Separation of chiral sulfoxides by liquid chromatography using macrocyclic glycopeptide chiral stationary phases

A set of 42 chiral compounds containing stereogenic sulfur was prepared. There were 31 chiral sulfoxide compounds, three tosylated sulfilimines and eight sulfinate esters. The separations were done using five different macrocyclic glycopeptide chiral stationary phases (CSPs), namely ristocetin A, teicoplanin, teicoplanin aglycone (TAG), vancomycin and vancomycin aglycone (VAG) and seven eluents, three normal-phase mobile phases, two reversed phases and two polar organic mobile phases. Altogether the macrocyclic glycopeptide CSPs were able to separate the whole set of the 34 sulfoxide enantiomers and tosylated derivatives. Five of the eight sulfinate esters were also separated. The teicoplanin and TAG CSPs were the most effective CSPs able to resolve 35 and 33 of the 42 compounds. The three other CSPs each were able to resolve more than 27 compounds. The normal-phase mode was the most effective followed by the reversed-phase mode with methanol-water mobile phases. Few of these compounds could be separated in the polar organic mode with 100% methanol mobile phases. Acetonitrile was also not a good solvent for the resolution of enantiomers of sulfur-containing compounds, neither in the reversed-phase nor in the polar organic mode. The structure of the chiral molecules was compared to the enantioselectivity factors obtained with the teicoplanin and TAG CSP. It is shown that the polarity, volume and shape of the sulfoxide substituents influence the solute enantioselectivity factor. Changing the oxidation state of the sulfur atom from sulfoxides to sulfinate esters is detrimental to the compound's enantioselectivity. The enantiomeric retention order on the teicoplanin and TAG CSPs was very consistent: the (S)-(+)-sulfoxide enantiomer was always the less retained enantiomer. In contrast, the (R)-(-)-enantiomer was less retained by the ristocetin A, vancomycin and vancomycin aglycone columns, showing the complementarity of these CSPs. The macrocyclic glycopeptide CSPs provided broad selectivity and effective separations of chiral sulfoxides.     

Investigations of mobile phase contributions to enantioselective anion- and zwitterion-exchange modes on quinine-based zwitterionic chiral stationary phases

Novel chiral stationary phases (CSPs) based on zwitterionic Cinchona alkaloid-type low-molecular mass chiral selectors (SOs), as they have been reported recently, were investigated in HPLC towards effects on their chromatographic behavior by mobile phase composition. Mobile phase characteristics like acid-to-base ratio and type of acidic and basic additives as well as effect of type of bulk solvents in nonaqueous polar organic and aqueous reversed-phase (RP) eluent systems were varied in order to illustrate the variability and applicability of zwitterionic CSPs with regard to mobile phase aspects. Chiral SOs of the five zwitterionic CSPs investigated herein contained weak and strong cation-exchange (WCX, SCX) sites at C9- and C6′-positions of the Cinchona alkaloid scaffold which itself accommodated the weak anion-exchange (WAX) site. The study focused on zwitterion-exchange (ZX) operational mode and chiral amino acids as target analytes. Besides, also the anion-exchange (AX) mode for chiral N-blocked amino acid analytes was considered, because of the intramolecular counterion (IMCI) property available in AX mode. Overall, most general and successful conditions in ZX mode were found to be weakly acidic methanolic mobile phases. In aqueous eluents RP contributions to retention came into play but only at low organic modifier content because of the highly polar character of zwitterionic analytes. At higher acetonitrile content, HILIC-related retention phenomena were observed. When using weakly basic eluent system in AX mode remarkably fast enantiomer separations involving exclusion phenomena were possible with one enantiomer eluting before and the other after void volume.     

