Safe and Efficient Continuous-Flow Synthesis and Batchwise Hydrolysis of Ethyl 5-Acetyl-1H -pyrazole-3-carboxylate: A Key Synthon of Darolutamide

A safe and metal-free process using ethyl glycinate hydro-chloride as the starting material has been developed for the preparationof ethyl 5-acetyl-1H-pyrazole-3-carboxylate, a key intermediate for thesynthesis of potential blockbuster drug substance darolutamide. In thekey step, the toxic and explosive intermediate, ethyl diazoacetate wasgenerated and used in situ. Reaction parameters were optimized forboth the batchwise and the continuous-flow variant of the synthesis. Inthe next step, alkaline hydrolysis of the ester led to 5-acetyl-1H-pyra-zole-3-carboxylic acid, which can not only be used as a darolutamide in-termediate, but it can also be considered as a valuable building block forother types of organic and medicinal chemistry transformations