N1-(5-AMINO-2-METHYLPHENYL)ACETAMIDE

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: Example 253 was prepared from 253D and N-(5-amino-2-methylphenyl)acetamide following the procedure as described in Example 6. HPLC: Rt=3.110 min. (YMC S5 ODS (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min., hold at 100% 1 min., flow rate 4 mL/min.). MS (ES): m/z=512.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (1H, br. s.), 9.52-9.58 (2H, m), 9.21 (1H, s), 8.94 (1H, t, J=5.52 Hz), 8.18 (1H, s), 7.87 (1H, s), 7.59-7.63 (2H, m), 7.44-7.54 (2H, m), 7.06 (1H, d, J=8.28 Hz), 6.81-6.85 (1H, m), 3.59 (3H, q, J=5.69 Hz), 3.24 (2H, q, J=5.86 Hz), 2.73-2.84 (6H, m), 2.08 (3H, s), 1.98 (3H, s). B=100, gradient time 4 min. hold at 100% 1 min., flow rate 4 mL/min.

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

実験手順: Example 253 was prepared from 253D and N-(5-amino-2-methylphenyl)acetamide following the procedure as described in Example 6. HPLC: Rt=3.110 min. (YMC S5 ODS (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min., hold at 100% 1 min., flow rate 4 mL/min.). MS (ES): m/z=512.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.04 (1H, br. s.), 9.52-9.58 (2H, m), 9.21 (1H, s), 8.94 (1H, t, J=5.52 Hz), 8.18 (1H, s), 7.87 (1H, s), 7.59-7.63 (2H, m), 7.44-7.54 (2H, m), 7.06 (1H, d, J=8.28 Hz), 6.81-6.85 (1H, m), 3.59 (3H, q, J=5.69 Hz), 3.24 (2H, q, J=5.86 Hz), 2.73-2.84 (6H, m), 2.08 (3H, s), 1.98 (3H, s). B=100, gradient time 4 min. hold at 100% 1 min., flow rate 4 mL/min.

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5B (60 mg, 0.14 mmol), N-(5-amino-2-methylphenyl)acetamide (46.8 mg, 0.29 mmol), Pd2(dba)3 (13.1 mg, 0.014 mmol), Xantphos (18.2 mg, 0.031 mmol), copper(I) iodide (13.6 mg, 0.071 mmol) and Cs2CO3 (186 mg, 0.57 mmol) in DMA (1 mL) was purged with nitrogen and heated at 125° C. After 1.5 hours, the reaction mixture was diluted with ethyl acetate, washed with 15% NH4OH, dried over Na2SO4, and concentrated to dryness under reduced pressure. The resulting oil was purified by silica column chromatography (gradient=0%-100% hexanes to ethyl acetate in 12 min.) to isolate 5C (47.5 mg, 60.7% yield). HPLC: Rt=3.805 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=549.2 [M+H]+. was purged with nitrogen the reaction mixture was diluted with ethyl acetate washed with 15% NH4OH dried over Na2SO4 concentrated to dryness under reduced pressure The resulting oil was purified by silica column chromatography (gradient=0%-100% hexanes to ethyl acetate in 12 min.)

