SYNTHESIS OF O-17 (AND O-18) LABELED ISOPHOSPHORAMIDE MUSTARD

The ifosfamide metabolite isophosphoramide mustard (IPM) was synthesiz ed with isotopic enrichment at oxygen. Labelled benzaldehyde was made by exchange with isotopically enriched water (13.4 atom % O-17, 25.5 a tom % O-18) and this was then reduced with sodium borohydride to give labelled benzyl alcohol (72% yield). Triethylamine and labelled benzyl alcohol were added to POCl3/CHCl3 at -23-degrees-C. Subsequent additi on of 2-chloroethylamine hydrochloride (2 equiv) and then triethylamin e (4.4 equiv) (-15-degrees-C) provided O-17/O-18 enriched N,N'-bis-(2- chloroethyl)phosphorodiamidic acid phenylmethyl ester [61%, BzOP(O)(NH CH2CH2Cl)2] . Catalytic (10% Pd/C) hydrogenation of this ester at atmo spheric pressure gave IPM (22%). GC/MS was used to determine mole perc ent enrichments of 9.3% O-17 and 17.9% O-18 for IPM (single labelling within one molecule).