Novel urea-linked cinchona-calixarene hybrid-type receptors for efficient chromatographic enantiomer separation of carbamate-protected cyclic amino acids

Two novel diastereomeric cinchona-calixarene hybrid-type receptors (SOs) were synthesized by inter-linking 9-amino(9-deoxy)-quinine (AQN)/9-amino(9-deoxy)-epiquinine (eAQN) and a calix[4]arene scaffold via an urea functional unit. Silica-supported chiral stationary phases (CSPs) derived from these SOs revealed, for N-protected amino acids, complementary chiral recognition profiles in terms of elution order and substrate specificity. The AQN-derived CSP showed narrow-scoped enantioselectivity for open-chained amino acids bearing pi-acidic aromatic protecting groups, preferentially binding the (S)-enantiomers. In contrast, the eAQN congener exhibited broad chiral recognition capacity for open-chained as well as cyclic amino acids, and preferential binding of the (R)-enantiomers. Exceedingly strong retention due to nonenantioselective hydrophobic analyte-calixarene interactions observed with hydro-organic mobile phases could be largely suppressed with organic mobile phases containing small amounts of acetic acid as acidic modifier. With the eAQN-calixarene hybrid-type CSP particularly high levels of enantioselectivity could be achieved for tert-butoxycarbonyl (Boc)-, benzyloxycarbonyl (Z)- and fluorenylmethoxycarbonyl (Fmoc)-protected cyclic amino acids using chloroform as mobile phase, e.g. an enantioselectivty factor alpha >5.0 for Boc-proline. Increasing amounts of acetic acid compromised enantioselectivity, indicating the crucial contributions of hydrogen bonding to chiral recognition. Comparison of the performance characteristics of the urea-linked eAQN-calixarene hybrid-type CSP with those of structurally closely related mutants provided evidence for the active involvement of the urea and calixarene units in the chiral recognition process. The urea linker motif was shown to contribute to analyte binding via multiple hydrogen bonding interactions, while the calixarene module is believed to support stereodiscrimination by enhancing the shape complementarity of the SO binding site.     

Novel strong cation-exchange type chiral stationary phase for the enantiomer separation of chiral amines by high-performance liquid chromatography

The preparation of novel brush-type chiral cation-exchange materials based on de novo designed synthetic low molecular mass selectors (SOs) and their evaluation for enantioselective separation of chiral amines by HPLC are presented. The SO as the functional unit for enantioselectivity contains a beta-aminocyclohexanesulfonic acid moiety and is readily accessible via straightforward synthesis in both enantiomeric forms yielding chiral stationary phases (CSPs) with opposite configurations, CSPs 1 and 2, and reversed elution orders. For the evaluation of these novel CSPs by HPLC a sound set of chiral amines, mainly amino-alcohol type drug molecules, was selected. The chromatographic evaluations were carried out using polar organic mobile phase conditions. All of the analytes could be baseline separated, compared to common CSPs in parts with excellent peak efficiencies (up to 70000 theoretical plates per meter for the second eluted enantiomer). A number of experimental parameters have been varied to look at and prove the underlying ion-exchange process on CSPs 1 and 2, and to reveal suitable conditions for their operation. In this context, the influence of proton activity in the mobile phase and the effects of varying concentration and type of the counterion as well as type of co-ion and of bulk solvent components were thoroughly investigated.     

Low-molecular-weight chiral cation exchangers: novel chiral stationary phases and their application for enantioseparation of chiral bases by nonaqueous capillary electrochromatography

