Process Research and Development of a Dihydropyrimidine Dehydrogenase Inactivator:  Large-Scale Preparation of Eniluracil Using a Sonogashira Coupling

Eniluracil (5-ethynyluracil) is a potent inactivator of the enzyme dihydropyrimidine dehydrogenase, which is the rate-limiting enzyme in the metabolism of 5-fluorouracil, a widely used anti-cancer drug. The process research and development of a three-stage route to eniluracil is described. A Sonogashira coupling between 5-iodouracil and trimethylsilylacetylene was used to synthesise 5-(2-trimethylsilylethynyl)uracil on a >60 kg scale. Sodium hydroxide deprotection and acidification with acetic acid completed the synthesis of eniluracil in high yield and quality. The optimisation of this process is described with particular attention paid to minimising the input of palladium and copper catalysts and ensuring that the copper catalyst is well suspended in the reaction mixture.