化学原料药开发-异构体的分类 ISOMERS

ISOMERSDefinitionIsomersarecompoundsthathavethesamemolecular(empirical)formula,butdifferentstructures,anddemonstratephysico-chemicalandpharmacologicaldifferencesClassificationStructuralIsomersDefinitionCompoundswiththesameempiricalformula,butwhoseatomsareconnectedinadifferentsequenceChainisomers–havedifferentbranchingpatternsofcarbonchainsPositionisomers–thefunctionalgroupislocatedondifferentcarbonsinthechain–tendtohavesimilarchemicalpropertiesFunctionalgroupisomers–havedifferenttypesofbondsandhencedifferentfunctionalgroups–tendtohaveverydifferentchemicalpropertiesTautomers–compoundsinwhich,underdifferingconditionsegpH,thesubstituentgroupingsmayaltertheirposition–structuralisomersthatreadilyconvertfromoneisomericformtoanotherandhenceexistinequilibriumStereoisomersDefinitionCompoundswhichhavethesameempiricalformulaandwhoseatomsareattachedinthesamesequence,butdifferinthespatialarrangementoftheatomsSignificance–mayhavemarkedpharmacokineticandpharmacodynamicdifferenceseglevo-bupivacaineislesscardiotoxicthandextro-bupivacaine,onlylevoisomerofmorphinehasopioidactivity–different3dimensionalarrangement→differentabilitytointeractwithreceptors,enzymesandnon-specificbindingsites–isomer-specificabilityofadrugtoproduceapharmacologicaleffectisevidencesupportingthepresenceofreceptorsEnantiomers–stereoisomersthatarenon-superimposablemirrorimages(likeleftandrighthands)–containachiralcentre(anasymmetriccarbonwithfourdifferentgroupsattachedtoit)–identicalphysicalproperties,exceptthedirectioninwhichtheyrotatepolarisedlightClassificationSystemsa)Rotationofpolarisedlighttothe:left:levorotatoryl-(-)right:dextrototatoryd-(+)aracemicmixturecontainsequalamountsoflevoanddextroisomersandthereforehasnooverallrotatingeffectonpolarisedlightb)CahnIngoldPrelogconventionLigandsaroundthechiralcarbonareassignedaprioritybasedontheiratomicnumber(higheratomicnumber=higherpriority)Rectus(R-)prioritiesincreaseinclockwisedirectionSinister(S-)prioritiesincreaseinanti-clockwisedirectionNotimportanttoknowtheexactpriorityrules.Notethatthissystemhasnothingtodowithrotationofpolarisedlightandthereforeclassificationinonesystemdoesnotalwayscorrespondtothesameclassificationintheother.“Coincidentally”,thisseeminglyarbitrarynomenclature(R,S)aretheinitialsofMrR.S.Cahn.c)SimplesugarsandaminoacidscanbeclassifiedasD-orL-accordingtotheclockwiseoranticlockwisespatialarrangementofCOOH,NH3,Handhydrocarbonchainaroundthechiralcarbon.Thisisanoldclassificationsystem,don’tbotherlearningit,justbeawareofit.(D-andL-arenottobeconfusedwithd-andl-!!)Diastereoisomers–Stereoisomerswithdifferentorientationofsubstituentgroupsoneithersideofarigidbond(egdoublebondorringstructure)–Alternatively,canbethoughtofasisomerswithtwochiralcarbonsClassificationsystemsa)cis-andtrans-cis-functionalgroupsareonthesamesideofthedoublebondtrans-functionalgroupsareonoppositesidesofthedoublebondegmivacuriumispresentedasamixtureofisomers:trans-trans60%cis-trans30%cis-cis10%b)othersystemsincludesyn-/anti-andZ-/E-(forgetaboutthiscrap)Moredetailedinfoonisomerscanbefoundat:1.1StructuralIsomers:Compoundsthathavethesameatomspresentbutdifferintheirorderofconnectivity.Theyarealsocalledasconstitutionalisomers.Theyhavethesamemolecularformulabutdifferentstructures.Itcanbedistinguishedbyplanardiagramssuchasfischerprojections.1.1.1SkeletalIsomers:Compoundsthathavethesamefunctionalgroups,butdifferinthelengthofthesidechains.Theyarealsocalledaschainisomers.Forexample:pentane,2-methylbutaneand2,2dimethylpropane.1.1.2PositionalIsomers:Compoundsthathavethesamefunctionalgroups,butarepresentondifferentpositionsofthechain.Forexample:butan-1-olandbutan-2-ol.1.1.3FunctionalIsomers:Compoundsthathavedifferentfunctionalgroups.Forexample:ethanolandmethoxymethane.1.1.4Tautomers:Compoundswhosestructuresdifferinarrangementofatomsbutwhichareindynamicequilibriumwitheachother.1.1.4.1Keto-Enoltautomerism:1.1.4.2Ring-Chainisomerism:seenincaseofglucose1.2Stereoisomer:Compoundsthathavethesamechemicalformula,sameatoms,sameconnectivityanddifferonlyinthearrangementoftheiratomsinspace.1.2.1Anomers:Stereoisomerswherethemoleculeiscyclizedandthedifferenceinconfigurationisabouttheanomericcarbononly.IncaseofaldosestheanomericcarbonisC1andforketosesitisC2.e.g.sugarhemiacetal.GlucoseinopenchainformisnotchiralatC1butinringformhastwoopticallyactivestereoisomers:alpha&betaglucose.1.2.2RotamersandConformers:Onthebasisofspatialarrangementofatomsinthemoleculethatcanbeachievedbyrotation(ortorsion)aroundoneormoresinglebonds,theyareclassifiedasrotamersandconformers.Conformersassumethechair/boatandequitorial/axialforms.Rotamersassumethedifferentnewmannprojections(staggered/eclipsed/gauche).1.2.3ConfigurationalIsomershaveachiral(stereogeniccenter).Chi