An Efficient Synthesis of 2-Hydroxyethyl N,N,N‘,N‘-Tetrakis(2-chloroethyl)phosphorodiamidate

A process for the multikilogram preparation of 2-hydroxyethyl N,N,N‘,N‘-tetrakis(2-chloroethyl)phosphorodiamidate has been achieved in substantially pure form by a short synthetic sequence starting from phosphorus oxychloride and 2 equiv of bis(2-chloroethyl)amine. This process involves a two-step preparation of the intermediate mustard chloride in one pot, followed by the base-catalyzed reaction with excess ethylene glycol. This method has been carried out to provide 2.9 kg of this key drug substance intermediate in 52% overall yield.