Cation exchange type chiral stationary phases (CSPs) based on 3,5-dichlorobenzoyl amino acid and amino phosphonic acid derivatives as chiral selectors (SOs) and silica as chromatographic support were developed and applied to enantiomer separations of chiral bases by nonaqueous capillary electrochromatography (NA-CEC). As a rationale for efficient CSP development we adopted the combined use of the "reciprocity principle of chiral recognition" and nonaqueous ion-pair CE as screening assay. Thus, (S)-atenolol was employed as chiral counter-ion added to the BGE in CE and a series of N-derivatized amino acids and amino phosphonic acids were screened to derive reciprocally information on their chiral recognition abilities for atenolol enantiomers. Two SO candidates, namely N-(3,5-dichlorobenzoyl)-O-allyl-tyrosine and N-(4-allyloxy-3,5-dichlorobenzoyl)-1-amino-3-methylbutane phosphonic acid that have been identified as potential SOs in the CE screening were, after immobilization on thiol-modified silica, evaluated in cation-exchange NA-CEC. The strong chiral cation exchanger with the free phosphonic acid group exhibited enhanced enantioselectivity compared to the weak chiral cation exchanger with the carboxylic acid group. A wide variety of chiral bases could be successfully resolved on the strong chiral cation exchanger with alpha-values up to 2.2 and efficiencies up to 375000 m-1 including beta-blockers and other amino alcohols, local anesthetics like etidocaine, antimalarial agents like mefloquine, Tr?ger's base, phenothiazines like promethazine, and antihistaminics. The influence of several experimental parameters (electrolyte concentration, acid-base ratio and acetonitrile-methanol ratio) was evaluated.     

非甾体抗炎药对映体在冠醚手性固定相上的拆分

利用高效液相色谱法,采用从(18-冠-6)-2,3,11,12-四羧((18-crown-6)-2,3,11,12-tetracarboxylic acid,18-C-6-TA)衍生的冠醚类型手性固定相(CSPs),对非甾体抗炎药酰肼衍生物进行手性分离研究.为了手性酸类非甾体抗炎药在冠醚手性固定相上进行手性拆分,采用与肼合成方法导入氨基基团,合成了其酰肼衍生物.色谱条件为:流动相:80%甲醇/水(V/V)含10 mmol/L H2SO4;流速:1.0 mL/min;紫外检测波长:210 nm.结果表明,除酮洛芬之外,其它非甾体抗炎药的酰肼衍生物拆分效果较好(α=1.14～1.26,Rs=0.88～1.43).而且非甾体抗炎药酰肼衍生物在(+)18-C-6-TA衍生的CSP 1和(-)18-C-6-TA衍生的CSP 2上的洗脱顺序得到了相反结果.     

Reversed-phase chiral HPLC and LC/MS analysis with tris(chloromethylphenylcarbamate) derivatives of cellulose and amylose as chiral stationary phases

Three polysaccharide-derived chiral stationary phases (CSP) were evaluated for the resolution of more than 200 racemic compounds of pharmaceutical interest in the reversed-phase (RP) separation mode. The population of test probes was carefully evaluated in order to insure that it covers as completely as possible all structural diversity of chiral pharmaceuticals. RP showed the highest potential for successful chiral resolution in HPLC and LC/MS analysis when compared to normal phase and polar organic separation modes. Method development consisted of optimizing mobile phase eluting strength, nature of organic modifier, nature of additive and column temperature. The newer CSPs, cellulose tris(3-chloro-4-methylphenylcarbamate) and amylose tris(2-chloro-5-methylphenylcarbamate), were compared to the commonly used cellulose tris(3,5-dimethylphenylcarbamate) in regards to their ability to provide baseline resolution. Comparable success rates were observed for these three CSPs of quite complimentary chiral recognition ability. The same method development strategy was evaluated for LC/MS analysis. Diethylamine as additive had a negative effect on analyte response with positive ion mode electrospray (ESI⁺) MS(/MS) detection, even at very low concentration levels (e.g., 0.025%). Decreasing the organic modifier (acetonitrile or methanol) content in the mobile phase often improved enantioselectivity. The column temperature had only a limited effect on chiral resolution, and this effect was compound dependent. Ammonium hydrogencarbonate was the preferred buffer salt for chiral LC with ESI⁺ MS detection for the successful separation and detection of most basic pharmaceutical racemic compounds. Ammonium acetate is a viable alternative to ammonium hydrogencarbonate. Aqueous formic acid with acetonitrile or methanol can be successfully used in the separation of acidic and neutral racemates. Cellulose tris(3-chloro-4-methylphenylcarbamate) and amylose tris(2-chloro-5-methylphenylcarbamate) emerge as CSPs of wide applicability in either commonly used separation modes rivaling such well established CSPs as cellulose tris(3,5-dimethylphenylcarbamate). Screening protocols including these two new CSPs in the preferentially screened set of chiral columns have higher success rates in achieving baseline resolution in shorter screening time.     

