Studies of antitumor-active 5-fluorouracil derivatives. I. Synthesis of N-phthalidyl 5-fluorouracil derivatives.

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Abstract
Several 5-fluorouracil derivatives in which the phthalidyl (1,3-dihydro-3-oxoisobenzofuran-1-yl) group, appropriately substituted on its benzene ring, is substituted at the N(1)- or N(3)-position or at both positions were synthesized, and their antitumor activities were evaluated. Among these compounds, 1-(1,3-dihydro-3-oxoisobenzofuran-1-yl)-5-fluorouracil (3a, 590-S) was shown to be markedly active against several experimental tumor systems. Several methods for a simple and efficient large-scale preparation of 3a were examined. The large-scale preparation of 3a was effected most efficiently by the condensation of 5-fluorouracil with the quaternary ammonium salt of 3-bromophthalide in the presence of a base. The synthesis of (+)- and (-)-3a is also described.