(2,6-difluoro-4-methoxyphenyl)boronic acid

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) in THF and water (10:1, 0.1 M) was added 2,6-difluoro-4-methoxyphenylboronic acid (2.5 equiv.) and potassium fluoride (3.3 equiv.). The reaction was degassed with nitrogen, then Pd2(dba)3 (0.25 equiv.) and tri-tert-butylphosphine (0.5 equiv.) were added and the reaction was heated to 80° C. for one hour. LC/MS analysis indicated complete conversion of the starting material to product. The reaction was cooled to room temperature, then concentrated in vacuo and fused to silica gel. The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate) to provide methyl 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinate as a white solid in 85% yield. LC/MS=298.0 (M+H), Rt=0.89 min. The reaction was degassed with nitrogen The reaction was cooled to room temperature concentrated in vacuo The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) in THF and water (10:1, 0.1 M) was added 2,6-difluoro-4-methoxyphenylboronic acid (2.5 equiv.) and potassium fluoride (3.3 equiv.). The reaction was degassed with nitrogen, then Pd2(dba)3 (0.25 equiv.) and tri-tert-butylphosphine (0.5 equiv.) were added and the reaction was heated to 80° C. for one hour. LC/MS analysis indicated complete conversion of the starting material to product. The reaction was cooled to room temperature, then concentrated in vacuo and fused to silica gel. The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate) to provide methyl 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinate as a white solid in 85% yield. LC/MS=298.0 (M+H), Rt=0.89 min. The reaction was degassed with nitrogen The reaction was cooled to room temperature concentrated in vacuo The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) in THF and water (10:1, 0.1 M) was added 2,6-difluoro-4-methoxyphenylboronic acid (2.5 equiv.) and potassium fluoride (3.3 equiv.). The reaction was degassed with nitrogen, then Pd2(dba)3 (0.25 equiv.) and tri-tert-butylphosphine (0.5 equiv.) were added and the reaction was heated to 80° C. for one hour. LC/MS analysis indicated complete conversion of the starting material to product. The reaction was cooled to room temperature, then concentrated in vacuo and fused to silica gel. The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate) to provide methyl 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinate as a white solid in 85% yield. LC/MS=298.0 (M+H), Rt=0.89 min. The reaction was degassed with nitrogen The reaction was cooled to room temperature concentrated in vacuo The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-methoxyoxepan-4-yl)carbamate (Intermediate 101), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluoro-4-methoxyphenyl)boronic acid gave 265. 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.56 (s, 1H), 7.94 (s, 1H), 7.08-6.97 (m, 2H), 5.11 (t, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.84-3.75 (m, 1H), 3.71 (s, 3H), 3.47-3.38 (m, 1H), 3.31-3.22 (m, 1H), 3.04 (s, 3H), 2.49-2.36 (m, 1H), 1.75-1.49 (m, 3H), 1.41 (br, 2H). LCMS (ES+) m/z 494 (M+1).

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 2-bromothiazole-4-carboxylate (3.27 mmol, 741 mg) in tetrahydrofuran (15 mL) and water (1.5 mL) was added 2,6-difluoro-4-methoxyphenylboronic acid (1.8 equiv., 5.88 mmol, 1160 mg) and potassium fluoride (3.3 equiv., 10.8 mmol, 627 mg). The mixture was degassed with nitrogen, then tris(dibenzylideneacetone)dipalladium(0) (0.2 equiv., 0.654 mmol, 617 mg) and tri-tert-butylphosphine (1.0 M in toluene; 0.4 equiv., 1.31 mmol, 1.3 mL) were added and the reaction mixture was heated under microwave at 100° C. for 30 minutes. The reaction mixture was concentrated and the residue was purified on silica eluted with 0 to 50% EtOAc in heptane to afford methyl 2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxylate (2.40 mmol, 685 mg, 74% yield). The mixture was degassed with nitrogen The reaction mixture was concentrated the residue was purified on silica eluted with 0 to 50% EtOAc in heptane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-{4-[(3-bromobenzyl)oxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione (500 mg), 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg), tetrakistriphenylphosphine palladium (80 mg), lithium chloride (6 mg), a sodium carbonate aqueous solution (562 mg/5 ml), ethanol (5 ml) and 1,2-dimethoxyethane (25 ml) was stirred at 90° C. for 5 hours in an atmosphere of nitrogen. 2,6-Difluoro-4-methoxyphenyl boronic acid (325 mg) was further added thereto, followed by stirring at 90° C. for 13 hours. Further, 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg) was added thereto, followed by stirring at 90° C. for 2 hours. Further, 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg) was added thereto, followed by stirring at 90° C. for 5 hours and spontaneous cooling to room temperature. A 1 M hydrochloric acid (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate and filtered. Silica gel (3 g) was added to the filtrated, followed by concentration under a reduced pressure. The carrying product thus obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain a light yellow foamy substance (614 mg). The resulting foamy substance (614 mg) was dissolved in THF (5 ml)-ethanol (5 ml), a 1 M sodium hydroxide aqueous solution (1.32 ml) was added, followed by concentration under a reduced pressure. By recrystallizing the resulting residue from isopropanol-water, sodium 2-{4-[(2′,6′-difluoro-4′-methoxybiphenyl-3-yl)methoxy]benzyl}-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (366 mg) was obtained as a colorless solid. by stirring at 90° C. for 2 hours by stirring at 90° C. for 5 hours spontaneous cooling to room temperature followed by extraction with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate filtered Silica gel (3 g) was added to the filtrated followed by concentration under a reduced pressure The carrying product thus obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain a light yellow foamy substance (614 mg) followed by concentration under a reduced pressure By recrystallizing the resulting residue from isopropanol-water