Derivatized vancomycin stationary phases for LC chiral separations

In this work, synthetic and natural chiral selectors were combined to form two different chiral stationary phases (CSPs). These were made by bonding R- or S-(1-naphthylethyl) carbamate (R-NEC or S-NEC)-derivatized vancomycin molecules to a silica gel support. The two CSPs were evaluated using a set of 60 enantiomeric pairs. The results were compared to the ones obtained with the commercial underivatized vancomycin CSP. Three Chromatographic modes were used: (i) the normal-phase mode using a nonpolar mobile phase with different ratios of hexane and ethanol; (ii) the reversed-phase mode with hydro-organic mobile phases; and (iii) the polar aprotic organic mode with nonaqueous acetonitrile plus small amounts of methanol and an acid and/or base to control retention and selectivity. It is shown that the polarity of the underivatized vancomycin phase is higher than that of the two R- and S-NEC-derivatized CSPs. In the pH range 4-7, there is no ionization change of the chiral selector for the three CSPs. 43% of the studied compounds were resolved by the NEC-derivatized phases when they could not be resolved by the vancomycin CSP. However, the enantiorecognition for 12% of the compounds on the native vancomycin CSP was lost upon NEC derivatization. 45% of the studied compounds were resolved by the NEC-derivatized and native CSPs. The NEC derivatization procedure may block some useful active sites on the vancomycin molecule. Also, the R- and S-NEC moieties are chiral themselves and can contribute additional interaction sites not available on the native vancomycin molecule.     

Enantioseparation of selected chiral sulfoxides using polysaccharide-type chiral stationary phases and polar organic, polar aqueous-organic and normal-phase eluents

HPLC enantioseparation of selected chiral sulfoxides was studied using cellulose and amylose phenylcarbamate derivatives as chiral stationary phases (CSPs). The contributions of various functional groups of a chiral analyte as well as the polysaccharide derivatives in the analyte retention and chiral recognition were evaluated. A very high enantioseparation factor exceeding 110 was observed in the enantioseparation of 2-(benzylsulfinyl)benzamide (BSBA) on cellulose tris(3,5-dichlorophenylcarbamate) (CDCPC) CSP by using 2-propanol as a mobile phase. The enantiomer elution order was opposite on cellulose and amylose phenylcarbamates. For the polysaccharide-type CSPs, pure alcohols such as methanol, ethanol and 2-propanol represent a valuable alternative to more common alcohol-hydrocarbon and reversed-phase eluents.     

Novel enantioselective strong cation exchangers based on sulfodipeptide selectors: evaluation for enantiomer separation of chiral bases by nonaqueous capillary electrochromatography

Strong cation exchange (SCX)-type chiral stationary phases (CSPs) based on beta-amino sulfonic acid-terminated dipeptide derivatives as chiral selectors, immobilized on thiol-modified silica particles (3.5 microm), were synthesized and applied to enantiomer separations of chiral bases by nonaqueous capillary electrochromatography (CEC). The effect of structural variations of the sulfodipeptide selectors on the separation factors alpha was investigated. These studies included variation of the acid-terminal amino sulfonic acid residue, variation of the configurations, i.e., comparison of the diastereomeric (S,S)- and (R,S)-configurations of the sulfodipeptides, and finally comparison of sulfodipeptide selectors with corresponding beta-amino sulfonic acid analogs. In general, the capillary columns (100 microm ID) packed with the new SCX-type CSPs showed enantioselectivity for an elaborated set of chiral basic drugs in CEC acting by an enantioselective cation-exchange retention mechanism. N-[N-(4-Allyloxy-3,5-dichlorobenzoyl)-leucyl]-2-amino-3,3-dimethylbutane sulfonic acid, in particular with (R,S)-configuration, turned out to be a more effective SCX-type selector than a more rigid analog based on N-[N-(4-Allyloxy-3,5-dichlorobenzoyl)-leucyl]-2-pyrrolidinemethane sulfonic acid. Both of the former diastereomers were capable to baseline-resolve the enantiomers of ca. 40% of the tested basic chiral solutes including sympathomimetics and beta-blockers, while for the latter SCX-type CSPs only 10-20% of the selected solutes afforded resolutions > 1.5.     

