Synthesis of ¹⁷O (and ¹⁸O) labelled isophosphoramide mustard

The ifosfamide metabolite isophosphoramide mustard (IPM) was synthesized with isotopic enrichment at oxygen. Labelled benzaldehyde was made by exchange with isotopically enriched water (13.4 atom % 17 0, 25.5 atom % 18 0) and this was then reduced with sodium borohydride to give labelled benzyl alcohol (72% yield). Triethylamine and labelled benzyl alcohol were added to POCl 3 /CHCl 3 at −23°C. Subsequent addition of 2‐chloroethylamine hydrochloride (2 equiv) and then triethylamine (4.4 equiv) (−15°C) provided 17 0/ 18 0 enriched N,N ′‐bs‐(2‐chloroethyl)phosphorodiamidic acid phenylmethyl ester [61%, BzOP( O )(NHCH 2 CH 2 Cl) 2 ]. Catalytic (10% Pd/C) hydrogenation of this ester at atmospheric pressure gave IPM (22%). GC/MS was used to determine mole percent enrichments of 9.3% 17 0 and 17.9% 18 0 for IPM (single labelling within one molecule).