酒石酸酯-硼酸配合物手性拆分氨基醇类药物

密级：学校代码：10075分类号：学号：20091175理学硕士学位论文酒石酸酯-硼酸配合物手性拆分氨基醇类药物学位申请人:杨娟指导教师:杨更亮教授申请学位级别:理学硕士学科专业:药物分析授予学位单位:河北大学答辩日期:二○一二年六月ClassifiedIndex:CODE:10075U.D.C.:NO:20091175ADissertationfortheDegreeofM.Sc.EnantioseparationofAminoAlcoholsUsingdifferenttartrates-boricacidComplexCandidate:YangJuanSupervisor:Prof.YangGengliangAcademicDegreeAppliedfor:MasterofScienceSpecialty:PharmaceuticalAnalysisUniversity:HebeiUniversityDateofOralExamination:June,2012摘要I摘要酒石酸及其衍生物是一种广泛应用的手性选择剂。然而，单一的酒石酸酯的手性识别作用较弱，在手性分离的应用上有一定的局限性。近几年研究发现酒石酸酯-硼酸配合物的手性识别作用较强，本文将酒石酸酯-硼酸配合物应用于反相高效液相色谱法拆分氨基醇类药物，并对其拆分机理进行了讨论。本方法简便快捷，使用成本低廉，与手性色谱固定相法相比，具有明显的优势。第一章，概述了手性药物分离的目的和意义，以及高效液相色谱手性拆分技术，并重点介绍了高效液相色谱手性添加剂法及酒石酸及其衍生物的应用。第二章，以L-酒石酸正丁酯-硼酸配合物作手性添加剂，采用反相HPLC手性添加剂法对普萘洛尔、克仑特罗和环仑特罗3对对映体进了拆分研究。实验分别讨论了L-酒石酸正丁酯和硼酸的浓度，缓冲溶液种类、浓度、pH值，有机改性剂-甲醇含量以及对映体分子结构对对映体分离的影响。结果表明，手性选择剂和手性对映体的手性中心之间的静电相互作用、氢键作用和偶极-偶极作用对手性识别起主要作用。在昀佳条件下，3对对映体都达到了基线分离。第三章，在第二章研究的基础上，以普萘洛尔为例，研究了不同结构的酒石酸酯-硼酸配合物对拆分的影响。实验结果显示，随着酒石酸酯分子中醇烷基链的增长，分离度和保留时间随之增大，且带有相同碳原子数而结构（直链和支链）不同具有相近的手性分离效果和保留时间。同时本实验以分离效果昀好的L-酒石酸正己酯-硼酸配合物作手性添加剂，采用反相HPLC手性添加剂法拆分了4种β-受体阻滞剂和3种β-受体激动剂。实验还详细考察了L-酒石酸正己酯和硼酸浓度，缓冲溶液种类、浓度和pH值及有机改性剂-甲醇含量对手性分离的影响。关键词手性拆分手性流动相添加法酒石酸酯-硼酸配合物β-受体阻滞剂β-受体激动剂AbstractIIAbstractTothebestofourknowledge,tartrateisatypeofwidelyusedchiralselector.However,therecognitioneffectofsingletartaricacidestersisnotwell,tosomeextent,theapplicationhasbeenrestricted.Inrecentyears,theresearchfoundthattarticacidesters-boricacidcomplexhassuperiorchiralrecognition.Sointhispaper,weusedtarticacidesters-boricacidcomplexasthechiralmobilephaseadditivesinreversedphaseHPLCfortheenantioseparationoftenaminoalcoholsincludingfiveβ-blockerofpropranololandfiveβ-agonists.Comparedwithchiralstationaryphase,themethodhasobviousadvantages,suchassimpleandeconomic.Inchapter1,thepurposeandsignificanceofchiralseparation,aswellasthemethodofchiralhighperformanceliquidchromatographywerebrieflyoverviewed.ItwaspaidattentiontothetypesofchiraladditivesinHPLCandtheapplicationsoftartrate.Inchapter2,usingthedi-n-butylL-tartrate-boricacidcomplexasachiralselectorinreversedphaseHPLCfortheenantioseparationofthreeaminoalcohols.Inordertoobtainabetterenantioseparation,theeffectsofdi-n-butylL-tartrateandboricacidconcentration,thetype,concentrationandpHofthebuffer,methanolcontent，aswellasanalytesmolecularstructuresonenantioseparationwereextensivelyinvestigated.Asaresult,theinteractionsbetweenthechiralselectorandenantiomersviaelectrostatic,hydrogenbonding,anddipole-dipoleinteractioncontributetochiralrecognition.Underoptimizedconditions,threepairsofaminoalcoholsweresuccessfullyenantioseparated.Inchapter3,onthebasisofchapter2,theeffectsoffivedifferenttartrates-boricacidcomplexfortheenantioseparationwerestudied.Theresultshowedthatthetartratescontainingalkylgroupsofdifferentstructures(straightchainandbranchedchain)butthesamenumberofcarbonatomsprovidesimilarenantioseparations,andtheresolutionsforanalytesincreasewiththenumberofcarbonatomsofalkylgroups.Inaddition,sevenaminoalcoholswereenantioseparatedusingthedi-n-hexylL-tartrate-boricacidcomplexasachiralselector.Theinfluencesofdi-n-hexylL-tartrateandboricacidconcentration,thetype,concentrationandpHofthebuffer,aswellasmethanolcontentwereinvestigated.KeywordsChiralseparationChiralmobilephaseadditivesTartrate-boricacidcomplexβ-blockersβ-agonists目录III目录第1章绪论........................................................................................................................11.1引言................................................................................................................................11.2手性高效液相色谱拆分技术........................................................................................21.2.1手性衍生化试剂法.................................................................................................21.2.2手性固定相法.........................................................................................................21.2.3手性流动相添加剂法.............................................................................................31.3酒石酸及其衍生物的应用............................................................................................41.4氨基醇类药物................................................................................................................61.5小结与展望....................................................................................................................6第2章L-酒石酸正丁酯-硼酸配合物在反相高效液相色谱中的应用...............................82.1前言................................................................................................................................82.2实验部分........................................................................................................................92.2.1仪器与试剂.............................................................................................................92.2.2样品制备.................................................................................................................92.2.3色谱条件....................................................................................