tert-butyl 1-[(3-aminophenyl)methyl]cyclopropane-1-carboxylate

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

実験手順: 110.8 mg (0.41 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 129.0 mg (0.33 mmol) of 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoic acid and 52.9 mg (0.39 mmol) of 1-hydroxy-1H-benzotriazole hydrate in 1 ml of DMF. At 0° C., 142 μl (0.82 mmol) of DIEA and then, a little at a time, 136.5 mg (0.36 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 2.5 h. The mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 97.4 mg (47.6% of theory) of the title compound. extracted three times with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated under reduced pressure The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient)

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

実験手順: 77.5 mg (0.31 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 96 mg (0.26 mmol) of cyclopentyl{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetic acid in 1 ml of DMF. At 0° C., 136 μl (0.78 mmol) of DIEA and then, a little at a time, 119.2 mg (0.31 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 1 h. The reaction mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. This gave 146 mg (93% of theory) of the title compound. extracted three times with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated under reduced pressure

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

実験手順: 77.5 mg (0.31 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 96 mg (0.26 mmol) of cyclopentyl{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetic acid in 1 ml of DMF. At 0° C., 136 μl (0.78 mmol) of DIEA and then, a little at a time, 119.2 mg (0.31 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 1 h. The reaction mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. This gave 146 mg (93% of theory) of the title compound. extracted three times with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated under reduced pressure

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

実験手順: 6.98 g (22.43 mmol) of tert-butyl 1-[3-(benzylamino)benzyl]cyclopropanecarboxylate were dissolved in 50 ml of ethanol and 50 ml of THF, and 0.48 g (0.45 mmol) of palladium (10% on carbon) were added. At RT, the mixture was stirred under an atmosphere of hydrogen at atmospheric pressure for 2 h. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.66 g (65.9% of theory) of the title compound. The reaction mixture was then filtered off with suction through kieselguhr the residue was washed with THF the filtrate was concentrated The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1)

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

実験手順: 3.0 g (11.02 mmol) of (+/−)-cyclopentyl[4-(trifluoromethyl)phenyl]acetic acid were dissolved in 16.0 ml of DMF, and 1.79 g (13.22 mmol) of 1-hydroxy-1H-benzotriazole hydrate were added. The mixture was cooled to 0° C., and 3.8 ml (22.04 mmol) of N,N-diisopropylethylamine and 3.41 g (13.77 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, dissolved in a little DMF, were added. 5.03 g (13.22 mmol) of HATU were then added in several portions, and the reaction mixture was slowly warmed to RT and then stirred at RT for 3 h. The reaction was then added to water. After phase separation, the aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1). This gave 4.89 g of the target compound (88.5% of theory). were added the reaction mixture was slowly warmed to RT After phase separation the aqueous phase was extracted three times with ethyl acetate the combined organic phases were washed with saturated sodium chloride solution dried over magnesium sulphate concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1)

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

実験手順: 9.50 g (34.4 mmol) of (+/−)-[4-(acetoxymethyl)phenyl](cyclopentyl)acetic acid were dissolved in 67.5 ml of DMF, and 5.58 g (41.25 mmol) of 1-hydroxy-1H-benzotriazole hydrate (HOBt) were added. The mixture was cooled to 0° C., and 15.0 ml (85.95 mmol) of N,N-diisopropylethylamine and 10.63 g (42.97 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, dissolved in a little DMF, were added. 14.38 g (37.82 mmol) of HATU were then added in several portions, and the reaction mixture was slowly warmed to RT and then stirred overnight. The mixture was then added to saturated aqueous sodium carbonate solution. After phase separation, the aqueous phase was extracted repeatedly with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase dichloromethane/ethyl acetate 50:1→20:1). This gave 12.86 g of the target compound (69.4% of theory). were added the reaction mixture was slowly warmed to RT After phase separation the aqueous phase was extracted repeatedly with ethyl acetate the combined organic phases were washed with saturated sodium chloride solution dried over sodium sulphate concentrated under reduced pressure The crude product was purified by chromatography on silica gel (mobile phase dichloromethane/ethyl acetate 50:1→20:1)

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

実験手順: At RT, 453 mg (1191 μmol) of HATU and 479 μl (2750 μmol) of N,N-diisopropylethylamine were added to a solution of 200 mg (916 μmol) of (+)-(2S)-cyclopentyl(4-methylphenyl)acetic acid in 1 ml of DMF. The mixture was stirred for 30 min. 249 mg (1008 μmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were then added. The reaction mixture was stirred overnight and then directly separated into its components by preparative HPLC. This gave 328 mg (80% of theory) of the title compound. The reaction mixture was stirred overnight directly separated into its components by preparative HPLC

