2.6-二氟-3-乙氧基苯硼酸

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-ethoxy-2,6-difluorophenyl)boronic acid gave 285. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.63 (s, 1H), 7.79 (s, 1H), 7.39 (td, J=9.3, 5.2 Hz, 1H), 7.24 (td, J=9.6, 1.9 Hz, 1H), 4.80 (dd, J=11.0, 3.6 Hz, 1H), 4.49-4.25 (m, 1H), 4.16 (q, J=6.9 Hz, 3H), 4.08-3.90 (m, 1H), 3.78 (s, 3H), 3.29-3.18 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.77 (m, 1H), 1.74-1.64 (m, 2H), 1.36 (t, J=6.9 Hz, 3H). LCMS (ES+) m/z 496 (M+1).

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

实验步骤: To a solution of 3-ethoxy-2,6-difluoro-phenylboronic acid (5.0 g, 0.025 mol) in tetrahydrofuran (80 mL) was added glacial acetic acid (30 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 4 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 3-ethoxy-2,6-difluoro-phenol (4.25 g, 99%) as a brown oil. was added to come to room temperature The mixture was evaporated the residue was dissolved in ethyl acetate washed with hydrochloric acid (0.5N), water and brine The organic phase was dried filtered evaporated which

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

实验步骤: To a solution of 3-ethoxy-2,6-difluoro-phenylboronic acid (5.0 g, 0.025 mol) in tetrahydrofuran (80 mL) was added glacial acetic acid (30 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 4 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 3-ethoxy-2,6-difluoro-phenol (4.25 g, 99%) as a brown oil. was added to come to room temperature The mixture was evaporated the residue was dissolved in ethyl acetate washed with hydrochloric acid (0.5N), water and brine The organic phase was dried filtered evaporated which

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

实验步骤: A septum sealed microwave tube was charged with (S)-tert-butyl 1-(3-(5-(tert-butoxycarbonylamino)-2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (50 mg, 0.084 mmol), 2,6-difluoro-3-ethoxyphenyl-boronic acid (169 mg, 0.84 mmol), Pd(dppf)Cl2 (13.6 mg, 0.016 mmol) 1M Na2CO3 (0.6 mL, 14.1 mmol) and acetonitrile (3 mL). The mixture was irradiated for 30 min at 120 C. Upon completion of the reaction, the solvent was distilled off and the crude material was dissolved in CH2Cl2 (5 mL) and transferred to a scintillation vial. TFA (0.77 g, 6.7 mmol) was added and the mixture was stirred at room temperature for 30 min. The solvent was distilled off and the crude product was purified via reverse phase HPLC 40% to 80% MeOH in water with 0.1% NH4OH to afford (S)-5-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-2-(3-ethoxy-2,6-difluorophenyl)thiazole-4-carboxamide as a white solid (4.8 mg, 12%). 1H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 8.27-8.16 (m, 1H), 7.66 (s, 2H), 7.28 (td, J=9.2, 5.1, 1H), 7.23-7.09 (m, 2H), 4.15 (q, J=7.0, 2H), 3.06 (dd, J=41.9, 10.8, 5H), 2.65 (dd, J=15.7, 5.1, 1H), 1.89 (d, J=10.1, 1H), 1.82-1.67 (m, 2H), 1.36 (t, J=7.0, 3H). ESIMS m/z=475.1 (M+1). A septum sealed microwave tube The mixture was irradiated for 30 min at 120 C Upon completion of the reaction the solvent was distilled off the crude material was dissolved in CH2Cl2 (5 mL) The solvent was distilled off the crude product was purified via reverse phase HPLC 40% to 80% MeOH in water with 0.1% NH4OH

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

实验步骤: Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3-ethoxy-2,6-difluorophenyl)boronic acid gave 285. 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.63 (s, 1H), 7.79 (s, 1H), 7.39 (td, J=9.3, 5.2 Hz, 1H), 7.24 (td, J=9.6, 1.9 Hz, 1H), 4.80 (dd, J=11.0, 3.6 Hz, 1H), 4.49-4.25 (m, 1H), 4.16 (q, J=6.9 Hz, 3H), 4.08-3.90 (m, 1H), 3.78 (s, 3H), 3.29-3.18 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.77 (m, 1H), 1.74-1.64 (m, 2H), 1.36 (t, J=6.9 Hz, 3H). LCMS (ES+) m/z 496 (M+1).

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

实验步骤: To a solution of 3-ethoxy-2,6-difluoro-phenylboronic acid (5.0 g, 0.025 mol) in tetrahydrofuran (80 mL) was added glacial acetic acid (30 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 4 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 3-ethoxy-2,6-difluoro-phenol (4.25 g, 99%) as a brown oil. was added to come to room temperature The mixture was evaporated the residue was dissolved in ethyl acetate washed with hydrochloric acid (0.5N), water and brine The organic phase was dried filtered evaporated which