SYNTHESIS, BASE-CATALYZED HYDROLYTIC REACTIVITY, AND ANTI-CANCER EVALUATION OF O-ARYL PHOSPHORODIAMIDATES AS A NOVEL CLASS OF PRO(PHOSPHORODIAMIDIC ACID MUSTARDS)

Bis(2-chloroethyl)phosphoramidic dichloride [MP(O)Cl2, M = N(CH2CH2Cl)2] has been used as the starting material for the synthesis of O-aryl phosphorodiamidates having the general structure MP(O)(NHR)OAr: 9, R = H, Ar = 4-NO2C6H4; 10, R = H, Ar = C6F5; 11, R = C6H6, Ar = C6F5; 12, R = 4-MeC6H4, Ar = C6F5; and 13, R = 4-EtOC6H4, Ar = C6F5. The phosphorodiamidic chloride precursor to i3 (14) was also isolated. Kinetics for the base-catalyzed hydrolysis of compounds 9-13 were investigated by UV and NMR methods and are considered in connection with service of these compounds as pro(phosphorodiamidic acid mustards) [MP(O)(NHR)OAr → MP(O)(NHR)OH] via an ElcB mechanism involving the intermediacy of a mustard-bearing metaphosphorodiimide [MP(O)=NR]. Anticancer screening tests against L1210 lymphoid leukemia in mice indicated that 9-14 are inactive; similar negative results were obtained with the KB cell culture, except in the case of 14 which was marginally active. © 1979, American Chemical Society. All rights reserved.