4,4-bis(4-fluorophenyl)butan-1-amine;hydrochloride

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 335 mg (1.68 mmol) 2-(cyclohexylamino)-3-methylbutyric acid (Example 69, Step A), 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride, 0.29 mL (1.68 mmol) N,N-diisopropylethylamine, and 1.5 mL (3.36 mmol) benzyltrimethylammonium methoxide (40% solution in methanol) in 4 mL dry DMF was cooled to 3° C., and 637° mg (1.68 mmol) O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate was added and the resulting mixture stirred at 3° for 30 minutes, warmed to 25° C., and stirred an additional 30 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 4:1 ethyl acetate:hexanes as eluant, followed by conversion to the hydrochloride salt by treating with excess diethyl ether which had been saturated with hydrogen chloride gas to give 29 mg (4%) of titled compound: mp 49-53° C. APCI-MS m/z 443.4 (MH+). stirred an additional 30 minutes at which time it washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine dried over anhydrous sodium sulfate concentrated at reduced pressure The residue thus obtained was further purified by silica gel chromatography by treating with excess diethyl ether which

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 335 mg (1.68 mmol) 2-(cyclohexylamino)-3-methylbutyric acid (Example 69, Step A), 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride, 0.29 mL (1.68 mmol) N,N-diisopropylethylamine, and 1.5 mL (3.36 mmol) benzyltrimethylammonium methoxide (40% solution in methanol) in 4 mL dry DMF was cooled to 3° C., and 637° mg (1.68 mmol) O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate was added and the resulting mixture stirred at 3° for 30 minutes, warmed to 25° C., and stirred an additional 30 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 4:1 ethyl acetate:hexanes as eluant, followed by conversion to the hydrochloride salt by treating with excess diethyl ether which had been saturated with hydrogen chloride gas to give 29 mg (4%) of titled compound: mp 49-53° C. APCI-MS m/z 443.4 (MH+). stirred an additional 30 minutes at which time it washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine dried over anhydrous sodium sulfate concentrated at reduced pressure The residue thus obtained was further purified by silica gel chromatography by treating with excess diethyl ether which

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 358 mg (1.68 mmol) (S)-2-(cyclohexyl-methyl-amino)-3-methylbutyric acid, 0.88 mL (5 mmol) N,N-diisopropylethylamine, and 636 mg (1.68 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was stirred at 3° for 60 minutes, at which time 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride was added, and the reaction stirred an additional 10 minutes at 3°, then warmed to 25° C. for 50 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 40% ethyl acetate in hexanes as eluant, followed by conversion to the hydrochloride salt by treatment with excess diethyl ether which had been saturated with hydrogen chloride gas to give 577 mg (68%) mp 82-86° C. APCI-MS m/z 457.4 (MH+). was added washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine dried over anhydrous sodium sulfate concentrated at reduced pressure The residue thus obtained was further purified by silica gel chromatography to give 577 mg (68%) mp 82-86° C

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 297 mg (1.68 mmol) 2-(isopropyl-methyl-amino)-4-methyl-pentanoic acid, 0.88 mL (5 mmol) N,N-diisopropylethylamine, and 636 mg (1.68 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was stirred at 3° for 60 minutes, at which time 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride was added and the reaction stirred an additional 10 minutes at 3°, then warmed to 25° C. for 40 minutes at which time it was diluted with 20 mL diethyl ether and washed with 20 mL saturated aqueous sodium bicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 60% ethyl acetate in hexanes as eluant, followed by conversion to the hydrochloride salt by treating with excess diethyl ether which had been saturated with hydrogen chloride gas to give 648 mg (83%) of titled compound: mp 155-156° C. APCI-MS m/z 431.4 (MH+). was added washed with 20 mL saturated aqueous sodium bicarbonate solution and twice with 20 mL brine dried over anhydrous sodium sulfate concentrated at reduced pressure The residue thus obtained was further purified by silica gel chromatography by treating with excess diethyl ether which

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

実験手順: (S)-2-[(Azepane-1-carbonyl)-amino]-propanoic acid (0.300 g, 1.40 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.732 mL, 4.20 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.531 g, 1.40 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.412 g, 1.40 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexanes) to afford 0.42 g (65%) of the pure titled compound as a white foam: mp 29-49° C. APCI-MS m/z 458.3 (MH+). The resulting reaction mixture After stirring for, sequentially, 10 minutes at 0° C. 40 minutes at ambient temperature, reaction mixture the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL) was dried over Na2SO4 The solution was concentrated in vacuo affording an viscous oil The crude product was further purified by flash chromatography (70% EtOAc in hexanes)

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

実験手順: (S)-2-[(Azepane-1-carbonyl)-amino]-propanoic acid (0.300 g, 1.40 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.732 mL, 4.20 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.531 g, 1.40 mmol). The resulting reaction mixture was stirred at that temperature for 35 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.412 g, 1.40 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 40 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexanes) to afford 0.42 g (65%) of the pure titled compound as a white foam: mp 29-49° C. APCI-MS m/z 458.3 (MH+). The resulting reaction mixture After stirring for, sequentially, 10 minutes at 0° C. 40 minutes at ambient temperature, reaction mixture the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL) was dried over Na2SO4 The solution was concentrated in vacuo affording an viscous oil The crude product was further purified by flash chromatography (70% EtOAc in hexanes)

