Chiral ligand-exchange chromatography as the screening method for proposed modifications in exametazime synthesis to enhance diastereoselectivity.

N Nikolić, D Veselinović, S Vladimirov, K Karljiković-Rajić, H Lingeman

Index: J. Pharm. Biomed. Anal. 34(2) , 285-93, (2004)

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Abstract

99M Tc (V)-d,l-HM-PAO complex is well-known radiopharmaceutical for regional cerebral blood flow imaging. The proposed modifications in exametazime, hexamethylpropyleneamine oxime (HM-PAO) (4,8-diaza-3,6,6,9-tetramethylundecane-2,10-dione bisoxime) synthesis, for reduction of intermediary reactant diiminebisoxime (DI) (4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime) concerned two reductants (NaBH(4) and KBH(4)), two solvents (ethanol and 2-propanol), and three mole ratios of reactant/reductants (1:1, 1:1.5, and 1:2). The simultaneous analysis of diastereo-enantiomeric HM-PAO content, as well as the content of starting DI, in different reduction mixtures were performed using chiral ligand-exchange chromatography (CLEC). The separation of the samples of investigated reduction mixtures, obtained in the second step of HM-PAO synthesis, has been accomplished by using an achiral sorbent (RP-18) and a chiral mobile phase (CMP) containing copper(II) complex with N,N-dimethyl-l-phenylalanine (l-DM-PhA) as initial complex for CLEC. With 12 different reduction conditions, the obtained ratios of diastereoisomers d,l-HM-PAO: meso-HM-PAO varied from 69.2:30.8 to 15.9:84.1, in comparison to the reduction in routine synthesis of HM-PAO which gives an equal mixture of diastereoisomers. The ternary mixed complexes formation recorded spectrophotometrically on addition of HM-PAO or DI to the mobile phase with binary complex Cu(l-DM-PhA)(2), due to the evidence of bathochromic shift of 46nm for lambda(max) with significant difference in absorptivity contributes to separation mechanism.