3,3,3-trifluoro-N-(4-sulfanylphenyl)propanamide

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) were charged to a flask. Concentrated HCl (22.5 mL) was slowly added to keep the temperature below 30° C. The reaction was then heated to 50° C. for 17.5 h. The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) was added. The slurry was filtered and the filter cake was washed with H2O (3×35 mL). The solid was dried under vacuum to produce the desired compound (19.9 g, 58%). the temperature below 30° C The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C Cool the reaction to room temperature The slurry was filtered the filter cake was washed with H2O (3×35 mL) The solid was dried under vacuum

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) were charged to a flask. Concentrated HCl (22.5 mL) was slowly added to keep the temperature below 30° C. The reaction was then heated to 50° C. for 17.5 h. The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) was added. The slurry was filtered and the filter cake was washed with H2O (3×35 mL). The solid was dried under vacuum to produce the desired compound (19.9 g, 58%). the temperature below 30° C The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C Cool the reaction to room temperature The slurry was filtered the filter cake was washed with H2O (3×35 mL) The solid was dried under vacuum

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An slurry of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (61 g, 170 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mL) was heated to reflux for 1.5 hours. During this time, the slurry transforms from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0° C. and stirred at this temperature for 15 min. Filtered and washed with cold CH3CN (650 mL). The resulting solid was dried for 20 hours at 38° C. under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3 (sat) (1300 mL). The mixture was stirred until no more solid remained. Then, the layers were separated and washed the aqueous with EtOAc (390 mL). The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to minimal volume on rotavap. The resulting mixture was re-crystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%) 1H NMR (MeOD, 400 MHz): 0.40-0.45 (2H, m), 0.60-0.65 (2H, m), 1.3-1.4 (1H, m), 2.05 (2H, s), 3.25-3.40 (2H, m), 3.85-3.40 (4H, m), 5.40-5.50 (2H, m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+ 522. to reflux for 1.5 hours Filtered washed with cold CH3CN (650 mL) The resulting solid was dried for 20 hours at 38° C. under house vacuum The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3 (sat) (1300 mL) The mixture was stirred until no more solid Then, the layers were separated washed the aqueous with EtOAc (390 mL) The combined organic layers were dried over MgSO4 filtered washed with EtOAc (130 mL) concentrated to minimal volume on rotavap The resulting mixture was re-crystallized out of EtOAc and hexane

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) are charged to a flask. Concentrated HCl (22.5 mL) is slowly added to keep the temp below 30° C. The reaction is then heated to 50° C. for 17.5 h. The reaction mixture is reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) is added. The slurry is filtered and the filter cake is washed with H2O (3×35 mL). The solid is dried under vacuum to produce the desired compound (19.9 g, 58%). the temp below 30° C The reaction mixture is reduced to 41 mL by vacuum distillation at 50° C Cool the reaction to room temperature The slurry is filtered the filter cake is washed with H2O (3×35 mL) The solid is dried under vacuum

