1-Alkylcarbonyl-5-fluorouracil Prodrugs: Synthesis, Thermal and Hydrolytic Stability

Abstract

Six homologous 1 -alkylcarbonyl derivatives of 5-fluorouracil (5-FU) have been synthesized and characterized by ¹H NMR, infrared and UV spectroscopy. The derivatives were found to hydrolyze rapidly in pH 7.1 buffer at 32°C (t_1/2 = 3-5 min). Although the hydrolysis was found to be catalyzed by hydrated formaldehyde, only 5-FU was observed as a product of the hydrolysis: no 1- or 3-alkylcarbonyloxymethyl products were observed. The 1 -alkylcarbonyl derivatives were recovered intact upon heating at 145°C for 1 h, but, upon heating at 205°C for 1 h, 25% of the sample decomposed to 5-FU with the assumed loss of ketene. The 1-alkylcarbonyl derivatives were stable when stored in a desiccator but decomposed to carboxylic acid and 5-FU upon exposure to atmospheric moisture.