2-(2-乙炔基苯基)乙酰胺

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+. concentrated to dryness in vacuo purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+. concentrated to dryness in vacuo purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis (triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+. concentrated to dryness in vacuo purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis (triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+. concentrated to dryness in vacuo purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-(2-ethynylphenyl)acetamide (I8) (5.40 g, 33.9 mmol), 2,4-dichloro-5-methylpyrimidine (6.63 g, 40.7 mmol) and CuI (0.129 g, 0.678 mmol) in 1,4-dioxane (180 mL) and Et3N (14.2 mL, 101 mmol) was placed under nitrogen. PdCl2(PPh3)2 (0.238 g, 0.339 mmol) was added and the resulting mixture was stirred at 70° C. for 20 minutes, then adsorbed onto silica gel and purified by column chromatography (CombiFlash Rf, 120 g SiO2 Cartridge, 0-5% MeOH in DCM) to give the title compound I9 as a yellow solid (5.01 g, 51%); 1H NMR (300 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.35-7.52 (m, 4H), 6.97 (brs, 1H), 3.71 (s, 2H), 2.42 (s, 3H). LCMS-B: rt 5.689 min; m/z 286 [M+H]+. purified by column chromatography (CombiFlash Rf, 120 g SiO2 Cartridge, 0-5% MeOH in DCM)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 1.0 M solution of TBAF in THF (59.1 mL, 59.1 mmol) was slowly added to a cooled (5° C. water/ice bath) solution of 2-(2-((trimethylsilyl)ethynyl)phenyl)acetamide (I7) (11.4 g, 49.3 mmol) in DCM (150 mL) and acetic acid (3.66 mL, 64.1 mmol). The mixture was stirred at 5° C. for 1 hour before 10% aqueous NaHCO3 solution (150 mL) was added. The resulting mixture was extracted with DCM (3×50 mL) then the combined organics were dried (MgSO4), filtered and evaporated in vacuo until approximately 15 mL of solvent remained. This solution was diluted with Et2O (100 mL) and EtOAc (100 mL) resulting in the formation of a precipitate, which was filtered and dried to give 2.81 g of the title compound I8 as a brown solid. The remaining filtrate was adsorbed onto silica gel and purified using column chromatography (CombiFlash Rf, 80 g SiO2 Cartridge, 0-10% MeOH in DCM). An additional 2.62 g of the title compound I8 was isolated as a brown solid (combined total 5.43 g, 69%); 1H NMR (300 MHz, d6-DMSO) δ 7.44 (d, J=7.5 Hz, 1H), 7.21-7.37 (m, 4H), 6.93 (brs, 1H), 4.32 (s, 1H), 3.59 (s, 2H). LCMS-B: rt 4.734 min; m/z 160 [M+H]+. was added The resulting mixture was extracted with DCM (3×50 mL) the combined organics were dried (MgSO4) filtered evaporated in vacuo until approximately 15 mL of solvent This solution was diluted with Et2O (100 mL) and EtOAc (100 mL) resulting in the formation of a precipitate, which was filtered dried

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H). LCMS Method C: rt 6.52 min; m/z 578.3 [M−H]−. The reaction was concentrated to dryness in vacuo purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-iodophenyl)acetamide (I38) (1.75 g, 6.70 mmol) in dry THF (50 mL) and dry DMF (10 mL) was added Pd(PPh3)4 (0.194 g, 0.168 mmol) and Cu(I)I (0.064 g, 0.34 mmol), triethylamine (3.27 mL, 23.5 mmol). The mixture was stirred for 10 minutes and TMS-acetylene (1.52 mL, 10.7 mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours, concentrated in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid. This material was dissolved in dry THF (25 mL) under an atmosphere of nitrogen and TBAF (1.0 M in THF, 2.805 mL, 2.805 mmol) was added dropwise at 0° C. The solution was stirred at this temperature for 1 hour and 15 minutes after which water (5 mL) was added. The reaction mixture was concentrated in vacuo and diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and aqueous layer was extracted with EtOAc (100 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I39) (0.239 g, 22% yield over 2 steps) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.21 (dd, J=7.6, 1.1 Hz, 1H), 7.18-7.05 (m, 3H), 7.04-6.98 (m, 1H), 6.70 (s, 1H), 4.08 (s, 1H), 3.36 (s, 2H). LCMS Method C: rt 4.71 min; m/z 160.2 [M+H]+. The reaction mixture was then stirred at room temperature for 18 hours concentrated in vacuo purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid was added The reaction mixture was concentrated in vacuo diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL) The layers were separated aqueous layer was extracted with EtOAc (100 mL) washed with water (100 mL), brine (100 mL) dried (MgSO4) filtered concentrated in vacuo to give the crude product The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H). The reaction was concentrated to dryness in vacuo purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-iodophenyl)acetamide (I38) (1.75 g, 6.70 mmol) in dry THF (50 mL) and dry DMF (10 mL) was added Pd(PPh3)4 (0.194 g, 0.168 mmol) and Cu(I)I (0.064 g, 0.34 mmol), triethylamine (3.27 mL, 23.5 mmol). The mixture was stirred for 10 minutes and TMS-acetylene (1.52 mL, 10.7 mmol) was added. The reaction mixture was then stirred at room temperature for 18 hours, concentrated in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid. This material was dissolved in dry THF (25 mL) under an atmosphere of nitrogen and TBAF (1.0 M in THF, 2.805 mL, 2.805 mmol) was added dropwise at 0° C. The solution was stirred at this temperature for 1 hour and 15 minutes after which water (5 mL) was added. The reaction mixture was concentrated in vacuo and diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL). The layers were separated and aqueous layer was extracted with EtOAc (100 mL), the organic layers were combined and washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I39) (0.239 g, 22% yield over 2 steps) as a beige solid; 1H NMR (400 MHz, d6-DMSO) δ 7.21 (dd, J=7.6, 1.1 Hz, 1H), 7.18-7.05 (m, 3H), 7.04-6.98 (m, 1H), 6.70 (s, 1H), 4.08 (s, 1H), 3.36 (s, 2H). LCMS Method C: rt 4.71 min; m/z 160.2 [M+H]+. The reaction mixture was then stirred at room temperature for 18 hours concentrated in vacuo purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid was added The reaction mixture was concentrated in vacuo diluted with EtOAc (100 mL) and sat. aq. NaHCO3 (100 mL) The layers were separated aqueous layer was extracted with EtOAc (100 mL) washed with water (100 mL), brine (100 mL) dried (MgSO4) filtered concentrated in vacuo to give the crude product The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I41) (0.029 g, 0.18 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I48) (0.082 g, 0.15 mmol) in dry DMF (4 mL) were added triethylamine (0.085 mL, 0.61 mmol), triphenylphosphine (6.0 mg, 0.023 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.011 g, 0.015 mmol) and Cu(I)I (4.0 mg, 0.023 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes, concentrated to dryness in vacuo and purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I49) (0.073 g, 73% yield) as a pale yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.11 (s, 1H), 8.74 (s, 1H), 7.58 (dd, J=7.7, 6.2 Hz, 2H), 7.53-7.47 (m, 1H), 7.42-7.27 (m, 5H), 6.99 (s, 1H), 4.14-4.03 (m, 2H), 3.67 (s, 2H), 2.87-2.72 (m, 3H), 1.79 (d, J=12.8 Hz, 2H), 1.50 (qd, J=12.5, 4.1 Hz, 2H), 1.42 (s, 9H). LCMS Method C: rt 6.63 min; m/z 564.0 [M-Boc+2H]+. concentrated to dryness in vacuo purified by silica gel chromatography (12 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)