tert-butyl 4-bromo-2-fluorobenzoate

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:0.00; pressure:0.00; stir:

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

Procedure: Compound 79d (100 mg, 0.246 mmol) was coupled with tert-butyl 4-bromo-2-fluorobenzoate (102 mg, 0.370 mmol) using the procedures described in Example 20, Step A to afford compound 81a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H31ClFN5O3: 600.2 (M+H). found: 600.2.

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

Procedure: A slurry of 4-bromo-2-fluorobenzoic acid (20.16 g, 92 mmol) in dioxane (90 mL) and conc. H2SO4 (5 mL) was cooled to 0° C., and then bubbled through with isobutene for 2 h. The reaction was allowed to gradually warm up to room temperature overnight. Solid NaHCO3 (40 g) was carefully added to the reaction and the mixture was stirred for 1 h. The mixture was concentrated, and then redissolved in water and ethyl acetate. The layers were separated. The aqueous phase was washed with ethyl acetate. The combined organics were washed with sat aq NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated. The resulting oily tert-butyl 4-bromo-2-fluorobenzoate was used without further purification. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.79-7.70 (m, 1H), 7.42-7.23 (m, 3H), 1.59 (s, 11H). bubbled through with isobutene for 2 h Solid NaHCO3 (40 g) was carefully added to the reaction The mixture was concentrated redissolved in water The layers were separated The aqueous phase was washed with ethyl acetate The combined organics were washed with sat aq NaHCO3 and brine dried over Na2SO4 filtered concentrated The resulting oily tert-butyl 4-bromo-2-fluorobenzoate was used without further purification

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

Procedure: A slurry of 4-bromo-2-fluorobenzoic acid (20.16 g, 92 mmol) in dioxane (90 mL) and conc. H2SO4 (5 mL) was cooled to 0° C., and then bubbled through with isobutene for 2 h. The reaction was allowed to gradually warm up to room temperature overnight. Solid NaHCO3 (40 g) was carefully added to the reaction and the mixture was stirred for 1 h. The mixture was concentrated, and then redissolved in water and ethyl acetate. The layers were separated. The aqueous phase was washed with ethyl acetate. The combined organics were washed with sat aq NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated. The resulting oily tert-butyl 4-bromo-2-fluorobenzoate was used without further purification. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.79-7.70 (m, 1H), 7.42-7.23 (m, 3H), 1.59 (s, 11H). bubbled through with isobutene for 2 h Solid NaHCO3 (40 g) was carefully added to the reaction The mixture was concentrated redissolved in water The layers were separated The aqueous phase was washed with ethyl acetate The combined organics were washed with sat aq NaHCO3 and brine dried over Na2SO4 filtered concentrated The resulting oily tert-butyl 4-bromo-2-fluorobenzoate was used without further purification

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A degassed mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.4 g, 10.91 mmol), tert-butyl 4-bromo-2-fluorobenzoate (3.30 g, 12.00 mmol), Pd(PPh3)4 (0.63 mg, 0.0.545 mmol), 2.0 M Na2CO3aqueous solution (10.91 mL) in n-butanol (26 mL) was microwave heated to 130° C. for 10 min. The reaction was diluted with ethyl acetate (30 mL), and then washed with water (10 mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered, concentrated, and then purified by flash chromatography (10-60% ethyl acetate/heptane eluent) to provide tert-butyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate (1.35 g, 43% yield). LCMS (m/z): 289.4 (MH+), 0.67 min. washed with water (10 mL) and brine (10 mL) The organics were dried over sodium sulfate filtered concentrated purified by flash chromatography (10-60% ethyl acetate/heptane eluent)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A degassed mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.4 g, 10.91 mmol), tert-butyl 4-bromo-2-fluorobenzoate (3.30 g, 12.00 mmol), Pd(PPh3)4 (0.63 mg, 0.0.545 mmol), 2.0 M Na2CO3aqueous solution (10.91 mL) in n-butanol (26 mL) was microwave heated to 130° C. for 10 min. The reaction was diluted with ethyl acetate (30 mL), and then washed with water (10 mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered, concentrated, and then purified by flash chromatography (10-60% ethyl acetate/heptane eluent) to provide tert-butyl 4-(2-aminopyridin-3-yl)-2-fluorobenzoate (1.35 g, 43% yield). LCMS (m/z): 289.4 (MH+), 0.67 min. washed with water (10 mL) and brine (10 mL) The organics were dried over sodium sulfate filtered concentrated purified by flash chromatography (10-60% ethyl acetate/heptane eluent)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-bromo-2-fluorobenzoic acid (60 g, 274 mmol) in anhydrous THF (700 mL) at 0° C. was added DMF (2 mL) followed by oxalyl chloride (48 mL, 548 mmol) portionwise over 1 hour. The mixture was stirred at 0° C. for 30 min, and then at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue dissolved in DCM (700 mL). tert-Butyl alcohol (97 g, 1315 mmol) and pyridine (150 mL) were added, and the reaction mixture was stirred at room temperature for 64 h. The mixture was transferred to a separating funnel and washed with water (400 mL), 2 N NaOH aqueous solution (400 mL) and brine (2×200 mL), dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0 to 5% ethyl acetate in heptane over 30 min) to give tert-butyl 4-bromo-2-fluorobenzoate (60 g, 80%) as an oil. LCMS (m/z): 218/220 (MH+ (−tBu)), 1.11 min; 1H NMR (500 MHz, CDCl3) δ ppm 7.81-7.71 (m, 1H) 7.39-7.30 (m, 2H) 7.29 (s, 1H) 1.68-1.55 (m, 9H). at room temperature for 1 hour The solvent was removed under reduced pressure the residue dissolved in DCM (700 mL) the reaction mixture was stirred at room temperature for 64 h The mixture was transferred to a separating funnel washed with water (400 mL), 2 N NaOH aqueous solution (400 mL) and brine (2×200 mL) dried over magnesium sulfate filtered concentrated under vacuum The residue was purified by flash chromatography on silica gel (0 to 5% ethyl acetate in heptane over 30 min)

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

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