A Facile Total Synthesis of Kilogram-Scale Production of SKLB1039: A Novel and Selective Hexahydroisoquinolin-Containing EZH2 Inhibitor

Background: SKLB1039 is a potent, highly selective, and orally bioavailable EZH2 inhibitor, which significantly inhibited breast tumor growth and metastasis in pre-clinical studies. In a previously reported synthesis of SKLB1039, the yields of several steps were low, which led to an overall yield of less than 10%. In addition, flash chromatography was required for the purification of several intermediates using this route. Objective: To optimize the synthesis and establish an efficient commercial-scale method for the production of SKLB1039. Methods: The reaction time, solvent, reactant ratio, temperature, and mode of addition of reactants in the reductive amination, hydrolysis, hexahydroisoquinoline formation, hydrogenolysis, condensation and Suzuki crosscoupling reactions were optimized. Results: A chromatography-free seven-step process starting from a commercially available material was developed that afforded SKLB1039 in 36% overall yield with > 99% purity. Conclusion: A cost-effective, high-yielding, and convergent kilo-scale synthesis for the EZH2 inhibitor SKLB1039 was developed. The operation was simple, and the pure product was easily obtained without column chromatography. This method will be economical and convenient for the subsequent industrial scale-up production of SKLB1039, which will be conducive for this promising EZH2 inhibitor to enter clinical studies of its antitumor effects.