Preparative chiral chromatography

Note here that for (semi)industrial scale production, both enantiomers were obtained starting from the racemic mixture by preparative chiral chromatography. 

The critical point In the preceding Utopian prediction Is whether or not chiral coluonns can be devised which will Indeed efficiently and predictably separate the enantiomers of a wide array of solutes. Work conducted In our laboratory In Urbana leads us to believe that such Broad Spectrum CSP s are clearly possible, that their chiral recognition mechanisms can be discerned, and that an understanding of these mechanisms can be used for the rational design of still more effective CSP s (5-10). To support this belief, let us describe a simply prepared chiral chromatography column capable of separating the enantiomers of thousands of compounds of diverse functional types. 

The logical conclusion of these recent trends in preparative chiral chromatography ought to be that the next step would be to carry out SFC in an SMB system. Unfortunately it seems that the technological difficulties would almost certainly outweigh any potential benefits (personal communication [CIO]). 

Nevertheless, the operating procedure and the problems associated with preparative chiral chromatography are very similar to those met in general preparative work. Consequently, the general operating conditions and procedures in general preparative LC will be discussed, but particular emphasis will be given to those aspects that are important in chiral preparative work. 

In addition to giving detailed information on chiral separations, it also discusses the principles involved in chiral selectivity and, for those new to the technique, describes the fundamentals of a chromatographic separation and the essential apparatus needed to carry it out. To make the book as complete as possible we have included chapters on preparative chiral chromatography and some basic... 

Preparative Chiral Chromatography The Loading Capacity of a Column The Maximum Sample Volume Sample Volume Overload Sample Mass Overload Preparative Chromatography Apparatus Solvent Reservoirs Pumps... 

It is interesting to note that the inventors of (/ )-K-13675, in the first reported synthetic approach, targeted the racemic compound 1, and contracted separation of the enantiomers by preparative chiral chromatography to the expert company in this field, Diacel Chemical Indistries Ltd. [37]. Continuing scale-up investigations, the authors succeeded in replacing the Mitsunobu method, in the ether bond-forming reaction, by the technically much more simple use of triflate 21, prepared on a kg scale from (5)-n-butyl-2-hydroxybutanoate 20 (Scheme 3.8) [38]. 

Andersson S (2006) Preparative chiral chromatography - a powerful and efficient tool in drug discovery. In Subramanian G (ed) Chiral separation techniques. A practical approach, 3rd edn. Wiley-VCH, Weinheim... 

Since the first separation of enantiomers by SMB chromatography, described in 1992 [95], the technique has been shown to be a perfect alternative for preparative chiral resolutions [10, 21, 96, 97]. Although the initial investment in the instrumentation is quite high - and often prohibitive for small companies - the savings in solvent consumption and human power, as well as the increase in productivity, result in reduced production costs [21, 94, 98]. Therefore, the technique would be specially suitable when large-scale productions (>100 g) of pure enantiomers are needed. Despite the fact that SMB can produce enantiomers at very high enantiomeric excesses, it is sometimes convenient to couple it with another separation... 

W. H. Pirkle and B. C. Hamper, The direct preparative resolution of enantiomers by liquid chromatography on chiral stationary phases in Preparative Liquid Chromatography, B. A. Bidling-meyer (Ed.), Journal Chromatography Library Vol. 38, 3 Edition, Elsevier Science Publishers B. V, Amsterdam (1991) Chapter 7. 

Racemic mixtures of sulfoxides have often been separated completely or partially into the enantiomers. Various resolution techniques have been used, but the most important method has been via diastereomeric salt formation. Recently, resolution via complex formation between sulfoxides and homochiral compounds has been demonstrated and will likely prove of increasing importance as a method of separating enantiomers. Preparative liquid chromatography on chiral columns may also prove increasingly important it already is very useful on an analytical scale for the determination of enantiomeric purity. 

Capillary gas chromatography (GC) using modified cyclodextrins as chiral stationary phases is the preferred method for the separation of volatile enantiomers. Fused-silica capillary columns coated with several alkyl or aryl a-cyclo-dextrin, -cyclodextrin and y-cyclodextrin derivatives are suitable to separate most of the volatile chiral compounds. Multidimensional GC (MDGC)-mass spectrometry (MS) allows the separation of essential oil components on an achiral normal phase column and through heart-cutting techniques, the separated components are led to a chiral column for enantiomeric separation. The mass detector ensures the correct identification of the separated components [73]. Preparative chiral GC is suitable for the isolation of enantiomers [5, 73]. 

Grill, C.M., and Miller, LM. (2005) Steady-state recycling and its use in chiral separations, in Preparative Enantioselective Chromatography, 1st edn (ed. G.B. Cox), Wiley-Blackwell,... 

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