DETERMINATION OF RESIDUAL AMINES USED IN BULK DRUG SYNTHESIS BY PRECOLUMN DERIVATIZATION WITH 3,5-DINITROBENZOYL CHLORIDE AND HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY

A rapid, simple and general method for determining residual amines use d in bulk drug manufacturing is described. The method uses a modified Schotten-Baumann reaction to prepare the 3,5-dinitrobenzoyl derivative s of primary and secondary amines. Unlike previously reported procedur es, the method does not require the isolation of the derivative and th e reaction solution is chromatographed directly without further sample treatment. Application of the method to the determination of residual piperazine in 2-methylpiperazine (I), of 3-aminopyrrolidine in 3-(ter t-butoxycarbonylamino)pyrrolidine (II) and N-(2-tetrahydrofuroyl)piper azine in l]-1-piperazinyl)-6,7-dimethoxy-4-quinazolinamine, monohydroc hloride, dihydrate (III) is described. Linearity was demonstrated with correlation coefficients greater than or equal to 0.9999 for all exam ples. Assay precision (R.S.D. values) ranged from +/-2.9% for the dete rmination of 2.6% 3-aminopyrrolidine in (II) to +/-11% for the determi nation of 0.21% N-(2-tetrahydrofuroyI)piperazine in (III). The accurac y of the determination ranged from 100.7 to 103.8%. The procedure is a lso used to determine the chiral purity of (3S)-(-)-(tert-butoxycarbon ylamino)pyrrolidine.