Synthesis of ¹⁵N and ¹⁷O labelled phosphoramide mustards

Abstract

Abstract The cyclophosphamide metabolite phosphoramide mustard (PM) was synthesized with isotopic enrichment at each nitrogen and oxygen site. Sequential reaction of N,N ‐bis(2‐chloroethyl)phosphoramidic dichloride [Cl 2 P( O )N(CH 2 CH 2 Cl) 2 ] with benzyl alcohol and ammonia gave N,N ‐bis(2‐chloroethyl)phosphorodiamidic acid phenylmethyl ester [BzO(H 2 N)P( O )N(CH 2 CH 2 Cl) 2 ]. Catalytic hydrogenation of this benzyl ester followed by the addition of cyclohexylamine (CHA) provided PM as the CHA salt. Incorporation of 15 NH 3 into this general scheme gave PM with a 15 NH 2 moiety. Glycine‐ 15 N was converted to bis(2‐chloro‐ethyl)amine‐ 15 N hydrochloride which, in turn, provided for N,N ‐bis(2‐chloroethyl)phosphoramidic‐ 15 N dichloride. Use of this compound in the general synthetic pathway yielded PM°CHA with 15 N in the mustard moiety. 17 O‐Enriched PM was generated through the use of benzyl alcohol‐ 17 O . To obtain the alcohol, labelled benzaldehyde was made by exchange with 17 OH 2 and was then reduced with sodium borohydride.