Chiralcel

The potential for use of chiral natural materials such as cellulose for separation of enantiomers has long been recognized, but development of efficient materials occurred relatively recently. Several acylated derivatives of cellulose are effective chiral stationary phases. Benzoate esters and aryl carbamates are particularly useful. These materials are commercially available on a silica support and imder the trademark Chiralcel. Figure 2.4 shows the resolution of y-phenyl-y-butyrolactone with the use of acetylated cellulose as the adsorbent material. 

Metyrapone human plasma/urine liq-liq extraction silica Chiralcel OJ UV 42... 

Pimobendan and its human plasma liq-liq extraction silica Chiralcel OD UV 48 ... 

Figure 11.4 Chromatograms of plasma samples on a silica-chiralcel OJ coupled column system (a) plasma spiked with oxprenolol (internal standard) (b) plasma spiked with 040 p-g/ml metyrapone and 0.39 p-g/ml metyrapol (racemate) (c) plasma sample obtained after oral administration of 750 mg metaiypone. Peaks are as follows 1, metyrapone 2, metyrapol enantiomers 3, oxprenolol. Reprinted from Journal of Chromatography, 665, J. A. Chiarotto and I. W. Wainer, Determination of metyrapone and the enantiomers of its chfral metabolite metyrapol in human plasma and urine using coupled achfral-chfral liquid cltro-matography, pp. 147-154, copyright 1995, with permission from Elsevier Science.

Chiralcel OD Cellulose tris(3,5-dimetltylphenylcarbamate) coated on silica gel [11,19,67,68] Daicel, [67,68]... 

Starting from a collection of samples remarkably well resolved (alpha > 6) on Chiralcel OD (Cellulose tris(3,5-dimethylphenylcarbamate) coated on aminopropyl silica), a putative three-point enantiophore for binding to CSR was derived (Fig. 4-10). This enantiophore query was used to search (CFS 3D search) within a list comprising 4203 compounds tested on Chiralcel OD. From this search domain of CHIRBASE 3D, 191 structures were found to match the enantiophore. 

In order to enhance our ligand-based query hypothesis, the structural fragments of the initial query were generalized but linked with the same distance constraints. A search of this final query (see Fig. 4-10) in the same list yielded 690 hits and a statistically significant correlation of the presence of this enantiophore and the enan-tioselectivity of the compounds was found (94 % of those are well resolved on Chi-ralcel OD). Note that out of the 4203 compounds of the Chiralcel OD domain search, a 2D search found 1900 structures that contain the substructural features of the generalized query. 

Fig. 4-11. Examples of structure fitting the generalized Chiralcel OD ligand-based query.

Chiralcel OD Cellulose tris(3,5-dimethylphenylcarbamate coated on amino-propyl silica. 

Fig. 4-12. Similarity maps of Crownpak CR, Whelk-O 1 and Chiralcel OD. L luminance value of the image.

To demonstrate the excellent correlation (r- = 0.99) between the luminance of the images and molecular diversity, we plotted the luminance values of the map versus the mean similarity values of data sets (Fig. 4-13). From this plot, a scoring scheme for the classification of CSPs from specific to broad application range can be well established Crownpak CR > Pirkle DNBPG > Whelk > Chiralpak AD > Chiralcel OD. 

Chiralcel OD and Chiralpak AD are associated with the largest mean values of molecular diversity. 

For comparative purposes, Chiralcel OD and Crownpak CR could be used as an extreme case to delineate the basis of a molecular diversity scale. 

A quick inspection of similarity maps in Fig. 4-14, allows one to see at once that Chiralcel OD and Whelk-0 1 molecule sets contain notable structural differences, whereas AGP and OVM data sets contain much more structurally related molecules. 

The purpose of this study is only intended to illustrate and evaluate the decision tree approach for CSP prediction using as attributes the 166 molecular keys publicly available in ISIS. This assay was carried out a CHIRBASE file of 3000 molecular structures corresponding to a list of samples resolved with an a value superior to 1.8. For each solute, we have picked in CHIRBASE the traded CSP providing the highest enantioselectivity. This procedure leads to a total selection of 18 CSPs commercially available under the following names Chiralpak AD [28], Chiral-AGP [40], Chiralpak AS [28], Resolvosil BSA-7 [41], Chiral-CBH [40], CTA-I (microcrystalline cellulose triacetate) [42], Chirobiotic T [43], Crownpak CR(-i-) [28], Cyclobond I [43], DNB-Leucine covalent [29], DNB-Phenylglycine covalent [29], Chiralcel OB [28], Chiralcel OD [28], Chiralcel OJ [28], Chiralpak OT(-i-) [28], Ultron-ES-OVM [44], Whelk-0 1 [29], (/ ,/ )-(3-Gem 1 [29]. 

