Thomas D. Doyle

Application of high-performance liquid chromatographic chiral stationary phases to pharmaceutical analysis structural and conformational effects in the direct enantiomeric resolution of α-methylarylacetic acid antiinflammatory agents

Abstract A series of four α-methylarylacetic acids of pharmaceutical interest were directly resolved as enantiomeric amide derivatives on a high-performance liquid chromatographic chiral stationary phase consisting of covalently bound ( R )-N-(3,5-dinitrobenzoyl)phenylglycine. Enantiomers of ibuprofen, naproxen fenoprofen and benoxaprofen all exhibited optimum separation (α = 1.12, 1.23, 1.12 and 1.10, respectively) as 1-naphthalenemethylamides. Derivatives of ibuprofen were studied in detail; measurable separations were observed for secondary and tertiary amides of diverse structural types, but not for the primary amide or for ester derivatives. The results, which are consistent with an interaction model involving stacking of amide dipoles, with or without supplementary π—π and hydrogen-bonding effects, appear to be strongly dependent on conformational requirements of both the solute and the chiral stationary phase.

The Application of HPLC Chiral Stationary Phases to Stereochemical Problems of Pharmaceutical Interest: A General Method for the Resolution of Enantiomeric Amines as β-Naphthylcarbamate Derivatives

Abstract The enantiomers of primary, secondary and some tertiary amines are resolved as carbamate derivatives formed by reaction with β-naphthylchloroformate. The enantiomeric carbamates are resolved on a commercially available Pirkle-type HPLC chiral stationary phase (CSP), consisting of (R)-N-(3,5-dinitrobenzoyl)-phenylglycine covalently bonded to silica, by using a mobile phase consisting of mixtures of isopropanol in hexane. In this manner, 12 amines structurally related to amphetamine were resolved, including such pharmacologically important compounds as methamphetamine and pseudoephedrine, neither of which had been previously resolved on Pirkle-type CSPs. Reaction of the haloformate with phenolic amines may be controlled to give either mono- or bis-derivatives; both gave useful resolutions. Simple aliphatic amines such as sec-butylamine were also resolved. The order of elution of the carbamates was consistently R,S; this elution pattern is discussed in terms of specific interactions between the carb...

Application of high-performance liquid chromatographic chiral stationary phases to pharmaceutical analysis : Direct enantiomeric resolution of amide derivatives of 1-phenyl-2-aminopropane

Abstract A series of amide derivatives of the enantiomers of 1-phenyl-2-aminopropane (amphetamine) were resolved by high-performance liquid chromatography on a chiral stationary phase (CSP), (R)-N-(3,5-dinitrobenzoyl)phenylglycine, which is commercially available in ionically and covalently bonded columns. The separation factor ranged from 1.01 to 1.09 and was consistently larger when the compounds were chromatographed on the covalent column. Chromatographic parameters correlate in detail with a solute-CSP interaction model requiring up to four binding sites and a fifth repulsive interaction which is steric in origin and which provides the key chiral discriminant.

Chiral recognition model for the resolution of ephedrine and related α,β-aminoalcohols as enantiomeric oxazolidine derivatives

The mechanism of chiral recognition has been investigated for a series of enantiomeric cis-oxazolidines on a commercially available high-performance liquid chromatographic chiral stationary phase (HPLC-CSP). The oxazolidine molecules were synthesized through the condensation of ephedrine and ephedrine-related molecules with aromatic aldehydes. The resulting molecules are rigid five-membered rings whose configuration has been determined by proton magnetic resonance and single-crystal X-ray diffraction. The oxazolidines derived from the condensation of ephedrine and aldehydes containing a pi-basic moiety such as naphthaldehyde were resolved on the HPLC-CSP as were those oxazolidines synthesized by using a pi-acidic aldehyde such as p-nitrobenzaldehyde. However, there was a reversal in the elution order for the two types of oxazolidines. Oxazolidines resulting from the condensation of ephedrine and a pi-neutral aldehyde such as benzaldehyde were not resolved. The results of this study suggest a chiral recognition model based on the formation of diastereomeric solute-CSP complexes through a single attractive interaction and chiral discrimination resulting from the difference in steric fit.

The Application Of Hplc Chiral Stationary Phases To Pharmaceutical Analysis; The Resolution Of Some Tropic Acid Derivatives

A number of amide and ester derivatives of tropic acid were chromatographed by using a commercially available covalently bonded HPLC chiral stationary phase, (R)-N-(3,5-dinitrobenzoyl)-phenylglycin...

SPECTROPHOTOMETRIC STUDY OF DIENESTROL PHOTOISOMERIZATION

Abstract— Photolysis of synthetic estrogen dienestrol resulted in formation of a 4a,4b‐dihydrophenanthrene, a rare example of a stable intermediate of the classical stilbene → phenanthrene photocyclization. Time‐lapse spectrometric investigation suggested an initial cis‐trans isomerization in the dimethylbuta‐dime moiety of dienestrol followed by a photochemical [1, 51 sigmatropic proton transfer which converted the two cross‐conjugated p‐hydroxystyrene halves into a vinyl‐stilbene. A subsequent electrocyclic ring‐closure in an electronically excited state generated a cyclic nonaromatic heptenediol. This last photoproduct tautomerized rapidly in the dark to a stable, crystalline, tricyclic pentenedione. The final diketone product is an example of a 4a.4b‐dihydrophenanthrene self‐stabilized by a double ketoenol tautomerism. The three sequential photoisomerizations of dienestrol are made possible by a fortuitous coincidence of steric and orbital symmetry requirements.