Synthesis of cyclophosphamide‐4,4,5,5‐d4

Abstract

Abstract3‐Hydroxypropionitrile was subjected to a base‐catalyzed exchange reaction in D2O which provided 2,2‐dideuterio‐3‐deuteroxypropionitrile (DOCH2CD2CN) in 70% yield. Reduction of the nitrile with LiAlD4 gave 3‐amino‐2,2,3,3‐tetradeuteriopropan‐1‐o1 (HOCH2CD2CD2NH2) in a crude yield of 71%. Reaction of this intermediate with N,N‐bis(2‐chloroethyl)phosphoramidic dichloride [Cl2P(O)N(CH2CH2Cl)2] followed by the combination of those chromatography fractions which contained only pure material gave cyclophosphamide‐4,4,5,5‐d4 as a white oil in 13% yield. A portion of this oil was converted to the monohydrate by the addition of water (1.1 equivalents) and crystallization from ether/petroleum ether (62% yield). For the hydrate, MS analyses gave an average mole percent enrichment (with average deviation over 5 determinations) of 89.1 ± 0.5% d4.