Industrial-scale enantiomer separation

Separation of enantiomers can often be challenging especially when chromatographic methods fail. Cocrystallization can and indeed is used to achieve chiral resolution. The classic example of the utility of cocrystals in this regard is the industrial-scale enantiomeric separation of 3-(ammoniomethy 1) -5-methyUiexanoate (Figure 25a). ... 

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N-CH2-COOH and the corresponding amino acid from symmetrical ketones R-CO-R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well. ... 

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. 

An equimolar mixture of two enantiomers is called a racemate. The separation of two enantiomers that constitute a racemate is called optical resolution or resolution. Their crystalline forms best characterize types of racemates. A racemic mixture is a crystal where two enantiomers are present in equal amounts. A conglomerate is a case where each enantiomer has its own crystalline form. Sometimes their crystals have so-called hemihedral faces, which differentiate left and right crystals. For over a hundred years, crystallization processes have been used for the separation and purification of isomers and optical resolution, both in the laboratory and on an industrial scale. 

For preparative and industrial scale separations of enantiomers the supercritical fluid extraction (SFE) seems very promising. The process of SFE with carbon dioxide allows variations in extraction parameters (pressure, temperature and extraction time) to find an optimal range both for maximum quantity and maximum optical purity of the product[4]... 

A characteristic feature of non-chromatographic separations utilizing cyclodextrins is that they are aimed at preparative separations. Unfortunately only incomplete separations or enrichments can be attained. By repeating the separations in multistage processes, the required component can be enriched on preparative, and even industrial, scale. Many examples have been published both for partial separation of compounds, isomers, or enantiomers through selective crystallization of their complexes (3). 

The second important observation on stereoisomer separation also involved ammonium sodium tartrate. Thirty-four years after Pasteur s observation, Jungfleisch (1882) observed that carefully introducing crystals of the individual isomers into different areas of a supersaturated solution of ammonium sodium tartrate resulted in the growth of isomerically pure crystals. These two observations form the basis for most industrial scale crystallizations for the purification of enantiomers or diastereoi-somers. However, it is more common for a solute to crystallize with the thermodynamically stable crystal form being a compound of the two isomers. This is typically denoted as a racemic compound. Secor (1963) made the first systematic review of optical isomer separation by crystallization, based upon phase behavior. Collet, Brienne, and Jacques (1980) applied systematic thermodynamics to the phase behavior, and developed straightforward methods for correlating the solubilities of isomers. 

Chiral recognition by CyDs is of primary importance for the pharmaceutical industry since the second enantiomer of a drug, usually present as 50% impurity as the result of chemical synthesis, can be harmful. Therefore, an effective preparative separation of enantiomers is one of the important goals of applied CyD research since at present it has not reached the industrial scale. Today the main CyD application in the pharmaceutical industry is their use as drug carriers, since CyD containers in most cases stabilize and solubilize the included drugs (see, how-... 

DL-Met is prepared on the industrial scale (more than 100,000 tons annually) by a Strecker synthesis, using P-methylmercaptopropionaldehyde prepared from acrolein and methylmercaptan. nt-Met is used to supplement poltry feed. Both d- and L-forms are effective, so that no prior separation of enantiomers is necessary. [F.Takusagawa et al. Crystal Structure of S-Adenosylmethionine Synthetase / BioL Chem. 271 (1996) 136-147]... 

The only stable product of the industrial method is para-nitrophenyl hydantoine the other proposed but not isolated intermediates are in parentheses. The hydantoine derivative possesses a stereogenic center on the C-5 atom and is racemic. Separation of enantiomers on an industrial scale is completed by selective biocat-alytic hydrolysis of / -enantiomer by hydantoinases, a group of hydrolytic enzymes. The wrong S-enantiomer can be easily racemized by heating in weak basic medium or by the enzyme hydantoin racemase and racemate recycled to separation. 

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