* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium carbonate In 1,4-dioxane; water; acetonitrile at 100℃; for 4 h; Inert atmosphere
Step 7: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-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-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by addition of Na2CO3 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh3)4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100° C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10percent MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71percent). Analytical Data: LCMS: 573.35 (M+1)+; HPLC: 99.5percent ( 254 nm) (Rt; 3.999; Method: Column: YMC ODS-A 150 mm*4.6 mm*5μ; Mobile Phase: A; 0.05percent TFA in water/B; 0.05percent TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5percent B to 95percent B in 8 min, Hold for 1.5 min, 9.51-12 min 5percent B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8 Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
71%
Stage #1: With sodium carbonate In 1,4-dioxane; water for 0.25 h; Inert atmosphere Stage #2: With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane at 100℃; for 4.2 h; Inert atmosphere
[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 Na2C03 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh )4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100°C for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10percent MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100- 200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71 percent). Analytical Data: LCMS: 573.35 (M + 1)+; HPLC: 99.5percent ( 254 nm) (R,;3.999; Method: Column: YMC ODS-A 150 mm x 4.6 mm x 5 μ; Mobile Phase: A; 0.05percent TFA in water/ B; 0.05percent TFA in acetonitrile; Inj. Vol: 10 μ, Col. Temp.: 30 °C; Flow rate: 1.4 mL/min.; Gradient: 5percent B to 95percent B in 8 min, Hold for 1.5 min, 9.51-12 min 5percent B); 1H NMR (DMSO-J6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
71%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 100℃; for 4 h; Inert atmosphere
N - [(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 71percent
Reference：
[1] Patent: US2012/264734, 2012, A1, . Location in patent: Page/Page column 128
[2] Patent: WO2013/155464, 2013, A1, . Location in patent: Paragraph 0336; 0337
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1556 - 1564
[4] Patent: CN105440023, 2016, A, . Location in patent: Paragraph 0090; 0091; 0092
2
[ 1173081-96-3 ]
[ 1403254-99-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: With triethylamine In dimethyl sulfoxide at 15 - 25℃; for 0.5 h; Stage #2: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dimethyl sulfoxide at 20℃; for 16 h; Stage #3: With triethylamine In water; dimethyl sulfoxide at 19 - 30℃; for 4 h;
N-((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) A mixture of 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'- (morpho linomethyl)-[ 1,1 '-biphenyl] -3 -carboxylic acid (540 g, 1.23 mol) and 3-(aminomethyl)- 4,6-dimethyl-dihydro-pyridin-2(lH)-one hydrochloride (279 g, 1.48 mol) was suspended in DMSO (2.70 L) and treated with triethylamine (223 ml, 1.60 mol). The mixture was stirred at 25 °C for 30 min and treated with EDC-HC1 (354 g, 1.85 mol) and HOBT hydrate (283 g, 1.85 mol). The reaction mixture was stirred at rt for 16 h. After addition of triethylamine (292 ml, 2.09 mol), the mixture was cooled to 15 °C, diluted with water (10.1 L) maintaining the temperature below 30 °C, and stirred at 19-25 °C for 4 h. The resulting precipitate was filtered, washed twice with water (2.70 L), and dried under vacuum to give a crude product (695 g, wt-wt analysis = 78percent). For the further purification of the product, recrystallization was conducted. A crude product (20.00 g, 34.92 mmol) was suspended in a mixture of ethanol (190 ml) and water (10.00 ml) and heated to 75°C until a clear solution was obtained. The solution was allowed to cool to rt overnight. The precipitate was filtered, washed twice with a mixture of ethanol (30.0 ml) and water (30.0 ml), and dried under vacuum at 35 °C to give the title compound as an off white solid (14.0 g, 70percent recovery from the crude and 90percent> yield based on wt-wt assay).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; acetonitrile; at 100℃; for 4h;Inert atmosphere;
Step 7: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide To a stirred solution of <strong>[1403257-80-6]5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide</strong> (14 g, 29.5 mmol) in dioxane/water mixture (70 mL/14 mL) was added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by addition of Na2CO3 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh3)4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100 C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71%). Analytical Data: LCMS: 573.35 (M+1)+; HPLC: 99.5% ( 254 nm) (Rt; 3.999; Method: Column: YMC ODS-A 150 mm*4.6 mm*5mu; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 muL, Col. Temp.: 30 C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) delta 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8 Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
71%
[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 Na2C03 (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh )4 (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100C for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100- 200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71 %). Analytical Data: LCMS: 573.35 (M + 1)+; HPLC: 99.5% ( 254 nm) (R,;3.999; Method: Column: YMC ODS-A 150 mm x 4.6 mm x 5 mu; Mobile Phase: A; 0.05% TFA in water/ B; 0.05% TFA in acetonitrile; Inj. Vol: 10 mu, Col. Temp.: 30 C; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-J6, 400 MHz) delta 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
71%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere;
N - [(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 71%
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