5-Fluorouracil Derivatives. I. The Synthesis of 1-Carbamoyl-5-fluorouracils

The toxicity and tumor affinity of 5-fluorouracil (1) have been modified by the introduction of a carbamoyl group. Carbamoylation by three general methods were studied extensively: (i) The reaction of 1 with isocyanate, (ii) the reaction of 1-chloroformyl-5-fluorouracil with amine, and (iii) the reaction of 1 with carbamoyl chloride. These three methods usually give 1 -carbamoyl-5-fluorouracils (2). 3-Carbamoyl-5-fluorouracils were not obtained by any method. The 2 substances take a hydrogen-bonded structure in chloroform, a non hydrogen-bonded structure in DMSO at 80 °C, and mixed structures in DMSO at 25 °C. Thirty-six homologues shown by 2 were prepared all of these compounds showed antitumor activity. Of them, 1-hexylcarbamoyl-5-fluorouracil (HCFU) appeared to be the most promising antitumor agent when administered orally in that HCFU retains well balanced lipo- and hydro-philicity, is stable in acid in the stomach, and moreover, decomposed moderately in a tumor. Isocyanate was obtained from the reaction of amine with trichloromethyl chloroformate (TCF) by simply heating these two reagents in toluene; this offers a convenient new method for synthesizing isocyanate from amine. Several new isocyanate were obtained from amino acids.