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 dihydrop yrimidine dehydrogenase, which is the rate-limiting enzyme in the metabolis m of 5-fluorouracil, a widely used anticancer drug. The process research an d development of a three-stage route to eniluracil is described. A Sonogash ira coupling between 5-iodouracil and trimethylsilylacetylene was used to s ynthesise 5-(2-trimethylsilylethynyl)uracil on a >60 kg scale. Sodium hydro xide deprotection and acidification with acetic acid completed the synthesi s of eniluracil in high yield and quality. The optimisation of this process is described with particular attention paid to minimising the input of pal ladium and copper catalysts and ensuring that the copper catalyst is well s uspended in the reaction mixture.