化学原料药开发-异构体的分类 ISOMERS

化学原料药开发-异构体的分类 ISOMERSDefinitionIsomers are compounds that have the same molecular (empirical) formula, but different structures, and demonstrate physico-chemical and pharmacological differe ncesClassificationStructural IsomersDefinitionCompounds with the same empirical formula, but whose atoms are connected in a different sequenceChain isomershave different branching patterns of carbon chainsPosition isomersthe functional group is located on different carbons in the chaintend to have similar chemical propertiesFunctional group isomershave different types of bonds and hence different functional groupstend to have very different chemical propertiesTautomerscompounds in which, under differing conditions eg pH, the substituent groupi ngs may alter their positionstructural isomers that readily convert from one isomeric form to another and hence exist in equilibriumStereoisomersDefinitionCompounds which have the same empirical formula and whose atoms are atta ched in the same sequence, but differ in the spatial arrangement of the atomsSignificancemay have marked pharmacokinetic and pharmacodynamic differences eg levo-bupivacaine is less cardiotoxic than dextro-bupivacaine, only levo isomer of morph ine has opioid activitydifferent 3 dimensional arrangement → different ability to interact with recept ors, enzymes and non-specific binding sitesisomer-specific ability of a drug to produce a pharmacological effect is eviden ce supporting the presence of receptorsEnantiomersstereoisomers that are non-superimposable mirror images (like left and right h ands)contain a chiral centre (an asymmetric carbon with four different groups attach ed to it)identical physical properties, except the direction in which they rotate polarise d lightClassification Systemsa) Rotation of polarised light to the:left: levorotatory l- (-)right: dextrototatory d- (+)a racemic mixture contains equal amounts of levo and dextro isomers and ther efore has no overall rotating effect on polarised lightb) Cahn Ingold Prelog conventionLigands around the chiral carbon are assigned a priority based on their atomic number(higher atomic number = higher priority)Rectus (R-) priorities increase in clockwise directionSinister (S-) priorities increase in anti-clockwise directionNot important to know the exact priority rules. Note that this system has nothi ng to do withrotation of polarised light and therefore classification in one system does not a lwayscorrespond to the same classification in the other. “Coincidentally”, this see mingly arbitrary nomenclature (R, S) are the initials of Mr R. S. Cahn.c) Simple sugars and amino acids can be classified as D- or L- according to th e clockwise or anticlockwise spatial arrangement of COOH, NH3, H and hydrocar bon chain around the chiral carbon. This is an old classification system, don’t bot her learning it, just be aware of it.(D- and L- are not to be confused with d- and l-!!)DiastereoisomersStereoisomers with different orientation of substituent groups on either side of a rigid bond (eg double bond or ring structure)Alternatively, can be thought of as isomers with two chiral carbonsClassification systemsa) cis- and trans-cis- functional groups are on the same side of the double bondtrans- functional groups are on opposite sides of the double bondeg mivacurium is presented as a mixture of isomers:trans-trans 60%cis-trans 30%cis-cis 10%b) other systems include syn-/anti- and Z-/E- (forget about this crap)Classification of IsomersIsomers: Compounds that have identical chemical and molecular formulas but differ in the nature of sequence of bonding of their atoms or in their arrangement of atoms in space. According to their topology they are classified as either structural o r stereoisomers. Isomers are broadly classified into two broad categories:1.1Structural Isomers: Compounds that have the same atoms present but differ in their order of connectivity. They are also called as constitutional isomers. They hav e the same molecular formula but different structures. It can be distinguished by pla nar diagrams such as fischer projections.1.1.1Skeletal Isomers: Compounds that have the same functional groups, but differ in the length of the side chains. They are also called as chain isomers. For example: pentane, 2-methyl butane and 2,2 dimethyl propane.1.1.2Positional Isomers: Compounds that have the same functional groups, but are present on different positions of the