tert-butyl 5-chloro-2,4-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:

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: 3-chloro-4-(trifluoromethoxy)phenol (22.6 g, 0.106 mol) and tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 26.4 g, 0.106 mol) were dissolved in dimethlysulfoxide (105 mL). Then potassium carbonate (29.4 g, 0.213 mol) was added portionwise to the mixture, which was stirred at room temperature for 18 hours. The reaction mixture was dropped into iced water (500 mL) and stirred vigorously for 4 hours. The resulting solid was collected by filtration then taken up in isopropanol (75 mL) and water (15 mL). The reaction was heated to 55° C., then cooled down to room temperature. The resulting solid was collected by filtration to yield the title compound as an off-white white solid (35.3 g, 75%). stirred vigorously for 4 hours The resulting solid was collected by filtration The reaction was heated to 55° C. cooled down to room temperature The resulting solid was collected by filtration

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

Procedure: tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 160, 416 mg, 1.68 mmol) was added to a mixture of potassium carbonate (694 mg, 5.02 mmol), 3,4-dichlorothiophenol (300 mg, 1.77 mmol) in DMSO (16.7 mL) and the reaction stirred at room temperature for 18 hours. The reaction was quenched by addition of 0.5 N aqueous NaOH (20 mL) and EtOAc (30 mL) and the mixture partitioned. The aqueous was further extracted with EtOAc (3×10 mL), the organics combined, washed with brine (10 mL), dried (MgSO4), filtered and evaporated to give a yellow solid. Silica gel column chromatography eluting with 9:1 DCM:heptanes resulted in isolation of the title compound as a white solid (571 mg, 83%). The reaction was quenched by addition of 0.5 N aqueous NaOH (20 mL) and EtOAc (30 mL) the mixture partitioned The aqueous was further extracted with EtOAc (3×10 mL) washed with brine (10 mL) dried (MgSO4) filtered evaporated to give a yellow solid Silica gel column chromatography eluting with 9:1 DCM

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

Procedure: tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 160, 416 mg, 1.68 mmol) was added to a mixture of potassium carbonate (694 mg, 5.02 mmol), 3,4-dichlorothiophenol (300 mg, 1.77 mmol) in DMSO (16.7 mL) and the reaction stirred at room temperature for 18 hours. The reaction was quenched by addition of 0.5 N aqueous NaOH (20 mL) and EtOAc (30 mL) and the mixture partitioned. The aqueous was further extracted with EtOAc (3×10 mL), the organics combined, washed with brine (10 mL), dried (MgSO4), filtered and evaporated to give a yellow solid. Silica gel column chromatography eluting with 9:1 DCM:heptanes resulted in isolation of the title compound as a white solid (571 mg, 83%). The reaction was quenched by addition of 0.5 N aqueous NaOH (20 mL) and EtOAc (30 mL) the mixture partitioned The aqueous was further extracted with EtOAc (3×10 mL) washed with brine (10 mL) dried (MgSO4) filtered evaporated to give a yellow solid Silica gel column chromatography eluting with 9:1 DCM

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

Procedure: tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 160, 416 mg, 1.68 mmol) was added to a mixture of potassium carbonate (694 mg, 5.02 mmol), 3,4-dichlorothiophenol (300 mg, 1.77 mmol) in DMSO (16.7 mL) and the reaction stirred at room temperature for 18 hours. The reaction was quenched by addition of 0.5 N aqueous NaOH (20 mL) and EtOAc (30 mL) and the mixture partitioned. The aqueous was further extracted with EtOAc (3×10 mL), the organics combined, washed with brine (10 mL), dried (MgSO4), filtered and evaporated to give a yellow solid. Silica gel column chromatography eluting with 9:1 DCM:heptanes resulted in isolation of the title compound as a white solid (571 mg, 83%). The reaction was quenched by addition of 0.5 N aqueous NaOH (20 mL) and EtOAc (30 mL) the mixture partitioned The aqueous was further extracted with EtOAc (3×10 mL) washed with brine (10 mL) dried (MgSO4) filtered evaporated to give a yellow solid Silica gel column chromatography eluting with 9:1 DCM

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

Procedure: To a stirred solution of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 200 mg, 0.80 mmol) in DMSO (4 mL) was added K2CO3 (333 mg, 2.41 mmol) followed by 4-chloro-3-(trifluoromethyl)phenol (190 mg, 0.97 mmol) and the reaction stirred at room temperature for 18 h. Water (10 mL) and EtOAc (15 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO4) filtered and the solvent removed under reduced pressure to give the title compound (245 mg, 72%) as a solid. the layers separated The aqueous layer was extracted with EtOAc (15 mL) The combined organic extracts were washed with brine (15 mL) dried (MgSO4) filtered the solvent removed under reduced pressure

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

Procedure: To a stirred solution of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 200 mg, 0.80 mmol) in DMSO (4 mL) was added K2CO3 (333 mg, 2.41 mmol) followed by 4-chloro-3-(trifluoromethyl)phenol (190 mg, 0.97 mmol) and the reaction stirred at room temperature for 18 h. Water (10 mL) and EtOAc (15 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO4) filtered and the solvent removed under reduced pressure to give the title compound (245 mg, 72%) as a solid. the layers separated The aqueous layer was extracted with EtOAc (15 mL) The combined organic extracts were washed with brine (15 mL) dried (MgSO4) filtered the solvent removed under reduced pressure

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

Procedure: tert-Butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 8.3 g, 33.4 mmol) was added to a solution of 5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-ol (Preparation 231, 16.2 g, 66.8 mmol) and potassium carbonate (27.8 g, 200 mmol) in dimethyl sulfoxide (100 mL). The reaction mixture was stirred at room temperature for 18 hours then quenched with an aqueous solution of sodium hydroxide (1 M, 100 mL). A white precipitate formed and was collected by filtration to give the title compound as a white solid (9.2 g). then quenched with an aqueous solution of sodium hydroxide (1 M, 100 mL) A white precipitate formed was collected by filtration