1,3-BISALKYLCARBONYL-5-FLUOROURACIL AND 3-ALKYLCARBONYL-5-FLUOROURACIL PRODRUGS - SYNTHESES, THERMAL, AND HYDROLYTIC STABILITY

Four homologous 1,3-bisalkylcarbonyl and the corresponding 3-alkylcarb onyl derivatives of 5-fluorouracil (1, 5-FU) have been synthesized and characterized by H-1 nuclear magnetic resonance, and infrared and ult raviolet spectroscopy. The 1,3-bisacetyl derivative hydrolyzed rapidly in pH 7.1 buffer at 32 degrees C (t(1/2) = 0.8 min) to give the 3-ace tyl derivative. The hydrolyses of 3-acetyl-, 6, and 3-propionyl-5-FU, 7, were much slower (t(1/2) = 200 and 300 min, respectively) and they were biexponential. Both the 1,3- and the 3-derivatives hydrolyzed in the presence of formaldehyde to give significant, and approximately eq ual amounts of 1- and 3-alkylcarbonyloxymethyl-5-FU derivatives, in ad dition to 5-FU, which suggested that for both types of derivatives the hydrolyses of the 3-alkylcarbonyl group went through a symmetrical O- 2-alkylcarbonyl intermediate. The 1,3-derivatives were thermally unsta ble above about 110 degrees C, giving up to about 20% of the correspon ding 1-alkylcarbonyl derivatives at 140 degrees C. On the other hand, the 3-derivatives were thermally unstable even at 95 degrees C, where complete decomposition to 1- and I, 3-derivatives as well as 5-FU was observed.