TETRAHEDRON: ASYMMETRY Tetrahedron: Asymmetry 13 (2002) 1429–1434 Pergamon Effect of achiral support on the resolution of tetramisole by supercritical fluid extraction Edit Sze ´kely, a, * Be ´la Sima ´ndi, a Krisztina La ´szlo ´, b Eleme ´r Fogassy, c Gyo ¨ rgy Pokol d and Ildiko ´ Kmecz a a Department of Chemical Engineering, Budapest University of Technology and Economics, H-1521 Budapest, Hungary b Department of Physical Chemistry, Budapest University of Technology and Economics, H-1521 Budapest, Hungary c Department of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary d Institute of General and Analytical Chemistry, Budapest University of Technology and Economics, H-1521 Budapest, Hungary Received 21 June 2002; accepted 27 June 2002 Abstract—The enantiomers of tetramisole were produced by partial diastereomeric salt formation with O,O-dibenzoyl-(2R,3R )- tartaric acid monohydrate and subsequent supercritical fluid extraction (SFE) of the unreacted enantiomers in the presence of an achiral support. The effect of the activated carbon and Perfil 100™ on the efficiency of chiral separation were studied. The kinetics of the process was found to be an important factor affecting enantioselectivity. When the parameters were properly set, much better resolution efficiency (F ) and higher enantiomeric purity were achieved than in the equilibrium. The presence of Perfil 100™ and activated carbon caused an increase as high as 53 and 84% in F, respectively, compared to that achieved without using any support. Thus during the development of a resolution procedure, beside the proper resolution agent, optimised molar ratio and other parameters, the selection of achiral additive(s) may be also an important point. © 2002 Elsevier Science Ltd. All rights reserved. 1. Introduction According to the US Food and Drug Administration’s policy statement, marketing of new chiral pharmaceuti- cals has been allowed only as pure enantiomers from the beginning of 1992, except when the therapeutic properties of the racemic mixture are better. 1 In many cases these enantiopure drugs are produced by asym- metric synthesis followed by chiral resolution. In recent years growing interest has been shown in new and environmentally friendly resolution processes. 2 Beside membrane separation, procedures using super- critical fluids have also become promising on industrial scale. 3,4 Our group developed a novel technique based on partial diastereomeric salt formation followed by supercritical fluid extraction (SFE) of the free enan- tiomers. 3 The method was successfully applied to the resolution of racemic organic acids and bases. Mean- while, Bauza et al. also proved the feasibility of SFE of enantiomers for analytical purposes. 5,6 The development of a widely applicable method requires a deep understanding of the influencing fac- tors. The effect of the molar ratio, extraction pressure and temperature on the resolution of different organic acids 3 and bases has been reported recently. 7 Herein the effect of the achiral support is examined. 2. Materials and methods Racemic tetramisole (6-phenyl-2,3,5,6-tetrahydro-imi- dazo-[2,1b]-thiazole) was prepared in our laboratory and checked analytically by HPLC prior use. It was found to be of 99.9% purity. The resolving agent (O,O - dibenzoyl-(2R,3R )-tartaric acid=DBTA) and all other reagents and solvents were purchased from Reanal Ltd., Budapest. Perfil 100™ (expanded and milled perlite for use as a filtering-aid) was obtained from Baumit Co. (Budapest). The activated carbon applied was of medi- cal grade, commercially available in pharmacies. The specific surface area (S a,BET ) and the total pore volume values are listed in Table 1. * Corresponding author. Tel. +36-1-4632246; fax.: +36-1-4633197; e-mail: sz-edit@vhsz.bme.hu 0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII:S0957-4166(02)00337-3