31P NMR Studies of the Kinetics of Bisalkylation by Isophosphoramide Mustard: Comparisons with Phosphoramide Mustard

Article abstract of DOI:10.1021/jm00128a018

31P nuclear magnetic resonance spectroscopy was used to measure the pK_a (4.28 +/- 0.2) of isophosphoramide mustard (IPM) at 20 deg C and to study the kinetics and products of the decomposition of IPM at a solution pH value of ca. 7.4 and at temperatures between 20 and 47 deg C in the presence of nucleophilic trapping agents.At 37 deg C, the half-life for the first alkylation was ca. 77 min and ca. 171 min for the second alkylation; these data may be compared with those for phosphoramide mustard (Engle, T.W.; Zon, G.; Egan, W.J.Med.Chem. 1982, 25, 1347), wherein the half-lives for the first and second alkylations are approximately the same (18 min).The rate of fragmentation of aldoifosfamide to IPM and acrolein was also studied by NMR spectroscopy (pH 7.0; 37 deg C; 0.07 M phosphate); under the noted conditions, the half-life of aldoifosfamide was fouund to be ca. 60 min.