Latent inhibitors part 11. The synthesis of 5-spirocyclopropyl dihydroorotic acid

Approaches to the synthesis of 5-spirocyclopropyldihydroorotic acid are described. Difficulties were encountered in the lack of reactivity of diethyl 2-oxobutandicarboxylate and its derivatives towards cyclopropanation. Potential intermediates were prepared from ethyl 4-acetoxy-3-oxobutanoate but rearrangements involving ring expansion of the cyclopropane ring and hindrance towards condensation reactions of the ketone prevented formation of the pyrimidine. A successful route involving Strecker synthesis of a precursor aminoacid from ethyl 1-formyl-cyclopropane-1-carboxylate in which the formyl group was converted into the corresponding the urea led to the target compound.