(2R)-2-(trifluoromethyl)pyrrolidine

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

実験手順: Was prepared in the same manner as described in Example 87a) using (E)-2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (100 mg, 299 μmol, Eq: 1.00) instead of 2-[(E)-2-(5-Bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine and (R)-2-(trifluoromethyl)-pyrrolidine (83.3 mg, 598 μmol, Eq: 2) instead of pyrrolidin-2-one affording 5,8-dimethyl-2-{(E)-2-[2-methyl-5-((R)-2-trifluoromethyl-pyrrolidin-1-yl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-c]pyrimidine (17 mg, 14.5%) as a light yellow solid. MS: m/z=393.4 (M+H+) Was prepared in the same manner

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 8-[(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11h) (62 mg, 0.187 mmol) in dimethylformamide (0.6 ml) was added 1-hydroxybenzotriazole (28 mg, 0.206 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.206 mmol). The mixture was stirred for 3 h at 50° C., then (R)-2-trifluoromethyl-pyrrolidine (42 mg, 0.206 mmol) and triethylamine (38 mg, 0.37 mmol) were added and the mixture was stirred at 25° C. for 24 h. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and dried in vacuo to give 66 mg (68%) of 6-((R)-2-trifluoromethyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 5): Rt=4.55 min; m/z=519.13 (M+H+). the mixture was stirred at 25° C. for 24 h the solid which precipitated was filtered off washed with a small amount of water dried in vacuo

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 8-[(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11h) (62 mg, 0.187 mmol) in dimethylformamide (0.6 ml) was added 1-hydroxybenzotriazole (28 mg, 0.206 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.206 mmol). The mixture was stirred for 3 h at 50° C., then (R)-2-trifluoromethyl-pyrrolidine (42 mg, 0.206 mmol) and triethylamine (38 mg, 0.37 mmol) were added and the mixture was stirred at 25° C. for 24 h. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and dried in vacuo to give 66 mg (68%) of 6-((R)-2-trifluoromethyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 5): Rt=4.55 min; m/z=519.13 (M+H+). the mixture was stirred at 25° C. for 24 h the solid which precipitated was filtered off washed with a small amount of water dried in vacuo

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv), (R)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.68 mmol, 2.36 equiv), n-BuOH (1.5 mL). The resulting solution was stirred for 3 days at 110° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 30 mg (26%) of (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid. Into a 8-mL sealed tube The resulting mixture was concentrated under vacuum This resulted in 30 mg (26%) of (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid

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

実験手順: To a solution of N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.200 g, 0.261 mmol, prepared from 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and (1S,2R,4S)-4-acetamido-2-methylcyclopentanecarboxylic acid [prepared from ethyl 4-amino-2-methyl-cyclopentanecarboxylate (WO2009152133) using G, AA, and Z] using H, OO, BB, and ZZ) and (R)-2-trifluoromethylpyrrolidine (0.055 g, 0.392 mmol) in MeCN (1.4 mL) was added TEA (0.073 mL, 0.523 mmol). The reaction was irradiated in a CEM microwave at about 120° C. for about 0.5 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure to afford a residue. The crude material was purified by silica gel chromatography eluting with a gradient of 0-70% EtOAc in DCM to afford (R)-N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide (0.12 g, 75%, 72% purity) as an off-white solid: LC/MS (Table 1, Method a) Rt=2.79 min; MS m/z: 611 (M+H)+. The reaction was irradiated in a CEM microwave at about 120° C. for about 0.5 h concd under reduced pressure to afford a residue The crude material was purified by silica gel chromatography eluting with a gradient of 0-70% EtOAc in DCM

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv), (R)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.68 mmol, 2.36 equiv), n-BuOH (1.5 mL). The resulting solution was stirred for 3 days at 110° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 30 mg (26%) of (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid. Into a 8-mL sealed tube The resulting mixture was concentrated under vacuum This resulted in 30 mg (26%) of (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (270 mg, 0.85 mmol) in DMSO (1 mL) was added (R)-2-(trifluoromethyl)pyrrolidine (275 mg, 1.99 mmol). The resulting solution was stirred 7 days at 130° C. and then evaporated in vacuo. The residue was diluted with petroleum ether (15 mL) and filtered. The filtrate was concentrated and purified by a silica gel column chromatography with 2%-10% ethyl acetate in petroleum ether to afford (R)-methyl 2-(4-fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (35 mg, crude). evaporated in vacuo The residue was diluted with petroleum ether (15 mL) filtered The filtrate was concentrated purified by a silica gel column chromatography with 2%-10% ethyl acetate in petroleum ether

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (270 mg, 0.85 mmol) in DMSO (1 mL) was added (R)-2-(trifluoromethyl)pyrrolidine (275 mg, 1.99 mmol). The resulting solution was stirred 7 days at 130° C. and then evaporated in vacuo. The residue was diluted with petroleum ether (15 mL) and filtered. The filtrate was concentrated and purified by a silica gel column chromatography with 2%-10% ethyl acetate in petroleum ether to afford (R)-methyl 2-(4-fluorophenyl)-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (35 mg, crude). evaporated in vacuo The residue was diluted with petroleum ether (15 mL) filtered The filtrate was concentrated purified by a silica gel column chromatography with 2%-10% ethyl acetate in petroleum ether

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

実験手順: Was prepared in the same manner as described in Example 87a) using (E)-2-(2-(3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (100 mg, 299 μmol, Eq: 1.00) instead of 2-[(E)-2-(5-Bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine and (R)-2-(trifluoromethyl)-pyrrolidine (83.3 mg, 598 μmol, Eq: 2) instead of pyrrolidin-2-one affording 5,8-dimethyl-2-{(E)-2-[2-methyl-5-((R)-2-trifluoromethyl-pyrrolidin-1-yl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-c]pyrimidine (17 mg, 14.5%) as a light yellow solid. MS: m/z=393.4 (M+H+) Was prepared in the same manner

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 8-[(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propylcarbamoyl]-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carboxylic acid (Comp. No. 11h) (62 mg, 0.187 mmol) in dimethylformamide (0.6 ml) was added 1-hydroxybenzotriazole (28 mg, 0.206 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.206 mmol). The mixture was stirred for 3 h at 50° C., then (R)-2-trifluoromethyl-pyrrolidine (42 mg, 0.206 mmol) and triethylamine (38 mg, 0.37 mmol) were added and the mixture was stirred at 25° C. for 24 h. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and dried in vacuo to give 66 mg (68%) of 6-((R)-2-trifluoromethyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 5): Rt=4.55 min; m/z=519.13 (M+H+). the mixture was stirred at 25° C. for 24 h the solid which precipitated was filtered off washed with a small amount of water dried in vacuo

反応条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv), (R)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.68 mmol, 2.36 equiv), n-BuOH (1.5 mL). The resulting solution was stirred for 3 days at 110° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 30 mg (26%) of (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid. Into a 8-mL sealed tube The resulting mixture was concentrated under vacuum This resulted in 30 mg (26%) of (R)-methyl 2-phenyl-3-(2-(trifluoromethyl)pyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid