1-(4-broMo-2-fluorophenyl)ethanaMine

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: 61 mg (1 eq, 0.24 mmol) of 1-(4-bromo-2-fluorophenyl)ethanamine from Stage 1 were dissolved in 4 ml of dichloromethane, and 24 mg (1.1 eq, 23 μl, 0.264 mmol) of propanoyl chloride and 70 mg (2.2 eq, 90 μl) of Hünig's base were added. The mixture was stirred at room temperature for 5 h and then concentrated. The crude product was dissolved in ethyl acetate and washed 1× with 1M HCl, 1× with sat. sodium carbonate solution and then with water, and dried over magnesium sulphate. After concentrating under reduced pressure, the resulting crude product was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate). 50 mg (67%) of N-[1-(4-bromo-2-fluorophenyl)ethyl]propanamide were obtained. concentrated The crude product was dissolved in ethyl acetate washed 1× with 1M HCl, 1× with sat. sodium carbonate solution with water, and dried over magnesium sulphate After concentrating under reduced pressure the resulting crude product was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate)

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

実験手順: To a solution of 12 g of 4-bromo-2-fluorobenzonitrile (60 mM) in THF (120 ml) were added 75 ml (150 mM) of a 2 M solution of methylmagnesium bromide in diethyl ether at 0° C. The reaction mixture was stirred at 0° C. for 6 h. Then 200 ml of methanol were added gradually to the reaction mixture. Subsequently, 5.7 g (150 mM) of sodium borohydride were added in portions, and the mixture was stirred at room temperature for 16 h. Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added. The pH was adjusted to pH=˜1 with 2 M HCl, and the aqueous solution was extracted with chloroform. Subsequently, the pH was adjusted to pH=˜9 with 2M NaOH, and extraction was effected with chloroform (2×100 ml). The combined chloroform extracts were dried, and the solvent was removed under reduced pressure. 7.3 g (44%) of 1-(4-bromo-2-fluorophenyl)ethanamine were obtained as a yellow oil. the mixture was stirred at room temperature for 16 h Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added the aqueous solution was extracted with chloroform Subsequently, the pH was adjusted to pH=˜9 with 2M NaOH, and extraction The combined chloroform extracts were dried the solvent was removed under reduced pressure

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

実験手順: 61 mg (1 eq, 0.24 mmol) of 1-(4-bromo-2-fluorophenyl)ethanamine from Stage 1 were dissolved in 4 ml of dichloromethane, and 24 mg (1.1 eq, 23 μl, 0.264 mmol) of propanoyl chloride and 70 mg (2.2 eq, 90 μl) of Hünig's base were added. The mixture was stirred at room temperature for 5 h and then concentrated. The crude product was dissolved in ethyl acetate and washed 1× with 1M HCl, 1× with sat. sodium carbonate solution and then with water, and dried over magnesium sulphate. After concentrating under reduced pressure, the resulting crude product was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate). 50 mg (67%) of N-[1-(4-bromo-2-fluorophenyl)ethyl]propanamide were obtained. concentrated The crude product was dissolved in ethyl acetate washed 1× with 1M HCl, 1× with sat. sodium carbonate solution with water, and dried over magnesium sulphate After concentrating under reduced pressure the resulting crude product was purified by means of chromatography on silica gel (eluent: cyclohexane/ethyl acetate)

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

実験手順: To a solution of 12 g of 4-bromo-2-fluorobenzonitrile (60 mM) in THF (120 ml) were added 75 ml (150 mM) of a 2 M solution of methylmagnesium bromide in diethyl ether at 0° C. The reaction mixture was stirred at 0° C. for 6 h. Then 200 ml of methanol were added gradually to the reaction mixture. Subsequently, 5.7 g (150 mM) of sodium borohydride were added in portions, and the mixture was stirred at room temperature for 16 h. Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added. The pH was adjusted to pH=˜1 with 2 M HCl, and the aqueous solution was extracted with chloroform. Subsequently, the pH was adjusted to pH=˜9 with 2M NaOH, and extraction was effected with chloroform (2×100 ml). The combined chloroform extracts were dried, and the solvent was removed under reduced pressure. 7.3 g (44%) of 1-(4-bromo-2-fluorophenyl)ethanamine were obtained as a yellow oil. the mixture was stirred at room temperature for 16 h Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added the aqueous solution was extracted with chloroform Subsequently, the pH was adjusted to pH=˜9 with 2M NaOH, and extraction The combined chloroform extracts were dried the solvent was removed under reduced pressure

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

実験手順: 1-(3,5′-Difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine was prepared in a similar manner to 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (Example 34) using 4′-bromo-2′-fluoroacetophenone to give 1-(4-bromo-2-fluoro-phenyl)-ethylamine. To a solution of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20.0 mg, 0.08 mmol) in dichloromethane (1 ml) was added triethylamine (8.1 mg, 0.08 mmol) and 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight then the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound (20 mg). 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.21-7.16 (m, 2H), 7.14-7.09 (m, 1H), 7.05-6.95 (m, 2H), 6.93-6.88 (m, 1H), 5.11 (d, 1H), 4.76 (dq, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 1.55 (d, 3H) ppm; MS (ESI) m/z: 498.3 [M+Na]+.