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A slurry of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (61 g, 170 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mL) was heated to reflux for 1.5 hours. During this time, the slurry transformed from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0° C. and stirred at this temperature for 15 min. The mixture was then filtered and washed with cold CH3CN (650 mL). The resulting solid was dried for 20 hours at 38° C. under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3(sat) (1300 mL). The mixture was stirred until no more solid remained. Then, the aqueous and organic layers were separated and the aqueous layer was washed with EtOAc (390 mL). The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to a minimal volume on rotavap. The resulting mixture was re-crystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%) 1H NMR (MeOD, 400 MHz): 0.40-0.45 (2H, m), 0.60-0.65 (2H, m), 1.3-1.4 (1H, m), 2.05 (2H, s), 3.25-3.40 (2H, m), 3.85-3.40 (4H, m), 5.40-5.50 (2H, m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+ 522. to reflux for 1.5 hours The mixture was then filtered washed with cold CH3CN (650 mL) The resulting solid was dried for 20 hours at 38° C. under house vacuum The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3(sat) (1300 mL) The mixture was stirred until no more solid Then, the aqueous and organic layers were separated the aqueous layer was washed with EtOAc (390 mL) The combined organic layers were dried over MgSO4 filtered washed with EtOAc (130 mL) concentrated to a minimal volume on rotavap The resulting mixture was re-crystallized out of EtOAc and hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-5-fluoro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (64 mg, 0.17 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (47 mg, 0.20 mmol) in DMF (3 ml) was heated to 80° C. and stirred for 6 hrs. The reaction was diluted with ethylacetate (20 ml) and Sat. NaHCO3 (20 ml) and the organic layer washed with brine (20 ml), dried (Na2SO4) and concentrated to give an oil. Compound was purified by mass directed preparative HPLC, eluted with acetonitrile/water/TFA to give the title compound as a white solid (TFA salt, 41.2 mg, 37%). 1H NMR (DMSO, 400 MHz) 0.46-0.50 (2H, m), 0.61-0.64 (2H, m), 1.38-1.45 (1H, m), 1.93 (3H, s), 3.55 (2H, q), 4.00-4.18 (4H, m), 5.27 (1H, s), 7.54 (2H, d), 7.71 (2H, d), 9.39 (1H, s), 10.57 (1H, s). ES+ 540. the organic layer washed with brine (20 ml) dried (Na2SO4) concentrated to give an oil Compound was purified by mass eluted with acetonitrile/water/TFA

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-5-fluoro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (64 mg, 0.17 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (47 mg, 0.20 mmol) in DMF (3 ml) was heated to 80° C. and stirred for 6 hrs. The reaction was diluted with ethylacetate (20 ml) and Sat. NaHCO3 (20 ml) and the organic layer washed with brine (20 ml), dried (Na2SO4) and concentrated to give an oil. Compound was purified by mass directed preparative HPLC, eluted with acetonitrile/water/TFA to give the title compound as a white solid (TFA salt, 41.2 mg, 37%). 1H NMR (DMSO, 400 MHz) 0.46-0.50 (2H, m), 0.61-0.64 (2H, m), 1.38-1.45 (1H, m), 1.93 (3H, s), 3.55 (2H, q), 4.00-4.18 (4H, m), 5.27 (1H, s), 7.54 (2H, d), 7.71 (2H, d), 9.39 (1H, s), 10.57 (1H, s). ES+ 540. the organic layer washed with brine (20 ml) dried (Na2SO4) concentrated to give an oil Compound was purified by mass eluted with acetonitrile/water/TFA

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) were charged to a flask. Concentrated HCl (22.5 mL) was slowly added to keep the temperature below 30° C. The reaction was then heated to 50° C. for 17.5 h. The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) was added. The slurry was filtered and the filter cake washed with H2O (3×35 mL). The solid was dried under vacuum to produce the desired compound (19.9 g, 58%). the temperature below 30° C The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C Cool the reaction to room temperature The slurry was filtered the filter cake washed with H2O (3×35 mL) The solid was dried under vacuum

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) were charged to a flask. Concentrated HCl (22.5 mL) was slowly added to keep the temperature below 30° C. The reaction was then heated to 50° C. for 17.5 h. The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) was added. The slurry was filtered and the filter cake washed with H2O (3×35 mL). The solid was dried under vacuum to produce the desired compound (19.9 g, 58%). the temperature below 30° C The reaction mixture was reduced to 41 mL by vacuum distillation at 50° C Cool the reaction to room temperature The slurry was filtered the filter cake washed with H2O (3×35 mL) The solid was dried under vacuum

