6-bromo-2,3-dihydroisoindol-1-one

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-bromo-2,3-dihydro-1H-isoindol-1-one (150 g, 0.71 mol), Pd(OAc)2 (7.92 g, 0.036 mol), PPh3 (27.9 g, 0.106 mol), Zn(CN)2 (124.6 g, 1.065 mol) and 500 ml of DMF was stirred at 100° C. overnight. Cooled to rt, the solvent was removed and the residue was dissolved in EtOAc. The solid was removed and the filtrate was washed with brine, dried over Na2SO4, evaporated to afford the crude product, which was purified by flash column chromatography on silica gel to afford 3-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (87.5 g, 78% yield). Cooled to rt the solvent was removed the residue was dissolved in EtOAc The solid was removed the filtrate was washed with brine dried over Na2SO4 evaporated to afford the crude product, which was purified by flash column chromatography on silica gel

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-bromo-2,3-dihydro-1H-isoindol-1-one (150 g, 0.71 mol), Pd(OAc)2 (7.92 g, 0.036 mol), PPh3 (27.9 g, 0.106 mol), Zn(CN)2 (124.6 g, 1.065 mol) and 500 ml of DMF was stirred at 100° C. overnight. Cooled to rt, the solvent was removed and the residue was dissolved in EtOAc. The solid was removed and the filtrate was washed with brine, dried over Na2SO4, evaporated to afford the crude product, which was purified by flash column chromatography on silica gel to afford 3-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (87.5 g, 78% yield). Cooled to rt the solvent was removed the residue was dissolved in EtOAc The solid was removed the filtrate was washed with brine dried over Na2SO4 evaporated to afford the crude product, which was purified by flash column chromatography on silica gel

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-bromo-2,3-dihydro-1H-isoindol-1-one (150 g, 0.71 mol), Pd(OAc)2 (7.92 g, 0.036 mol), PPh3 (27.9 g, 0.106 mol), Zn(CN)2 (124.6 g, 1.065 mol) and 500 ml of DMF was stirred at 100° C. overnight. Cooled to rt, the solvent was removed and the residue was dissolved in EtOAc. The solid was removed and the filtrate was washed with brine, dried over Na2SO4, evaporated to afford the crude product, which was purified by flash column chromatography on silica gel to afford 3-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (87.5 g, 78% yield). Cooled to rt the solvent was removed the residue was dissolved in EtOAc The solid was removed the filtrate was washed with brine dried over Na2SO4 evaporated to afford the crude product, which was purified by flash column chromatography on silica gel

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40° C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H). The mixture was cooled to room temperature the resultant white solid was collected

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

実験手順: To a 25 mL round bottom flask containing (S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Intermediate 1) (120 mg, 0.336 mmol) was added toluene (3 mL). The resulting mixture was stirred at rt for 2 min. At this time, sodium carbonate (143 mg, 1.346 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.89 mg, 6.73 mol), palladium (II) acetate (1.5 mg, 6.7 mol) and 6-bromo-2,3-dihydro-isoindol-1-one (71.3 mg, 0.336 mmol) were added to the flask. The reaction vessel was flushed with argon and then left under 1.0 atm of carbon monoxide gas (from a lecture bottle, in hood). The flask was heated to 85° C. overnight, filtered though Celite® brand filter agent, and eluted with EtOAc. Purification by reverse phase HPLC, and concentration of the containing fractions gave (S)-3-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide as a yellow foamy solid. 1H NMR (300 MHz, CDCl3): δ ppm 8.92 (d, J=4.5 Hz, 1H), 8.40 (d, J=7.7 Hz, 1H), 7.60-7.56 (m, 5H), 7.46-7.48 (m, 2H), 6.90 (d, J=7.6 Hz, 1H), 4.54 (s, 2H). MS (ESI pos. ion) m/z: 480.1 (M+H). The reaction vessel was flushed with argon left under 1.0 atm of carbon monoxide gas (from a lecture bottle The flask was heated to 85° C. overnight filtered though Celite® brand filter agent eluted with EtOAc Purification by reverse phase HPLC, and concentration of the containing fractions

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 6-bromo-2,3-dihydro-1H-isoindol-1-one (150 g, 0.71 mol), Pd(OAc)2 (7.92 g, 0.036 mol), PPh3 (27.9 g, 0.106 mol), Zn(CN)2 (124.6 g, 1.065 mol) and 500 ml of DMF was stirred at 100° C. overnight. Cooled to rt, the solvent was removed and the residue was dissolved in EtOAc. The solid was removed and the filtrate was washed with brine, dried over Na2SO4, evaporated to afford the crude product, which was purified by flash column chromatography on silica gel to afford 3-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (87.5 g, 78% yield). Cooled to rt the solvent was removed the residue was dissolved in EtOAc The solid was removed the filtrate was washed with brine dried over Na2SO4 evaporated to afford the crude product, which was purified by flash column chromatography on silica gel