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

実験手順: 1-(3,5′-Difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine was prepared in a similar manner to 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (Example 34) using 4′-bromo-2′-fluoroacetophenone to give 1-(4-bromo-2-fluoro-phenyl)-ethylamine. To a solution of 1-(3,5′-difluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (20.0 mg, 0.08 mmol) in dichloromethane (1 ml) was added triethylamine (8.1 mg, 0.08 mmol) and 1-methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight then the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound (20 mg). 1H NMR (400 MHz, CDCl3): δ 7.51 (s, 1H), 7.21-7.16 (m, 2H), 7.14-7.09 (m, 1H), 7.05-6.95 (m, 2H), 6.93-6.88 (m, 1H), 5.11 (d, 1H), 4.76 (dq, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 1.55 (d, 3H) ppm; MS (ESI) m/z: 498.3 [M+Na]+.

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

実験手順: To a solution of 12 g of 4-bromo-2-fluorobenzonitrile (60 mM) in THF (120 ml) were added 75 ml (150 mM) of a 2 M solution of methylmagnesium bromide in diethyl ether at 0° C. The reaction mixture was stirred at 0° C., for 6 h. Then 200 min of methanol were added gradually to the reaction mixture. Subsequently, 5.7 g (150 mM) of sodium borohydride were added in portions, and the mixture was stirred at room temperature for 16 h. Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added. The pH was adjusted to pH=˜1 with 2 M HCl, and the aqueous solution was extracted with chloroform. Subsequently, the pH was adjusted to pH=˜9 with 2M NaOH, and extraction was effected with chloroform (2×100 ml). The combined chloroform extracts were dried, and the solvent was removed under reduced pressure. 73 g (44%) of 1-(4-bromo-2-fluorophenyl)ethanamine were obtained as a yellow oil. the mixture was stirred at room temperature for 16 h Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added the aqueous solution was extracted with chloroform Subsequently, the pH was adjusted to pH=˜9 with 2M NaOH, and extraction The combined chloroform extracts were dried the solvent was removed under reduced pressure

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

実験手順: To a solution of 1-(4-bromo-2-fluorophenyl)ethanone (2.0 g, 9.2 mmol) in methanol (50 mL) was added ammonia (7 N in methanol, 8.0 mL, 55 mmol) and titanium(IV) isopropoxide (5.4 mL, 18 mmol). The reaction mixture was stirred at room temperature for 18 h, cooled to 0° C. and sodium borohydride (520 mg, 14 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 20 min, quenched with 2 M ammonium hydroxide and filtered. The reaction mixture was extracted with methylene chloride and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford the desired product (1.2 g, 63%) as an oil: ESI MS m/z 219 [C8H9BrFN+H]+. cooled to 0° C. The reaction mixture was warmed to room temperature stirred for 20 min quenched with 2 M ammonium hydroxide filtered The reaction mixture was extracted with methylene chloride the combined organic layers were dried over sodium sulfate filtered concentrated

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

実験手順: To C-Azido-C-(2-fluoro-4-bromo-phenyl)-methylamine (0.35 g, 1.43 mmol) was added triphenyl phospine (0.45 g, 1.72 mmol), 2N HCl (2 mL), and THF (2 mL). The reaction mixture was stirred at r.t. for 2 h and the reaction quenched with NaHCO3 (10 mL) and pH adjusted to 8, extracted with dichloromethane (2×30 mL) and washed with brine. The combined organic phases were dried over Na2SO4, filtered and evaporated yielding the crude product. Purification by chromatography (silica, EtOAc/Heptane, 1:1, followed by CH—2Cl2/MeOH 9:1 and with addition of a SCX colon) yielded 93 mg (30%) of 1-(2-Fluoro-4-bromo-phenyl)-ethylamine. 1H NMR δ (CDCl3): 1.44 (3H, d), 2.48 (2H, br s), 4.41 (1H, q), 7.19-7.40 (3H, m). the reaction quenched with NaHCO3 (10 mL) extracted with dichloromethane (2×30 mL) washed with brine The combined organic phases were dried over Na2SO4 filtered evaporated yielding the crude product Purification by chromatography (silica, EtOAc/Heptane, 1:1 with addition of a SCX colon)