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DOI: 10.1055/s-0042-1751389
Safe and Efficient Continuous-Flow Synthesis and Batchwise Hydrolysis of Ethyl 5-Acetyl-1H-pyrazole-3-carboxylate: A Key Synthon of Darolutamide
This project was supported by National Research, Development and Innovation (NRDI) Office (2020-1.1.2-PIACI-KFI-2020-00039). The work reported here was a validation study for the PharmaLab project (RRF-2.3.1-21-2022-00015) sponsored by NRDI Office.
Dedicated to the memory of late Professor Ferenc Fülöp (1952–2021)
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.
Key words
active pharmaceutical ingredient - key intermediate - cycloaddition - flow chemistry - hydrolysisPublication History
Received: 01 August 2022
Accepted after revision: 02 November 2022
Article published online:
23 November 2022
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