酰胺型手性固定相反相拆分布洛芬药物对映体

利用酰胺型手性固定相反相拆分了布洛芬对映异构体,用有０．０１ｍｏｌ／Ｌ ＮＨ４Ａｃ的甲醇和水作流动相。在优化分离条件的同时,研究了不同的有机调节和对分离的影响,并探讨了分离的机理。     

Triazolo-linked cinchona alkaloid carbamate anion exchange-type chiral stationary phases: Synthesis by click chemistry and evaluation

Immobilization strategy based on Huisgen 1,3-dipolar cycloaddition (click chemistry) of 10,11-didehydrocinchona tert-butylcarbamates to azido-grafted silica gels has been evaluated for preparation of novel chiral stationary phases (CSP 1-3). The resultant 1,2,3-triazole-linked CSPs were tested under various mobile phase conditions (polar organic and reversed phase mode) with a representative set of structurally diverse racemic acids including N-protected aminoacids, aromatic and aryloxycarboxylic acids as well as binaphthol phosphate. The chiral recognition performance of the C3-triazole-linked CSPs was found to mirror largely that of the known C3-thioether-linked CSP in terms of elution order, enantioselectivity and retention behavior. In an effort to assess the non-specific binding expressed as retention increment of these triazole-linked CSPs, the parent azidopropyl- and triazole-modified silica materials (thus not containing the chiral head ligand) were studied independently. Compared with the corresponding CSPs, the analyte retention on the azidopropyl control column was very low, and practically negligible on the corresponding triazole-modified reference column. Only minor losses in analyte retention behavior (<5%) were observed with triazole-linked CSPs after two month of continuous use with polar-organic and reversed-phase-type mobile phases, highlighting the excellent stability of the 1,2,3-triazole linker.     

Comparison of the chiral resolution on cis-trans isomeric chiral stationary phases derived from (S)-1-(1-naphthyl)ethylamine

A pair of cis-trans isomeric chiral stationary phases (CSPs) derived from (S)-1-(1-naphtyl)ethylamine was prepared. The chromatographic behaviours on both CSPs with regard to the resolution of enantiomeric amino acids, amino alcohols, amines, and carboxylic acid were studied. According to separation factors, the trans-CSP showed better chiral recognition ability for the separation of most analytes chosen in this study. Three homologous series of the alkyl esters of racemic amino acids were resolved on both CSPs using n-hexane-2-propanol and n-hexane-dichloromethane as mobile phases. The trans-CSP also showed better enantioselectivity for the resolution of homologues. A reverse of elution order was observed for the resolution of the homologous series of phenylglycine alkyl esters on both CSPs. It was found that the relationship between the separation factor and the alkyl chain length of the ester homologous series depended upon the components of mobile phase. A higher magnitude of difference between the two CSPs in enantioselectivity for the resolution of a given homologue was obtained when n-hexane-dichloromethane was used as a mobile phase. A chiral recognition process, in which steric repulsion, face-to-face π-π interaction, face-to-edge π-π interaction and hydrogen bonding interaction were involved, was also suggested to describe the separation of enantiomeric homologues on both CSPs. This study clearly indicates that the chiral resolution is influenced by the geometry of the double bond in a CSP.     

