methyl 2,3,4,5,6-pentafluorobenzoate

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

実験手順: In 500 ml of N,N-dimethylformamide was suspended 10.2 g of 60% sodium hydride. Thereinto was dropped 55.0 g of di-tert-butyl malonate in 1 hour with ice-cooling. The resulting mixture was stirred for 10 minutes at the same temperature. Thereto was added 48.0 g of methyl pentafluorbenzoate. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was added to a mixture of 1 liter of water and 400 ml of ethyl acetate. The resulting mixture was adjusted to pH 3 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in 150 ml of trifluoroacetic acid. The resulting solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. To the residue obtained were added 200 ml of diethyl ether and 600 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue obtained was added 50 ml of toluene. The resulting mixture was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and n-hexane was added to the residue obtained. The resulting crystals were collected by filtration to obtain 31.3 g (yield: 55.5%) of methyl 4-carboxymethyl-2,3,5,6-tetrafluorobenzoate. cooling The resulting mixture was stirred for 2 hours at room temperature The organic layer was separated washed with water a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure The residue obtained The resulting solution was stirred at room temperature for 20 hours The reaction mixture was concentrated under reduced pressure To the residue obtained The organic layer was separated washed with water a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure To the residue obtained The resulting mixture was refluxed for 1.5 hours The reaction mixture was concentrated under reduced pressure, and n-hexane was added to the residue obtained The resulting crystals were collected by filtration

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

実験手順: All reaction steps were carried out with protection from light due to the sensitive nature of the azido group. First, a mixture of NaN3 (300 mg, 4.6 mmol) and methyl pentafluorobenzoate (0.972 g, 4.3 mmol) in acetone (8 mL) and water (3 mL) was refluxed for 8 hours. The mixture was cooled, diluted with 10 mL of water, and then extracted with diethyl ether (3×10 mL). The extract was dried (anhydrous Na2SO4) and evaporated to give methyl 4-azido-2,3,5,6-tetrafluorobenzoate (1.01 g, 94%), as off-white flakes, mp 53.6-54.3° C. All reaction steps was refluxed for 8 hours The mixture was cooled extracted with diethyl ether (3×10 mL) The extract was dried (anhydrous Na2SO4) evaporated

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl pentafluorobenzoate (41.4 g, 183 mmol) was treated with N-methylpyrrolidinone (36.0 g) and the solution stirred and cooled to 5° C. under a N2 atmosphere. Benzylamine (19.8 g, 185 mmol) was added dropwise over 27 min. at 5° C.–20° C. The resulting thick yellow slurry was cooled to 2° C. over 25 min. and N,N-diisopropyl ethylamine (27.0 g, 209 mmol) was added over 30 min. at 3° C.–10° C. The mixture was allowed to warm to 18° C. and stirred for 2 hrs. It was then heated to 60° C. and stirred another 2 hs at 58° C.–67° C. The resulting solution was cooled to room temperature and stirred overnight. The mixture was treated with toluene (200 mL) and methyl tert-butyl ether (120 mL) and extracted with water (150 mL) followed by 10% aqueous acetic acid (2×50 mL). The organic layer was concentrated to a solid, which was recrystallized from toluene (45 mL) and heptane (50 mL). After cooling to −20° C., the crystals were collected, washed with heptane (2×25 mL) and vacuum dried at 35° C. to give methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (49.3 g, 157 mmol): mp 96–97° C. The resulting thick yellow slurry was cooled to 2° C. over 25 min. to warm to 18° C. stirred for 2 hrs It was then heated to 60° C. stirred another 2 hs at 58° C.–67° C The resulting solution was cooled to room temperature stirred overnight extracted with water (150 mL) The organic layer was concentrated to a solid, which was recrystallized from toluene (45 mL) and heptane (50 mL) After cooling to −20° C. the crystals were collected washed with heptane (2×25 mL) and vacuum dried at 35° C.

