2-fluoro-N-methylaniline

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylic acid (75 mg, 0.20 mmol), (2-fluoro-phenyl)-methyl-amine (23 mg, 0.61 mmol), HATU (193 mg, 0.51 mmol), TEA (114 μL, 0.81 mmol) and 0.5 mL NMP were combined in a 4 mL vial and stirred overnight at 60° C. HPLC purification (10 to 95% gradient of MeCN-water) provided 3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: 1H NMR (400 MHz, CDCl3) 9.98 (s, 1H), 8.01 (s, 1H), 7.82 (d, 2H), 7.63 (s, 1H), 7.51 (d, 2H), 7.13 (m, 1H), 6.92 (t, 1H), 6.84 (t, 1H), 6.37 (m, 1H), 3.38 (t, 3H), 1.26 (s, 9H); MS m/z 476.1. HPLC purification (10 to 95% gradient of MeCN-water)

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

実験手順: 5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (2-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 522.1.

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

実験手順: To a solution of methyl 3-chloro-3-oxopropanoate (1.75 mL, 15.99 mmol) in dry DCM (32 ml) was added 2-fluoro-N-methylaniline (2 g, 15.99 mmol) and the reaction mixture was stirred at 0° C. for 1 h, evaporated then redissolved in EtOAc, washed with dilute NaHCO3, and brine. The organic phase was dried over sodium sulfate, and concentrated under reduced pressure to afford methyl 3-((2-fluorophenyl)(methyl)amino)-3-oxopropanoate as yellow oil which was used without further purification (3.3 g, 16 mmol, 97%, crude). To a solution of this material (3.3 g, 16 mmol) in THF (16 ml) and water (16 ml) was added LiOHH2O (1.35 g, 31.5 mmol) and the reaction mixture was stirred overnight, evaporated (to remove the THF) and then extracted with EtOAc. The aqueous phase was acidified to pH˜1 by addition of 1N HCl and extracted with EtOAc. The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound 245 as a brown solid, which was used without further purification (2.75 g, 13.03 mmol, 81% yield). MS (m/z): (M+1) 218.0 (88%), (2M+Li) 429.0 (100%). evaporated then redissolved in EtOAc washed with dilute NaHCO3, and brine The organic phase was dried over sodium sulfate concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: 8-Methyl-4H-thieno[3,2-c]chromene-2-carboxylic acid was converted to the acid chloride as in Example 3, then treated with N-methyl-2-fluoroaniline (1.5 equiv), and triethylamine (5 equiv) in dichloromethane and N,N-dimethyl-4-aminopyridine (0.2 equiv) at 24° C. After about 24 hr, the reaction mixture was diluted with dichloromethane, and the resulting solution was washed with saturated aqueous sodium bicarbonate. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:2/hexanes:ethylacetate) provided 169bp. 1H NMR (500 MHz, CDCl3) δ 7.40 (m, 1H), 7.31 (m, 1H), 7.18-7.22 (m, 2H), 6.80 (s, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 6.60 (s, 1H), 5.00 (s, 2H), 3.42 (s, 3H), 2.26 (s, 3H). LCMS (ESI) m/z: 354.1 the resulting solution was washed with saturated aqueous sodium bicarbonate The collected organic was dried over anhydrous sodium sulfate filtered concentrated Purification by flash column chromatography (5:2/hexanes:ethylacetate) provided 169bp

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylic acid (75 mg, 0.20 mmol), (2-fluoro-phenyl)-methyl-amine (23 mg, 0.61 mmol), HATU (193 mg, 0.51 mmol), TEA (114 μL, 0.81 mmol) and 0.5 mL NMP were combined in a 4 mL vial and stirred overnight at 60° C. HPLC purification (10 to 95% gradient of MeCN-water) provided 3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: 1H NMR (400 MHz, CDCl3) 9.98 (s, 1H), 8.01 (s, 1H), 7.82 (d, 2H), 7.63 (s, 1H), 7.51 (d, 2H), 7.13 (m, 1H), 6.92 (t, 1H), 6.84 (t, 1H), 6.37 (m, 1H), 3.38 (t, 3H), 1.26 (s, 9H); MS m/z 476.1. HPLC purification (10 to 95% gradient of MeCN-water)

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

実験手順: 5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (2-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 μL, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 522.1.

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

実験手順: To a solution of methyl 3-chloro-3-oxopropanoate (1.75 mL, 15.99 mmol) in dry DCM (32 ml) was added 2-fluoro-N-methylaniline (2 g, 15.99 mmol) and the reaction mixture was stirred at 0° C. for 1 h, evaporated then redissolved in EtOAc, washed with dilute NaHCO3, and brine. The organic phase was dried over sodium sulfate, and concentrated under reduced pressure to afford methyl 3-((2-fluorophenyl)(methyl)amino)-3-oxopropanoate as yellow oil which was used without further purification (3.3 g, 16 mmol, 97%, crude). To a solution of this material (3.3 g, 16 mmol) in THF (16 ml) and water (16 ml) was added LiOHH2O (1.35 g, 31.5 mmol) and the reaction mixture was stirred overnight, evaporated (to remove the THF) and then extracted with EtOAc. The aqueous phase was acidified to pH˜1 by addition of 1N HCl and extracted with EtOAc. The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound 245 as a brown solid, which was used without further purification (2.75 g, 13.03 mmol, 81% yield). MS (m/z): (M+1) 218.0 (88%), (2M+Li) 429.0 (100%). evaporated then redissolved in EtOAc washed with dilute NaHCO3, and brine The organic phase was dried over sodium sulfate concentrated under reduced pressure

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

実験手順: To a solution of methyl 3-chloro-3-oxopropanoate (1.75 mL, 15.99 mmol) in dry DCM (32 ml) was added 2-fluoro-N-methylaniline (2 g, 15.99 mmol) and the reaction mixture was stirred at 0° C. for 1 h, evaporated then redissolved in EtOAc, washed with dilute NaHCO3, and brine. The organic phase was dried over sodium sulfate, and concentrated under reduced pressure to afford methyl 3-((2-fluorophenyl)(methyl)amino)-3-oxopropanoate as yellow oil which was used without further purification (3.3 g, 16 mmol, 97%, crude). To a solution of this material (3.3 g, 16 mmol) in THF (16 ml) and water (16 ml) was added LiOHH2O (1.35 g, 31.5 mmol) and the reaction mixture was stirred overnight, evaporated (to remove the THF) and then extracted with EtOAc. The aqueous phase was acidified to pH˜1 by addition of 1N HCl and extracted with EtOAc. The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound 245 as a brown solid, which was used without further purification (2.75 g, 13.03 mmol, 81% yield). MS (m/z): (M+1) 218.0 (88%), (2M+Li) 429.0 (100%). evaporated then redissolved in EtOAc washed with dilute NaHCO3, and brine The organic phase was dried over sodium sulfate concentrated under reduced pressure