STRUCTURE OF 3-ACETYL-5-FLUOROURACIL (5-FU) - IMPLICATION FOR ITS REARRANGEMENTS DURING HYDROLYSIS AND UPON HEATING

Single-crystal X-ray diffraction data show that the 3-acetyl group in 1,3-diacetyl-5-FU (FU = fluorouracil) is perpendicular to the plane of the 5-FU ring, while the 1-acetyl group is coplanar with the ring. An alyses of H-1 NMR and IR spectra provide evidence that the 1- and 3-ac yl groups are in different electronic environments, which is consisten t with the X-ray diffraction structure. 3-Acetyl-5-FU is thermally uns table, giving mainly 1-acetyl-5-FU (80%) and 5-FU (20%) upon heating. The hydrolysis of 3-acyl derivatives of 5-FU showed a biexponential re lationship between ln concentration and time which had not been previo usly observed. The behavior of 3-acetyl-5-FU during hydrolysis can be explained by postulating its initial rapid equilibrium with an interme diate, 2-acetyl-5-FU, which subsequently hydrolyzes to 5-FU or rearran ges to 1-acetyl-5-FU, which hydrolyzes to 5-FU. The 2-acetyl intermedi ate was trapped by its reaction with formaldehyde. The formaldehyde ad ducts of the symmetrical 2-acetyl intermediate rearranged to yield equ al amounts of 1- and 3-acetyloxymethyl-5-FU.