chain. For example: butan-1-ol and butan-2-ol.1.1.3Functional Isomers: Compounds that have different functional groups. For exa mple: ethanol and methoxy methane.1.1.4Tautomers: Compounds whose structures differ in arrangement of atoms but w hich are in dynamic equilibrium with each other.1.1.4.1Keto-Enol tautomerism:1.1.4.2Ring-Chain isomerism: seen in case of glucose1.2Stereoisomer: Compounds that have the same chemical formula, same atoms, same connectivity and differ only in the arrangement of their atoms in space.1.2.1Anomers: Stereoisomers where the molecule is cyclized and the difference in configuration is about the anomeric carbon only. In case of aldoses the anomeric ca rbon is C1 and for ketoses it is C2. e.g. sugar hemiacetal. Glucose in open chain for m is not chiral at C1 but in ring form has two optically active stereoisomers: alpha & beta glucose.1.2.2Rotamers and Conformers: On the basis of spatial arrangement of atoms in the molecule that can be achieved by rotation(or torsion) around one or more single bo nds, they are classified as rotamers and conformers. Conformers assume the chair/b oat and equitorial/axial forms. Rotamers assume the different newmann projections (staggered/eclipsed/gauche).1.2.3Configurational Isomers have a chiral (stereogenic center). Chiral center refers to a carbon atom attached to four different groups. The molecule is said to possess chirality and to have a stereogeniccenter.1.2.3.1Enantiomer: Stereoisomers that are non-identical, mirror-symmetric for all ato ms, nonsuperimposable, optically active (e.g. levo/dextro-rotatory), inverted only b y breaking bonds and remaking them in the reverse sense. e.g.: D-glucose and L-gl ucose.1.2.3.2Diastereomer: Stereoisomers that are not mirror images, but have identical con figuration for at least one asymmetric center and at least one different configuration for the remaining asymmetric centers. e.g. Threonine has 2 chiral centers and there fore 4 diastereomers.1.2.3.2.1Epimers: They are a special case of diastereoisomerism where there is a differ ence for one and only one asymmetric center. e.g. D-glucose and D-mannose; D-gl ucose and D-galactose are epimers.1.2.3.3Meso-isomer (Achiral molecules): super-imposable mirror images which have more than one stereogenic center. Meso-isomers have two planes of symmetry; the usual mirror plane of reflection and a second plane perpendicular to it through the molecule (in the ``middle'' of the molecule). The asymmetric centers are distribute d around this second place so that they are mirror inverses of each other. Hence opt ical rotations from the two ``halves'' of the molecule cancel out.1.2.3.4Geometric Isomers: Stereoisomers which are isomeric about double bonds. If the bond is C=C, the terms are cis/trans; if the bond is C=N, the terms are syn (cis-l ike) and anti (trans-like). For example: cis-2-butene and trans-2-butene.Chiral Center Naming Classification:• +/- Indicates the direction in which plane of polarized light is rotated(clock wise/anticlockwise).• D/L (Dextrorotatory/Levorotatory): Plane of polarized light is rotated to the right or left.• alpha/beta stereochemistry of the anomeric carbon. It is used for sugars.• R-S convention: The four groups surrounding the stereocenter are given a p riority from a -> d (from highest to lowest). The molecule is then observed from the side with the lowest priority group. If the remaining three groups form a clockwise array (a->b->c), then it is R convention. If it is in anti-clockwise then S conventio n. Priority is assigned according to atomic number, with the higher the atomic num ber the higher the priority. This is used for chiral molecules (enantiomers/diastereo mers/epimers).• E-Z convention: The two groups attached to the carbon around the double b ond are given the priority. If the two highest priority groups are on the same side of the double bond, then the molecule is given the Z convention(similar to cis); and if on the opposite side then E convention(similar to trans). e.g.: 1-chloro-1-bromo-2-i odoethene is differentiated on basis of E-Z convention. Priority is assigned accordin g to the atomic number; with the higher the atomic number, the higher the priority. Hyrdogen always has the lowest priority. If there are two identical atoms attached t o the stereocenter (say the carbon of the methyl group and carbon of the ethyl grou p) then work along the chain of the attached group until a difference occurs.。