The preparation of some potentially polymerizable derivatives of uracil and 5-fluorouracil

Abstract

Potentially polymerizable derivatives of uracil and 5-fluorouracil were prepared using various isocyanates. These derivatives may, at some later date, find applications as antineoplastic, polymeric drugs with reduced toxic side effects. The products prepared in the reactions were: 1) 5-fluoro-N1 (N-ethylcarbamoyl) uracil; 2) 5-fluoro-N1(N-allylcarbamoyl)uracil; 3) 5-fluoro-N1 (N-isopropylidenecarbamoyl) uracil; 4) 5-fluoro-N1 (N-vinylcarbamoyl) uracil; 5) N1 (N-ethylcarbamoyl) uracil and 6) N1 (N-vinylcarbamoyl) uracil. These compounds were all soluble in boiling chloroform. The assigned structures are supported by elemental analyses and infrared spectroscopy. They all showed amide III Bands at 1300cm-1 and double bonds in the 895-945 cm-1 region as would be expected for these structures. These compounds are the first reported 5-fluorouracil monomers.

While 5-fluorouracil reacted readily in benzene with all of the isocyanates used in this study, uracil reacted readily only with vinyl isocyanate. It was also found that a catalyst, triethylamine, was necessary for the reaction to proceed in all cases. Several factors are believed to be responsible for this phenomenon and these include : 1)solvent polarity; 2)pKa (acidity); 3) conjugation and 4) steric factors. The fact that uracil reacted well only with the vinyl isocyanate in the non polar solvent, benzene, while it reacted with ethyl isocyanate and other isocyanates in the more polar solvent, dimethylsulfoxide, supports the presence of solvent effects in this reaction. The fact that 5-fluorouracil, with the lower pKa and hence more acidic nature, reacts better with all isocyanates than does uracil supports the possibility of pKa effects. Since uracil reacts readily with vinyl isocyanate in the non polar solvent, benzene, conjugation appears to have an important effect on this reaction. The fact that isopropylidene isocyanate, which is also conjugated,did not react readily with uracil and also produced the lowest yield in reaction with 5-Fluorouracil supports the hypothesis that steric factors are important in this reaction. The vinylcarbamoyl derivative of 5-fluorouracil appears to polymerize when treated with boiling chloroform. The material becomes insoluble and the IR spectrum showed the disappearance of the peak at 1540 cm-1 which was presumed due to a carbon-carbon double bond. Further studies are necessary.

Isopropylidene isocyanate was prepared for the first time and its structure was substantiated by its IR spectrum and its chemical reactions.

Some polymerization reactions have been run on the isopropylidene isocyanate derivative of 50fluorouracil and the vinyl derivative of uracil, but no polymer properties were studied.