2,4-dibromo-1-fluorobenzene

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: 14.1 g of 30% strength sodium methylate solution was added to 10.9 g (0.078 mol) of methyl 2-methylimidazole-4-carboxylate in 100 ml of dimethylformamide; the methanol which formed was removed completely. 38.1 g (0.15 mol) of 1-fluoro-2,4-dibromobenzene was added to the dimethylformamide solution remaining, and the mixture was refluxed for 2 hours. Water was then added, extraction carried out with ethyl acetate and the ethyl acetate phase was washed with water. After removal of the solvent from the organic phase, there was obtained a residue which crystallized on trituration with diisopropyl ether. was removed completely the mixture was refluxed for 2 hours extraction the ethyl acetate phase was washed with water After removal of the solvent from the organic phase there was obtained a residue which crystallized on trituration with diisopropyl ether

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

Procedure: 14.1 g of 30% strength sodium methylate solution was added to 10.9 g (0.078 mol) of methyl 2-methylimidazole-4-carboxylate in 100 ml of dimethylformamide; the methanol which formed was removed completely. 38.1 g (0.15 mol) of 1-fluoro-2,4-dibromobenzene was added to the dimethylformamide solution remaining, and the mixture was refluxed for 2 hours. Water was then added, extraction carried out with ethyl acetate and the ethyl acetate phase was washed with water. After removal of the solvent from the organic phase, there was obtained a residue which crystallized on trituration with diisopropyl ether. was removed completely the mixture was refluxed for 2 hours extraction the ethyl acetate phase was washed with water After removal of the solvent from the organic phase there was obtained a residue which crystallized on trituration with diisopropyl ether

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

Procedure: A solution of 2,4-dibromofluorobenzene (12.7 g, containing 30% 3,4-dibromofluorobenzene) in dry tetrahydrofuran (THF) (10 ml) is added over 5 min to a stirred suspension of magnesium turnings (1.15 g) in dry THF (50 ml) under an atmosphere of nitrogen and cooled in a water bath. After 1 hour, when all the magnesium has reacted, this reagent is added over 20 min to a stirred solution of trimethoxyborane (7 ml) in dry diethyl ether (80 ml) under an atmosphere of nitrogen and cooled at -78° C. The mixture is stirred at -78° C. for a further 15 min. and glacial acetic acid (6 ml) added followed by water (50 ml). The mixture is warmed to room temperature, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The residue is stirred with carbon tetrachloride (30 ml) and then cooled at 0° C. The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off and washed with a little carbon tetrachloride. Yield 2.8 g m.pt. 173°-174° C. cooled in a water bath The mixture is warmed to room temperature extracted with diethyl ether (x3) washed with water dried the solvent evaporated under reduced pressure The residue is stirred with carbon tetrachloride (30 ml) cooled at 0° C The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off washed with a little carbon tetrachloride

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

Procedure: A solution of 2,4-dibromofluorobenzene (12.7 g, containing 30% 3,4-dibromofluorobenzene) in dry tetrahydrofuran (THF) (10 ml) is added over 5 min to a stirred suspension of magnesium turnings (1.15 g) in dry THF (50 ml) under an atmosphere of nitrogen and cooled in a water bath. After 1 hour, when all the magnesium has reacted, this reagent is added over 20 min to a stirred solution of trimethoxyborane (7 ml) in dry diethyl ether (80 ml) under an atmosphere of nitrogen and cooled at -78° C. The mixture is stirred at -78° C. for a further 15 min. and glacial acetic acid (6 ml) added followed by water (50 ml). The mixture is warmed to room temperature, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The residue is stirred with carbon tetrachloride (30 ml) and then cooled at 0° C. The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off and washed with a little carbon tetrachloride. Yield 2.8 g m.pt. 173°-174° C. cooled in a water bath The mixture is warmed to room temperature extracted with diethyl ether (x3) washed with water dried the solvent evaporated under reduced pressure The residue is stirred with carbon tetrachloride (30 ml) cooled at 0° C The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off washed with a little carbon tetrachloride

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

Procedure: 14.1 g of 30% strength sodium methylate solution was added to 10.9 g (0.078 mol) of methyl 2-methylimidazole-4-carboxylate in 100 ml of dimethylformamide; the methanol which formed was removed completely. 38.1 g (0.15 mol) of 1-fluoro-2,4-dibromobenzene was added to the dimethylformamide solution remaining, and the mixture was refluxed for 2 hours. Water was then added, extraction carried out with ethyl acetate and the ethyl acetate phase was washed with water. After removal of the solvent from the organic phase, there was obtained a residue which crystallized on trituration with diisopropyl ether. was removed completely the mixture was refluxed for 2 hours extraction the ethyl acetate phase was washed with water After removal of the solvent from the organic phase there was obtained a residue which crystallized on trituration with diisopropyl ether

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

Procedure: 1,3-Dibromo-4-fluorobenzene (837 mg) was dissolved in a toluene-THF (10:1) mixture (15 ml). The mixture was cooled to −78° C. and n-butyllithium (2.64 M, 1.19 ml) was added dropwise. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (200 mg) in toluene-THF (10:1) (5.0 ml) and a boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time. After stirring at the same temperature for three hours, the reaction was terminated with an ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (365 mg). a boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time After stirring at the same temperature for three hours the reaction was terminated with an ammonium chloride solution The aqueous layer was extracted with ethyl acetate the organic layer was washed with water and brine The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography

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

Procedure: 1,3-Dibromo-4-fluorobenzene (837 mg) was dissolved in a toluene-THF (10:1) mixture (15 ml). The mixture was cooled to −78° C. and n-butyllithium (2.64 M, 1.19 ml) was added dropwise. After stirring at the same temperature for one hour, a solution of (±)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c]isoxazole obtained in Preparation Example 1-(2) (200 mg) in toluene-THF (10:1) (5.0 ml) and a boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time. After stirring at the same temperature for three hours, the reaction was terminated with an ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (365 mg). a boron trifluoride-diethyl ether complex (394 μl) were added dropwise at the same time After stirring at the same temperature for three hours the reaction was terminated with an ammonium chloride solution The aqueous layer was extracted with ethyl acetate the organic layer was washed with water and brine The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography

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

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

Procedure: 14.1 g of 30% strength sodium methylate solution was added to 10.9 g (0.078 mol) of methyl 2-methylimidazole-4-carboxylate in 100 ml of dimethylformamide; the methanol which formed was removed completely. 38.1 g (0.15 mol) of 1-fluoro-2,4-dibromobenzene was added to the dimethylformamide solution remaining, and the mixture was refluxed for 2 hours. Water was then added, extraction carried out with ethyl acetatem and the ethyl acetate phase was washed with water. After removal of the solvent from the organic phase, there was obtained a residue which crystallized on trituration with diisopropyl ether. was removed completely the mixture was refluxed for 2 hours extraction the ethyl acetate phase was washed with water After removal of the solvent from the organic phase there was obtained a residue which crystallized on trituration with diisopropyl ether