Separation of mixtures racemic

At present moment, no generally feasible method exists for the large-scale production of optically pure products. Although for the separation of virtually every racemic mixture an analytical method is available (gas chromatography, liquid chromatography or capillary electrophoresis), this is not the case for the separation of racemic mixtures on an industrial scale. The most widely applied method for the separation of racemic mixtures is diastereomeric salt crystallization [1]. However, this usually requires many steps, making the process complicated and inducing considerable losses of valuable product. In order to avoid the problems associated with diastereomeric salt crystallization, membrane-based processes may be considered as a viable alternative. 

For the separation of racemic mixtures, two basic types of membrane processes can be distinguished a direct separation using an enantioselective membrane, or separation in which a nonselective membrane assists an enantioselective process [5]. The most direct method is to apply enantioselective membranes, thus allowing selective transport of one of the enantiomers of a racemic mixture. These membranes can either be a dense polymer or a liquid. In the latter case, the membrane liquid can be chiral, or may contain a chiral additive (carrier). Nonselective membranes can also... 

Fig. 5-19. Cascaded system for countercurrent 99 %+ separation of racemic mixtures [75].

Kcurentjes et al. (1996) have also reported the separation of racemic mixtures. Two liquids are made oppositely chiral by the addition of R- or S-enantiomers of a chiral selector, respectively. These liquids are miscible, but are kept separated by a non-miscible liquid contained in a porous membrane. These authors have used different types of hollow-fibre modules and optimization of shell-side flow distribution was carried out. The liquid membrane should be permeable to the enantiomers to be separated but non-permeable to the chiral selector molecules. Separation of racemic mixtures like norephedrine, ephedrine, phenyl glycine, salbutanol, etc. was attempted and both enantiomers of 99.3 to 99.8% purity were realized. 

Bicchi C, Artuffo G, D Amato A, Nano GM, Galfl A, GaUi M, Permethylated cyclodextrins in the GC separation of racemic mixtures of volatiles Part 1, J High Resolut Chromatogr 14 301-305, 1991. 

Bicchi C, ArtufFo G, D Amato A, Manzin V, Galli A, Galli M, Cyclodextrin derivatives for the GC separation of racemic mixtures of volatile compotmds, Part VI The influence of the diluting phase on the enantioselectivity of 2,6-di-O-methyl-3-O-pentyl-fi-cyclodextrin, /Resolut Chromatogr 16 209—214, 1993. 

In fluorine-18 chemistry some enzymatic transformations of compounds already labelled with fluorine-18 have been reported the synthesis of 6-[ F] fluoro-L-DOPA from 4-[ F]catechol by jS-tyrosinase [241], the separation of racemic mixtures of p F]fluoroaromatic amino acids by L-amino acylase [242] and the preparation of the coenzyme uridine diphospho-2-deoxy-2-p F]fluoro-a-o-glucose from [ F]FDG-1-phosphate by UDP-glucose pyrophosphorylase [243]. In living nature compounds exhibiting a carbon-fluorine bond are very rare. 

Optically active aldehydes are available in abundance from amino and hydroxy acids or from carbohydrates, thereby providing a great variety of optically active nitrile oxides via the corresponding oximes. Unfortunately, sufficient 1,4- or 1,3-asymmetric induction in cycloaddition to 1-alkenes or 1,2-disubstituted alkenes has still not been achieved. This represents an interesting problem that will surely be tackled in the years to come. On the other hand, cycloadditions with achiral olefins lead to 1 1 mixtures of diastereoisomers, that on separation furnish pure enantiomers with two or more stereocenters. This process is, of course, related to the separation of racemic mixtures, also leading to both enantiomers with 50% maximum yield for each. There has been a number of applications of this principle in synthesis. Chiral nitrile oxides are stereochemicaUy neutral, and consequently 1,2-induction from achiral alkenes can fully be exploited (see Table 6.10). 

Bicchi, C., D Amato, A., Manzin, V., Galli, A., and Galli, M. (1997) Cyclodextrin derivatives in GC separation of racemic mixtures of volatiles - Part XII thick-film wide-bore columns for enantiomer GC preparation. J. High Resol. Chromatogr. 20, 493-498. 

Analytical Properties Baseline and near-baseline separations of racemic mixtures of /V-perfluoroacyl-2-aminoethyl benzenes, trifluoroacetyl (TFA), pentafluoropropionyl (PFP), heptafluorobutyl (HFB)... 

