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

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