ANTINEOPLASTIC AGENTS 389 - NEW SYNTHESES OF THE COMBRETASTATIN A-4 PRODRUG

Combretastatin A-4 (1) as the phosphate eater prodrug (3d) is a potent antineoplastic and antiangiogenesis substance and is in advanced prec linical development. For the purpose of improving the phosphorylation synthetic sequence from combretastatin A-4, new routes were investigat ed. The phosphorylation step was found to be considerably improved usi ng in situ-generated dibenzyl chlorophosphite. Cleavage of the benzyl eaters employing a trimethylchlorosilane/sodium iodide procedure, foll owed by treatment with sodium methoxide, led to the water-soluble prod rug (3d) in high yield.