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Synthesis 2023; 55(06): 959-966
DOI: 10.1055/s-0042-1751389
paper

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

Bence Szilágyi
a   Medicinal Chemistry Research Group, Drug Innovation Centre, Research Centre for Natural Sciences, Magyar tudósok krt. 2., 1117 Budapest, Hungary
b   National Laboratory for Drug Research and Development, Magyar tudósok krt. 2., 1117 Budapest, Hungary
,
Attila Egyed
a   Medicinal Chemistry Research Group, Drug Innovation Centre, Research Centre for Natural Sciences, Magyar tudósok krt. 2., 1117 Budapest, Hungary
b   National Laboratory for Drug Research and Development, Magyar tudósok krt. 2., 1117 Budapest, Hungary
,
István Mándity
b   National Laboratory for Drug Research and Development, Magyar tudósok krt. 2., 1117 Budapest, Hungary
c   Artificial Transporters Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2., 1117 Budapest, Hungary
,
Tamás Nagy
d   Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary
,
Katalin Kátai-Fadgyas
d   Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary
,
Balázs Volk  ∗
d   Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary
,
György M. Keserű∗
a   Medicinal Chemistry Research Group, Drug Innovation Centre, Research Centre for Natural Sciences, Magyar tudósok krt. 2., 1117 Budapest, Hungary
b   National Laboratory for Drug Research and Development, Magyar tudósok krt. 2., 1117 Budapest, Hungary
› Author AffiliationsThis 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.
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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 - hydrolysis


Publication History

Received: 01 August 2022

Accepted after revision: 02 November 2022

Article published online:
23 November 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
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