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

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

Publikationsverlauf

Eingereicht: 14. März 2024

Angenommen: 10. Oktober 2024

Artikel online veröffentlicht:
28. November 2024

• References

• 1 Wang J, Feng S, Zhang Q. et al. Roles of histone acetyltransferases and deacetylases in the retinal development and diseases. Mol Neurobiol 2023; 60 (04) 2330-2354
• 2 Blixt NC, Faulkner BK, Astleford K. et al. Class II and IV HDACs function as inhibitors of osteoclast differentiation. PLoS One 2017; 12 (09) e0185441
• 3 Gu X, Peng X, Zhang H. et al. Discovery of indole-containing benzamide derivatives as HDAC1 inhibitors with in vitro and in vivo antitumor activities. Pharmaceutical Fronts 2022; 4: e61-e70
• 4 Jiao M, Han B, Gu X. et al. Design, synthesis, and evaluation of benzoheterocyclic-containing derivatives as novel HDAC1 inhibitors. Pharmaceutical Fronts 2022; 4: e22-e29
• 5 König B, Watson PR, Reßing N. et al. Difluoromethyl-1,3,4-oxadiazoles are selective, mechanism-based, and essentially irreversible inhibitors of histone deacetylase 6. J Med Chem 2023; 66 (19) 13821-13837
• 6 Zhang Z, Zhang Q, Zhang H. et al. Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities. Bioorg Chem 2021; 117: 105407
• 7 Xiong K, Zhang H, Du Y, Tian J, Ding S. Identification of HDAC9 as a viable therapeutic target for the treatment of gastric cancer. Exp Mol Med 2019; 51 (08) 1-15
• 8 Gu X, Zhang H, Jiao M. et al. Histone deacetylase 6 inhibitors with blood-brain barrier penetration as a potential strategy for CNS-Disorders therapy. Eur J Med Chem 2022; 229: 114090
• 9 Han B, Wang M, Li J. et al. Perspectives and new aspects of histone deacetylase inhibitors in the therapy of CNS diseases. Eur J Med Chem 2023; 258: 115613
• 10 Liang T, Fang H. Structure, functions and selective inhibitors of HDAC6. Curr Top Med Chem 2018; 18 (28) 2429-2447
• 11 Lee YS, Lim KH, Guo X. et al. The cytoplasmic deacetylase HDAC6 is required for efficient oncogenic tumorigenesis. Cancer Res 2008; 68 (18) 7561-7569
• 12 Zhang X, Yuan Z, Zhang Y. et al. HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell 2007; 27 (02) 197-213
• 13 Kovacs JJ, Murphy PJ, Gaillard S. et al. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell 2005; 18 (05) 601-607
• 14 Li T, Zhang C, Hassan S. et al. Histone deacetylase 6 in cancer. J Hematol Oncol 2018; 11 (01) 111
• 15 LoPresti P. The selective HDAC6 inhibitor ACY-738 impacts memory and disease regulation in an animal model of multiple sclerosis. Front Neurol 2019; 10: 519
• 16 Zanin M, DeBeauchamp J, Vangala G, Webby RJ, Husain M. Histone deacetylase 6 knockout mice exhibit higher susceptibility to influenza a virus infection. Viruses 2020; 12 (07) 728
• 17 Amengual JE, Prabhu SA, Lombardo M. et al. Mechanisms of acquired drug resistance to the HDAC6 selective inhibitor ricolinostat reveals rational drug-drug combination with ibrutinib. Clin Cancer Res 2017; 23 (12) 3084-3096
• 18 Vogl DT, Raje N, Jagannath S. et al. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin Cancer Res 2017; 23 (13) 3307-3315
• 19 Moore N, Min C. Pharmaceutical combinations comprising a histone deacetylase inhibitor and a BCL-2 inhibitor and methods of use thereof. WO Patent 2018085652. May, 2018
• 20 Li J, Zhang Q, Guo Z, Pu Q, Zeng J, Qian H. Sulfhydryl compound as histone deacetylase inhibitor and composition and application in preparing medicine for treating diseases caused by abnormal gene expression thereof [in Chinese]. CN Patent 110885316 A. March, 2020
• 21 Deng Z, Fan W, Liu J. et al. A novel approach to α-arylacetonitrile skeletons via para-selective alkylation of protected anilines. Chemistry 2023; 29 (44) e202300905
• 22 Quayle S, Jones SS, Hideshima T, Anderson KC. Pharmaceutical combinations comprising a histone deacetylase inhibitor and a programmed death-ligand 1 (PD-L1) inhibitor and methods of use thereof. WO Patent 2018098168. May, 2018
• 23 Pozzi S, Cosenza M, Civallero M. Methods of use and pharmaceutical combinations comprising histone deacetylase inhibitors and JAK1/2 inhibitors. WO Patent 2019106633. June, 2019
• 24 Raje N, Santo L. Preparation of hydroxamic acid derivatives as histone deacetylase 6 selective inhibitors for the treatment of bone disease. WO Patent 2013013113. March, 2013
• 25 Lygaitis R, Getautis V, Grazulevicius JV. Hole-transporting hydrazones. Chem Soc Rev 2008; 37 (04) 770-788
• 26 Hassan J, Sévignon M, Gozzi C, Schulz E, Lemaire M. Aryl-aryl bond formation one century after the discovery of the Ullmann reaction. Chem Rev 2002; 102 (05) 1359-1470
• 27 Bariwal J, Van der Eycken E. C-N bond forming cross-coupling reactions: an overview. Chem Soc Rev 2013; 42 (24) 9283-9303
• 28 Ali MH, Buchwald SL. An improved method for the palladium-catalyzed amination of aryl iodides. J Org Chem 2001; 66 (08) 2560-2565
• 29 Li JJ, Wang Z, Mitchell LH. A practical Buchwald-Hartwig amination of 2-bromopyridines with volatile amines. J Org Chem 2007; 72 (09) 3606-3607