methyl 4-bromo-2,6-difluorobenzoate

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: Nitromethane (10 mL, 169 mmol, 8 equiv.) is added cautiously to a suspension of sodium hydride (4.05 g, 169 mmol, 8 equiv.) and MgSO4 (40 g) in DMSO (100 mL) at rt and the resulting slurry is stirred for 0.25 h. To the resulting yellow slurry is added 4-bromo-2,6-difluorobenzoic acid methyl ester (5.3 g, 21 mmol) and the mixture is stirred at rt for 3 days at which point all the starting material has been consumed. Water (200 mL) and 6M HCl (50 mL) is added followed by DCM (200 mL). More water (500 mL) is added to yield a clear biphasic system. The aqueous layer is extracted with DCM (3×100 mL), the DCM layers are then combined, washed with saturated NaHCO3 and brine, and dried over MgSO4. Evaporation of the solvent affords an orange solid containing 64% of the desired material, used without further purification. LCMS; Rt=1.27 min (64%). the mixture is stirred at rt for 3 days at which point all the starting material has been consumed Water (200 mL) and 6M HCl (50 mL) is added More water (500 mL) is added to yield a clear biphasic system The aqueous layer is extracted with DCM (3×100 mL) washed with saturated NaHCO3 and brine dried over MgSO4 Evaporation of the solvent affords an orange solid used without further purification

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

Procedure: To a suspension of 4-Bromo-2,6-difluoro-benzoic acid (5 g, 21 mmol) in DCM (10 mL) is added thionyl chloride (15 mL) and DMF (0.5 mL). The mixture is stirred at room temperature for 2.5 h. It is then cooled to 0° C. and MeOH (20 mL) is added carefully causing vigorous HCl evolution. After stirring for an additional 0.5 h, the clear solution is partitioned between DCM (50 mL) and water (50 mL). The organic layer is washed with saturated NaHCO3, brine, dried over MgSO4 and the solvent is removed under vacuum to afford the title compound as a pale yellow oil which is used without further purification. It is then cooled to 0° C. After stirring for an additional 0.5 h the clear solution is partitioned between DCM (50 mL) and water (50 mL) The organic layer is washed with saturated NaHCO3, brine dried over MgSO4 the solvent is removed under vacuum

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

Procedure: To a suspension of 4-Bromo-2,6-difluoro-benzoic acid (5 g, 21 mmol) in DCM (10 mL) is added thionyl chloride (15 mL) and DMF (0.5 mL). The mixture is stirred at room temperature for 2.5 h. It is then cooled to 0° C. and MeOH (20 mL) is added carefully causing vigorous HCl evolution. After stirring for an additional 0.5 h, the clear solution is partitioned between DCM (50 mL) and water (50 mL). The organic layer is washed with saturated NaHCO3, brine, dried over MgSO4 and the solvent is removed under vacuum to afford the title compound as a pale yellow oil which is used without further purification. It is then cooled to 0° C. After stirring for an additional 0.5 h the clear solution is partitioned between DCM (50 mL) and water (50 mL) The organic layer is washed with saturated NaHCO3, brine dried over MgSO4 the solvent is removed under vacuum

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

Procedure: To a solution of 4-bromo-2,6-difluorobenzoic acid (800 mg, 3.38 mmol) in MeOH (11 mL) at room temperature, trimethylsilyldiazomethane (5.63 mL, 3.38 mmol) was slowly added until yellow solution was turned on. The small amount of AcOH was added until yellow color disappered. All volatile materials were removed in vacuo yielding methyl 4-bromo-2,6-difluorobenzoate (47%). LCMS (m/z): 251.1 (MH+), 0.86 min. All volatile materials were removed in vacuo

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

Procedure: Methyl 4-bromo-2,6-difluorobenzoate (0.5 g, 2.0 mmol), 2-butyn-1-ol (0.16 ml, 2.1 mmol), potassium tertbutoxide (0.47 g, 4.2 mmol) in dry DMSO (5 ml) was heated in a microwave oven at 125° C. for 2.5 min. The reaction mixture was cooled to ambient temperature and quenched with water. The mixture was acidified with aqueous HCl (1 M) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated to dryness to afford an oil. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (0.19 g, 35%). MS m/z (rel. intensity, 70 eV) 250 (M+, 43), 248 (M+, 44), 218 (96), 216 (bp), 190 (44),188 (45). quenched with water extracted with EtOAc dried (Na2SO4) filtered evaporated to dryness to afford an oil Purification by flash column chromatography (isooctane/EtOAc 10:1)

