Synthesis of 1-(hydroxyalkoxy)pyrimidines, a novel series of acyclic nucleoside analogues

Abstract

Syntheses of 1-(3-hydroxypropoxy), 1-[3-hydroxy-2-(hydroxymethyl)propoxy], 1-(2,3-dihydroxypropoxy), and 1-(3,4-dihydroxybutoxy) derivatives of thymine (1a–d) and uracil (2a–d) are described. These acyclonucleosides were obtained by cyclisation of appropriately functionalised ureas with either ethyl 3,3-diethoxy-2-methylpropionate (4) or methyl 3,3-dimethoxypropionate (5). The uracils (2a–d) were converted into cytosine analogues (3a–d)via intermediate 4-(1,2,4-triazol-1-yl) derivatives. (E)-5-(2-Bromovinyl)(36) and 5-vinyl (37) analogues of (2a) were prepared by palladium(II)-catalysed cross-coupling reactions on the 5-iodo derivative (32). The 5-fluoro-1-(hydroxyalkoxy)uracils (41) and (42) were obtained by alkylation of 5-fluoro-1-hydroxyuracil with a suitably functionalised halide. None of this series of acyclonucleosides showed activity in antiviral tests in cell cultures.