The chemical and thermal stability of the acetamido group of (R)‐ and (S)‐atenolol: Synthetic and chromatographic studies

Abstract

The chemical stability of the acetamido moiety of the P-blocker atenolol toward possible dehydration causing a nitrile formation during an acid-catalyzed chiral derivatization procedure with 0,O'-(R,R)-diacylated tartaric acid anhydrides was elucidated. All the necessary reference compounds including the oxazolidine-Zone derivatives of the respective aminopropanols were synthesized, their structures confirmed by various spectroscopic methods, and chromatographically compared using HPLC and GC-MS. In the course of this work it was shown that the acetamido moiety of atenolol is quite stable toward dehydrating agents but shows a significant thermolability, e. g., in the injection system of a GC, which leads to the dehydrated form of atenolol namely, "nitriloatenolol." o 1994 Wiley-Liss, Inc.KEY WORDS: atenolol, nitrile formation, stability, chromatography (R, S)-Atenolol is a highly hydrophilic aryloxypropanolamine type P-blocker. * It is a selective PI-adrenoceptor antagonist and has been used for the treatment of hypertension, angina pectoris and cardiac arrhythmia. In contrast to other P-blockers, atenolol is eliminated unmetabolized by the kidneys.2 Like most P-blockers, atenolol is currently administered as racemic (1:l) mixture of (R)-and 6)-atenolol. However, it was recently shown by us2 that the P-blocking activity of the marketed (R,S)-atenolol can be ascribed mainly to the 6)-enantiomer.In order to prepare optically pure aminoalcohol type compounds such as atenolol, propranolol and several other P-blockers for pharmacological studies, a simple separation method was developed by US.^ It is based on the derivatization of atenolol (selectand) with a (R, R)-or (S,S)-O,O'-disubstituted tartaric acid anhydride (selector) at the hydroxyl group while the amino function is protected via ion pair formation by a strong organic acid, e.g., trichloroacetic acide. Due to the significantly different physicochemical properties of the resulting diastereomeric monoesters, they can be separated on a large scale either by fractional crystallization or by preparative chromatography. Cleavage of the selector-selectand ester bond of the optically pure diastereomers by alkaline hydrolysis yields the optically pure enantiomers of the parent Wilson and co-workers4 recently reported the unwanted acid-catalyzed dehydration of (R, S)-atenolol during the above derivatization step, reportedly leading to the corresponding nitriloatenolol (Scheme 1). This was determined by mass spectroscopy, however, exact conditions were not given.In this contribution we show synthetically and analytically that dehydration of the acetamido moiety of atenolol occurs only under very harsh conditions or thermally at a P-blocking drug.0 1994 Wiley-Liss. Inc. temperature > 220°C but certainly not during the general derivatization p r~c e d u r e .~ HPLC and GC-MS have been employed as analytical tools. MATERIALS AND METHODSMelting points were measured on a Gallenkamp melting point apparatus and are uncorrected. 'H-NMR spectra were recorded on a Varian...

Chiral separation by chromatographic and electromigration techniques. A Review

“…(O,O 0 -R,R)-diacylated tartaric acid anhydrides were used for derivatization of b blockers [24]. Kleidernigg et al [25] introduced a new chiral derivatization reagent, (1R,2R)-or (1S,2S)-N-[(2-isothiocyanato)cyclohexyl]-3,5 dinitrobenzoylamide (DDITC) for the derivatization of primary and secondary amines and amino alcohols.…”

“…More recently applied derivatization reagents are isopinocampheylamine [272] and O,O 0 -(R,R)-diacylated tartaric acid anhydrides [273].…”

Synthesis of new stable aliphatic isothiocyanate-based chiral derivatizing agent and application to indirect separation of chiral amino and thiol compounds

“…As with any isothiocyanate [3,4,25,29], (S,S)-PDITC reacts selectively in aqueous or non-aqueous media with chiral primary and secondary amino functions of amines, amino alcohols, amino acids and peptides forming the corresponding diastereomeric thioureas. Another functionality which can be derivatized by isothio- Derivatization scheme of amino-and thiol-compounds using (S,S)-PDITC as CDA cyanates is the thiol group [29,35] which leads to the corresponding dithiocarbamates.…”

“…Another functionality which can be derivatized by isothio- Derivatization scheme of amino-and thiol-compounds using (S,S)-PDITC as CDA cyanates is the thiol group [29,35] which leads to the corresponding dithiocarbamates.…”

“…This CDA belongs to a family of structurally related CDAs reported recently [29][30][31]. Further, the reactivity towards primary and secondary amines, amino alcohols of the [3-blocker type and thiols was evaluated.…”