Synthesis of (-)-bevantolo1 hydrochloride from 3,4-dimethoxyphenethylamine and (S)-(+)-m-tolyl glycidyl ether derived from (R)-(-)-epichlorohydrin established the absolute configuration of the ( + ) and (-) enantiomer as R and S, respectively. The purity of the enantiomers was determines using a chiral cellulose column (CHIRALCEL OD@) which allowed drect separation of the enantiomers. A separation factor (a) of 4.20 and a resolution factor (Rs) of 9.21 were obtained. o 1995 Wiey-Liss, Inc.KEY WORDS: P-blockers, bevantolol, NC-1400, epichlorohydrin, absolute configuration, enantiomer, chiral cellulose column, dn-ect separationVarious p-adrenergic blocking agents (P-blockers), especially, l-amino-3-aryloxy-2-propanol derivatives, have been widely used for the treatment of cardiovascular disorders such as hypertension or angina pectoris. ' It has potent cardioselective P-blocking activity, and also possesses a-blocking and calcium blocking activities.3r4 These additional properties may be of advantage in the treatment of hypertension and may attenuate the disorders of P-blockers. In healthy subjects, it has been shown to cause a lowering effect on peripheral vascular resistance, and in patients with angina pectoris favorable effects on blood lipids have been reported.Most of the frequently prescribed p-blockers are supplied as racemates, but there are many reports suggesting differences in pharmacological and pharrnacodynamic andor pharmacokinetic properties between enantiomers of @-blockers. With respect to (+)-5, the differences in some pharmacological properties between enantiomers have already been reported. Furthermore, it is important to develop methods for determination of enantiomeric purity in order to investigate the metabolic pathways of (+)-5.In this paper, we report the absolute configuration of (-1-5, and describe a method for the direct column chromatographic separation of the enantiomers of (-+)-5. MATERIALS AND METHODSThe melting points were determined on a Yamato MP-21 and were uncorrected. The values of specific rotations were obtained on a JASCO DIP-360 digital polarimeter. 'H NMR 0 1995 Wiley-Liss, Inc.spectra were recorded on a JEOL JNM-EX400 NMR spectrometer with tetramethylsilane as the internal standard. Elemental analyses (C,H,N) were performed on a Heraus C,H,NRapid instrument. Optically active epichlorohydrins [(+)-or (-)-1 (over 98% ee)] were purchased from Daiso Co., Ltd. (Osaka, Japan). 3,4-Dimethoxyphenethyl~e (4) was purchased from Aldrich Japan Inc. (Tokyo, Japan) and Recordati Industria Chmica e Farmaceutica S.p. A. (Milano, Italy). High-Performance Liquid Chromatography (HPLC)The HPLC-system consisted of a JASCO BIP-1 HPCL pump and a JASCO UVIDEC-100-V W-spectrophotometer. The chiral analybcal columns contained CHIRALCEL OD@ (250 x 4.6 and 250 x 20 mi n; Daicel Chemical Industries, Ltd. (Osaka, Japan)). The mobile phase was composed of (1)
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