1-ALKYLCARBONYL-5-FLUOROURACIL PRODRUGS - SYNTHESIS, THERMAL AND HYDROLYTIC STABILITY

Six homologous 1-alkylcarbonyl derivatives of 5-fluorouracil (5-FU) ha ve been synthesized and characterized by H-1 MMR, infrared and UV spec troscopy. The derivatives were found to hydrolyze rapidly in pH 7.1 bu ffer at 32 degrees C (t(1/2) = 3-5 min). Although the hydrolysis was f ound to be catalyzed by hydrated formaldehyde, only 5-FU was observed as a product of the hydrolysis: no 1- or 3-alkylcarbonyl-oxymethyl pro ducts were observed. The 1-alkylcarbonyl derivatives were recovered in tact upon heating at 145 degrees C for 1 h, but, upon heating at 205 d egrees C for 1 h, 25% of the sample decomposed to 5-FU with the assume d loss of ketene. The 2-alkylcarbonyl derivatives were stable when sto red in a desiccator but decomposed to carboxylic acid and 5-FU upon ex posure to atmospheric moisture.