5-bromo-7-fluoro-2,3-dihydroinden-1-one

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

実験手順: To a mixture of 144d (10.35 g, 45.19 mmol) in DCM (75 mL) was added methanesulfonic acid (52.73 mL, 70.92 g, 737.90 mmol) at 0° C., followed by sodium azide (5.88 g, 90.44 mmol) in several portions. See FIG. 3. The reaction mixture was stirred at 0° C. for 2 h, and 20% aq. NaOH solution (40 mL) was added. The reaction mixture was stirred for 30 min, and the aqueous phase was extracted with DCM (400 mL×3). The combined organic layers were washed with saturated brine (200 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=10/1 to 2/1) to afford the 5.2 g (47.1%) of 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one 144e. 1H NMR (400 MHz, CDCl3) δ 7.22-7.25 (d, J=10.4 Hz, 1H), 7.20 (s, 1H), 6.94 (s, 1H), 3.46-3.53 (m, 2H), 2.88-2.97 (m, 2H); MS-ESI [M+H]+=243.9/245.9. The reaction mixture was stirred for 30 min the aqueous phase was extracted with DCM (400 mL×3) The combined organic layers were washed with saturated brine (200 mL×2) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (PE/EA=10/1 to 2/1)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 144d (10.35 g, 45.19 mmol) in DCM (75 mL) was added methanesulfonic acid (52.73 mL, 70.92 g, 737.90 mmol) at 0° C., followed by sodium azide (5.88 g, 90.44 mmol) in several portions. See FIG. 3. The reaction mixture was stirred at 0° C. for 2 h, and 20% aq. NaOH solution (40 mL) was added. The reaction mixture was stirred for 30 min, and the aqueous phase was extracted with DCM (400 mL×3). The combined organic layers were washed with saturated brine (200 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=10/1 to 2/1) to afford the 5.2 g (47.1%) of 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one 144e. 1H NMR (400 MHz, CDCl3) δ 7.22-7.25 (d, J=10.4 Hz, 1H), 7.20 (s, 1H), 6.94 (s, 1H), 3.46-3.53 (m, 2H), 2.88-2.97 (m, 2H); MS-ESI [M+H]+=243.9/245.9. The reaction mixture was stirred for 30 min the aqueous phase was extracted with DCM (400 mL×3) The combined organic layers were washed with saturated brine (200 mL×2) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (PE/EA=10/1 to 2/1)

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of sodium chloride (333 g, 5.69 mol) and aluminum trichloride (1270 g, 9.52 mol) was added to 144c (210 g, 0.79 mol) in several portions at 130° C. See FIG. 3. The neat reaction mixture was then stirred at 180° C. After 5 h the reaction mixture was poured into a stirred solution of ice water (1000 mL) and concentrated HCl (100 mL). The quenched reaction was stirred for 40 min and then extracted with DCM (4000 mL×3). The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1) to afford 55.0 g (30.4%) of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one 144d. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.10-7.12 (d, J=8.4 Hz, 1H), 3.04-3.10 (m, 2H), 2.50-2.66 (m, 2H). The quenched reaction was stirred for 40 min extracted with DCM (4000 mL×3) The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(4-Bromo-2-fluoro-phenyl)-3-chloro-propan-1-one (27.45 g, 103 mmol) was added to a slurry of aluminum chloride (164 g, 1.23 mol) and sodium chloride (43.19 g, 0.739 mol) at 130° C. The mixture was stirred with a mechanical stirrer and heated to 180° C. for 6 hours. The whole mixture was quenched with ice and concentrated hydrochloric solution (122 ml, 1.24 mol). The resulting mixture was extracted with dichloromethane. The organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and filtered. After concentrating under reduced pressure, purification by silica gel chromatography afforded 5-Bromo-7-fluoro-indan-1-one (5 g, 21.8 mmol). The whole mixture was quenched with ice The resulting mixture was extracted with dichloromethane The organic phase was washed with water, saturated sodium bicarbonate solution and brine dried over sodium sulfate filtered After concentrating under reduced pressure, purification by silica gel chromatography

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

実験手順: In analogy to the procedure described for the preparation of intermediates A-4 [A], 5-bromo-7-fluoro-indan-1-one was reacted with sodium cyanoborohydride and ammonium acetate in 2-propanol at reflux to yield the title compound as light yellow oil. MS: 228 (M−H−, 1Br). In analogy to the procedure described for the preparation of intermediates at reflux

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of AlCl3 (37.5 g, 282.48 mmol) and NaCl (11 g, 188.32 mmol) was added 1-(4-bromo-2-fluoro-phenyl)-3-chloro-propan-1-one (5 g, 18.83 mmol) at 130° C. The reaction temperature was slowly increased to 180° C. and kept for 1 hour. It was cooled, the mixture was poured into ice and extracted twice with ethyl acetate (2×100 ml). The combined ethyl acetate phases were dried over Na2SO4 and evaporated to get the crude product which was purified by column chromatography (silica gel, 5-10% ethyl acetate/hexane) to give 2.4 g (55%) of the title compound as brown solid. MS: 229.2 (MH+, 1Br). It was cooled the mixture was poured into ice extracted twice with ethyl acetate (2×100 ml) The combined ethyl acetate phases were dried over Na2SO4 evaporated to get the crude product which was purified by column chromatography (silica gel, 5-10% ethyl acetate/hexane)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 144d (10.35 g, 45.19 mmol) in DCM (75 mL) was added methanesulfonic acid (52.73 mL, 70.92 g, 737.90 mmol) at 0° C., followed by sodium azide (5.88 g, 90.44 mmol) in several portions. See FIG. 3. The reaction mixture was stirred at 0° C. for 2 h, and 20% aq. NaOH solution (40 mL) was added. The reaction mixture was stirred for 30 min, and the aqueous phase was extracted with DCM (400 mL×3). The combined organic layers were washed with saturated brine (200 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=10/1 to 2/1) to afford the 5.2 g (47.1%) of 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one 144e. 1H NMR (400 MHz, CDCl3) δ 7.22-7.25 (d, J=10.4 Hz, 1H), 7.20 (s, 1H), 6.94 (s, 1H), 3.46-3.53 (m, 2H), 2.88-2.97 (m, 2H); MS-ESI [M+H]+=243.9/245.9. The reaction mixture was stirred for 30 min the aqueous phase was extracted with DCM (400 mL×3) The combined organic layers were washed with saturated brine (200 mL×2) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (PE/EA=10/1 to 2/1)

反応条件: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of sodium chloride (333 g, 5.69 mol) and aluminum trichloride (1270 g, 9.52 mol) was added to 144c (210 g, 0.79 mol) in several portions at 130° C. See FIG. 3. The neat reaction mixture was then stirred at 180° C. After 5 h the reaction mixture was poured into a stirred solution of ice water (1000 mL) and concentrated HCl (100 mL). The quenched reaction was stirred for 40 min and then extracted with DCM (4000 mL×3). The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1) to afford 55.0 g (30.4%) of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one 144d. 1H NMR (400 MHz, CDCl3) δ 7.37 (s, 1H), 7.10-7.12 (d, J=8.4 Hz, 1H), 3.04-3.10 (m, 2H), 2.50-2.66 (m, 2H). The quenched reaction was stirred for 40 min extracted with DCM (4000 mL×3) The combined organic phase was washed with saturated NaHCO3 solution (1000 mL), brine (2000 mL×2) dried with anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by silica gel chromatography (PE/EA=50/1, 10/1)