang(OrganicChemistry) DirectedbyProfessorNai-XingWang Abstract 867555, a,a，一I【minobis(methylene)bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2- methanol]]belongstoB,-adrenergicantagonistblockingagentthatbearbenzopran ringsandp-aminoalcoholunits.Itisapseudosymmetricalmoleculewithfourasym- -metriccarbonatoms,thereforehavingtenstereoisomers,comprisingfourenantiomer -icpairsandtwomesoforms.Asymmetricalsubstitutionevenleadstoamixtureof sixteenstereoisomers.8067138,(SR,R,R)一(+)-isomerisoneofenantiomericconfigu- -rationofthetwoenantiomersof867555usedinclinic.(R,SSS)-8067145isanother isomerof867555.Clinicalandthepharmacologicalstudiesdemonstratethatthe adrenergicantagonismresidesinthe(SR,R,R)-enantiomer,whereasthe(R,S,S,S)- enantiomerhasasingificantsynergisticeffectonthehemodynamicprofile. Thisdissertationmainlystudiesthefourstagesofthedesignandthesynthesisof 867555.The伍R,R,R)一(+)-8067138and itsmethanesulfonicacidsaltwere synthesized,thesyntheticmethodofthereactionmodelof(R,S,S,S-(一)-8067145and itsmethanesulfonicacidsaltweresetup.Themainlyresearchworkwere: 1.Theracemicchromane-2-carboxylicacidwassynthesizedthroughaseriesof reactionsbyusingp-fluorophenosalylasstartingmaterial.Thenthechromane- 2-methanol,chromane-2-carboxaldehydeandtheracemicmixtureofepoxidewere synthesizedseparately.Aftertheenantiomericpairsof(RR)一，(S,S)-eopxideandthe (R,S)-,(SR)-epoxidewereseparatedthroughthesilicagelchromatographytheywere resolvedviatheHydrolyticKineticResolutionofterminalepoxideofJacobsen catalyzedfrom (R,R)-SalenCo.Thekeychiralintermediatesof(SS)-eopxideand (R,R)一