Bistrifluoromethylaryl derivatives for drug analysis by gas chromatography electron capture negative ion chemical ionization mass spectrometry. Application to the measurement of (N-dicyclopropylmethyl)amino-2-oxazoline in plasma.

Abstract

A gas chromatographic mass spectrometric assay for (N-dicyclopropylmethyl) amino-2-oxazoline in plasma with a detection limit of 0.1 ng ml-1 was required. Various fluoroaryl derivatives of this compound (code name S3341) were synthesized and their positive ion chemical ionization and electron capture negative ion chemical ionization mass spectra recorded. While fluorobenzyl derivatives of S3341 could be made by heating with the requisite benzyl bromide and diisopropylethylamine in acetonitrile, initial efforts to synthesize corresponding fluorobenzoyl derivatives using a benzoyl chloride in dry ethyl acetate at 60 degrees C were unsuccessful. Mass spectral data indicated that only a fragment of the oxazoline ring was retained in the reaction product and that an N-(2-chloroethyl)benzamide was formed. However, when diisopropylethylamine was included in the reaction mixture, a benzoyl derivative of the complete molecule was obtained. The mechanisms of these reactions are discussed. The negative ion mass spectrum of the 3,5-bistrifluoromethylbenzoyl derivative of S3341 has a base peak at m/z 420 (the molecular ion) and, when this ion is specifically monitored, an amount of derivative equivalent to 1 pg of S3341 can be detected. This allowed the development of an assay for S3341 in plasma with a precision of 9% (SD) at 0.2 ng ml-1 and a lower limit for quantitative determination of 0.1 ng ml-1.