Use of binary and ternary mobile phases in reversed-phase high performance liquid chromatographic separation of chiral compounds

The influence of the nature of typical organic modifiers, used in reversed-phase systems diluted with water, on retention and selectivity of chiral acetylated diamines and acetonitriles possessing pharmacological activity was investigated. Linear, semi-logarithmic relationships between the logarithm of the retention factor, k, of the enantiomer and the volume fraction, phi, of the organic modifier in the binary aqueous-organic eluent were established for chiral stationary phases. The slope of a plot of log k vs. the modifier volume fraction depends not only on the chemical structure of the chromatographed enantiomers, but also on the nature of the modifier. Moreover, the enantioselectivity of the studied racemates also depends on the nature and concentration of the modifier and is higher for a methanol mobile phase than for acetonitrile.     

Enantioseparation of selected chiral sulfoxides in high‐performance liquid chromatography with polysaccharide‐based chiral selectors in polar organic mobile phases with emphasis on enantiomer elution order

The separation of the enantiomers of 17 chiral sulfoxides was studied on polysaccharide‐based chiral columns in polar organic mobile phases. Enantiomer elution order (EEO) was the primary objective in this study. Two of the six chiral columns, especially those based on amylose tris(3,5‐dimethylphenylcarbamate) and cellulose tris(4‐chloro‐3‐methylphenylcarbamate) (Lux Cellulose‐4) proved to be most successful in the separation of the enantiomers of the studied sulfoxides. Interesting examples of EEO reversal were observed depending on the chiral selector or the composition of the mobile phase. For instance, the R‐(+) enantiomer of lansoprazole eluted before the S‐(?) enantiomer on Lux Cellulose‐1 in both methanol or ethanol as the mobile phase, while the elution order was opposite in the same eluents on amylose tris(3,5‐dimethylphenylcarbamate) with the S‐(?) enantiomer eluting before the R‐(+) enantiomer. The R‐(+) enantiomer of omeprazole eluted first on Lux Amylose‐2 in methanol but it was second when acetonitrile was used as the mobile phase with the same chiral selector. Several other examples of reversal in EEO were observed in this study. An interesting example of the separation of four stereoisomers of phenaminophos sulfoxide containing chiral sulfur and phosphor atoms is also reported here.     

Effect of the Orientation of Amide Linkage Groups on the Enantioselectivity of Two Related Synthetic Polymeric Chiral Stationary Phases

Two new synthetic polymeric chiral stationary phases (CSPs) based on trans-(1S,2S)-cyclohexanedicarboxylic acid bis-4-vinylphenylamide (I) and trans-N,N′-(1R,2R)-cyclohexanediyl-bis-4-ethenylbenzamide (II) monomers were prepared and evaluated by normal phase high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC). A variety of chiral compounds were separated on these two new CSPs. The different orientation of the amide groups in the two CSPs resulted in a striking difference in the enantioselectivity properties of these two CSPs. Their differences in enantioselectivity with HPLC and SFC were compared.     

Investigation of brush-type chiral stationary phases based on O,O'-diaroyl tartardiamide and O,O'-bis-(arylcarbamoyl) tartardiamide

Four chiral organosilanes based on O,O'-dibenzoyl tartardiamide, O,O'-bis-(3,5-dimethylbenzoyl) tartardiamide, O,O'-bis-(phenylcarbamoyl) tartardiamide and O,O'-bis-[(3,5-dimethylphenyl)carbamoyl] tartardiamide were synthesized and immobilized on silica to afford corresponding brush-type chiral stationary phases (CSPs) with well-defined structures. Using 54 compounds containing a wide variety of structures as analytes, the enantioselectivities of the four CSPs were evaluated under normal-phase modes. 3,5-Dimethyl substituent in the aryl group was found to significantly affect the enantioselectivity of CSPs containing aryl ester moieties. Aryl carbamate moieties in CSPs were observed more beneficial for enantioseparation than aryl ester moieties. The additional hydrogen-bond donors (NH) present in the carbamate groups contributed greatly to the enantioselectivity of CSPs, which is contrary to the results that have been found in network-polymeric CSPs.     

