9


higher productivity figures were observed for the enantiomer separation of racemic dichlorprop with a phase systemconsisting of mono-11-octadecylthio-bis-10,11- dihydroquinidinyl)]-1,4-phthalazine in tert- butylmethylether as stationary phase and 100 mMphosphate buffer pH 8.0 asmobile phase, with baseline separation achieved for sample loads up to 370mg [39]


. A


representative separation avhieved with this phase systemis depicted in Figure 8. In addition to the high loading capacity, excellent selector economy could be achieved, generally with themolar amount of racemic analyte separated exceeding the molar amount chiral extractant employed.


Despite of the highly promising preparative capacity of CPC, the technique suffers from limitations concerning scalability. This problemhas been addressedmost recently in a study employing the readily scalable centrifugal contactor separator (CCS) devices. A CCS device is essentially a centrifuge designed for the continuous high throughput extraction of two phase systems, effecting highly efficientmixing and separation of immiscible solvent systems. AdoptingO-(1- tert-Butylcarbamoyl)-11-octadecylsulfinyl- 10,11-dihydroquinine as chiral extractant and racemic 3,5-dinitrobenzoyl leucine asmodel system, a fully optimized pilot-scale countercurrent extraction enantiomer separation process was developed [41]


. The


chiral extractant was employed in 1,2- dichloroethane and the racemic analyte in phosphate buffer at pH 5.7. A single back extraction stage performed with phosphate buffer at pH 9.0 was employed to recover the product with an enantiomeric enrichment of 34%ee and in 61% yield fromthe organic phase. To achieve complete enantiomer separationmultiple extraction stages were performed by coupling 6 CCS devices in a countercurrent fashion. A schematic representation of the countercurrent extraction process is depicted in Figure 9.


This process configuration was capable of producing the (S)-enantiomer in 98% ee and 55% yield.With the pilot scale unit used the possible productivity was estimated to be 17.7 kg/week. The amount of chiral extractant required to achieve this productivity figure was favorably low (60 g), corresponding to turnover number of 400 to 700 per week, a figure that was judged to be highly economic from a process viewpoint. The authors of this study estimated that with the largest CCS units commercially available a productivity of 5 - 10 tons per week would be feasible. It was concluded that the developed extraction process has similar potential as simulated moving bed chromatography for the ton scale separation of enantiomers.


3. Conclusions


Cinchona alkaloid-derived selectors operating on anion-exchange principles present highly efficient tools for the analytical and preparative enantiomer separation of chiral acidic compounds. The combined benefits of broad mobile phase compatibility; ease ofmethod development; adjustment of retention without compromising selectivity; convenient control of enantiomer elution orders on demand by the use of pseudoenantiomeric selectors; and the excellent compatibility withmass sensitive detectionmodes render cinchona-based anion-exchangers attractive options for a wide range of (bio)analytical applications. High loading capacity, often in combination with exceptional levels of enantioselectivitymake these chiral selectors efficient tools for preparative chromatography, and also promising candidates for the advancement of innovative large-scale enantiomer separation techniques based onmembrane and liquid- liquid extraction principles.


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