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-{4-[(3-bromobenzyl)oxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione (500 mg), 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg), tetrakistriphenylphosphine palladium (80 mg), lithium chloride (6 mg), a sodium carbonate aqueous solution (562 mg/5 ml), ethanol (5 ml) and 1,2-dimethoxyethane (25 ml) was stirred at 90° C. for 5 hours in an atmosphere of nitrogen. 2,6-Difluoro-4-methoxyphenyl boronic acid (325 mg) was further added thereto, followed by stirring at 90° C. for 13 hours. Further, 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg) was added thereto, followed by stirring at 90° C. for 2 hours. Further, 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg) was added thereto, followed by stirring at 90° C. for 5 hours and spontaneous cooling to room temperature. A 1 M hydrochloric acid (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate and filtered. Silica gel (3 g) was added to the filtrated, followed by concentration under a reduced pressure. The carrying product thus obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain a light yellow foamy substance (614 mg). The resulting foamy substance (614 mg) was dissolved in THF (5 ml)-ethanol (5 ml), a 1 M sodium hydroxide aqueous solution (1.32 ml) was added, followed by concentration under a reduced pressure. By recrystallizing the resulting residue from isopropanol-water, sodium 2-{4-[(2′,6′-difluoro-4′-methoxybiphenyl-3-yl)methoxy]benzyl}-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (366 mg) was obtained as a colorless solid. by stirring at 90° C. for 2 hours by stirring at 90° C. for 5 hours spontaneous cooling to room temperature followed by extraction with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate filtered Silica gel (3 g) was added to the filtrated followed by concentration under a reduced pressure The carrying product thus obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain a light yellow foamy substance (614 mg) followed by concentration under a reduced pressure By recrystallizing the resulting residue from isopropanol-water

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-{4-[(3-bromobenzyl)oxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione (500 mg), 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg), tetrakistriphenylphosphine palladium (80 mg), lithium chloride (6 mg), a sodium carbonate aqueous solution (562 mg/5 ml), ethanol (5 ml) and 1,2-dimethoxyethane (25 ml) was stirred at 90° C. for 5 hours in an atmosphere of nitrogen. 2,6-Difluoro-4-methoxyphenyl boronic acid (325 mg) was further added thereto, followed by stirring at 90° C. for 13 hours. Further, 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg) was added thereto, followed by stirring at 90° C. for 2 hours. Further, 2,6-difluoro-4-methoxyphenyl boronic acid (325 mg) was added thereto, followed by stirring at 90° C. for 5 hours and spontaneous cooling to room temperature. A 1 M hydrochloric acid (50 ml) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate and filtered. Silica gel (3 g) was added to the filtrated, followed by concentration under a reduced pressure. The carrying product thus obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain a light yellow foamy substance (614 mg). The resulting foamy substance (614 mg) was dissolved in THF (5 ml)-ethanol (5 ml), a 1 M sodium hydroxide aqueous solution (1.32 ml) was added, followed by concentration under a reduced pressure. By recrystallizing the resulting residue from isopropanol-water, sodium 2-{4-[(2′,6′-difluoro-4′-methoxybiphenyl-3-yl)methoxy]benzyl}-3,5-dioxo-1,2,4-oxadiazolidin-4-ide (366 mg) was obtained as a colorless solid. by stirring at 90° C. for 2 hours by stirring at 90° C. for 5 hours spontaneous cooling to room temperature followed by extraction with ethyl acetate The organic layer was washed with a saturated sodium chloride aqueous solution dried over anhydrous magnesium sulfate filtered Silica gel (3 g) was added to the filtrated followed by concentration under a reduced pressure The carrying product thus obtained was purified by silica gel column chromatography (chloroform-methanol) to obtain a light yellow foamy substance (614 mg) followed by concentration under a reduced pressure By recrystallizing the resulting residue from isopropanol-water