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

✍ Scribed by Shawn P. Walsh; Ellen M. Shulman-Roskes; Lawrence W. Anderson; Young H. Chang; Susan M. Ludeman

• Book ID: 102372161
• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: French
• Weight: 251 KB
• Volume: 36
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580361209

✦ Synopsis

Abstract

3‐Hydroxypropionitrile was subjected to a base‐catalyzed exchange reaction in D~2~O which provided 2,2‐dideuterio‐3‐deuteroxypropionitrile (DOCH~2~CD~2~CN) in 70% yield. Reduction of the nitrile with LiAlD~4~ gave 3‐amino‐2,2,3,3‐tetradeuteriopropan‐1‐o1 (HOCH~2~CD~2~CD~2~NH~2~) in a crude yield of 71%. Reaction of this intermediate with N,N‐bis(2‐chloroethyl)phosphoramidic dichloride [Cl~2~P(O)N(CH~2~CH~2~Cl)~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 ± 0.5% d~4~.