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CC BY 4.0 · Pharmaceutical Fronts 2024; 06(04): e430-e438
DOI: 10.1055/s-0044-1792125
Original Article

An Improved Synthesis Process of Ricolinostat: The First Orally Selective HDAC6 Inhibitor

Mengfei Wang
1   Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
3   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
,
Niubing Sun
1   Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
4   School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
,
Qiushi Chen
1   Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
3   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
,
Qingwei Zhang
1   Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
3   Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, People's Republic of China
› Author Affiliations Funding This work was supported by the National Science and Technology Major Project (Grant No. 2018ZX09711002-002-009), the National Natural Science Foundation of China (Grant No. 81703358), the Science and Technology Commission of Shanghai Municipality (Grant Nos. 17431903900, 18QB1404200, 21S11908000, 22ZR1460300, 23DZ2292600), and the National Key Laboratory of Lead Druggability Research (Grant No. NKLYT2023001).
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Abstract

Ricolinostat (1) is the first orally available histone deacetylase 6 inhibitor in phase II clinical trials. The results from phase II clinical studies showed that the combination of Ricolinostat with bortezomib and dexamethasone is safe and active for the treatment of multiple myeloma. However, the reported synthesis routes of Ricolinostat were plagued by several limitations, including severe reaction conditions, elevated cost factors, and the employment of environmentally unfriendly reagents. This study aimed to improve the synthesis process of Ricolinostat, in which ethyl 2-chloropyrimidine-5-carboxylate (2) was used as the starting material, the target product was obtained through the reaction of nucleophilic aromatic substitution, the Ullmann coupling, hydrolyzation amide condensation, and aminolysis. The nucleophilic substitution (2 to 3) was performed in the presence of 1.2 equiv. aniline, 2.0 equiv. K2CO3 under 100°C, with a yield of 96%; the Ullmann reaction was performed in the presence of 0.5 equiv. CuI and 2.0 equiv. cesium carbonate; the post-processes of 3 and the desired product (1) that previously required column chromatography were replaced with recrystallization using the solvent of EtOH/H2O and DMF/H2O, respectively. Through the improved process, Ricolinostat was obtained with an isolated yield of 65.8% and a purity of 99.73%, which was much higher than the reported study. This route was both cost-effective and eco-friendly, making it suitable for industrial applications.

Keywords

ricolinostat - synthesis process - recrystallization - Ullmann reaction

Supplementary Material



Publication History

Received: 14 March 2024

Accepted: 10 October 2024

Article published online:
28 November 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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