N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide

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:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with acetyl chloride (205.5 g, 2.62 mole) and cooled to 0-5° C. Aluminum chloride was added in portions (4×36.4 g [145.5 g, 1.09 mole]) at 0-5° C., while maintaining the internal temperature below 15° C. The slurry was cooled to 0-5° C. and stirred for 15 minutes. N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (5×20 g, 0.436 mole) was added in portions over 40 minutes at 10-minute intervals, while maintaining temperature at 0-10° C. The resulting tan solution was stirred at 0-5° C. for 1 hour. To the solution was added 400 mL of heptane, while maintaining the temperature at 0-5° C. The resulting bi-phasic mixture was added to a 0° C. to −5° C. mixture of 1 N HCl (650 mL) and isopropyl acetate (125 mL) in a 5 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes. The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL), followed by heptane (110 mL) and added to the batch. The reaction mixture was warmed to 22-24° C. over a period of 30 minutes and then heated to 40-45° C. and stirred at 40-45° C. for 1 hour. The slurry was cooled to 21-25° C. and stirred for 1 hour. The solids were collected by filtration using a Büchner funnel with suction over a polypropylene filter paper. The filter cake was washed with heptane (2×200 mL) followed by 1 N HCl (350 mL), and deionized water (2×200 mL). The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 106.1 g (yield 90%) of N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (m.p. 113-115° C.). A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, cooling bath, and nitrogen inlet-outlet while maintaining the internal temperature below 15° C The slurry was cooled to 0-5° C. while maintaining temperature at 0-10° C The resulting tan solution was stirred at 0-5° C. for 1 hour while maintaining the temperature at 0-5° C The resulting bi-phasic mixture was added to a 0° C. to −5° C. 3-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL) added to the batch The reaction mixture was warmed to 22-24° C. over a period of 30 minutes heated to 40-45° C. stirred at 40-45° C. for 1 hour The slurry was cooled to 21-25° C. stirred for 1 hour The solids were collected by filtration filter paper The filter cake was washed with heptane (2×200 mL) The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with acetyl chloride (205.5 g, 2.62 mole) and cooled to 0-5° C. Aluminum chloride was added in portions (4×36.4 g [145.5 g, 1.09 mole]) at 0-5° C., while maintaining the internal temperature below 15° C. The slurry was cooled to 0-5° C. and stirred for 15 minutes. N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (5×20 g, 0.436 mole) was added in portions over 40 minutes at 10-minute intervals, while maintaining temperature at 0-10° C. The resulting tan solution was stirred at 0-5° C. for 1 hour. To the solution was added 400 mL of heptane, while maintaining the temperature at 0-5° C. The resulting bi-phasic mixture was added to a 0° C. to −5° C. mixture of 1 N HCl (650 mL) and isopropyl acetate (125 mL) in a 5 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes. The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL), followed by heptane (110 mL) and added to the batch. The reaction mixture was warmed to 22-24° C. over a period of 30 minutes and then heated to 40-45° C. and stirred at 40-45° C. for 1 hour. The slurry was cooled to 21-25° C. and stirred for 1 hour. The solids were collected by filtration using a Büchner funnel with suction over a polypropylene filter paper. The filter cake was washed with heptane (2×200 mL) followed by 1 N HCl (350 mL), and deionized water (2×200 mL). The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 106.1 g (yield 90%) of N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (m.p. 113-115° C.). A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, cooling bath, and nitrogen inlet-outlet while maintaining the internal temperature below 15° C The slurry was cooled to 0-5° C. while maintaining temperature at 0-10° C The resulting tan solution was stirred at 0-5° C. for 1 hour while maintaining the temperature at 0-5° C The resulting bi-phasic mixture was added to a 0° C. to −5° C. 3-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL) added to the batch The reaction mixture was warmed to 22-24° C. over a period of 30 minutes heated to 40-45° C. stirred at 40-45° C. for 1 hour The slurry was cooled to 21-25° C. stirred for 1 hour The solids were collected by filtration filter paper The filter cake was washed with heptane (2×200 mL) The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with 2-aminoindan, (104 g, 0.781 mole) and isopropyl acetate (200 mL) at 20-25° C. The solution was cooled to 0-5° C. Ethyl trifluoroacetate (133 g, 0.936 mol) was added over 40 minutes while maintaining the internal temperature at 0-10° C. (in a 0-5° C. bath). The thick slurry was stirred at 0-10° C. for 2 hours. The reaction mixture is warmed to 20-25° C. over 30 minutes and heptane (60 mL) was added. The slurry was stirred for 30 minutes and the solids were collected by filtration over a polypropylene filter paper in a Büchner funnel with suction. The filter cake was washed with 0.003% (w/v) Stadis-450 (4.5 mg Lot # 200 Dolder)/heptane (3×50 mL) or until the filtrate was colorless. The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 149.2 g (83.4% yield) of N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide as a beige white solid. A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, cooling bath, and nitrogen inlet-outlet while maintaining the internal temperature at 0-10° C. (in a 0-5° C. bath) The reaction mixture is warmed to 20-25° C. over 30 minutes The slurry was stirred for 30 minutes the solids were collected by filtration over a polypropylene filter paper in a Büchner funnel with suction The filter cake was washed with 0.003% (w/v) Stadis-450 (4.5 mg Lot # 200 Dolder)/heptane (3×50 mL) The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding

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

実験手順: Preferably in Step (i), 2-aminoindan is reacted with ethyl trifluoroacetate to form N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide.

