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ΓΒ1 5-Bromo-7-fluoro-indan-l-oneTo a mixture of A1C13 (37.5 g, 282.48 mmol) and NaCl (11 g, 188.32 mmol) was added 1- (4-bromo-2-fluoro-phenyl)-3-chloro-propan-l-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 (2x 100 ml). The combined ethyl acetate phases were dried over Na2S04 and evaporated to get the crude product which was purified by column chromatography (silica gel, 5-10percent ethyl acetate/hexane) to give 2.4 g (55percent) of the title compound as brown solid. MS: 229.2 (MH+, IBr).
55%
at 130 - 180℃; Inert atmosphere
[B] 5-Bromo-7-fluoro-indan-1-one 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, 5-10percent ethyl acetate/hexane) to give 2.4 g (55percent) of the title compound as brown solid. MS: 229.2 (MH+, 1Br).
30.4%
at 130 - 180℃; for 5 h;
Step 3: 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 Figure 3. The neat reaction mixture was then stirred at 180°C. After 5h the reaction mixture was poured into a stirred solution of ice water (1000 mL) and concentrated HC1 (100 mL). The quenched reaction was stirred for 40 min and then extracted with DCM (4000 mL x 3). The combined organic phase was washed with saturated NaHCC>3 solution (1000 mL), brine (2000 mL x 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 (30.4percent) of 5-bromo-7-fluoro-2,3-dihydro-lH-inden-l-one 144d. *H NMR (400 MHz, CDC13) δ 7.37 (s, 1H), 7.10-7.12 (d, 7=8.4 Hz, 1H), 3.04-3.10 (m, 2H), 2.50-2.66 (m, 2H).
Reference：
[1] Patent: WO2015/949, 2015, A1,
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 512 - 516
3
[ 1242157-14-7 ]
[ 1242157-15-8 ]
Yield
Reaction Conditions
Operation in experiment
47.1%
Stage #1: With sodium azide; methanesulfonic acid In dichloromethane at 0℃; for 2 h; Stage #2: With sodium hydroxide In dichloromethane; water for 0.5 h;
Step 4: 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 Figure 3. The reaction mixture was stirred at 0 °C for 2h, and 20percent 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 x 3). The combined organic layers were washed with saturated brine (200 mL x 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 (47.1percent) of 6-bromo-8-fluoro-3,4-dihydroisoquinolin- l(2H)-one 144e. *H NMR (400 MHz, CDC13) δ 7.22-7.25 (dJ=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.
Reference：
[1] Patent: WO2015/949, 2015, A1, . Location in patent: Page/Page column 106-107
[2] Patent: US2010/222325, 2010, A1, . Location in patent: Page/Page column 140-141
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 1, p. 512 - 516
Step 4: 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 Figure 3. The reaction mixture was stirred at 0 C for 2h, 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 x 3). The combined organic layers were washed with saturated brine (200 mL x 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- l(2H)-one 144e. *H NMR (400 MHz, CDC13) delta 7.22-7.25 (dJ=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.
5-Bromo-7-fluoro-indan-1-one (2.07 g, 90.7 mmol) was dissolved in 15 ml dichloromethane and cooled to 0 C. Methanesulfonic acid (10.6 ml, 163 mmol) was added. After that sodium azide (1.18 g, 18.14 mmol) was added very slowly to the solution. The reaction was stirred 2 hours at 0 C. 40 ml of 20% sodium hydroxide solution was added slowly to the mixture at 0 C. After the addition the reaction mixture was extracted with dichloromethane. The organic phase was washed with water, brine, dried over sodium sulfate and filtered. After concentrating under reduced pressure, 5-Bromo-7-fluoro-indan-1-one (2 g, 81.95 mmol) was obtained. MS (ESI) 244.0 (M+H)+.
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