methyl 3-fluoro-4-formylbenzoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In the same manner as that described in Example 3(3), a reaction was carried out using methyl 3-fluoro-4-formylbenzoate (105 mg, 0.58 mmol) obtained in Example 5(1), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (207 mg, 0.58 mmol) and p-toluenesulfonic acid monohydrate (199 mg, 1.04 mmol) and the reaction mixture was treated according to a similar procedure to that described in Example 3(3) to give methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-3-fluorobenzoate (trans isomer, 106 mg, yield 35%) and methyl 4-[cis-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-3-fluorobenzoate (cis isomer, 29 mg, yield 10%) as a colorless oil. the reaction mixture was treated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-fluoro-4-bromomethylbenzoate (80 mg, 0.32 mmol), described in J. Med. Chem., 35(5) 877 (1992), was dissolved in a mixture of anhydrous dimethyl sulfoxide (4.5 ml) and anhydrous dichloromethane (3 ml). To the solution cooled to 0° C. was added dropwise with stirring triethylamine N-oxide dihydrate (180 mg, 1.62 mmol) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:10) as the eluant to give methyl 3-fluoro-4-formylbenzoate (29 mg, yield 48%) as a white solid. NMR spectrum (400 MHz, CDCl3) δ ppm: 3.97 (3H, s), 7.85 (1H, d, J=11 Hz), 7.9-8.0 (2H, m), 10.43 (1H, s). Mass spectrum m/z (EI): 182 (M+, 100%). this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water The organic layer was washed with saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was chromatographed on a silica gel column

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 3-fluoro-4-bromomethylbenzoate (80 mg, 0.32 mmol), described in J. Med. Chem., 35(5) 877 (1992), was dissolved in a mixture of anhydrous dimethyl sulfoxide (4.5 ml) and anhydrous dichloromethane (3 ml). To the solution cooled to 0° C. was added dropwise with stirring triethylamine N-oxide dihydrate (180 mg, 1.62 mmol) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:10) as the eluant to give methyl 3-fluoro-4-formylbenzoate (29 mg, yield 48%) as a white solid. NMR spectrum (400 MHz, CDCl3) δ ppm: 3.97 (3H, s), 7.85 (1H, d, J=11 Hz), 7.9-8.0 (2H, m), 10.43 (1H, s). Mass spectrum m/z (EI): 182 (M+, 100%). this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water The organic layer was washed with saturated aqueous sodium chloride solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was chromatographed on a silica gel column

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 80% NaClO2 (0.13 mol) in H2O (50 mL) is added dropwise to a solution of crude 3-fluoro-4-formyl benzoic acid methyl ester (4, 0.12 mol) and sulfamic acid (0.13 mol) in H2O (50 mL) and CH3CN (100 mL). After stirring for 1 h, the reaction mixture is poured into saturated Na2SO3 aqueous solution and 1 N HCl, and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, and evaporated in vacuo. The crystals are collected by filtration and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 4-methyl ester (5) as white solid. extracted three times with EtOAc The combined organic layers are washed with brine dried over MgSO4 evaporated in vacuo The crystals are collected by filtration washed with ether/hexane (1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 80% NaClO2 (0.13 mol) in H2O (50 mL) is added dropwise to a solution of crude 3-fluoro-4-formyl benzoic acid methyl ester (4, 0.12 mol) and sulfamic acid (0.13 mol) in H2O (50 mL) and CH3CN (100 mL). After stirring for 1 h, the reaction mixture is poured into saturated Na2SO3 aqueous solution and 1 N HCl, and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, and evaporated in vacuo. The crystals are collected by filtration and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 4-methyl ester (5) as white solid. extracted three times with EtOAc The combined organic layers are washed with brine dried over MgSO4 evaporated in vacuo The crystals are collected by filtration washed with ether/hexane (1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 80% NaClO2 (0.13 mol) in H2O (50 mL) is added dropwise to a solution of crude 3-fluoro-4-formyl benzoic acid methyl ester (4, 0.12 mol) and sulfamic acid (0.13 mol) in H2O (50 mL) and CH3CN (100 mL). After stirring for 1 h, the reaction mixture is poured into saturated Na2SO3 aqueous solution and 1 N HCl, and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, and evaporated in vacuo. The crystals are collected by filtration and washed with ether/hexane (1:1) to give 2-fluoroterephthalic acid 4-methyl ester (5) as white solid. extracted three times with EtOAc The combined organic layers are washed with brine dried over MgSO4 evaporated in vacuo The crystals are collected by filtration washed with ether/hexane (1:1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 60% NaH (0.14 mol) is added portionwise to a solution of 3-fluoro-4-formyl benzoic acid (3, 0.12 mol) in dry DMF (330 mL). The mixture is stirred at room temperature for 30 min. Methyl iodide (0.14 mol) is added dropwise to the mixture. After stirring at room temperature for 5 h, the reaction mixture is poured into 1 N HCl (ca. 1000 mL) and extracted twice with EtOAc. The combined organic layers are washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and evaporated in vacuo to give crude 3-fluoro-4-formyl benzoic acid methyl ester (4). After stirring at room temperature for 5 h extracted twice with EtOAc The combined organic layers are washed with saturated aqueous NaHCO3, brine dried over MgSO4 evaporated in vacuo