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40° C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H). The mixture was cooled to room temperature the resultant white solid was collected

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40° C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H). The mixture was cooled to room temperature the resultant white solid was collected

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

実験手順: To a 25 mL round bottom flask containing (S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Intermediate 1) (120 mg, 0.336 mmol) was added toluene (3 mL). The resulting mixture was stirred at rt for 2 min. At this time, sodium carbonate (143 mg, 1.346 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.89 mg, 6.73 μmol), palladium (II) acetate (1.5 mg, 6.7 μmol) and 6-bromo-2,3-dihydro-isoindol-1-one (71.3 mg, 0.336 mmol) were added to the flask. The reaction vessel was flushed with argon and then left under 1.0 atm of carbon monoxide gas (from a lecture bottle, in hood). The flask was heated to 85° C. overnight, filtered though Celite® brand filter agent, and eluted with EtOAc. Purification by reverse phase HPLC, and concentration of the containing fractions gave (S)-3-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide as a yellow foamy solid. 1H NMR (300 MHz, CDCl3): δ ppm 8.92 (d, J=4.5 Hz, 1H), 8.40 (d, J=7.7 Hz, 1H), 7.60-7.56 (m, 5H), 7.46-7.48 (m, 2H), 6.90 (d, J=7.6 Hz, 1H), 4.54 (s, 2H). MS (ESI pos. ion) m/z: 480.1 (M+H). The reaction vessel was flushed with argon left under 1.0 atm of carbon monoxide gas (from a lecture bottle The flask was heated to 85° C. overnight filtered though Celite® brand filter agent eluted with EtOAc Purification by reverse phase HPLC, and concentration of the containing fractions

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40° C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H). The mixture was cooled to room temperature the resultant white solid was collected

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40° C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H). The mixture was cooled to room temperature the resultant white solid was collected

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

実験手順: Methyl 2-bromomethyl-5-bromobenzoate (0.1 mol) was dissolved in THF/methanol (200 ml) (1:1) and the solution obtained was saturated with dry ammonia gas. The solvent was removed and the residue was triturated with water, diethyl ether and hexane and then recrystallised from ethanol/dichloromethane to obtain 6-bromo-2,3-dihydro-isoindol-1-one (12.5 g). 1H NMR (400 MHz, d6 DMSO) δ 8.70 (1H, bs), 7.78 (1H,s), 7.77 (1H, d, J=7 Hz), 7.55 (1H, d, J=7 Hz), 4.35 (2H,s). m/z (ES+) 212 (M+). b) 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate Prepared in a similar manner to that of Example 1a using 6-bromo-2,3-dihydro-isoindol-1-one. 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 8.05 (1H,d, J=1 Hz), 7.94 (1H, dd, J=7 and 1 Hz), 7.66 (1H, dd, J=7 and 1 Hz), 5.07 (2H, s), 4.60 (3H, s). m/z (ES+) 226 (M+). c) (6-Bromo-3H-isoindol-1-yl)hydrazine 5-Bromo-3-methoxy-1H-isoindolium trifluoromethanesulfonate (3.7 g) was dissolved in THF (35 ml) and triethylamine (2.8 ml) was added followed by hydrazine (1 M in THF, 35 ml). After an hour the solid which had precipitated was filter off and dried to give title compound (2.8 g) 1H NMR (360 MHz, CDCl3) δ 12.5 (1H, brs), 7.85 (1H,d, J=1 Hz), 7.51 (1H, dd, J=7 and 1 Hz), 7.25 (1H, dd, J=7 and 1 Hz), 4.49 (2H, s). m/z (ES+) 226 (M+). d) 8-Bromo-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-a]isoindole (6-Bromo-3H-isoindol-1-yl)hydrazine (2.8 g) was stirred in 10% trifluoroacetic acid in dichloromethane (40 ml) and 5-methyl-3-phenyl-4-isoxazole carboxaldehyde was added (2.33 g) and the reaction was stirred for 0.5 hours. The solvent was removed and the residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated sodium hydrogen carbonate, dried, filtered and evaporated. The residue was taken up into methanol and dichloromethane, sodium acetate was added and the stirred suspension was treated dropwise with bromine (0.5 ml). The reaction was diluted with water and extracted into dichloromethane and dried, filtered and evaporated. The product was purified by silica chromatography using ethyl acetate as eluant to yield the title compound (1.46 g). The solvent was removed the residue was partitioned between ethyl acetate and water the organic layer was washed with saturated sodium hydrogen carbonate dried filtered evaporated was added the stirred suspension was treated dropwise with bromine (0.5 ml) The reaction was diluted with water extracted into dichloromethane dried filtered evaporated The product was purified by silica chromatography