ethyl 2,4,5-trifluorobenzoate

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

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 14.8 g, 72.4 mmol) in acetonitrile (225 mL) is added triethylamine (65 mL, 466 mmol) and pyrrolidin-3-ylcarbamic acid tert-butyl ester (16.07 g, 86.2 mmol). After 45 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford an oil. The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes) to afford the title compound. MS (ES, M+1) m/z 371, mp 98-100° C. washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated to afford an oil The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes)

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 4.32 g, 21.2 mmol) in acetonitrile (25 mL) is added triethylamine (5.9 mL, 42.3 mmol) and pyrrolidine (2.2 mL, 25.4 mmol). After 24 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (5.25 g). MS CI: m/z 256 (MH+). washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid (10.85 g, 61.6 mmol) in dichloromethane (100 mL) is added oxalyl chloride (13.5 mL, 154 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes, the reaction mixture is concentrated under vacuum. The resulting residue is dissolved in dichloromethane (100 mL), and to this solution is added ethanol (18 mL, 310 mmol). After 30 minutes, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (12.23 g). 1H NMR (CDCl3): δ 7.85-7.73 (m, 1H), 7.06-6.94 (m, 1H), 4.38 (q, 2H), 1.38 (t, 3H). the reaction mixture is concentrated under vacuum The resulting residue is dissolved in dichloromethane (100 mL) After 30 minutes washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 14.8 g, 72.4 mmol) in acetonitrile (225 mL) is added triethylamine (65 mL, 466 mmol) and pyrrolidin-3-ylcarbamic acid tert-butyl ester (16.07 g, 86.2 mmol). After 45 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford an oil. The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes) to afford the title compound. MS (ES, M+1) m/z 371, mp 98–100° C. washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated to afford an oil The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes)

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 4.32 g, 21.2 mmol) in acetonitrile (25 mL) is added triethylamine (5.9 mL, 42.3 mmol) and pyrrolidine (2.2 mL, 25.4 mmol). After 24 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (5.25 g). MS CI: m/z 256 (MH+). washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid (10.85 g, 61.6 mmol) in dichloromethane (100 mL) is added oxalyl chloride (13.5 mL, 154 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes, the reaction mixture is concentrated under vacuum. The resulting residue is dissolved in dichloromethane (100 mL), and to this solution is added ethanol (18 mL, 310 mmol). After 30 minutes, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (12.23 g). 1H NMR(CDCl3): δ 7.85–7.73 (m, 1H), 7.06–6.94 (m, 1H), 4.38 (q, 2H), 1.38 (t, 3H). the reaction mixture is concentrated under vacuum The resulting residue is dissolved in dichloromethane (100 mL) After 30 minutes washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 14.8 g, 72.4 mmol) in acetonitrile (225 mL) is added triethylamine (65 mL, 466 mmol) and pyrrolidin-3-ylcarbamic acid tert-butyl ester (16.07 g, 86.2 mmol). After 45 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford an oil. The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes) to afford the title compound. MS (ES, M+1) m/z 371, mp 98–100° C. washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated to afford an oil The resulting residue is purified by flash chromatography (1:5 ethyl acetate/hexanes)

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid ethyl ester (Example 1e, 4.32 g, 21.2 mmol) in acetonitrile (25 mL) is added triethylamine (5.9 mL, 42.3 mmol) and pyrrolidine (2.2 mL, 25.4 mmol). After 24 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (5.25 g). MS CI: m/z 256 (MH+). washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated

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

Procedure: To a solution of 2,4,5-trifluorobenzoic acid (10.85 g, 61.6 mmol) in dichloromethane (100 mL) is added oxalyl chloride (13.5 mL, 154 mmol) and N,N-dimethylformamide (1 drop). After 45 minutes, the reaction mixture is concentrated under vacuum. The resulting residue is dissolved in dichloromethane (100 mL), and to this solution is added ethanol (18 mL, 310 mmol). After 30 minutes, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (12.23 g). 1H NMR(CDCl3): δ 7.85–7.73 (m, 1H), 7.06–6.94 (m, 1H), 4.38 (q, 2H), 1.38 (t, 3H). the reaction mixture is concentrated under vacuum The resulting residue is dissolved in dichloromethane (100 mL) After 30 minutes washed with saturated NaHCO3, water, and brine The organic layer is dried over MgSO4 filtered the filtrate is concentrated

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

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

Procedure: Ethyl 2,4,5-trifluorobenzoate (135 mg, 0.661 mmol) and potassium carbonate (156 mg, 1.129 mmol) were dissolved in DMSO (3.0 mL). 5-Chloro-6-isobutoxypyridin-3-ol (Preparation 16, 127.5 mg, 0.632 mmol) was added portion wise and the mixture was stirred at room temperature for 2 hours. The reaction was diluted in EtOAc (10.0 mL) and washed with brine (3×10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0 to 10% EtOAc in heptane to yield the title compound as a clear oil that solidified upon standing (155 mg, 35%): washed with brine (3×10 mL) The organic layer was dried over sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel chromatography eluting with 0 to 10% EtOAc in heptane