反応条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: DMA (1.5 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was degassed by bubbling argon through it for 10 minutes. 1G (0.15 g, 0.42 mmol), N-(5-amino-2-methylphenyl)acetamide (0.104 g, 0.636 mmol), copper(I) iodide (0.040 g, 0.212 mmol), xantphos (0.049 g, 0.085 mmol), and Pd2(dba)3 (0.039 g, 0.042 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE®, washing with THF. The filtrate was then diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted EtOAc (3×10 mL). The organics were combined, washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and concentration afforded a tan solid, which was triturated in DCM and cooled to 0° C. The resulting precipitate was filtered and washed with cold DCM. The filtrate was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm). The appropriate fractions were pooled and concentrated under reduced pressure. The material isolated from chromatography, and the solid were combined, suspended in DCM (3 mL) and treated with triethylsilane (0.68 mL, 4.24 mmol) and TFA (0.3 mL). After 30 minutes, the suspension was cooled in an ice bath and filtered. The solid was suspended in EtOAc (20 mL) and stirred with saturated aqueous sodium bicarbonate (15 mL). After 30 minutes, the solid was isolated via filtration, washed with water and EtOAc, and dried overnight in vacuo to afford Example 1 (0.154 g, 0.422 mmol, 100%) as a white solid. HPLC: Rt=3.496 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=362.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1H, s), 9.21 (1H, s), 8.10 (1H, s), 7.81 (1H, s), 7.64 (2H, s), 7.11 (1H, d, J=8.03 Hz), 6.25 (1H, s), 2.52-2.55 (1H, m), 2.15 (3H, s), 2.06 (3H, s), 0.75-0.82 (2H, m), 0.61-0.68 (2H, m). cap the solvent was degassed by bubbling argon through it for 10 minutes the suspension was pump/purged three times with argon cooled to room temperature The solids were removed via filtration through CELITE® washing with THF The filtrate was then diluted with water and EtOAc The layers were separated the aqueous phase extracted EtOAc (3×10 mL) washed with water and brine dried over anhydrous sodium sulfate Filtration and concentration afforded a tan solid, which was triturated in DCM cooled to 0° C The resulting precipitate was filtered washed with cold DCM The filtrate was dissolved in a small amount of DCM purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm) concentrated under reduced pressure The material isolated from chromatography the suspension was cooled in an ice bath filtered After 30 minutes the solid was isolated via filtration washed with water and EtOAc dried overnight in vacuo

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

実験手順: A solution of N-(5-Amino-2-methyl-phenyl)-acetamide (0.51 g, 3.1 mmol) in THF (12 mL) was added to a suspension of NaH (186 mg, 4.65 mmol, 60% dispersion in mineral oil) in THF (12 mL) at 0° C. under an atmosphere of argon. The mixture was stirred for 30 min. at room temperature and cooled to 0° C. A solution of 2-chloro-oxazole-5-carboxylic acid methyl ester (0.5 g, 3.1 mmol) in THF (12 mL) was added dropwise to the mixture. After 30 min., at 0° C., the reaction was poured into ice water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and filtered. After removal of solvent the residue was silica gel column chromatographed (CH2Cl2/Ethanol:99/1) to give 0.54 g of 2-(5-Amino-2-methyl-phenylamino)-oxazole-5-carboxylic acid methyl ester (71%) as a Colorless syrup. cooled to 0° C After 30 min. extracted with ethyl acetate The organic layer was washed with brine dried (MgSO4) filtered After removal of solvent the residue chromatographed (CH2Cl2/Ethanol:99/1)

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

実験手順: A solution of N-(5-Amino-2-methyl-phenyl)-acetamide (0.51 g, 3.1 mmol) in THF (12 mL) was added to a suspension of NaH (186 mg, 4.65 mmol, 60% dispersion in mineral oil) in THF (12 mL) at 0° C. under an atmosphere of argon. The mixture was stirred for 30 min. at room temperature and cooled to 0° C. A solution of 2-chloro-oxazole-5-carboxylic acid methyl ester (0.5 g, 3.1 mmol) in THF (12 mL) was added dropwise to the mixture. After 30 min., at 0° C., the reaction was poured into ice water (30 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and filtered. After removal of solvent the residue was silica gel column chromatographed (CH2Cl2/Ethanol:99/1) to give 0.54 g of 2-(5-Amino-2-methyl-phenylamino)-oxazole-5-carboxylic acid methyl ester (71%) as a Colorless syrup. cooled to 0° C After 30 min. extracted with ethyl acetate The organic layer was washed with brine dried (MgSO4) filtered After removal of solvent the residue chromatographed (CH2Cl2/Ethanol:99/1)

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

実験手順: The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(2,3-dimethylphenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=91%.

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

実験手順: The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(3,5-dimethoxyphenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=85%.

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

実験手順: The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(3,5-dimethoxyphenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=85%.

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

実験手順: The same procedure outlined above in the preparation 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(6-chloro-2-methyl-phenyl)-acetamide was used instead N-(5-amino-2-methyl-phenyl)-acetamide. Yield=89%.

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

実験手順: The same procedure outlined above in the preparation of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile was used. However N-(2-methyl-5-nitro-phenyl)-acetamide was used instead N-(5-Amino-2-methyl-phenyl)-acetamide. Yield=83%. m.p.>228° C.