化学原料药开发-异构体的分类 ISOMERS

1、ISOMERSDefinitionIsomers are compounds that have the same molecular (empirical) formula, but different structures, and demonstrate physico-chemical and pharmacological differencesClassifficatiionStructuural IIsomerrsDefinittionCompounnds wiith thhe samme emppiricaal forrmula, but whosee atomms aree

2、connnectedd in aa diffferentt sequuenceChain iisomerrs have diiffereent brranchiing paatternns of carboon chaainsPositioon isoomers the funnctionnal grroup iis loccated on diiffereent caarbonss in tthe chhain tend too havee simiilar cchemiccal prroperttiesFunctioonal ggroup isomeers have diiffereent

3、 tyypes oof bonnds annd hennce diiffereent fuunctioonal ggroupss tend too havee veryy diffferentt chemmical propeertiess Tautomeers compounnds inn whicch, unnder ddifferring ccondittions eg pHH, thee subsstitueent ggroupiings mmay allter ttheir posittion structuural iisomerrs thaat reaadily conveert

4、 frrom onne isoomericc formm to aanotheer andd hencce exiist inn equiilibriiumStereoiisomerrsDefinittionCompounnds whhich hhave tthe saame emmpiriccal foormulaa and whosee atomms aree attaached in thhe samme seqquencee, butt difffer inn the spatiial arrrangeement of thhe atoomsSignifiicanceemay havv

5、e marrked ppharmaacokinnetic and ppharmaacodynnamic diffeerencees eg levo-bupivvacainne is less cardiiotoxiic thaan dexxtro-bbupivaacainee, onlly levvo isoomer oof morrphinee has opioiid acttivityydiffereent 3 dimennsionaal arrrangemment diffferentt abillity tto intteractt withh receeptorss, enzzyme

6、s and nnon-sppecifiic binnding sitessisomer-speciific aabilitty of a druug too prodduce aa pharrmacollogicaal efffect iis eviidencee suppportinng thee pressence of reeceptoorsEnantioomersstereoiisomerrs thaat aree non-superrimpossable mirroor imaages (like left and rright handss)containn a chhiral c

7、entrre (ann asymmmetriic carrbon wwith ffour ddifferrent ggroupss attaached to itt)identiccal phhysicaal proopertiies, eexceptt the direcction in whhich tthey rrotatee polaarisedd lighhtClassifficatiion Syystemssa) Rotaation of poolarissed liight tto thee:left: levorrotatooryl-(-)right: dextrrototaa

8、toryd-(+)a racemmic miixturee conttains equall amouunts oof levvo andd dexttro issomerss and thereefore has nno oveerall rotatting eeffectt on ppolariised llightb) Cahnn Ingoold Prrelog conveentionnLigandss arouund thhe chiiral ccarbonn are assiggned aa prioority basedd on ttheir atomiic nummber(hig

9、herr atommic nuumber = higgher pprioriity)Rectus (R-) priorritiess incrrease in cllockwiise diirectiionSinisteer (S-)priorritiess incrrease in annti-cllockwiise diirectiionNot impportannt to know the eexact priorrity rrules. Notee thatt thiss systtem haas notthing to doo withhrotatioon of polarrised

10、 lightt and thereefore classsificaation in onne sysstem ddoes nnot allways corresppond tto thee samee classsificcationn in tthe otther. “Coinncidenntallyy”, thhis seeeminggly arrbitraary noomencllaturee (R, S) arre thee inittials of Mrr R. SS. Cahhn.c) Simpple suugars and aamino acidss can be cllass

11、iffied aas D- or L- accoordingg to tthe cclockwwise oor antticlocckwisee spattial aarranggementt of CCOOH, NH3, H annd hyddrocarrbon cchain arounnd thee chirral caarbon. Thiss is aan oldd classsificcationn systtem, ddont botheer leaarningg it, just be awware oof it.(D- andd L- aare noot to be coonfu

12、seed witth d- and l-!)DiasterreoisoomersStereoiisomerrs witth diffferennt oriientattion oof subbstituuent ggroupss on eeitherr sidee of aa rigiid bonnd (egg doubble boond orr ringg struucturee)Alternaativelly, caan be thougght off as iisomerrs witth twoo chirral caarbonssClassifficatiion syystemssa)

13、 cis- and transs-cis-ffunctiional groupps aree on tthe saame siide off the doublle bonndtrans-functtionall grouups arre on oppossite ssides of thhe douuble bbondeg mivaacuriuum is preseented as a mixtuure off isommers: trans-transs60%cis-trrans30%cis-ciis10% b) otheer sysstems incluude syyn-/annti-

14、aand Z-/E- (forgeet aboout thhis crrap)More deetaileed inffo on isomeers caan be foundd at HYPERLINK hhttp:/Classifficatiion off IsommersIsomerss: Commpoundds thaat havve ideenticaal cheemicall and moleccular formuulas bbut diiffer in thhe natture oof seqquencee of bbondinng of theirr atomms or in t

15、hheir aarranggementt of aatoms in sppace. Accorrding to thheir ttopoloogy thhey arre claassifiied ass eithher sttructuural oor steereoissomerss. Isoomers are bbroadlly claassifiied innto twwo brooad caategorries:1.1Structuural IIsomerrs: Coompounnds thhat haave thhe samme atooms prresentt but diffee

16、r in theirr ordeer of conneectiviity. TThey aare allso caalled as coonstittutionnal issomerss. Theey havve thee samee moleecularr formmula bbut diiffereent sttructuures. It caan be distiinguisshed bby plaanar ddiagraams suuch ass fisccher pprojecctionss. 1.1.1Skeletaal Isoomers: Comppoundss thatt ha

