High selectivity, enantiomer separations

In general, high selectivities can be obtained in liquid membrane systems. However, one disadvantage of this technique is that the enantiomer ratio in the permeate decreases rapidly when the feed stream is depleted in one enantiomer. Racemization of the feed would be an approach to tackle this problem or, alternatively, using a system containing the two opposite selectors, so that the feed stream remains virtually racemic [21]. Another potential drawback of supported enantioselective liquid membranes is the application on an industrial scale. Often a complex multistage process is required in order to achieve the desired purity of the product. This leads to a relatively complicated flow scheme and expensive process equipment for large-scale separations. 

For preparative or semipreparative-scale enantiomer separations, the enantiose-lectivity and column saturation capacity are the critical factors determining the throughput of pure enantiomer that can be achieved. The above-described MICSPs are stable, they can be reproducibly synthesized, and they exhibit high selectivities - all of which are attractive features for such applications. However, most MICSPs have only moderate saturation capacities, and isocratic elution leads to excessive peak tailing which precludes many preparative applications. Nevertheless, with the L-PA MICSP described above, mobile phases can be chosen leading to acceptable resolution, saturation capacities and relatively short elution times also in the isocratic mode (Fig. 6-6). 

With capillary electrophoresis (CE), another modern primarily analytically oriented separation methodology has recently found its way into routine and research laboratories of the pharmaceutical industries. As the most beneficial characteristics over HPLC separations the extremely high efficiency leading to enhanced peak capacities and often better detectability of minor impurities, complementary selectivity profiles to HPLC due to a different separation mechanism as well as the capability to perform separations faster than by HPLC are frequently encountered as the most prominent advantages. On the negative side, there have to be mentioned detection sensitivity limitations due to the short path length of on-capillary UV detection, less robust methods, and occasionally problems with run-to-run repeatability. Nevertheless, CE assays have now been adopted by industrial labs as well and this holds in particular for enantiomer separations of chiral pharmaceuticals. While native cyclodextrins and their derivatives, respectively, are commonly employed as chiral additives to the BGEs to create mobility differences for the distinct enantiomers in the electric field, it could be demonstrated that cinchona alkaloids [128-130] and in particular their derivatives are applicable selectors for CE enantiomer separation of chiral acids [19,66,119,131-136]. 

Highly selective and is very effective in producing separation of enantiomers. 

The use of sulfoximines in the syntheses of optically active compounds has been reported [429]. A remarkable ketone methylcnation with optical resolution was realized. A highly selective diastereofacial addition of an enantiopure sulfoximine to a racemic ketone, chromatographic separation of the two diastereoisomers and reductive cleavage yielded both enantiomers of p-panasinsene [430], isolated from the root of ginseng, a herb used in Chinese folk medicine. 

MIPs used as chiral stationary phases in o-CEC, p-CEC as well as in rod-CEC have shown high selectivity but relatively low efficiency. Most of the reported enantiomer separations on these phases were performed without pressurization of the flow system. Only Schweitz et al. described on the enantiomer separation of propranolol and metoprolol (print molecule R-propranolol or S-metoprolol) [57] and ropivacaine, mepivacaine and bupivacaine (print molecule S-ropivacaine) [58] by... 

The use of stoichiometric, covalently bound chiral auxiliaries as a method of asymmetric synthesis is generally impractical and cannot compete with catalytic methods on a commercial scale. However, at the laboratory scale, the oxathiane method provides a predictable method to obtain a desired enantiomer with high selectivity. Since the intermediate compounds prior to hydrolysis are diastereomeric, they are easily separated (often by crystallization) and thus enantiomerically pure compounds are readily obtained. 

When compared to the batchwise preparative chromatography, Simulated moving bed (SMB) units exhibit a number of advantages. These advantages are primarily because of the continuous nature of the operation and the efficient use of the stationary and mobile phases, which allows a decrease in desorbent requirement and an improvement of the productivity per unit time and per unit mass of stationary phase. In addition, high performances can be achieved even at rather low values of selectivity and with a relatively small number of theoretical plates. Due to these positive features, SMB is particularly attractive in the case of enantiomer separations, since it is difTicult to separate enantiomers by conventional techniques. More recent applications related to chiral technology were reported [1-3]. 

The template la can be split off by water or methanol to an extent of up to 95% (see Scheme 4.II). The accuracy of the steric arrangement of the binding sites in the resulting imprinted cavity can be tested by the ability of the polymer to resolve the racemate of the template, namely phenyl-a-D,L-mannopyranoside. The polymer was equilibrated in a batch procedure with a solution of the racemate under conditions that allowed a thermodynamically controlled partition of the enantiomers between polymer and solution. The enrichment of the antipodes in the polymer and in solution was determined and the separation factor a, i.e. the ratio of the distribution coefficients of the d- and L-enantiomer between polymer and solution, was calculated. After extensive optimisation of the procedure, a values between 3.5 and 6.0 were obtained [4]. This is an extremely high selectivity for racemic resolution that cannot be reached by most other methods. 

Although enantiomer separation of amino adds has always been a domain of chiral diamide phases such as Chirasil-val (1] or XE-60-L-val- S)-a-phenylethylamide [2], the development of hydrophobic cyclodextrm derivatives has affected even this field of applications of enantioselective gas chromatography. Octakis(3-O-butyryl-2,6-di-0-pentyI)-7-cyclodextrin [Lipodex E , (32) (see footnote on p. 115)] is highly selective for amino acid enantiomers. Since hydrogen bonding is not necessary for a determination of the enantiomers, some unusual amino adds can be separated that could not be resolved before, including p-amino adds, a-alkylated, and N-alkyl-ated amino adds. 

Selectivity (or separation factor) (a) A thermodynamic factor that is a measure of relative retention of two substances, in the case of enantioselective separation enantiomers, fixed by a certain stationary phase and mobile phase composition. Higher selectivity value indicates highly discriminative separation conditions due to CSP and other chromatographic parameters, such as mobile phase composition, pH, temperature, etc.). 

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