Resolution, classical chiral HPLC

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... 

The team carried an extensive screening process to determine the optimum conditions for a classical resolution of the racemate 29, and thus avoid the need for a chiral HPLC separation. Accordingly, the amine was treated with dibenzoyl-L-tartaric acid as the resolving chiral acid. Eventually, the desired isomer (R)-29 was obtained in a 74% yield with an ee of 96% by treating with a 4 1 mixture of isopropyl acetate/methanol (25 vol.) and aging for 16 h at room temperature. This ee proved to be sufficient to prepare the desired API at an acceptable quality (as determined by evaluating the downstream chemistry). 

Chiral HPLC separation techniques have some significant advantages over classical resolution methods ... 

Although classical column chromatography over chiral stationary phases has been used for several years, HPLC has until recently been regarded mainly as an analytical tool. However, methods have now been developed and many papers have been published on the various applications of particular stationary phases in preparative HPLC, which may be the method of choice when the preparation of small amounts of material are required for screening purposes, for use in biological assays, or as standards in purity assays. The use of chromatographic techniques may be quicker and less risky than custom synthesis and resolution and can guarantee material to a defined specification. 

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