Enantiomers chromatographic resolution

HPLC separations are one of the most important fields in the preparative resolution of enantiomers. The instrumentation improvements and the increasing choice of commercially available chiral stationary phases (CSPs) are some of the main reasons for the present significance of chromatographic resolutions at large-scale by HPLC. Proof of this interest can be seen in several reviews, and many chapters have in the past few years dealt with preparative applications of HPLC in the resolution of chiral compounds [19-23]. However, liquid chromatography has the attribute of being a batch technique and therefore is not totally convenient for production-scale, where continuous techniques are preferred by far. 

The chromatographic resolution of bi-naphthol enantiomers was considered for simulation purposes [18]. The chiral stationary phase is 3,5-dinitrobenzoyl phenyl-glycine bonded to silica gel and a mixture of 72 28 (v/v) heptane/isopropanol was used as eluent. The adsorption equilibrium isotherms, measured at 25 °C, are of bi-Langmuir type and were proposed by the Separex group ... 

Miller, L., Orihuela, C., Fronek, R., and Murphy, J., Preparative chromatographic resolution of enantiomers using polar organic solvents with polysaccharide chiral stationary phases,. Chromatogr. A, 865, 211, 1999. 

Enantiomers were generated and tumbled at specific angles around each NH proton and the C=0 oxygen at the 2-, 3-, and 6-positions of the carbamoyl group of 23a and 23x, which are considered to be the most important adsorbing sites from chromatographic resolution and NMR studies,... 

The results of both calculations were in good agreement with the chromatographic resolution data for 40 and 19.211 The lowest or averaged interaction energy between 23a and (S, S)-4() obtained in the calculation is lower than that between 23a and (R, / )-40, whereas an opposite enantiomer preference was observed for 23x and 40. 

Allenamide ( )-13 was prepared by trapping the corresponding lithioallene with carbon dioxide, followed by conversion of the carboxylate to the amide. Chromatographic resolution of the enantiomers of 13 was easily accomplished on a 10x250mm Chiralcel OD HPLC column. Addition of vinyllithium 14 to (+)-13, followed by quenching the reaction with aqueous NaH2P04, led to cyclopentenone (—)-15 in 64% yield with >95% chirality transfer (Eq. 13.4). The absolute stereochemistry of (-)-5 is consistent with the mechanistic hypothesis put forth in Eq. 13.3 [8]. 

This report presents various methods developed primarily at our laboratory for chromatographic resolution of racemates of several pharmaceuticals (e.g., -blockers, NSAIDS, anta-acids, DL-amino acids, Bupropion, Baclofen, Etodolac, Carnitine, Mexiletine). Recently, we developed methods for establishing molecular dissymmetry and determining absolute configuration of diastereomers (and thus the enantiomers) of (/< .S )-Baclofcn, (/d.SJ-Bctaxolol with complimentary application of TLC, HPLC, H NMR, LCMS this ensured the success of diastereomeric synthesis and the reliability of enantioseparation. 

Keywords enantioseparation, racemic mixtures, single enantiomer of drug, chromatography, chromatographic resolution. 

The optical activity of biologically-active chemicals is important to their activity and toxicology. Pure enantiomers, or optical isomers, of pharmaceuticals and agrochemicals can in many cases be made by enantiospecific synthesis. An alternative method is to use a less complicated synthesis followed by chromatographic resolution of the racemic mixture into its enantiomers. 

Since all the physical properties of two given enantiomers are the same in the absence of a chiral, or optically active, medium, their chromatographic resolution needs a different approach from the relatively simple separation of geometrical isomers, stereoisomers or positional isomers. Two methods are used. The older technique of indirect resolution, requires conversion of the enantiomers to diastereoisomers using a suitable chiral reagent, followed by separation of the diastereoisomers on a non-chiral GC or LC stationary phase. This technique has now been largely superseded by direct resolution, using either a chiral mobile phase (in LC) or a chiral stationary phase. A variety of types of chiral stationary phase have been developed for use in GC, LC and SFC(21 23). 

A simple and efficient alternative to the traditional UV detection of amino acids and related compounds is nowadays represented by the evaporative light scattering (ELS) detector, which allows the direct chromatographic separation, with no need for preliminary derivatization. In the field of glycopeptides-based CSPs, it was applied for the first time in the chromatographic resolution of carnitine and 0-acylcarnitine enantiomers on a TE CSP [61]. The considered compounds are nonvolatile solids and gave optimal ELS response under a variety of experimental conditions (buffered and unbuffered mobile phases, flow-rates from 0.5 to 1.5 mL/min, different kind and... 

D Acquarica, I. et al., Direct chromatographic resolution of carnitine and O-acylcarnitine enantiomers on a teicoplanin-bonded chiral stationary phase,... 

