Synthesis of cyclophosphamide-4,4,5,5-d4

Abstract

3-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 LiALD(4) gave 3-amino-2,2,3,3-tetradeuteriopropan-1-ol (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-d(4) 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 +/- 0.58 d(4).