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

Procedure: Methyl 4-bromo-2,6-difluorobenzoate (0.5 g, 2.0 mmol), 2-butyn-1-ol (0.16 ml, 2.1 mmol), potassium tertbutoxide (0.47 g, 4.2 mmol) in dry DMSO (5 ml) was heated in a microwave oven at 125° C. for 2.5 min. The reaction mixture was cooled to ambient temperature and quenched with water. The mixture was acidified with aqueous HCl (1 M) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated to dryness to afford an oil. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (0.19 g, 35%). MS m/z (rel. intensity, 70 eV) 250 (M+, 43), 248 (M+, 44), 218 (96), 216 (bp), 190 (44),188 (45). quenched with water extracted with EtOAc dried (Na2SO4) filtered evaporated to dryness to afford an oil Purification by flash column chromatography (isooctane/EtOAc 10:1)

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

Procedure: A mixture of 4-bromo-2,6-difluorobenzoic acid (6.7 g, 28.3 mmol), MeOH (200 ml) and concentrated HCl (2.0 ml) was heated at reflux for 12 h. The reaction mixture was brought to ambient temperature and the volatiles were evaporated. EtOAc was added and the organic phase was extracted with a aquous solution of Na2CO3 (10%). The combined alkaline phases was acidified at 0° C. with aqueous HCl (10%) to pH 1 and extracted with EtOAc. The combined organic phases was dried (Na2SO4), filtered and concentrated in vacuo to afford pure title compound (3.1 g). MS m/z (rel. intensity, 70 eV) 252 (M+, 22), 250 (M+, 23), 221 (99), 219 (bp), 112 (44). was heated at reflux for 12 h was brought to ambient temperature the volatiles were evaporated EtOAc was added the organic phase was extracted with a aquous solution of Na2CO3 (10%) was acidified at 0° C. with aqueous HCl (10%) to pH 1 extracted with EtOAc The combined organic phases was dried (Na2SO4) filtered concentrated in vacuo

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, a microwave vessel was charged with 54 mg (0.22 mmol) of methyl 4-bromo-2,6-difluorobenzoate, 118 mg (1.01 mmol, 4.7 eq.) of tert-butyl carbamate, 4.6 mg (0.02 mmol, 0.1 eq.) of palladium(II) acetate, 15 mg (0.026 mmol, 0.13 eq.) of Xantphos, 137 mg (0.42 mmol, 2 eq.) of caesium carbonate and 2 ml of 1,4-dioxane. A stream of argon was passed through the suspension for 2 min. The reaction mixture was heated in the microwave at 140° C. for 20 min. After filtration through kieselguhr, the filtrate was concentrated under reduced pressure. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 10-50% mixtures). Yield: 37 mg (60% of theory) After filtration through kieselguhr the filtrate was concentrated under reduced pressure The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 10-50% mixtures)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon, a microwave vessel was charged with 54 mg (0.22 mmol) of methyl 4-bromo-2,6-difluorobenzoate, 118 mg (1.01 mmol, 4.7 eq.) of tert-butyl carbamate, 4.6 mg (0.02 mmol, 0.1 eq.) of palladium(II) acetate, 15 mg (0.026 mmol, 0.13 eq.) of Xantphos, 137 mg (0.42 mmol, 2 eq.) of caesium carbonate and 2 ml of 1,4-dioxane. A stream of argon was passed through the suspension for 2 min. The reaction mixture was heated in the microwave at 140° C. for 20 min. After filtration through kieselguhr, the filtrate was concentrated under reduced pressure. The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 10-50% mixtures). Yield: 37 mg (60% of theory) After filtration through kieselguhr the filtrate was concentrated under reduced pressure The crude product was purified by normal phase chromatography (mobile phase: dichloromethane/methanol 10-50% mixtures)

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

Procedure: Nitromethane (10 mL, 169 mmol, 8 equiv.) is added cautiously to a suspension of sodium hydride (4.05 g, 169 mmol, 8 equiv.) and MgSO4 (40 g) in DMSO (100 mL) at rt and the resulting slurry is stirred for 0.25 h. To the resulting yellow slurry is added 4-bromo-2,6-difluorobenzoic acid methyl ester (5.3 g, 21 mmol) and the mixture is stirred at rt for 3 days at which point all the starting material has been consumed. Water (200 mL) and 6M HCl (50 mL) is added followed by DCM (200 mL). More water (500 mL) is added to yield a clear biphasic system. The aqueous layer is extracted with DCM (3×100 mL), the DCM layers are then combined, washed with saturated NaHCO3 and brine, and dried over MgSO4. Evaporation of the solvent affords an orange solid containing 64% of the desired material, used without further purification. LCMS; Rt=1.27 min (64%). the mixture is stirred at rt for 3 days at which point all the starting material has been consumed Water (200 mL) and 6M HCl (50 mL) is added More water (500 mL) is added to yield a clear biphasic system The aqueous layer is extracted with DCM (3×100 mL) washed with saturated NaHCO3 and brine dried over MgSO4 Evaporation of the solvent affords an orange solid used without further purification