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

実験手順: 1.0 g (4.40 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate was initially charged in 10.0 ml of acetonitrile, and 540 mg (4.40 mmol) of N-chlorosuccinimide were added a little at a time at 0° C. After 30 min, the mixture was warmed to RT and stirred at this temperature overnight. After concentration under reduced pressure, the residue was taken up in dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. By chromatography on silica gel (mobile phase gradient cyclohexane/ethyl acetate 10:1→6:1), 217 mg of a mixed fraction (about 1:1) consisting of tert-butyl 1-(3-amino-2-chlorobenzyl)cyclo-propanecarboxylate and tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate, and also 995.5 mg of tert-butyl 1-(5-amino-2-chlorobenzyl)cyclopropanecarboxylate, slightly contaminated by the starting material tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate, were isolated from the crude product obtained in this manner. The mixed fraction (217 mg) was separated further by preparative RP-HPLC [column: Sunfire C18 5 μm, 250 mm×20 mm; injection volume: 0.50 ml; temperature: 25° C.; mobile phase: 55% acetonitrile/40% water/5% (water+1% TFA); flow rate: 35 ml/min; detection: 210 nm]. In this manner, it was possible to isolate 85 mg (7.5% of theory) of tert-butyl 1-(3-amino-2-chlorobenzyl)cyclopropanecarboxylate (Example 22A). Starting with 995.5 mg of the slightly contaminated material, 677.6 mg (59.5% of theory) of pure tert-butyl 1-(5-amino-2-chlorobenzyl)cyclopropanecarboxylate (Example 23A) were isolated by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). After concentration under reduced pressure washed with saturated sodium bicarbonate solution and saturated sodium chloride solution The organic phase was dried over sodium sulphate concentrated under reduced pressure were isolated from the crude product obtained in this manner The mixed fraction (217 mg) was separated further by preparative RP-HPLC [column: Sunfire C18 5 μm, 250 mm×20 mm; injection volume: 0.50 ml; temperature: 25° C.; mobile phase: 55% acetonitrile/40% water/5% (water+1% TFA); flow rate: 35 ml/min; detection: 210 nm]

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

実験手順: 6.98 g (22.43 mmol) of tert-butyl 1-[3-(benzylamino)benzyl]cyclopropanecarboxylate were dissolved in 50 ml of ethanol and 50 ml THF, and 0.48 g (0.45 mmol) of palladium (10% on carbon) were added. At RT, the mixture was stirred under a hydrogen atmosphere at atmospheric pressure for 2 h. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.66 g (65.9% of theory) of the title compound. The reaction mixture was then filtered off with suction through kieselguhr the residue was washed with THF the filtrate was concentrated The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1)

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

実験手順: 110.8 mg (0.41 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 129.0 mg (0.33 mmol) of 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoic acid and 52.9 mg (0.39 mmol) of 1-hydroxy-1H-benzotriazole hydrate in 1 ml of DMF. At 0° C., 142 μl (0.82 mmol) of DIEA and then, a little at a time, 136.5 mg (0.36 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 2.5 h. The mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 97.4 mg (47.6% of theory) of the title compound. extracted three times with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated under reduced pressure The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient)

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

実験手順: 77.5 mg (0.31 mmol) of tert-butyl 1-(3-aminobenzyl)cyclopropanecarboxylate were added to a solution of 96 mg (0.26 mmol) of cyclopentyl{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetic acid in 1 ml of DMF. At 0° C., 136 μl (0.78 mmol) of DIEA and then, a little at a time, 119.2 mg (0.31 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and stirred at RT for 1 h. The reaction mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. This gave 146 mg (93% of theory) of the title compound. extracted three times with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated under reduced pressure

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

実験手順: 6.98 g (22.43 mmol) of tert-butyl 1-[3-(benzylamino)benzyl]cyclopropanecarboxylate were dissolved in 50 ml of ethanol and 50 ml of THF, and 0.48 g (0.45 mmol) of palladium (10% on carbon) were added. At RT, the mixture was stirred under an atmosphere of hydrogen at atmospheric pressure for 2 h. The reaction mixture was then filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 3.66 g (65.9% of theory) of the title compound. The reaction mixture was then filtered off with suction through kieselguhr the residue was washed with THF the filtrate was concentrated The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1)