Among the possible uses of optically active polymers, the preparation of stationary chiral phases for chromatographic resolution of enantiomers is the... 

For the separation of crystalline diastereomeric p,n-pairs, the same principles as for enantiomers are followed. Similar to the chromatographic resolution of enantiomers, the scale may vary significantly, but, in general, the separations of diastereomeric pairs are more reliable. For example, acids and lactones which may be separated via their phenylglycinol amide derivatives by MPLC on silica gel. Some examples with their derivatives and chromatographic method used for separation arc listed in Table 10. 

Examples for and have been observed under certain experimental conditions for reactive and/or strained chiral oxiranes which were separated by complexation gas chromatography (Figure 21)133. The first eluted peak was diminished in the separation of racemic 2-methyl-3-phenylo.xirane. In this case two enantioselective processes are mediated by the chiral metal chelate, i.e., chromatographic resolution and kinetic resolution (in favor of the first eluted enantiomer). Since two enantioselective processes are involved, the elution profile will be the same svhen the chirality of the metal chelate is inverted. 

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

Novel methods for reversed-phase, pressurized liquid-chromatographic resolution of nonesterified amino acid enantiomers by the formation of diastereoisomers using two chiral reagents, namely, 2,3,4,6-tetra-0-acetyl-/3-D-glucopyranosyl isothiocyanate (2) and 2,3,4-tri-O-acetyl-a-D-arabinopyranosyl isothiocyanate (30), have been reported.96,97... 

Davankov VA, Introduction to chromatographic resolution of enantiomers, in Chiral Separations hy HPLC, Krstulovic A (Ed.), Ellis Horwood, Chichester, p. 175 (1989). 

L. Miller, C. Orihuela, R. Fronek, D. Honda and O. Dapremont, Chromatographic resolution of the enantiomers of a pharmaceutical intermediate from the milligram to the kilogram scale , 7. Chromatogr. 849 309-317 (1999). 

Okamoto, Y. Kawashima, M., and Hatada, K. (1984) Useful chiral packing materials for high-performance liquid chromatographic resolution of enantiomers phenylcarbamates of polysaccharides coated on silica gel,... 

Lochmuller, C.H. and Souter, R.W., Direct gas chromatographic resolution of enantiomers on optically active mesophases, J. Chromatogr., 88, 41, 1974. 

Sinibaldi, M., Carunchio, V., Coradini, C., and Girelli, A.M., High-performance liquid chromatographic resolution of enantiomers on chiral amine bonded silica gel, Chromatographia, 18,459, 1984. 

C. Pettersson, T. Arvidsson, A.-L. Karlsson, and I. Marie, Chromatographic resolution of enantiomers using albumin as complexing agent in the mobile phase, J. Pharm. Biomed. Anal., 4 221 (1986). 

R. W. Souter, Gas chromatographic resolution of enantiomeric amphetamine and related amines. II. Effect of cyclic structures on diastereomer and enantiomer resolution, J. Chromatogr., 114 301 (1975). 

The extent of stereoselectivity in the chiral synthesis can be checked by determining the enantiomeric excess of the optically active olefins in the products. The optical purity was determined by gas chromatographic resolution of enantiomers by means of an optically active column. Thermostable substituted cyclodextrins are well suited as asymmetric phases (206). The trimer, 2,4-dimethyl-l-heptene, was resolved into its enantiomers by capillary gas chromatography with an octakis(6-0-methyl-2,3-r/-0-pentyl-)-7-cyclodextrine phase. 

Chromatograms of the optical resolution of (I) and (II) Eire shown in Figure. 1. Compound (II) is completely resolved into its enantiomers chromatographically. The g-factor remains at its constant optimum value throughout the elution band of each enantiomer. Compound (I) in contrast is incompletely resolved, giving a single absorbance elution band, but a double bisignate difference absorbance band. The fractions of (I) eluted in the volume between the vertical dashed lines are incompletely resolved. Values for the g-max factors have been determined from the CD and absorption spectra of (I) and (II). 

Chromatographic resolution of enantiomers. The enantiomers of the racemic compound form diastereomeric complexes with the chiral material on the column packing. One of the enantiomers binds more tightly than the other, so it moves more slowly through the column. 

The chances of the chromatographic resolution by inclusion chromatography were systematically studied on a series of enantiomer pairs of indole alkaloids as model compounds (e.g. Table V) and promising results were achieved on both analytical and preparative scale (26). 

X-ray crystal structures were used for the production of computer projected images of inclusion complexes of structural isomers, enantiomers and dlastereomers with a- or B-cyclodextrin. These projections allow for a visual evaluation of the interaction that occurs between various molecules and cyclodextrin, and an understanding of the mechanism for chromatographic resolution of these agents with bonded phase chromatography. 

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