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

実験手順: A mixture of NaN3 (0.6 g, 9.22 mmol) and methyl pentafluorobenzoate (1.76 g, 7.78 mmol) in acetone (16 mL) and water (6 mL) was refluxed for 8 hours. The mixture was cooled and then water (20 mL) was added, and the solution was extracted using diethyl ether (3×10 mL). The extracts were dried with Na2SO4 and the mixture was filtered. Solvent was evaporated to give 2 as a white power (1.67 g, yield=86%) was refluxed for 8 hours The mixture was cooled the solution was extracted The extracts were dried with Na2SO4 the mixture was filtered Solvent was evaporated to give 2 as a white power (1.67 g, yield=86%)

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

実験手順: In 500 ml of N,N-dimethylformamide was suspended 10.2 g of 60% sodium hydride. Thereinto was dropped 55.0 g of di-tert-butyl malonate in 1 hour with ice-cooling. The resulting mixture was stirred for 10 minutes at the same temperature. Thereto was added 48.0 g of methyl pentafluorbenzoate. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was added to a mixture of 1 liter of water and 400 ml of ethyl acetate. The resulting mixture was adjusted to pH 3 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was dissolved in 150 ml of trifluoroacetic acid. The resulting solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure. To the residue obtained were added 200 ml of diethyl ether and 600 ml of water in this order. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue obtained was added 50 ml of toluene. The resulting mixture was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and n-hexane was added to the residue obtained. The resulting crystals were collected by filtration to obtain 31.3 g (yield: 55.5%) of methyl 4-carboxymethyl-2,3,5,6-tetrafluorobenzoate. cooling The resulting mixture was stirred for 2 hours at room temperature The organic layer was separated washed with water a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure The residue obtained The resulting solution was stirred at room temperature for 20 hours The reaction mixture was concentrated under reduced pressure To the residue obtained The organic layer was separated washed with water a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate The solvent was removed by distillation under reduced pressure To the residue obtained The resulting mixture was refluxed for 1.5 hours The reaction mixture was concentrated under reduced pressure, and n-hexane was added to the residue obtained The resulting crystals were collected by filtration

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

実験手順: All reaction steps were carried out with protection from light due to the sensitive nature of the azido group. First, a mixture of NaN3 (300 mg, 4.6 mmol) and methyl pentafluorobenzoate (0.972 g, 4.3 mmol) in acetone (8 mL) and water (3 mL) was refluxed for 8 hours. The mixture was cooled, diluted with 10 mL of water, and then extracted with diethyl ether (3×10 mL). The extract was dried (anhydrous Na2SO4) and evaporated to give methyl 4-azido-2,3,5,6-tetrafluorobenzoate (1.01 g, 94%), as off-white flakes, mp 53.6-54.3° C. All reaction steps was refluxed for 8 hours The mixture was cooled extracted with diethyl ether (3×10 mL) The extract was dried (anhydrous Na2SO4) evaporated

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl pentafluorobenzoate (41.4 g, 183 mmol) was treated with N-methylpyrrolidinone (36.0 g) and the solution stirred and cooled to 5° C. under a N2 atmosphere. Benzylamine (19.8 g, 185 mmol) was added dropwise over 27 min. at 5° C.–20° C. The resulting thick yellow slurry was cooled to 2° C. over 25 min. and N,N-diisopropyl ethylamine (27.0 g, 209 mmol) was added over 30 min. at 3° C.–10° C. The mixture was allowed to warm to 18° C. and stirred for 2 hrs. It was then heated to 60° C. and stirred another 2 hs at 58° C.–67° C. The resulting solution was cooled to room temperature and stirred overnight. The mixture was treated with toluene (200 mL) and methyl tert-butyl ether (120 mL) and extracted with water (150 mL) followed by 10% aqueous acetic acid (2×50 mL). The organic layer was concentrated to a solid, which was recrystallized from toluene (45 mL) and heptane (50 mL). After cooling to −20° C., the crystals were collected, washed with heptane (2×25 mL) and vacuum dried at 35° C. to give methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (49.3 g, 157 mmol): mp 96–97° C. The resulting thick yellow slurry was cooled to 2° C. over 25 min. to warm to 18° C. stirred for 2 hrs It was then heated to 60° C. stirred another 2 hs at 58° C.–67° C The resulting solution was cooled to room temperature stirred overnight extracted with water (150 mL) The organic layer was concentrated to a solid, which was recrystallized from toluene (45 mL) and heptane (50 mL) After cooling to −20° C. the crystals were collected washed with heptane (2×25 mL) and vacuum dried at 35° C.