17、vee the same functtionall grouups, bbut diiffer in thhe lenngth oof thee sidee chaiins. TThey aare allso caalled as chhain iisomerrs. Foor exaample: penttane, 2-metthyl bbutanee and 2,2 ddimethhyl prropanee.1.1.2 Positioonal IIsomerrs: Coompounnds thhat haave thhe samme funnctionnal grroups, but are

18、 ppresennt on diffeerent posittions of thhe chaain. FFor exxamplee: buttan-1-ol annd buttan-2-ol.1.1.3Functioonal IIsomerrs: Coompounnds thhat haave diiffereent fuunctioonal ggroupss. Forr exammple: ethannol annd metthoxy methaane.1.1.4Tautomeers: CCompouunds wwhose struccturess difffer inn arraange

19、meent off atomms butt whicch aree in ddynamiic equuilibrrium wwith eeach oother.1Keto-Ennol taautomeerism: 2Ring-Chhain iisomerrism: seen in caase off gluccose1.2Stereoiisomerr: Commpoundds thaat havve thee samee chemmical formuula, ssame aatoms, samee connnectivvity aand diiffer only in thhe arrran

20、gemment oof theeir attoms iin spaace.1.2.1Anomerss: Steereoissomerss wherre thee moleecule is cyyclizeed andd the diffeerencee in cconfigguratiion iss abouut thee anommeric carboon onlly. Inn casee of aaldosees thee anommeric carboon is C1 annd forr ketooses iit is C2. ee.g. ssugar hemiaacetall. Glu

21、ucose in oppen chhain fform iis nott chirral att C1 bbut inn ringg formm has two oopticaally aactivee sterreoisoomers: alphha & bbeta gglucosse.1.2.2 Rotamerrs andd Confformerrs: Onn the basiss of sspatiaal arrrangemment oof atooms inn the moleccule tthat ccan bee achiieved by rootatioon(or torsiion

22、) aaroundd one or moore siingle bondss, theey aree classsifieed as rotammers aand coonformmers. Confoormerss assuume thhe chaair/booat annd equuitoriial/axxial fforms. Rotaamers assumme thee diffferentt newmmann pprojecctionss (staaggereed/ecllipsedd/gaucche).1.2.3Configuuratioonal IIsomerrs havve a

23、 cchirall (steereogeenic ccenterr). Chhiral centeer reffers tto a ccarbonn atomm attaached to foour diiffereent grroups. The moleccule iis saiid to posseess chhiraliity annd to have a steereogeeniccenter.1Enantioomer: Stereeoisommers tthat aare noon-ideenticaal, miirror-symmeetric for aall attoms, n

24、onsuuperimmposabble, oopticaally aactivee (e.gg. levvo/dexxtro-rrotatoory), inverrted oonly bby breeakingg bondds andd remaaking them in thhe revverse sensee. e.gg.: D-glucoose annd L-gglucosse.2 Diasterreomerr: Steereoissomerss thatt are not mmirrorr imagges, bbut haave iddenticcal coonfiguuratioon

25、 forr at lleast one aasymmeetric centeer andd at lleast one ddifferrent cconfigguratiion foor thee remaainingg asymmmetriic cennters. e.g. Threeoninee has 2 chiiral ccenterrs andd therreforee 4 diiasterreomerrs.2.1Epimerss: Theey aree a sppeciall casee of ddiasteereoissomeriism whhere tthere is a di

26、ffeerencee for one aand onnly onne asyymmetrric ceenter. e.g. D-gllucosee and D-mannnose; D-gllucosee and D-gallactosse aree epimmers.3Meso-issomer (Achiiral mmolecuules): supeer-impposablle mirrror iimagess whicch havve morre thaan onee sterreogennic ceenter. Mesoo-isommers hhave ttwo pllanes of sy

27、ymmetrry; thhe usuual miirror planee of rreflecction and aa secoond pllane pperpenndicullar too it tthrouggh thee moleecule (in tthe middlle oof thee moleecule). Thhe asyymmetrric ceenterss are distrributeed aroound tthis ssecondd placce so that they are mmirrorr inveerses of eaach otther. Hencce op

28、ttical rotattions from the ttwo halvees oof thee moleecule canceel outt.4 Geometrric Issomerss: Steereoissomerss whicch aree isommeric aboutt doubble boonds. If tthe boond iss C=C, the termss are cis/ttrans; if tthe boond iss C=N, the termss are syn (cis-llike) and aanti (transs-likee). Foor exaampl

29、e: cis-2-buttene aand trrans-22-buteene.Chiral Centeer Namming CClassiificattion: +/- IIndicaates tthe diirectiion inn whicch plaane off polaarizedd lighht is rotatted(cllockwiise/annticloockwisse). D/L (Dextrrorotaatory/Levorrotatoory): Planee of ppolariized llight is rootatedd to tthe riight oor l

30、efft. alphaa/betaa sterreocheemistrry of the aanomerric caarbon. It iis useed forr sugaars. R-S cconvenntion: The four groupps surrroundding tthe sttereoccenterr are givenn a prrioritty froom a - d (from higheest too loweest). The mmolecuule iss thenn obseerved from the sside wwith tthe loowest priorrity ggroup. If tthe reemainiing thhree ggroupss formm a cllockwiise arrray (a-b-c), then it iss R coonventtion. If itt is iin antti-cloockwisse theen S cconvenntion. Prioority is asssigneed acccordinng to atomiic num