The separation of racemic mixture is the most difficult process and involves several steps. The selective hydroboration sequence provides a convenient procedure 199 200 for the resolution of 1,3-disubstituted allenes, while the process is tedious and lengthy by other methods201. Thus, the treatment of ( + )-1,3-dimethyl allene with 50 mol percent of (+)-IPC2BH provided unreacted (R)-(-)-l,3-dimethylallene (Eq. 128). The configuration of allenes is consistently R when resolved by ( + )-IPC2BH. As both forms of IPC2BH are available, it should be possible to obtain the allenes of opposite configuration. 

Figure 9 shows the examples of separations of racemic mixtures of methylphenobarbital and mephenytoin performed under optimal conditions available (37). It has been found that ( -CD complexation resuTts in a distinct enantioselectivity in the case of mephenytoin and barbiturates which have a chiral center in the pyrimidine ring. The resolution of barbiturate enantiomers is due to the different stabilities of their diastereo-isomeric -CD complexes, while the separation of mephenytoin enantiomers results from the difference in their adsorption on the RP phase. The latter case should be considered further. It has been already suggested (18) that the adsorption of CD complexes in which guest molecules are entirely immersed in the CD cavity is low on RP phases. The distinct adsorption arises from the part of the molecule which is outside the cavity. Taking into account this fact and the remarkable difference in the adsorption of -CD mephenytoin diastereoisomers one may conclude that a significant difference must exist between immersion of mephenytoin enantiomers in the -CD cavity. 

Of the methods for the separation of racemic mixtures into dieir components one of the most useful is the formation of salts with optically active acids or bases. Early attempts to apply this method to the amino acids failed, since these compounds are not only weak acids, and therefore form rather unstable salts widi bases, but are also weak bases, and form unstable salts with acids. Fischer overcame this difficulty by converting the amino acids into their benzoyl derivatives, which he found to be stronger acids and so formed stable salts with optically active bases such as the alkaloids strychnine and brucine. Ordinary methods of benzoylation failed in this instance, but good yields were obtained in the presence of sodium bicarbonate. 

Fig. 17.9. Separation of racemic mixtures of naproxen, ibuprofen, and ketoprofen on poly(4-vinylpyridine-co-EDMA) CSPs (4.6 x 100 mm columns) imprinted with (S)-naproxen. (a) The column was packed with particles prepared by grinding and sieving a bulk polymer. Iso-cratic elution at 0.1 mL/min with THF-heptane-HOAc (250 250 1) and detection at 260 nm. (Adapted from [45], with permission from Elsevier Science, UK.) (b) The column was packed with beads prepared by a two-step swelling and polymerisation method. Isocratic elution at 1.0 mL/min with CHjCN-phosphate buffer (20 mM, pH 4.0) (1 1) and detection at 254 nm. (Adapted from [28], with permission from the Chemical Society of Japan.)...

Process options for the production of homochiral compounds are summarized in Fig. 2. The three basic routes are separation of racemic mixture, synthesis using a naturally occurring chiral synthon, and asymmetric synthesis using a prochiral intermediate. Historically, the efficiency of asymmetric synthesis has been capricious in terms of chemical and optical yield. Hence, from a practical, commercial process perspective, resolution via diastereomer crystallization has remained important for many commercial scale processes, for example, diltiazem. 

C. R. Bayley, The development of resolution methods for the separation of racemic mixtures. Proceedings of Chiral Synthesis Symposium and Workup, Manchester, England, Spring Innovations, Stockport, 1989, pp. 11-12. 

In the second scenario, target products and impurities are present in similar amounts. The separation of racemic mixtures exemplifies this scenario. The problem of racemic mixture formation often occurs during chemical synthesis, where 50% of the mixture consists of the wanted enantiomer (eutomer) and 50% is the unwanted enantiomer (distomer). In this case competitive adsorption and the elution order of the enantiomers are of special interest (Section 4.3.4). 

Two types of optically active barbiturates attract the attention of chemists and pharmacologists. In the first, the center of chirality is outside the ring in one of the substituents at C-5 (e.g., 51), in the second, the chirality is associated with the dissymetry of the ring (e.g., 52). Separation of racemic mixtures of... 

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