2,3-difluoro-6-methoxybenzaldehyde

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

Procedure: To a stirred solution of 5-bromo-2,4-dichloropyrimidine (Aldrich, 3.02 g, 13.25 mmol) in 20 mL of THF at −30° C., isopropyl magnesium chloride (Aldrich, 2M solution in THF, 7.12 mL, 13.25 mmol) was added dropwise and the mixture was stirred for 20 minutes. Then 2,3-difluoro-6-methoxy-benzaldehyde (Matrix, 2.28 g, 13.25 mmol) was added and the mixture was warmed to 0° C. and stirred for 40 minutes. The reaction was quenched with saturated ammonium chloride solution and the resulting mixture was extracted with EtOAc. The extract was dried with sodium sulfate. The solvent was removed on a rotary evaporator and the solid was treated with hexane (8 mL). The solid was filtered and dried to give an off-white solid. 3.42 g; Yield, 80.5%. MS (M+H)+, 322. stirred for 40 minutes The reaction was quenched with saturated ammonium chloride solution the resulting mixture was extracted with EtOAc The extract was dried with sodium sulfate The solvent was removed on a rotary evaporator the solid was treated with hexane (8 mL) The solid was filtered dried to give an off-white solid Yield

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

Procedure: To a solution of 2,3-difluoro-6-methoxybenzaldehyde (2.58 g) in methylene chloride (45 mL) was added 3-chloroperbenzoic acid (5.97 g) under ice-cooling, and the mixture was heated for reflux overnight. The reaction mixture was cooled in ice. To the mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 20 minutes. The organic layer was separated and washed with water twice, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL)-methanol (7.5 mL). To the solution was added sodium methoxide (28% methanol solution, 3.75 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) and column chromatography on aminopropylated silica gel (eluent: ethyl acetate/methanol=9/1−3/2) successively to give the title compound (1.7 g). cooling the mixture was heated for reflux overnight The reaction mixture was cooled in ice The organic layer was separated washed with water twice a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was dissolved in tetrahydrofuran (15 mL)-methanol (7.5 mL) To the solution was added sodium methoxide (28% methanol solution, 3.75 mL) the mixture was stirred at room temperature for 1 hour The reaction mixture was poured into 1 mol/L hydrochloric acid the resulting mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) and column chromatography on aminopropylated silica gel (eluent: ethyl acetate/methanol=9/1−3/2) successively

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

Procedure: To a solution of 2,3-difluoro-6-methoxybenzaldehyde (2.58 g) in methylene chloride (45 mL) was added 3-chloroperbenzoic acid (5.97 g) under ice-cooling, and the mixture was heated for reflux overnight. The reaction mixture was cooled in ice. To the mixture was added 10% aqueous sodium sulfite solution, and the resulting mixture was stirred for 20 minutes. The organic layer was separated and washed with water twice, a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL)-methanol (7.5 mL). To the solution was added sodium methoxide (28% methanol solution, 3.75 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) and column chromatography on aminopropylated silica gel (eluent: ethyl acetate/methanol=9/1−3/2) successively to give the title compound (1.7 g). cooling the mixture was heated for reflux overnight The reaction mixture was cooled in ice The organic layer was separated washed with water twice a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was dissolved in tetrahydrofuran (15 mL)-methanol (7.5 mL) To the solution was added sodium methoxide (28% methanol solution, 3.75 mL) the mixture was stirred at room temperature for 1 hour The reaction mixture was poured into 1 mol/L hydrochloric acid the resulting mixture was extracted with ethyl acetate The extract was washed with brine dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) and column chromatography on aminopropylated silica gel (eluent: ethyl acetate/methanol=9/1−3/2) successively

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (14.6 mL, 103.5 mmol) in dry THF (50 mL) cooled to −78° C. was added a solution of BuLi (1.6 M in hexane, 47 mL, 75.9 mmol) dropwise under argon, keeping the temperature below −60° C. It was stirred at this temperature for 15 minutes after which a solution of 1,2-difluoro-4-(methyloxy)benzene (10 g, 69 mmol) in dry THF (50 mL) was added slowly. The mixture was left stirring at −78° C. for 45 minutes followed by slow addition of DMF (6.37 mL, 82.8 mmol) maintaining the temperature below −60° C. The resulting mixture was stirred at −78° C. for circa 3.5 hours after which water (100 mL) was added and the cooling removed to allow it to warm up to room temperature. It was diluted with EtOAc and the organic separated. The aqueous was re-extracted with EtOAc (3×) and the combined organics washed with brine and dried over MgSO4. The crude material (10.26 g) was purified by flash chromatography to afford the title compound (D25) (9 g). the temperature below −60° C was added slowly The mixture was left maintaining the temperature below −60° C was added the cooling removed to warm up to room temperature It was diluted with EtOAc The aqueous was re-extracted with EtOAc (3×) the combined organics washed with brine dried over MgSO4 The crude material (10.26 g) was purified by flash chromatography

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

Procedure: At 20-25° C., a solution of 29.4 g of 2-methoxy-5,6-difluorobenzaldehyde (according to Ex. 27 of WO 97/03071) was added dropwise with stirring to a mixture of 16.0 g of hydroxylamine hydrochloride, 18.9 g of sodium acetate and 110 ml of 90% strength aqueous methanol. The mixture was stirred for 16 hours, the methanol was evaporated, the mixture was made into a paste using 250 ml of water and then washed and dried, giving 28.3 g of the desired product of m.p. 199-201° C. the methanol was evaporated washed dried

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

Procedure: At 20-25° C., a solution of 29.4 g of 2-methoxy-5,6-difluorobenzaldehyde (according to Ex. 27 of WO 97/03071) was added dropwise with stirring to a mixture of 16.0 g of hydroxylamine hydrochloride, 18.9 g of sodium acetate and 110 ml of 90% strength aqueous methanol. The mixture was stirred for 16 hours, the methanol was evaporated, the mixture was made into a paste using 250 ml of water and then washed and dried, giving 28.3 g of the desired product of m.p. 199-201° C. the methanol was evaporated washed dried

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

Procedure: At 20-25° C., a solution of 29.4 g of 2-methoxy-5,6-difluorobenzaldehyde (according to Ex. 27 of WO 97/03071) was added dropwise with stirring to a mixture of 16.0 g of hydroxylamine hydrochloride, 18.9 g of sodium acetate and 110 ml of 90% strength aqueous methanol. The mixture was stirred for 16 hours, the methanol was evaporated, the mixture was made into a paste using 250 ml of water and then washed and dried, giving 28.3 g of the desired product of m.p. 199-201° C. the methanol was evaporated washed dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl thioglycolate (28.8 mL, 320 mmol) was added under nitrogen to a solution of triethylamine (86.6 mL) in dry NN-dimethylformamide (220 mL) at 80° C. Stirred at 100° C. for 15 mins. A solution of 2,3-difluoro-6-methoxybenzaldehyde (55.1 g, 320 mmol) in N,N-dimethylformamide (80mL) was added and the mixture heated at 130° C. for 3h. Allowed to cool then poured onto ice-water (2L). The resulting yellow solid was filtered, washing with water (2×200 mL). Dried under vacuum over phosphorus pentoxide at room temperature overnight to give the title compound (67.2 g, 87%); δH (300 MHz, CDCl3) 8.20 (1H, d, ArH), 7.06 (1H, t, ArH), 6.68 (1H, m, ArH) and 3.99 (6H, s, OCH3 and CO2CH3). the mixture heated at 130° C. for 3h Allowed to cool The resulting yellow solid was filtered washing with water (2×200 mL) Dried under vacuum over phosphorus pentoxide at room temperature overnight