Synthesis of 3-Hydroxycyclophosphamide and Studies Related to Its Possible Role in the Metabolism of Cyclophosphamide

Article abstract of DOI:10.1021/jm00144a007

Hydrogenolysis of 3-(benzyloxy)cyclophosphamide (10) using Pd/C catalyst and ethyl acetate as solvent leads to the formation of 3-hydroxycyclophosphamide (3, ca. 20percent) and cyclophosphamide (1, ca. 10percent), accompanied by regioselective hydrogen-exchange reactions at the C-4 and C-5 positions in 3 and 1.A variety of oxidizing reagents and liver microsomal incubation failed to provide evidence (31P NMR) for conversion of 1 into 3, whereas identical incubation of 3 led to its reduction to 1.Compound 3 is stable at pH 6.5-8.2, 37 deg C, and exhibits anticancer activity comparable to 1 when tested against L1210 leukemia in mice.Data are discussed with regard to a previously reported suggestion that metabolism of 1 may involve oxidation to give 3 followed by rearrangement of 3 to 2.