Naproxen Specific CSPs Using the Immobilized Guest Method

As mentioned earlier, one of the most general Pirkle-type CSPs resulted from a study aimed at developing something which would be useful for separating the enantiomers of the drug, naproxen. At the time of the inception of this project, separation of the enantio-mers of naproxen and related NSAIDs with Pirkle-type CSPs generally required formation of derivatives. The finding that underivatized naproxen enantiomers could be marginally resolved on the ^-GEM 1 CSP prompted an investigation into the development of improved separations. Drawing on the familiar principle of reciprocity, a new approach termed the 'immobilized guest method' was utilized in this study. Two CSPs were prepared from enantiopure naproxen, and these were used to investigate the enantioseparation of a variety of different chiral analytes. This study led to an understanding of the structural requirements for enantioselective naproxen recognition, and a new chiral selector incorporating

Structure [XI] (ULMO CSP)

Structure [XII] (a-Burke I CSP)

many of these key structural features was proposed. This new selector was synthesized and found to be well separated on the immobilized guest naproxen CSPs. Larger scale synthesis, resolution, and immobilization of the selector afforded a CSP which resolved naproxen enantiomers with a very high degree of enantioselectivity (a = 2.25). In addition, structurally related NSAIDs such as ibuprofen, ketopro-fen, flurbiprofen, etc. are also resolved. Subsequent mechanism-based structural modifications led to the development and commercialization of the Whelk-O 1 CSP (CSP structure [X]) which affords improved resolution of NSAID enantiomers. In addition to resolving the enantiomers of NSAIDs, the Whelk-O 1 CSP has proven to be the most general CSP developed to date in the Pirkle laboratories, as it is capable of resolving the enantiomers of racemates from a host of functional group classes.

A number of variations on the Whelk-O structure have been developed in the Pirkle laboratories and at Regis Technologies. For example, the same selector immobilized via a trifunctional silane linkage has been commercialized as the Whelk-O II CSP (structure [XIV]). This CSP is more resistant to selector cleavage under harsh mobile phase conditions.

Another analogue of the Whelk-O CSP has proven useful for separations utilizing supercritical or sub-critical carbon dioxide as an eluent. This phase, commercialized as the PolyWhelk-O CSP, is prepared by first immobilizing the Whelk-O chiral selector onto a polysiloxane polymer, then covalently bonding the resulting polymer to silica gel. The resulting material often shows improved efficiency and enantioselectiv-ity when operated in the SFC mode.

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