多糖衍生物手性固定相上采用酸性或碱性添加剂的流动相拆分β受体阻滞剂对映体

考察了多糖类手性固定相在含有酸性或碱性添加剂的流动相下高效液相色谱法拆分β受体阻滞剂对映体的效果。色谱条件: 流动相为10%～30%(体积分数,下同)乙醇-正己烷(含0.1%三氟乙酸)和10%～30%乙醇-正己烷(含0.1%三乙胺),流速1.0 mL/min,紫外检测波长254 nm。结果表明,在直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)衍生物手性固定相(Chiralpak AD和Chiralpak IA)上拆分β受体阻滞剂对映体,酸性添加剂的流动相体系与碱性添加剂的流动相体系相比,碱性添加剂的流动相的拆分效果比酸性添加剂的流动相要好。而在纤维素-三(3,5-二甲基苯基氨基甲酸酯)衍生物的手性固定相(Chiralcel OD和Chiralpak IB)上分离β受体阻滞剂,比较酸性添加剂的流动相与碱性添加剂的流动相的拆分效果,发现酸性添加剂的流动相条件下对映体的保留减弱,但对映体的选择性增大,特别是在Chiralcel OD上,酸性添加剂的流动相体系对对映体的选择性非常理想,而且随着流动相中酸性添加剂含量的增加,β受体阻滞剂对映体的分离效果更佳。     

Analytical and semipreparative resolution of ranolazine enantiomers by liquid chromatography using polysaccharide chiral stationary phases

Novel HPLC methods were developed for the analytical and semipreparative resolution of new antianginal drug ranolazine enantiomers. Good baseline enantioseparation was achieved using cellulose tris (3,5-dimethylphenylcarbamate) (CDMPC) chiral stationary phases (CSPs) under both normal-phase and polar organic modes. The validation of the analytical methods including linearity, LODs, recovery, and precision, and the semipreparative resolution of ranolazine racemate were carried out using methanol as mobile phase without any basic and acidic additives under polar organic mode, using CDMPC CSPs. At analytical scale, the elution times of both enantiomers were less than 7.5 min at 20 degrees C and 1.0 mL/min, with the separation factor (a) 1.88 and the resolution factor (R(s)) 2.95. At semipreparative scale, about 14.3 mg/h enantiomers could be isolated and elution times of both enantiomers were less than 13 min at 2.0 mL/min. To increase the throughput, the technique of overlapping injections was used. The first eluted enantiomer was isolated with a purity of 99.6% enantiomer excess (e.e.) and > 99.0% yield. The second enantiomer was isolated with a purity of 98.8% e.e. and > 99.0% yield. In addition, optical rotation and circular dichroism spectroscopy of both ranolazine enantiomers isolated were also investigated.     

Enantiomer separation of mandelates and their analogs on cyclodextrin derivative chiral stationary phases by capillary GC.

Enantiomer separation of mandelates and their analogs, which are important intermediates in asymmetric synthetic and pharmaceutical chemistry, was investigated by capillary gas chromatography using different cyclodextrin derivative chiral stationary phases (CD CSPs). The used cyclodextrin derivatives included permethylated beta-CD (PMBCD), permethylated gamma-CD, heptakis(2,6-di-O-butyl-3-O-butyryl)-beta-CD, heptakis(2,6-di-O-pentyl-3-O-acetyl)-beta-CD and heptakis(2,6-di-O-nonyl-3-O-trifluoroacetyl)-beta-CD (DNTBCD), respectively. Among all the CSPs used, PMBCD and DNTBCD exhibited the broadest and best enantioselectivity for all the racemates investigated. Some thermodynamic parameters were evaluated and an enthalpy-entropy compensation effect was observed in enantiomer separation processes of mandelates and their analogs. Based on thermodynamic data and molecular mechanics calculations, the chiral recognition mechanism of mandelate derivatives on CD CSPs is discussed.