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

Article abstract of DOI:10.1002/jlcr.2580361209

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 LIAlD₄ 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-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 (628 yield). For the hydrate, MS analyses gave an average mole percent enrichment (with average deviation over 5 determinations) of 89.1 ± 0.5% d₄.