Tazemetostat

Tazemetostat (EPZ-6438) is a potent, selective and orally available EZH2 inhibitor with Ki and IC50 of 2.5 and 11 nM, respectively.

Step 7:[0336] Step 7: Synthesis of N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-5- (ethyl (tetrahydro-2H-pyran-4-yl) amino)-4-methyl-4'-(morpholinomethyl)-[l, l'-biphenyl]-3- carboxamide [0337] To a stirred solution of 5-bromo-N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/ water mixture (70 mL/14 mL) was added 4-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzyl) morpholine (13.4 g, 44.2 mmol) followed by addition of NaN - [(4, 6- dimethyl-2-carboxy-1, 2-dihydro-3-pyridyl) methyl] -2-methyl-3- [ethyl (tetrahydro -2H- 4- pyran-yl) amino] -5-carboxamide bromobenzene (14g, 29.5mmol) was dissolved in dioxane / water mixture (70mL /14mL), added with stirring 4- (4-morpholino-methyl) phenylboronic acid pinacol ester (13.4g, 44.2mmol), followed by the addition of sodium carbonate (11.2g, 105.7mmol). Solution was purged with argon for 15min, then add tetrakis (triphenylphosphine) palladium (3.40g, 2.94mmol), a solution of purified argon and then 10min. The reaction mixture was heated to 100 reaction 4h. Tracking progress of the reaction TLC, eluent: methanol / dichloromethane (1:10), add water, 50mL, methanol / dichloromethane: extraction (19). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on silica gel column, eluent: methanol / dichloromethane (1:10) to give a solid product 12g, Yield 71percentN-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-4-methyl-4 '-(morpholinomethyl)- [1, 1 '-biphenyl] -3-carboxamide (Compound I)Step 7:[0336] Step 7: Synthesis of N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-5- (ethyl (tetrahydro-2H-pyran-4-yl) amino)-4-methyl-4'-(morpholinomethyl)-[l, l'-biphenyl]-3- carboxamide [0337] To a stirred solution of 5-bromo-N-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl) methyl)-3-(ethyl (tetrahydro-2H-pyran-4-yl) amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/ water mixture (70 mL/14 mL) was added 4-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzyl) morpholine (13.4 g, 44.2 mmol) followed by addition of NaN - [(4, 6- dimethyl-2-carboxy-1, 2-dihydro-3-pyridyl) methyl] -2-methyl-3- [ethyl (tetrahydro -2H- 4- pyran-yl) amino] -5-carboxamide bromobenzene (14g, 29.5mmol) was dissolved in dioxane / water mixture (70mL /14mL), added with stirring 4- (4-morpholino-methyl) phenylboronic acid pinacol ester (13.4g, 44.2mmol), followed by the addition of sodium carbonate (11.2g, 105.7mmol). Solution was purged with argon for 15min, then add tetrakis (triphenylphosphine) palladium (3.40g, 2.94mmol), a solution of purified argon and then 10min. The reaction mixture was heated to 100 reaction 4h. Tracking progress of the reaction TLC, eluent: methanol / dichloromethane (1:10), add water, 50mL, methanol / dichloromethane: extraction (19). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on silica gel column, eluent: methanol / dichloromethane (1:10) to give a solid product 12g, Yield 71percentN-((4, 6-dimethyl-2-oxo-l, 2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H- pyran-4-yl)amino)-4-methyl-4 '-(morpholinomethyl)- [1, 1 '-biphenyl] -3-carboxamide (Compound I)