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: After cooling chlorosulfonic acid (3.0 ml) to −78° C. under nitrogen, 2,2,2-trifluoro-N-(2,3-dihydro-1H-inden-2-yl)acetamide (500.0 mg, 2.2 mmol) was added and then allowed to warm up to rt. The solution was poured into an ice-water mixture (100.0 ml), followed by an extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with Et2O to obtain the product as a white solid (510.0 mg, 71% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.93-7.91 (m, 2H), 7.51-7.49 (m, 1H), 6.50 (s, 1H), 4.91-4.83 (m, 1H), 3.52 (dd, J=16.8, 7.3 Hz, 2H), 3.05 (dd, J=17.0, 4.8 Hz, 2H). followed by an extraction with EtOAc The organic layer was dried over MgSO4 evaporated in vacuo The residue was triturated with Et2O

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

実験手順: Under N2 at −75° C., trifluoroacetic acid was added to a stirring solution of 2,3-dihydro-1H-inden-2-amine (HCl salt, 8.0 g, 47.2 mmol), Et3N (14.9 ml, 106.7 mmol) and THF (160 ml). After the solution was allowed to warm up to rt, it was partitioned between H2O and DCM. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexanes:Et2O (1:1) to obtain the product as a white solid (8.9 g, 82% yield). 1H-NMR (400 MHz, CDCl3) δ 7.28-7.20 (m, 4H), 6.50 (s, 1H), 4.81-4.74 (m, 1H), 3.38 (dd, J=16.4, 7.1 Hz, 2H), 2.89 (dd, J=16.3, 4.2 Hz, 2H). it was partitioned between H2O and DCM The organic layer was dried over MgSO4 evaporated in vacuo The residue was triturated with hexanes:Et2O (1:1)

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

実験手順: After cooling chlorosulfonic acid (3.0 ml) to −78° C. under nitrogen, 2,2,2-trifluoro-N-(2,3-dihydro-1H-inden-2-yl)acetamide (500.0 mg, 2.2 mmol) was added and then allowed to warm up to rt. The solution was poured into an ice-water mixture (100.0 ml), followed by an extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with Et2O to obtain the product as a white solid (510.0 mg, 71% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.93-7.91 (m, 2H), 7.51-7.49 (m, 1H), 6.50 (s, 1H), 4.91-4.83 (m, 1H), 3.52 (dd, J=16.8, 7.3 Hz, 2H), 3.05 (dd, J=17.0, 4.8 Hz, 2H). followed by an extraction with EtOAc The organic layer was dried over MgSO4 evaporated in vacuo The residue was triturated with Et2O

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

実験手順: Under N2 at −75° C., trifluoroacetic acid was added to a stirring solution of 2,3-dihydro-1H-inden-2-amine (HCl salt, 8.0 g, 47.2 mmol), Et3N (14.9 ml, 106.7 mmol) and THF (160 ml). After the solution was allowed to warm up to rt, it was partitioned between H2O and DCM. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with hexanes: Et2O (1:1) to obtain the product as a white solid (8.9 g, 82% yield). 1H-NMR (400 MHz, CDCl3) δ 7.28-7.20 (m, 4H), 6.50 (s, 1H), 4.81-4.74 (m, 1H), 3.38 (dd, J=16.4, 7.1 Hz, 2H), 2.89 (dd, J=16.3, 4.2 Hz, 2H). it was partitioned between H2O and DCM The organic layer was dried over MgSO4 evaporated in vacuo The residue was triturated with hexanes: Et2O (1:1)

反応条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, cooling bath, and nitrogen inlet-outlet, was charged with acetyl chloride (205.5 g, 2.62 mole) and cooled to 0-5° C. Aluminum chloride was added in portions (4×36.4 g [145.5 g, 1.09 mole]) at 0-5° C., while maintaining the internal temperature below 15° C. The slurry was cooled to 0-5° C. and stirred for 15 minutes. N-(2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (5×20 g, 0.436 mole) was added in portions over 40 minutes at 10-minute intervals, while maintaining temperature at 0-10° C. The resulting tan solution was stirred at 0-5° C. for 1 hour. To the solution was added 400 mL of heptane, while maintaining the temperature at 0-5° C. The resulting bi-phasic mixture was added to a 0° C. to −5° C. mixture of 1 N HCl (650 mL) and isopropyl acetate (125 mL) in a 5 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes. The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL), followed by heptane (110 mL) and added to the batch. The reaction mixture was warmed to 22-24° C. over a period of 30 minutes and then heated to 40-45° C. and stirred at 40-45° C. for 1 hour. The slurry was cooled to 21-25° C. and stirred for 1 hour. The solids were collected by filtration using a Büchner funnel with suction over a polypropylene filter paper. The filter cake was washed with heptane (2×200 mL) followed by 1 N HCl (350 mL), and deionized water (2×200 mL). The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding to obtain 106.1 g (yield 90%) of N-(5-acetyl-2,3-dihydro-1H-inden-2-yl)-2,2,2-trifluoroacetamide (m.p. 113-115° C.). A 1 L, 3-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, cooling bath, and nitrogen inlet-outlet while maintaining the internal temperature below 15° C The slurry was cooled to 0-5° C. while maintaining temperature at 0-10° C The resulting tan solution was stirred at 0-5° C. for 1 hour while maintaining the temperature at 0-5° C The resulting bi-phasic mixture was added to a 0° C. to −5° C. 3-necked, round-bottomed flask, equipped with a mechanical stirrer digital thermometer, and a cooling bath, while maintaining the internal temperature at 0-25° C. over a period of 20 minutes The 5 L, round-bottomed flask was rinsed with acetyl chloride (20 mL) added to the batch The reaction mixture was warmed to 22-24° C. over a period of 30 minutes heated to 40-45° C. stirred at 40-45° C. for 1 hour The slurry was cooled to 21-25° C. stirred for 1 hour The solids were collected by filtration filter paper The filter cake was washed with heptane (2×200 mL) The solids were dried at 60-65° C. under vacuum (10-30 torr) with nitrogen bleeding