Synthesis of 15N and 17O labelled phosphoramide mustards

✍ Scribed by Susan M. Ludeman; Ellen M. Shulman-Roskes; Michael P. Gamcsik; Terence G. Hamill; Young H. Chang; Kyo I. Koo; O. Michael Colvin

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: French
• Weight: 564 KB
• Volume: 33
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580330410

✦ Synopsis

Abstract

The cyclophosphamide metabolite phosphoramide mustard (PM) was synthesized with isotopic enrichment at each nitrogen and oxygen site. Sequential reaction of N,N‐bis(2‐chloroethyl)phosphoramidic dichloride [Cl~2~P(O)N(CH~2~CH~2~Cl)~2~] with benzyl alcohol and ammonia gave N,N‐bis(2‐chloroethyl)phosphorodiamidic acid phenylmethyl ester [BzO(H~2~N)P(O)N(CH~2~CH~2~Cl)~2~]. Catalytic hydrogenation of this benzyl ester followed by the addition of cyclohexylamine (CHA) provided PM as the CHA salt. Incorporation of ^15^NH~3~ into this general scheme gave PM with a ^15^NH~2~ moiety. Glycine‐^15^N was converted to bis(2‐chloro‐ethyl)amine‐^15^N hydrochloride which, in turn, provided for N,N‐bis(2‐chloroethyl)phosphoramidic‐^15^N dichloride. Use of this compound in the general synthetic pathway yielded PM°CHA with ^15^N in the mustard moiety. ^17^O‐Enriched PM was generated through the use of benzyl alcohol‐^17^O. To obtain the alcohol, labelled benzaldehyde was made by exchange with ^17^OH~2~ and was then reduced with sodium borohydride.