1-bromo-2-fluoro-4-methylsulfonylbenzene

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: 2′-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.34 g, 65%) was prepared as an off-white solid from (4-hydroxyphenyl)boronic acid (0.30 g, 2.07 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (0.5 g, 1.98 mmol), 2M Na2CO3 (12 mL) and Pd(PPh3)4 (20 mg, 0.02 mmol) in DME (12 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 1H, Ja=8.0 Hz, Jb=1.5 Hz), 7.74-7.69 (m, 1H), 7.64-7.58 (m, 1H), 7.47 (d, 2H, J=7.1 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.94 (bs, 1H), 3.10 (s, 3H); LRMS (ESI), m/z 267 (M+H).

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-Butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-C, 5.0 g, 17 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.0 g, 1.7 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (6.4 g, 25 mmol) and NaOtBu (1.9 g, 20 mmol) were dissolved in degassed toluene (100 mL). Pd2 dba3 (0.77 g, 0.84 mmol) was added and the reaction heated in an 80° C. oil bath for 5 hours. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford tert-butyl 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (8.4 g, 18 mmol, 106% yield) as yellow solid. The reaction was concentrated purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2)

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

実験手順: 2′-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.34 g, 65%) was prepared as an off-white solid from (4-hydroxyphenyl)boronic acid (0.30 g, 2.07 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (0.5 g, 1.98 mmol), 2M Na2CO3 (12 mL) and Pd(PPh3)4 (20 mg, 0.02 mmol) in DME (12 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 1H, Ja=8.0 Hz, Jb=1.5 Hz), 7.74-7.69 (m, 1H), 7.64-7.58 (m, 1H), 7.47 (d, 2H, J=7.1 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.94 (bs, 1H), 3.10 (s, 3H); LRMS (ESI), m/z 267 (M+H).

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

実験手順: 2′-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.34 g, 65%) was prepared as an off-white solid from (4-hydroxyphenyl)boronic acid (0.30 g, 2.07 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (0.5 g, 1.98 mmol), 2M Na2CO3 (12 mL) and Pd(PPh3)4 (20 mg, 0.02 mmol) in DME (12 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 1H, Ja=8.0 Hz, Jb=1.5 Hz), 7.74-7.69 (m, 1H), 7.64-7.58 (m, 1H), 7.47 (d, 2H, J=7.1 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.94 (bs, 1H), 3.10 (s, 3H); LRMS (ESI), m/z 267 (M+H).

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-Butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-C, 5.0 g, 17 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.0 g, 1.7 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (6.4 g, 25 mmol) and NaOtBu (1.9 g, 20 mmol) were dissolved in degassed toluene (100 mL). Pd2 dba3 (0.77 g, 0.84 mmol) was added and the reaction heated in an 80° C. oil bath for 5 hours. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford tert-butyl 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (8.4 g, 18 mmol, 106% yield) as yellow solid. The reaction was concentrated purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-Butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-C, 5.0 g, 17 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.0 g, 1.7 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (6.4 g, 25 mmol) and NaOtBu (1.9 g, 20 mmol) were dissolved in degassed toluene (100 mL). Pd2 dba3 (0.77 g, 0.84 mmol) was added and the reaction heated in an 80° C. oil bath for 5 hours. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford tert-butyl 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (8.4 g, 18 mmol, 106% yield) as yellow solid. The reaction was concentrated purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2)

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-bromo-2-fluoro-4-(methylsulfonyl)benzene (Preparation 14, 1.5 g, 5.93 mmol) in MeOH (12 mL) was added sodium methoxide (480 mg, 8.89 mmol) and the reaction mixture was irradiated at 100° C. in the microwave for 1.5 hours. After this time the reaction was quenched with water (50 mL) and the product was extract with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptane to afford the title compound as colourless solid in 53% yield. the reaction mixture was irradiated at 100° C. in the microwave for 1.5 hours After this time the reaction was quenched with water (50 mL) the product was extract with EtOAc (3×50 mL) The combined organic layers were dried (Na2SO4) filtered concentrated under reduced pressure The residue was purified by silica gel column chromatography eluting with 20-40% EtOAc in heptane

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

実験手順: A solution of 4-bromo-3-fluorobenzene sulphonyl chloride (10 g, 36.56 mmol) in THF (100 mL) was cooled to 0° C. and hydrazine monohydrate (6.2 mL, 127.96 mmol) was added dropwise. After the addition, the reaction was left to stir at room temperature for 1 hour before adding heptane (500 mL). The precipitate formed was filtered off and re-dissolved in industrial methylated spirit (200 mL). Sodium acetate (18 g, 219.36 mmol) was added followed by iodomethane (11.38 mL, 182.8 mmol). The reaction mixture was stirred at reflux for 18 hours. The reaction was cooled to room temperature and the solvent was concentrated to half of the initial volume. Water (300 mL) was added and the product was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL) and dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting from 15% to 35% EtOAc/heptane to afford the title compound as a colourless solid in 48% yield, 4.40 g. After the addition the reaction was left The precipitate formed was filtered off re-dissolved in industrial methylated spirit (200 mL) The reaction mixture was stirred at reflux for 18 hours The reaction was cooled to room temperature the solvent was concentrated to half of the initial volume Water (300 mL) was added the product was extracted with EtOAc (3×300 mL) The combined organic layers were washed with brine (300 mL) dried (Na2SO4) filtered concentrated under reduced pressure The crude residue was purified by silica gel column chromatography eluting from 15% to 35% EtOAc/heptane

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

実験手順: 2′-Fluoro-4′-(methylsulfonyl)-4-biphenylol (0.34 g, 65%) was prepared as an off-white solid from (4-hydroxyphenyl)boronic acid (0.30 g, 2.07 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (0.5 g, 1.98 mmol), 2M Na2CO3 (12 mL) and Pd(PPh3)4 (20 mg, 0.02 mmol) in DME (12 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 7.76 (dd, 1H, Ja=8.0 Hz, Jb=1.5 Hz), 7.74-7.69 (m, 1H), 7.64-7.58 (m, 1H), 7.47 (d, 2H, J=7.1 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.94 (bs, 1H), 3.10 (s, 3H); LRMS (ESI), m/z 267 (M+H).

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (S)-tert-Butyl 3-amino-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-C, 5.0 g, 17 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.0 g, 1.7 mmol), 1-bromo-2-fluoro-4-(methylsulfonyl)benzene (6.4 g, 25 mmol) and NaOtBu (1.9 g, 20 mmol) were dissolved in degassed toluene (100 mL). Pd2 dba3 (0.77 g, 0.84 mmol) was added and the reaction heated in an 80° C. oil bath for 5 hours. The reaction was concentrated and purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2) to afford tert-butyl 3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (8.4 g, 18 mmol, 106% yield) as yellow solid. The reaction was concentrated purified over silica gel (50-100% EtOAc in hexanes followed by 5% ammoniated methanol in CH2Cl2)