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Synthesis of 15 N and 17 O labelled phosphoramide mustards
Author(s) -
Ludeman Susan M.,
ShulmanRoskes Ellen M.,
Gamcsik Michael P.,
Hamill Terence G.,
Chang Young H.,
Koo Kyo I.,
Colvin O. Michael
Publication year - 1993
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.2580330410
Subject(s) - chemistry , sodium borohydride , medicinal chemistry , benzyl alcohol , benzaldehyde , moiety , alcohol , hydrochloride , catalysis , ammonia , amine gas treating , nuclear chemistry , organic chemistry
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.