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 anticancer drug. The process research and development of a threestage 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.

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Therapeutic activity g. per kg. Sulfanilamide Sodium sulfanilamide formaldehyde sulfoxylate 4,4'-Diaminodiphenyl sulfone 4,4'-Diacetyldiaminodiphenyl sulfone Sodium 4,4 '-diaminodiphenyl sulfone Ws-formaldehyde sulfoxylate Sodium 4,4 '-diaminodiphenyl sulfone diformaldehyde bisulfite MTD subcut. (oil) 2.5; orally 2.5 MTD orally 0.15 MTD orally >4.0 MTD subcut. 3.0 MED subcut. 0.5; oral 0.75 Inferior MED 0.025 MED 0.2

Three catalysts were used to promote an imidazolide coupling. These catalysts were 2-hydroxypyridine (HOPy), endo-N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) (both reported for the first time to catalyse this type of reaction), and 1-hydroxybenzotriazole (HOBt). The thermal safety, cost, and catalytic effectiveness of these three catalysts are compared. In addition, kinetic modelling using the Dynochem software was used to optimise the HOBt- and HOPy-catalysed reactions. By use of this simulation method, the optimal reaction conditions, such as catalyst quantity, reaction time, and reaction temperature were predicted. Subsequent experiments confirmed that the predictions were accurate.