Scientific Publications by FDA Staff
J Labelled Compd Rad 1995 Dec;36(12):1193-8
Synthesis of cyclophosphamide-4,4,5,5-d4
Walsh SP, Shulman-Roskes EM, Anderson LW, Chang YH, Ludeman SM
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-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.
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|Entry Created: 2012-12-25|