Data on the absolute configuration of mexiletine (MEX) do not appear to have been published, although in several published reports the configuration is referred to as (-)-(R) and (+ )-(S), based on information from manufacturers providing the drug stereoisomers. We demonstrate that (-)-MEX has the (R)-contiguration by mean of a new stereospecific synthesis. X-Ray analysis of an optical active sample of (+)-MEX as its hydrobromide salt, obtained from chemical resolution of the racemic mixture, was carried out in order to obtain precise information on bond lengths and angles, useful for studies on structure-activity relationships. We also report the NMR analysis in presence of Eu(hfc), as shift reagent, which represents a simple method for the determination of enantiomeric excess (ee) in addition to the well-known chiral HPLC methods. o 1994 Wiley-Liss, hc.KEY WORDS: antiarrhythrmc drug, mexiletine, absolute configuration, chiroptical properties, X-ray analysis, is a class I-B antiarrhythmic agent which is quite useful in the long-term treatment of ventricular arrhythmias. 1-(2,6-dimethylphenoxy)-2-propanamine, (MEX) (1)Even though in the last few years the research for better antiarrhythmic agents has been intense,' the state of phannacological treatment of this disease is far from satisfactory because most of the drugs in routine clinical use are not well tolerated.,In addition, as is well known, the pharmacology and toxicity of chiral drugs should be investigated on isolated stereoisomers rather than on a racemic sample, because the stereoisomers may differ qualitatively and/or quantitatively in their actions at receptor sites."' Furthermore, for a precise definition of drug-receptor interactions, and in terms of the significance of stereospecificity in the activity of type I antiarrhyhmc drugs,8 it appears necessary to establish the absolute configuration of each drug without any doubt.In the case of MEX, it has been often reported that the (+)-isomer of MEX has the (3-absolute configuration, but we did not find proof of this chiral attribution in the literature.a1o the indications from the manufacturer providing the drug stereoisomers, but without chemical or structural proof.In this work, we have obtained the two enantiomers of MEX by chemical resolution with (-)-L-dibenzoyltartaric acid and have verified that the isomer which is dextrorotatory as free base [(+)-MEXI also shows a positive optical rotation as the hydrochloride salt.We then report a chemical correlation (Scheme 1) that allows us to attribute definitively the R absolute configuration Finally we present an X-ray study on (+)-(S)-MEX, as the hydrobromide salt, which gives a precise view of the threedimensional arrangement of the molecule in the solid phase. The X-ray data are useful for trustworthy structure-activity relationship evaluations in the domain of the class I-B antiarrhythnnc agents. These data are in agreement with our previous attribution of configuration based on the chemical correlation. MATERIALS AND METHODS Chemicals and R...

Optically active 3‐ethyl and 3‐n‐propylpyrrolidine were prepared by two independent routes from their corresponding succinic acids and the absolute configurations were assigned. Maximum optical rotation was also established through evaluation of the degree of racemization of the products obtained via both synthetic routes.

Absolute configuration was assigned to 3‐isopropylpyrrolidine by chemical correlation with R‐3‐isopropylsuccinic acid. The comparison between CD curves of 3‐substituted piperidines, morpholines and pyrrolidine having the same chirality shows that the chiroptical properties of these five and six‐membered cyclic amine derivatives are opposite.

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Die (Ihiralität der Verbindungen (1) ‐ (III) wird anhand von CD‐Daten untersucht.