However, it has provided some interesting results. At the top of the tree, the molecule population is first divided according to the presence or absence of the attribute NH2 (primary amine). If the answer is yes , the developed branches (on the right of the tree) mostly leads to the Crownpak CSP. The next attribute is Aromatic . If the answer is no , here the predominant CSP is Chiralpak AD. Aromatic compounds form the largest part of the tree and as expected the dominant CSP is Chiralcel OD which is disseminated in almost every region of the tree. 

CTA-I and Chiralcel OJ are found under the key AROMATIC and 8 member ring or larger . If sample also contains one amino group, then the tree leads to Chiralcel OJ. 

Chiralcel OB is associated with the separation of aromatic and nonaromatic sulfoxides and Chiralcel OD with aromatic alcohols. 

Fig. 12-1. Separation of primaquine enantiomers on a Chiralcel OD CSP. Chromatographic conditions 20 % methanol with 0.5 % isopropylamine in carbon dioxide, 2.0 mL min f 15 MPa, 30 °C.

Some of the initial enthusiasm surrounding chiral SFC was tempered by the fact that many of the same separations had already been achieved by LC [29]. Therefore, researchers were reluctant to add SFC to their analytical laboratories. In some instances, SFC does yield separations that can not be achieved on the same CSP in LC [30, 31]. The enantioseparation of primaquine, an antimalarial compound, on a Chiralcel OD CSP is illustrated in Fig. 12-1 [32]. This compound was not resolved on the same CSP in LC [33]. The reverse situation, where a separation obtained in LC may not be observed on the same CSP in SFC, can also occur [34]. These disparities seem to be related to differences in analyte-eluent and eluent-CSP interac-... 

The efficiency of many CSPs increases dramatically when liquid eluents are replaced with sub- or supercritical fluids. During a comparison of LC and SFC performed with a Chiralcel OD CSP, Lynam and Nicolas reported that the number of theoretical plates obtained was three to five times higher in SFC than in LC [26]. The separation of metoprolol enantiomers by LC and SFC on a Chiralcel OD CSP is illustrated in Fig. 12-2. Although impressive selectivity is achieved by both techniques, resolution is higher in SFC (R = 12.7) than in LC (R = 4.8), and the higher flowrate in SFC reduces the analysis time. The increased efficiency of SFC also improves peak symmetry. 

Benzodiazepine enantiomers have also been resolved on the Chiralcel OD CSP. Wang et al. utilized this CSP to determine the enantiomeric composition of camazepam and its metabolites [59]. SFC provided improved resolution of the compounds of interest in a shorter period of time than LC. Phinney et al. demonstrated the separation of a series of achiral and chiral benzodiazepines. An amino column was coupled in series with the Chiralcel OD CSP to achieve the desired separation [41]. 

The selectivity of another cellulose-based CSP, Chiralcel OJ, has also been examined in SFC [60]. Separations of racemic drugs such as benoxaprofen, temazepam, and mephobarbital were obtained. Acetonitrile proved to be a better modifier than methanol for some of the compounds investigated. The four optical isomers of a calcium channel blocker were resolved by Siret et al. on the Chiralcel OJ CSP [30]. In LC, two CSPs were required to perform the same separation. 

Derivatized amylose is the basis for the Chiralpak AD CSP. This CSP has been utilized for the resolution of ibuprofen and flurbiprofen, as well as other members of the family of nonsteroidal inflammatory drugs (NSAIDs) [39, 61]. Ibuprofen was not resolved on the Chiralpak AD CSP in LC. Pressure-related effects on stereoselectivity were observed by Bargmann-Leyder et al. on a Chiralpak AD CSP [58]. No corresponding effect of pressure on selectivity was observed with a Chiralcel OD CSP. The authors speculated that the helical conformation of the amylose-based CSP is more flexible than that of the cellulose-based CSP. 

The submitters report obtaining the product in 99% yield. The enantiomeric excess of the Mosher ester of 3 was measured to be 98% using a Chiralcel OD column (40% 2-propanol/hexane). This optical purity measurement substantiated the optical purity assessment made by 111 NMR studies of 3 and racemic 3 prepared using a different method3. Addition of the chiral shift reagent tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium (III) resulted in clear resolution of the respective aromatic proton signals for the two enantiomers, which was demonstrated with the racemate. Under similar conditions, NMR analysis of 3 showed that within the detectable limits of the experiment (ca. <3%), there was none of the disfavored enantiomer. 

The submitters determined the crystalline hydroxy esters to be >99.9% diastereomerically pure by supercritical fluid chromatography (EMdiol silica column and a Chiralcel (+) OD-(H) column (Chiral... 

Enantiomeric excesses were determined by chiral HPLC on ChiralCel OD (Hexane 2-PrOH 95 5). 

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