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

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.