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.

已开发出一种安全且无金属的工艺，以甘氨酸乙酯盐酸盐为原料制备 5-乙酰基-1H-吡唑-3-甲酸乙酯，这是合成潜在重磅药物 darolutamide 的关键中间体。在关键步骤中，就地生成并使用了有毒易爆的中间体重氮乙酸乙酯。针对合成的间歇式和连续流变体优化了反应参数。在下一步中，酯的碱水解生成 5-acetyl-1 H -pyrazole-3-carboxylic acid，它不仅可以用作 darolutamide 中间体，还可以被认为是其他有价值的构建块有机和药物化学转化的类型。