Synthesis of 4‐13C‐4‐hydroperoxycyclophosphamide and alpha‐13C‐4‐hydroperoxycyclophosphamide

Abstract

AbstractNew synthetic routes were developed for incorporating 13C into the oxazaphosphorine ring and nitrogen mustard functionality of cyclophosphamide metabolites. 1,2‐13C2‐Vinylbromide and ethylene oxide were used to synthesize 3,4‐13C2‐3‐butenyl N,N‐bis(2‐chloroethyl)phosphorodiamidate via the intermediacy of 3,4‐13C2‐3‐buten‐1‐ol. Ozonolysis of the phosphorodiamidate gave 4‐13C‐4‐hydroperoxycyclophosphamide with an overall yield of 16% which was 27‐times higher than a previously reported synthesis. As an extension of this synthetic pathway, 2‐13C‐ethyl bromoacetate was used to incorporate 13C into the C1 position of bis(2‐chloroethyl)amine hydrochloride which was used as a precursor to alpha‐13C‐4‐hydroperoxycyclophosphamide (obtained in 16% overall yield). Also discussed are applications of these pathways to the synthesis of diversely labelled (14C, 13C, 2H) 4‐hydroperoxycyclophosphamides, chirally‐labelled oxazaphosphorines, phosphoramide mustards, and related alkylating agents.