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An slurry of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (61 g, 170 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mL) was heated to reflux for 1.5 hours. During this time, the slurry transforms from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0° C. and stirred at this temperature for 15 min. Filtered and washed with cold CH3CN (650 mL). The resulting solid was dried for 20 hours at 38° C. under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3 (sat) (1300 mL). The mixture was stirred until no more solid remained. Then, the layers were separated and washed the aqueous with EtOAc (390 mL). The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to minimal volume on rotavap. The resulting mixture was re-crystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%) 1H NMR (MeOD, 400 MHz): 0.40-0.45 (2H, m), 0.60-0.65 (2H, m), 1.3-1.4 (1H, m), 2.05 (2H, s), 3.25-3.40 (2H, m), 3.85-3.40 (4H, m), 5.40-5.50 (2H, m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+ 522. to reflux for 1.5 hours Filtered washed with cold CH3CN (650 mL) The resulting solid was dried for 20 hours at 38° C. under house vacuum The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3 (sat) (1300 mL) The mixture was stirred until no more solid Then, the layers were separated washed the aqueous with EtOAc (390 mL) The combined organic layers were dried over MgSO4 filtered washed with EtOAc (130 mL) concentrated to minimal volume on rotavap The resulting mixture was re-crystallized out of EtOAc and hexane

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: S-4-(3,3,3-trifluoropropanamido)phenyl 3,3,3-trifluoropropanethioate (44.8 g, 189 mmol) and EtOH (70 mL) are charged to a flask. Concentrated HCl (22.5 mL) is slowly added to keep the temp below 30° C. The reaction is then heated to 50° C. for 17.5 h. The reaction mixture is reduced to 41 mL by vacuum distillation at 50° C. Cool the reaction to room temperature and H2O (51 mL) is added. The slurry is filtered and the filter cake is washed with H2O (3×35 mL). The solid is dried under vacuum to produce the desired compound (19.9 g, 58%). the temp below 30° C The reaction mixture is reduced to 41 mL by vacuum distillation at 50° C Cool the reaction to room temperature The slurry is filtered the filter cake is washed with H2O (3×35 mL) The solid is dried under vacuum

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A slurry of 6-(3-cyclopropyl-3-fluoroazetidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (61 g, 170 mmol) and 3,3,3-trifluoro-N-(4-mercaptophenyl)propanamide (41 g, 175 mmol) in CH3CN (1300 mL) was heated to reflux for 1.5 hours. During this time, the slurry transformed from thin and yellowish to thick and brilliant white. The mixture was then cooled to 0° C. and stirred at this temperature for 15 min. The mixture was then filtered and washed with cold CH3CN (650 mL). The resulting solid was dried for 20 hours at 38° C. under house vacuum. The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3(sat) (1300 mL). The mixture was stirred until no more solid remained. Then, the aqueous and organic layers were separated and the aqueous layer was washed with EtOAc (390 mL). The combined organic layers were dried over MgSO4, filtered, washed with EtOAc (130 mL) and concentrated to a minimal volume on rotavap. The resulting mixture was re-crystallized out of EtOAc and hexane to give the desired product as a white solid (56.2 g, 72%) 1H NMR (MeOD, 400 MHz): 0.40-0.45 (2H, m), 0.60-0.65 (2H, m), 1.3-1.4 (1H, m), 2.05 (2H, s), 3.25-3.40 (2H, m), 3.85-3.40 (4H, m), 5.40-5.50 (2H, m), 7.50-7.55 (2H, d), 7.65-7.70 (2H, d). ES+522. to reflux for 1.5 hours The mixture was then filtered washed with cold CH3CN (650 mL) The resulting solid was dried for 20 hours at 38° C. under house vacuum The white solid was charged to a suitable reactor with EtOAc (1300 mL) and NaHCO3(sat) (1300 mL) The mixture was stirred until no more solid Then, the aqueous and organic layers were separated the aqueous layer was washed with EtOAc (390 mL) The combined organic layers were dried over MgSO4 filtered washed with EtOAc (130 mL) concentrated to a minimal volume on rotavap The resulting mixture was re-crystallized out of EtOAc and hexane