Synthesis of Potential Dual Antagonists IV.

Synthesis of bis(aziridinyl)phosphinyl-N-hydroxyurethane derivatives as antineoplastic agents

“…IV-[Bis(2,2-dimethyl-l-aziridinyl)phosphinyl]-0-acetyl-jVhydroxyurethane (5). The procedure is the same as described in the synthesis of 3, except that the reaction was conducted at -15 to -10°, and ether was used as solvent.…”

“…To test this hypothesis, we synthesized a new series of "dual antagonists" (3)(4)(5)(6) in which the bifunctional alkylating moieties were linked to A^-hydroxyurethane rather than urethane. Presumably, these compounds would release on hydrolysis directly N-hydroxyurethane rather than urethane and, therefore, may prove to be more effective antitumor agents when compared to the previously studied series in the absence of X-irradiation.…”

“…In contrast, the rate of hydrolysis of 6 is significantly faster than those of other ring-C -unsubstituted aziridines [e.g., 2 or 4); the shift of the nmr peak corresponding to the acetyl protons (<3 2.21) indicates that the acetyl group is rapidly hydrolyzed, and this may promote the ring-opening hydrolysis of the aziridine rings (see above). All four compounds (3)(4)(5)(6) yield N-hydroxyurethane as one of their hydrolysis products which can be extracted from the aqueous mixture with ether in pure form. However, only 23-42% of the theoretical amount of ¿V-hydroxyurethane can be recovered in this manner even after complete hydrolysis.…”