methyl 3,5-difluorobenzoate

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

Procedure: To a solution of methyl 3,5-difluorobenzoate (1 gm, 5.8 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.621 gm, 5.8 mmol, 15% solution in tetrahydrofuran and heptane) was added at −78° C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.51 g, 6.9 mmol) was added drop wise to the reaction mixture and stirring was continued for about 3 hours at −78° C. The reaction was warm up to room temperature. Saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction mass. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford methyl 3,5-difluoro-4-formylbenzoate (0.5 gm, 31.25%). The resulting reaction mixture stirring was continued for about 3 hours at −78° C to quench the reaction mass The aqueous phase was extracted with ethyl acetate (3×50 mL) the combined organic layer dried over anhydrous sodium sulfate filtered concentrated The crude product was purified by column chromatography over silica gel (100-200) ethyl acetate/hexane gradient elution

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

Procedure: To a solution of 3,5-difluorobenzoic acid (10 gm, 63.2 mmol) in dichloromethane (100 mL) was added oxalyl chloride (11.96 gm, 94.9 mmol) at 0° C. followed by addition of dimethylformamide (2 mL). The resulting reaction mixture was stirred for about 3 hours at room temperature. Methanol (100 mL) was added to the reaction mass and stirring was continued further for 20-30 minutes. Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford colorless methyl 3,5-difluorobenzoate (10 gm, 91.91%). The resulting reaction mixture stirring was continued further for 20-30 minutes Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) ethyl acetate/hexane gradient elution

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

Procedure: To a solution of 3,5-difluorobenzoic acid (10 gm, 63.2 mmol) in dichloromethane (100 mL) was added oxalyl chloride (11.96 gm, 94.9 mmol) at 0° C. followed by addition of dimethylformamide (2 mL). The resulting reaction mixture was stirred for about 3 hours at room temperature. Methanol (100 mL) was added to the reaction mass and stirring was continued further for 20-30 minutes. Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford colorless methyl 3,5-difluorobenzoate (10 gm, 91.91%). The resulting reaction mixture stirring was continued further for 20-30 minutes Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) ethyl acetate/hexane gradient elution

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

Procedure: To a solution of methyl 3,5-difluorobenzoate (1 gm, 5.8 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.621 gm, 5.8 mmol, 15% solution in tetrahydrofuran and heptane) was added at −78° C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.51 g, 6.9 mmol) was added drop wise to the reaction mixture and stirring was continued for about 3 hours at −78° C. The reaction was warm up to room temperature. Saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction mass. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford methyl 3,5-difluoro-4-formylbenzoate (0.5 gm, 31.25%). The resulting reaction mixture stirring was continued for about 3 hours at −78° C to quench the reaction mass The aqueous phase was extracted with ethyl acetate (3×50 mL) the combined organic layer dried over anhydrous sodium sulfate filtered concentrated The crude product was purified by column chromatography over silica gel (100-200) ethyl acetate/hexane gradient elution

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

Procedure: To a solution of 3,5-difluorobenzoic acid (10 gm, 63.2 mmol) in dichloromethane (100 mL) was added oxalyl chloride (11.96 gm, 94.9 mmol) at 0° C. followed by addition of dimethylformamide (2 mL). The resulting reaction mixture was stirred for about 3 hours at room temperature. Methanol (100 mL) was added to the reaction mass and stirring was continued further for 20-30 minutes. Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford colorless methyl 3,5-difluorobenzoate (10 gm, 91.91%). The resulting reaction mixture stirring was continued further for 20-30 minutes Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) ethyl acetate/hexane gradient elution

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

Procedure: To a solution of methyl 3,5-difluorobenzoate (1 gm, 5.8 mmol) in dry tetrahydrofuran (20 mL), lithium diisopropylamide (0.621 gm, 5.8 mmol, 15% solution in tetrahydrofuran and heptane) was added at −78° C. The resulting reaction mixture was stirred for about 1 hour. Dimethylformamide (0.51 g, 6.9 mmol) was added drop wise to the reaction mixture and stirring was continued for about 3 hours at −78° C. The reaction was warm up to room temperature. Saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction mass. The aqueous phase was extracted with ethyl acetate (3×50 mL) and the combined organic layer dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford methyl 3,5-difluoro-4-formylbenzoate (0.5 gm, 31.25%). The resulting reaction mixture stirring was continued for about 3 hours at −78° C to quench the reaction mass The aqueous phase was extracted with ethyl acetate (3×50 mL) the combined organic layer dried over anhydrous sodium sulfate filtered concentrated The crude product was purified by column chromatography over silica gel (100-200) ethyl acetate/hexane gradient elution

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

Procedure: To a solution of 3,5-difluorobenzoic acid (10 gm, 63.2 mmol) in dichloromethane (100 mL) was added oxalyl chloride (11.96 gm, 94.9 mmol) at 0° C. followed by addition of dimethylformamide (2 mL). The resulting reaction mixture was stirred for about 3 hours at room temperature. Methanol (100 mL) was added to the reaction mass and stirring was continued further for 20-30 minutes. Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) using ethyl acetate/hexane gradient elution to afford colorless methyl 3,5-difluorobenzoate (10 gm, 91.91%). The resulting reaction mixture stirring was continued further for 20-30 minutes Solvents were evaporated to obtain an oily mass which was further purified by column chromatography over silica gel (100-200) ethyl acetate/hexane gradient elution