2-bromo-5-ethoxybenzaldehyde

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a degassed solution of 2-bromo-5-ethoxybenzaldehye (300 mg, 1.31 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (53.8 mg, 0.131 mmol; S-Phos ligand), palladium (II) acetate (14.7 mg, 0.065 mmol) in THF (8 mL) were added K3PO4 (834 mg, 3.93 mmol) and (2,3,4-trifluorophenyl)boronic acid (276, 1.57 mmol). Reaction mixture was stirred at 70° C. under a N2 atmosphere for 16 hours, cooled to room temperature and then filtered. The filtrate was concentrated by evaporation under reduced pressure. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to provide the title intermediate (255 mg) as white solid. Reaction mixture cooled to room temperature filtered The filtrate was concentrated by evaporation under reduced pressure The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g, 24.87 mmol) in DMF (20 mL) was added iodoethane (5.82 g, 37.3 mmol) and K2CO3 (6.88 g, 49.7 mmol) portion wise. The resulting reaction mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with EtOAc/hexanes (1:1) and water. Layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate (4.6 g) as white solid. The resulting reaction mixture After cooling Layers were separated the organic layer was washed with brine dried over sodium sulfate filtered concentrated

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a degassed solution of 2-bromo-5-ethoxybenzaldehye (300 mg, 1.31 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (53.8 mg, 0.131 mmol; S-Phos ligand), palladium (II) acetate (14.7 mg, 0.065 mmol) in THF (8 mL) were added K3PO4 (834 mg, 3.93 mmol) and (2,3,4-trifluorophenyl)boronic acid (276, 1.57 mmol). Reaction mixture was stirred at 70° C. under a N2 atmosphere for 16 hours, cooled to room temperature and then filtered. The filtrate was concentrated by evaporation under reduced pressure. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to provide the title intermediate (255 mg) as white solid. Reaction mixture cooled to room temperature filtered The filtrate was concentrated by evaporation under reduced pressure The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a degassed solution of 2-bromo-5-ethoxybenzaldehye (300 mg, 1.31 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (53.8 mg, 0.131 mmol; S-Phos ligand), palladium (II) acetate (14.7 mg, 0.065 mmol) in THF (8 mL) were added K3PO4 (834 mg, 3.93 mmol) and (2,3,4-trifluorophenyl)boronic acid (276, 1.57 mmol). Reaction mixture was stirred at 70° C. under a N2 atmosphere for 16 hours, cooled to room temperature and then filtered. The filtrate was concentrated by evaporation under reduced pressure. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to provide the title intermediate (255 mg) as white solid. Reaction mixture cooled to room temperature filtered The filtrate was concentrated by evaporation under reduced pressure The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g, 24.87 mmol) in DMF (20 mL) was added iodoethane (5.82 g, 37.3 mmol) and K2CO3 (6.88 g, 49.7 mmol) portion wise. The resulting reaction mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with EtOAc/hexanes (1:1) and water. Layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate (4.6 g) as white solid. The resulting reaction mixture After cooling Layers were separated the organic layer was washed with brine dried over sodium sulfate filtered concentrated

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: 2-Bromo-5-hydroxybenzaldehyde (0.96 g, 4.8 mmol) was dissolved in anhydrous DMSO (10 mL). Iodoethane (0.50 mL, 6.2 mmol) and Cs2CO3 (1.9 g, 6.3 mmol) were added and the mixture stirred at room temperature for 1.5 hours. Additional Cs2CO3 (1.45 g, 4.8 mmol) was added to the reaction mixture and then was stirred for 30 minutes. The reaction mixture was diluted with H2O and EtOAc and the layers were separated. Brine was added to the aqueous layer and it was extracted twice with EtOAc. The combined organics were washed with 1M NaOH twice and brine thrice, and then was dried over MgSO4. The solution was vacuum-filtered through Celite® and concentrated in vacuo to give 1.08 g of 2-bromo-5-ethoxybenzaldehyde. 2-Bromo-5-ethoxy-benzaldehyde (1.02 g, 4.45 mmol) was dissolved in anhydrous toluene (10 mL) under N2. Diethyl phosphite (0.57 mL, 4.4 mmol), then MgO (0.45 g, 11.2 mmol) was added and the N2 inlet was removed. The mixture was stirred at room temperature for 1.75 hours, and more diethyl phosphite (0.1 mL, 0.77 mmol) was then added. The mixture was stirred for an additional 2.75 hours, then diluted with EtOAc, H2O, and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine, dried over MgSO4, vacuum-filtered through Celite® and conc in vacuo to give 1.70 g of crude material. The product was used without purification. Diethyl(2-bromo-5-ethoxyphenyl)-(hydroxy)-methyl-phosphonate (1.13 g, 3.08 mmol) was dissolved in anhydrous dichloromethane (13 mL). Pyridinium chlorochromate (1.22 g, 4.6 mmol) was added and the mixture was stirred at room temperature for 17 hours at which time additional pyridinium chlorochromate (1.1 g, 5.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and then was refluxed for 45 minutes under a drying tube. The reaction was diluted with dichloromethane and washed with H2O and saturated aq. NaHCO3, dried over MgSO4, vacuum-filtered through Celite® and concentrated in vacuo. The product was chromatographed (EtOAc-hexanes) to give diethyl(2-bromo-5-ethoxyphenyl)-oxomethylphosphonate. The diethyl (2-bromo-5-ethoxyphenyl)oxo-methyl-phosphonate was reacted with DAST according to Example 80C to give diethyl (2-bromo-5-ethoxyphenyl)difluoromethylphosphonate. Compound 93 was synthesized according to procedures similar to those of Example 40 from this corresponding diethyl phosphonate. MS (ES-): m/z 329.0, 331.0 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.56 (d, J=8.8, 1H), 7.11 (d, J=2.7, 1H), 6.97 (dd, J=2.7, 8.8, 1H), 4.01 (q, J=7.2, 2H), 1.30 (t, J=7.2, 3H). was stirred for 30 minutes the layers were separated Brine was added to the aqueous layer and it was extracted twice with EtOAc The combined organics were washed with 1M NaOH twice brine thrice, and then was dried over MgSO4 The solution was vacuum-filtered through Celite® concentrated in vacuo

