Synthesis of 15N Labelled Isophosphoramide Mustard

Abstract

The ifosfamide metabolite isophosphoramide mustard (IPM) was synthesized with isotopic enrichment at each nitrogen site. Glycine-N-15 was converted to 2-chloroethylamine-N-15 hydrochloride (4 steps, 21% net yield) which was then reacted with phenyl dichlorophosphate to provide N,N'-bis(2-chloroethyl)phosphorodiamidic-N-15(2) acid phenyl ester [62%, PhOP(O) ((NHCH2CH2Cl)2)-N-15]. Catalytic hydrogenation of this phenyl ester followed by the addition of cyclohexylamine (CHA) provided IPM-N-15(2) as the CHA salt (63%).