methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate

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

Procedure: Methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (24.0 g, 76.6 mmol) was cooled to 5° C.–10° C. under a nitrogen atmosphere and a 25 weight % solution of sodium methoxide in methanol (53.5 mL, 234 mmol) was added dropwise over 5 minutes with continued cooling. The resulting mixture was stirred with ice bath cooling for another 10 minutes, the ice bath was removed and the mixture allowed to warm to 35° C.–40° C. It was recooled to room temperature and held for 4.5 hours before heating to 65° C.–70° C. where it was held for 3.5 hours. The mixture was cooled to room temperature and held overnight. Acetic acid (7.5 g) was added followed by methyl tert-butyl ether (250 mL) and water (100 mL). The lower aqueous layer was separated and the organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL) followed by water (25 mL). The organic solution was concentrated under vacuum to give methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate as a yellow oil (24.5 g). cooling for another 10 minutes the ice bath was removed to warm to 35° C.–40° C was recooled to room temperature before heating to 65° C.–70° C. where it was held for 3.5 hours held overnight Acetic acid (7.5 g) was added The lower aqueous layer was separated the organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL) The organic solution was concentrated under vacuum

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

Procedure: Methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (24.0 g, 76.6 mmol) was cooled to 5° C.–10° C. under a nitrogen atmosphere and a 25 weight % solution of sodium methoxide in methanol (53.5 mL, 234 mmol) was added dropwise over 5 minutes with continued cooling. The resulting mixture was stirred with ice bath cooling for another 10 minutes, the ice bath was removed and the mixture allowed to warm to 35° C.–40° C. It was recooled to room temperature and held for 4.5 hours before heating to 65° C.–70° C. where it was held for 3.5 hours. The mixture was cooled to room temperature and held overnight. Acetic acid (7.5 g) was added followed by methyl tert-butyl ether (250 mL) and water (100 mL). The lower aqueous layer was separated and the organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL) followed by water (25 mL). The organic solution was concentrated under vacuum to give methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate as a yellow oil (24.5 g). cooling for another 10 minutes the ice bath was removed to warm to 35° C.–40° C was recooled to room temperature before heating to 65° C.–70° C. where it was held for 3.5 hours held overnight Acetic acid (7.5 g) was added The lower aqueous layer was separated the organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL) The organic solution was concentrated under vacuum

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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.

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

Procedure: Methyl 4-(benzylamino)-2,3,5,6-tetrafluorobenzoate (24.0 g, 76.6 mmol) was cooled to 5° C.–10° C. under a nitrogen atmosphere and a 25 weight % solution of sodium methoxide in methanol (53.5 mL, 234 mmol) was added dropwise over 5 minutes with continued cooling. The resulting mixture was stirred with ice bath cooling for another 10 minutes, the ice bath was removed and the mixture allowed to warm to 35° C.–40° C. It was recooled to room temperature and held for 4.5 hours before heating to 65° C.–70° C. where it was held for 3.5 hours. The mixture was cooled to room temperature and held overnight. Acetic acid (7.5 g) was added followed by methyl tert-butyl ether (250 mL) and water (100 mL). The lower aqueous layer was separated and the organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL) followed by water (25 mL). The organic solution was concentrated under vacuum to give methyl 4-(benzylamino)-3,5-difluoro-2,6-dimethoxybenzoate as a yellow oil (24.5 g). cooling for another 10 minutes the ice bath was removed to warm to 35° C.–40° C was recooled to room temperature before heating to 65° C.–70° C. where it was held for 3.5 hours held overnight Acetic acid (7.5 g) was added The lower aqueous layer was separated the organic layer extracted with saturated, aqueous sodium bicarbonate solution (2×50 mL) The organic solution was concentrated under vacuum

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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.