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

実験手順: 2-Bromo-5-hydroxybenzaldehyde (0.96 g, 4.8 mmol) was dissolved in anhydrous DMSO (10 mL). Iodoethane (0.50 mL, 6.2 mmol) and Cs2CO3 (1.9 g, 6.3 mmol) were added and the mixture stirred at room temperature for 1.5 hours. Additional Cs2CO3 (1.45 g, 4.8 mmol) was added to the reaction mixture and then was stirred for 30 minutes. The reaction mixture was diluted with H2O and EtOAc and the layers were separated. Brine was added to the aqueous layer and it was extracted twice with EtOAc. The combined organics were washed with 1M NaOH twice and brine thrice, and then was dried over MgSO4. The solution was vacuum-filtered through Celite® and concentrated in vacuo to give 1.08 g of 2-bromo-5-ethoxybenzaldehyde. 2-Bromo-5-ethoxy-benzaldehyde (1.02 g, 4.45 mmol) was dissolved in anhydrous toluene (10 mL) under N2. Diethyl phosphite (0.57 mL, 4.4 mmol), then MgO (0.45 g, 11.2 mmol) was added and the N2 inlet was removed. The mixture was stirred at room temperature for 1.75 hours, and more diethyl phosphite (0.1 mL, 0.77 mmol) was then added. The mixture was stirred for an additional 2.75 hours, then diluted with EtOAc, H2O, and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine, dried over MgSO4, vacuum-filtered through Celite® and conc in vacuo to give 1.70 g of crude material. The product was used without purification. Diethyl (2-bromo-5-ethoxyphenyl)-(hydroxy)-methyl-phosphonate (1.13 g, 3.08 mmol) was dissolved in anhydrous dichloromethane (13 mL). Pyridinium chlorochromate (1.22 g, 4.6 mmol) was added and the mixture was stirred at room temperature for 17 hours at which time additional pyridinium chlorochromate (1.1 g, 5.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and then was refluxed for 45 minutes under a drying tube. The reaction was diluted with dichloromethane and washed with H2O and saturated aq. NaHCO3, dried over MgSO4, vacuum-filtered through Celite® and concentrated in vacuo. The product was chromatographed (EtOAc-hexanes) to give diethyl (2-bromo-5-ethoxyphenyl)-oxomethylphosphonate. The diethyl (2-bromo-5-ethoxyphenyl)oxo-methyl-phosphonate was reacted with DAST according to Example 80C to give diethyl (2-bromo-5-ethoxyphenyl)difluoromethylphosphonate. Compound 93 was synthesized according to procedures similar to those of Example 40 from this corresponding diethyl phosphonate. MS (ES−): m/z 329.0, 331.0 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.56 (d, J=8.8, 1H), 7.11 (d, J=2.7, 1H), 6.97 (dd, J=2.7, 8.8, 1H), 4.01 (q, J=7.2, 2H), 1.30 (t, J=7.2, 3H). the N2 inlet was removed The mixture was stirred for an additional 2.75 hours The layers were separated the organic layer was washed with brine dried over MgSO4 vacuum-filtered through Celite® and conc in vacuo to give 1.70 g of crude material The product was used without purification was added The mixture was stirred at room temperature for 3 hours was refluxed for 45 minutes under a drying tube washed with H2O and saturated aq. NaHCO3 dried over MgSO4 vacuum-filtered through Celite® concentrated in vacuo The product was chromatographed (EtOAc-hexanes)

