1,3-bis(bromomethyl)-2-fluorobenzene

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

実験手順: A solution of 2,6-bis(bromomethyl)-1-fluorobenzene (2.82 g, 0.010 mole) and trimethylphosphite (5.0 mL, 0.042 mole) in toluene (25 mL) is heated at reflux temperature for 24 hours, after which the solvent and excess trimethylphosphite are removed under reduced pressure. The solid residue is crystallized from ethyl acetate-hexane, giving 3.12 g (0.0089 mole, 89%) of of the title compound, mp 116.5°-117.5° C. Recrystallization gives 2.64 g, mp 117°-118° C. at reflux temperature for 24 hours after which the solvent and excess trimethylphosphite are removed under reduced pressure The solid residue is crystallized from ethyl acetate-hexane

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

実験手順: A solution of 2,6-bis(bromomethyl)-1-fluorobenzene (2.82 g, 0.010 mole) and trimethylphosphite (5.0 mL, 0.042 mole) in toluene (25 mL) is heated at reflux temperature for 24 hours, after which the solvent and excess trimethylphosphite are removed under reduced pressure. The solid residue is crystallized from ethyl acetate-hexane, giving 3.12 g (0.0089 mole, 89%) of of the title compound, mp 116.5°-117.5° C. Recrystallization gives 2.64 g, mp 117°-118° C. at reflux temperature for 24 hours after which the solvent and excess trimethylphosphite are removed under reduced pressure The solid residue is crystallized from ethyl acetate-hexane

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

実験手順: A solution of 2,6-bis(bromomethyl)-1-fluorobenzene (2.82 g, 0.010 mole) and trimethylphosphite (5.0 mL, 0.042 mole) in toluene (25 mL) is heated at reflux temperature for 24 hours, after which the solvent and excess trimethylphosphite are removed under reduced pressure. The solid residue is crystallized from ethyl acetate-hexane, giving 3.12 g (0.0089 mole, 89%) of the title compound, mp 116.5°-117.5° C. Recrystallization gives 2.64 g, mp 117°-118° C. at reflux temperature for 24 hours after which the solvent and excess trimethylphosphite are removed under reduced pressure The solid residue is crystallized from ethyl acetate-hexane

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (from Step 3, Example 74) (0.3 g, 0.95 mmol) in DMF (26 mL) was added K2CO3 (0.26 g, 1.9 mmol) and 2,6-bis(bromomethyl)fluorobenzene (1.6 g, 5.7 mmol), and the reaction mixture was stirred at 110° C. for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with a 50% aqueous solution of brine, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organics were washed with water, dried (Na2SO4), filtered, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 99:1 to 95:5 methylene chloride/methanol) afforded 3-bromo-1-(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as an off-white solid (0.24 g, 49%): 1H NMR (300 MHz, CDCl3) δ 7.55-7.40 (m, 3H), 7.35-7.25 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.80 (m, 2H), 6.14 (d, J=6 Hz, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 4.50 (s, 2H). The reaction mixture was cooled to room temperature the solvent was removed under reduced pressure The residue was diluted with a 50% aqueous solution of brine the aqueous layer was extracted with EtOAc (3×50 mL) The combined organics were washed with water dried (Na2SO4) filtered the solvent was removed under reduced pressure Purification by flash column chromatography (silica, eluent 99:1 to 95:5 methylene chloride/methanol)

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one (from Step 3, Example 74) (0.3 g, 0.95 mmol) in DMF (26 mL) was added K2CO3 (0.26 g, 1.9 mmol) and 2,6-bis(bromomethyl)fluorobenzene (1.6 g, 5.7 mmol), and the reaction mixture was stirred at 110° C. for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with a 50% aqueous solution of brine, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organics were washed with water, dried (Na2SO4), filtered, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 99:1 to 95:5 methylene chloride/methanol) afforded 3-bromo-1-(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)-1H-pyridin-2-one as an off-white solid (0.24 g, 49%): 1H NMR (300 MHz, CDCl3) δ 7.55-7.40 (m, 3H), 7.35-7.25 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.80 (m, 2H), 6.14 (d, J=6 Hz, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 4.50 (s, 2H). The reaction mixture was cooled to room temperature the solvent was removed under reduced pressure The residue was diluted with a 50% aqueous solution of brine the aqueous layer was extracted with EtOAc (3×50 mL) The combined organics were washed with water dried (Na2SO4) filtered the solvent was removed under reduced pressure Purification by flash column chromatography (silica, eluent 99:1 to 95:5 methylene chloride/methanol)

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

実験手順: A solution of 2,6-bis(bromomethyl)-1-fluorobenzene (2.82 g, 0.010 mole) and trimethylphosphite (5.0 mL, 0.042 mole) in toluene (25 mL) is heated at reflux temperature for 24 hours, after which the solvent and excess trimethylphosphite are removed under reduced pressure. The solid residue is crystallized from ethyl acetate-hexane, giving 3.12 g (0.0089 mole, 89%) of of the title compound, mp 116.5°-117.5° C. Recrystallization gives 2.64 g, mp 117°-118° C. at reflux temperature for 24 hours after which the solvent and excess trimethylphosphite are removed under reduced pressure The solid residue is crystallized from ethyl acetate-hexane