Stereospecific Synthesis of Chiral Metabolites of Ifosfamide and Their Determination in the Urine

The stereospecific synthesis of two chiral metabolites of ifosfamide (2), 4-ketoifosfamide (5) and 2-amino-3-(2-chloroethyl)tetrahydro-2H-l,3,2-oxazaphosphorine 2-oxide (9), is reported. The absolute configuration of both compounds was assigned on the basis of chemical correlation. In addition, two other achiral metabolites of 2, carboxyifosfamide (6) and IPAM (7), were synthesized. These and other organophosphorus metabolites of ifosfamide were found, by 31P NMR, in the urine of patients to whom racemic 2 was administered. The measurements performed in the presence of optically active lanthanide shift reagent [Eu(tfc)3] showed considerable stereoselectivity of in vivo formation of some chiral metabolites of ifosfamide.