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

実験手順: 2-Bromo-5-hydroxybenzaldehyde (0.96 g, 4.8 mmol) was dissolved in anhydrous DMSO (10 mL). Iodoethane (0.50 mL, 6.2 mmol) and Cs2CO3 (1.9 g, 6.3 mmol) were added and the mixture stirred at room temperature for 1.5 hours. Additional Cs2CO3 (1.45 g, 4.8 mmol) was added to the reaction mixture and then was stirred for 30 minutes. The reaction mixture was diluted with H2O and EtOAc and the layers were separated. Brine was added to the aqueous layer and it was extracted twice with EtOAc. The combined organics were washed with 1M NaOH twice and brine thrice, and then was dried over MgSO4. The solution was vacuum-filtered through Celite® and concentrated in vacuo to give 1.08 g of 2-bromo-5-ethoxybenzaldehyde. 2-Bromo-5-ethoxy-benzaldehyde (1.02 g, 4.45 mmol) was dissolved in anhydrous toluene (10 mL) under N2. Diethyl phosphite (0.57 mL, 4.4 mmol), then MgO (0.45 g, 11.2 mmol) was added and the N2 inlet was removed. The mixture was stirred at room temperature for 1.75 hours, and more diethyl phosphite (0.1 mL, 0.77 mmol) was then added. The mixture was stirred for an additional 2.75 hours, then diluted with EtOAc, H2O, and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine, dried over MgSO4, vacuum-filtered through Celite® and conc in vacuo to give 1.70 g of crude material. The product was used without purification. Diethyl (2-bromo-5-ethoxyphenyl)-(hydroxy)-methyl-phosphonate (1.13 g, 3.08 mmol) was dissolved in anhydrous dichloromethane (13 mL). Pyridinium chlorochromate (1.22 g, 4.6 mmol) was added and the mixture was stirred at room temperature for 17 hours at which time additional pyridinium chlorochromate (1.1 g, 5.1 mmol) was added. The mixture was stirred at room temperature for 3 hours, and then was refluxed for 45 minutes under a drying tube. The reaction was diluted with dichloromethane and washed with H2O and saturated aq. NaHCO3, dried over MgSO4, vacuum-filtered through Celite® and concentrated in vacuo. The product was chromatographed (EtOAc-hexanes) to give diethyl (2-bromo-5-ethoxyphenyl)-oxomethylphosphonate. The diethyl (2-bromo-5-ethoxyphenyl)oxo-methyl-phosphonate was reacted with DAST according to Example 80C to give diethyl (2-bromo-5-ethoxyphenyl)difluoromethylphosphonate. Compound 93 was synthesized according to procedures similar to those of Example 40 from this corresponding diethyl phosphonate. MS (ES−): m/z 329.0, 331.0 (M−H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.56 (d, J=8.8, 1H), 7.11 (d, J=2.7, 1H), 6.97 (dd, J=2.7, 8.8, 1H), 4.01 (q, J=7.2, 2H), 1.30 (t, J=7.2, 3H). was stirred for 30 minutes the layers were separated Brine was added to the aqueous layer and it was extracted twice with EtOAc The combined organics were washed with 1M NaOH twice brine thrice, and then was dried over MgSO4 The solution was vacuum-filtered through Celite® concentrated in vacuo

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a degassed solution of 2-bromo-5-ethoxybenzaldehye (300 mg, 1.31 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (53.8 mg, 0.131 mmol; S-Phos ligand), palladium (II) acetate (14.7 mg, 0.065 mmol) in THF (8 mL) were added K3PO4 (834 mg, 3.93 mmol) and (2,3,4-trifluorophenyl)boronic acid (276, 1.57 mmol). Reaction mixture was stirred at 70° C. under a N2 atmosphere for 16 hours, cooled to room temperature and then filtered. The filtrate was concentrated by evaporation under reduced pressure. The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes to provide the title intermediate (255 mg) as white solid. Reaction mixture cooled to room temperature filtered The filtrate was concentrated by evaporation under reduced pressure The residue was purified on a silica gel column eluting with 5 to 10% EtOAc in hexanes

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-bromo-5-hydroxybenzaldehyde (5 g, 24.87 mmol) in DMF (20 mL) was added iodoethane (5.82 g, 37.3 mmol) and K2CO3 (6.88 g, 49.7 mmol) portion wise. The resulting reaction mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with EtOAc/hexanes (1:1) and water. Layers were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the title intermediate (4.6 g) as white solid. The resulting reaction mixture After cooling Layers were separated the organic layer was washed with brine dried over sodium sulfate filtered concentrated