Method development chiral liquid chromatography

Owens PK, Fell AF, Coleman M, Berridge JC. Method development in liquid chromatography with a charged cyclodextrin additive for chiral resolution of rac-amlodipine utilizing a central composite design. Chirality 1996 8(7) 466-476. 

The development of liquid chromatography on a chiral support gave a decisive impulse to the study of atropisomerism since resolution can be quantitatively performed under very mild conditions without derivatiza-tion. The analytical methods can be easily extrapolated to preparative scale. Several atropisomeric systems, which do not present suitable functional groups to perform classical resolution through diastereomer resolution, can be readily separated into optically pure enantiomers. Dynamic chiral HPLC fills the gap between barriers attainable by DNMR and by thermal racemization of pure enantiomers. Chiral HPLC opens the way to several unexplored domains in the field of atropisomerism. We have... 

Despite the difficulties caused by the rapidly expanding literature, the use of chiral stationary phases (CSPs) as the method of choice for analysis or preparation of enantiomers is today well established and has become almost routine. It results from the development of chiral chromatographic methods that more than 1000 chiral stationary phases exemplified by several thousands of enantiomer separations have been described for high-performance liquid chromatography (HPLC). 

Initially, progress in this area was hampered by the lack of suitable analytical methods for chiral hydrocarbons. Early studies relied on optical rotation to determine enantiomeric excess (ee) values, but with the development of chiral gas chromatography (GC) and high-performance liquid chromatography (HPLC) columns, chromatographic methods have become more common. 

Liquid Chromatography. The development of rapid, simple liquid chromatographic methods for determining the enantiomeric purity of chiral compounds is probably one of the most important developments in the study of asymmetric synthesis in the last 10 years. Several books have been published providing thorough evaluations of various enantiomeric separation techniques and their practical applications.46... 

Matthijs, N., Perrin, C., Maftouh, M., Massart, D.L., Vander Heyden, Y. Definition and system implementation of strategies for method development of chiral separations in normal- or reversed-phase liquid chromatography using polysaccharide-based stationary phases. 7. Chromatogr. A 2004, 1041, 119-133. 

The CSPs based on chiral crown ethers were prepared by immobilizing them on some suitable solid supports. Blasius et al. [33-35] synthesized a variety of achiral crown ethers based on ion exchangers by condensation, substitution, and polymerization reactions and were used in achiral liquid chromatography. Later, crown ethers were adsorbed on silica gel and were used to separate cations and anions [36-39]. Shinbo et al. [40] adsorbed hydrophobic CCE on silica gel and the developed CSP was used for the chiral resolution of amino acids. Kimura et al. [41-43] immobilized poly- and bis-CCEs on silica gel. Later, Iwachido et al. [44] allowed benzo-15-crown-5, benzo-18-crown-6 and benzo-21-crown-7 CCEs to react on silica gel. Of course, these types of CCE-based phases were used in liquid chromatography, but the column efficiency was very poor due to the limited choice of mobile phases. Therefore, an improvement in immobilization was realized and new methods of immobilization were developed. In this direction, CCEs were immobilized to silica gel by covalent bonds. 

The analysis of chiral compounds to determine their optical purity is still not a trivial task. The analysis method has to differentiate between the two antipodes and, thus, has to involve a chiral agent. However, the development of chiral chromatography, especially HPLC (high-performance liquid chromatography), has done a significant amount to relieve this problem. The purpose of this book is to discuss large-scale synthetic reactions, but the reader is reminded that the development of chiral analytic methods may not have been a trivial undertaking in many examples. 

Chi C, Liang L, Padovani P et al. (2003) Development and validation of a liquid chromatography-mass spectrometric method for the determination of DPC 423, an antithrombotic agent, in rat and dog plasma. J Chromatogr B Analyt Technol Biomed Life Sci 783( 1) 163—172 Zimmer D, Muschalek V, Muller C (2000) Determination of met-rifonate enantiomers in blood and brain samples using liquid chromatography on a chiral stationary phase coupled to tandem mass spectrometry. Rapid Commun Mass Spec-trom 14(15) 1425-1432... 

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