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

Abstract

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