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

実験手順: (S)-2-[(4-Methyl-piperazine-1-carbonyl)-amino]-4-methyl pentanoic acid (0.300 g, 1.23 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.644 mL, 3.70 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.468 g, 1.23 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.367 g, 1.23 mmol) was then added. After stirring for, sequentially, 10 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (20% MeOH in EtOAc) to afford 0.45 g (73%) of the pure titled compound as a white foam; mp 73-91° C. APCI-MS m/z 501.3 (MH+). The resulting reaction mixture After stirring for, sequentially, 10 minutes at 0° C. 20 minutes at ambient temperature, reaction mixture the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL) was dried over Na2SO4 The solution was concentrated in vacuo affording an viscous oil The crude product was further purified by flash chromatography (20% MeOH in EtOAc)

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

実験手順: (S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (0.300 g, 1.39 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.728 mL, 4.18 mmol) and solid O-benzotriazol-1-yl-N,N,N″,N′-tetramethyluronium hexafluorophosphate (0.528 g, 1.39 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.415 g, 1.39 mmol) was then added. After stirring for, sequentially, 20 minutes at 0° C. and 60 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.460 g (65%) of the pure titled compound as a white foam: mp 37-46° C. APCI-MS m/z 459.4 (MH+). The resulting reaction mixture After stirring for, sequentially, 20 minutes at 0° C. 60 minutes at ambient temperature, reaction mixture the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL) was dried over Na2SO4 The solution was concentrated in vacuo affording an viscous oil The crude product was further purified by flash chromatography (40% EtOAc in hexane) treated with ethereal HCl Subsequent concentration in vacuo drying under vacuum

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

実験手順: (S)-4-Methyl-2-[methyl-(3-methyl-butyl)-amino]-pentanoic acid (0.300 g, 1.39 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.728 mL, 4.18 mmol) and solid O-benzotriazol-1-yl-N,N,N″,N′-tetramethyluronium hexafluorophosphate (0.528 g, 1.39 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.415 g, 1.39 mmol) was then added. After stirring for, sequentially, 20 minutes at 0° C. and 60 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (40% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.460 g (65%) of the pure titled compound as a white foam: mp 37-46° C. APCI-MS m/z 459.4 (MH+). The resulting reaction mixture After stirring for, sequentially, 20 minutes at 0° C. 60 minutes at ambient temperature, reaction mixture the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL) was dried over Na2SO4 The solution was concentrated in vacuo affording an viscous oil The crude product was further purified by flash chromatography (40% EtOAc in hexane) treated with ethereal HCl Subsequent concentration in vacuo drying under vacuum

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

実験手順: (S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.300 g, 1.31 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.684 mL, 3.93 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.496 g, 1.31 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.390 g, 1.31 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.432 g (63%) of the pure titled compound as a white foam; mp 75-92° C. APCI-MS m/z 473.4 (MH+). The resulting reaction mixture After stirring for, sequentially, 15 minutes at 0° C. 30 minutes at ambient temperature, reaction mixture the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL) was dried over Na2SO4 The solution was concentrated in vacuo affording an viscous oil The crude product was further purified by flash chromatography (70% EtOAc in hexane) treated with ethereal HCl Subsequent concentration in vacuo drying under vacuum

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

実験手順: (S)-4-Methyl-2-[methyl-(tetrahydro-pyran-4-yl)-amino]-pentanoic acid (0.300 g, 1.31 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.684 mL, 3.93 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.496 g, 1.31 mmol). The resulting reaction mixture was stirred at that temperature for 25 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.390 g, 1.31 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 30 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (70% EtOAc in hexane) and treated with ethereal HCl. Subsequent concentration in vacuo and drying under vacuum provided 0.432 g (63%) of the pure titled compound as a white foam; mp 75-92° C. APCI-MS m/z 473.4 (MH+). The resulting reaction mixture After stirring for, sequentially, 15 minutes at 0° C. 30 minutes at ambient temperature, reaction mixture the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL) was dried over Na2SO4 The solution was concentrated in vacuo affording an viscous oil The crude product was further purified by flash chromatography (70% EtOAc in hexane) treated with ethereal HCl Subsequent concentration in vacuo drying under vacuum

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

実験手順: (S2-[(Azepane-1-carbonyl)-amino]-3-methyl-butanoic acid (0.300 g, 1.23 mmol) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.647 mL, 3.71 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.470 g, 1.24 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (0.369 g, 1.24 mmol) was then added. After stirring for, sequentially, 15 minutes at 0° C. and 50 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording an viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.31 g (51%) of the pure titled compound as a white foam: mp 32-50° C. APCI-MS m/z 486.3 (MH+). The resulting reaction mixture After stirring for, sequentially, 15 minutes at 0° C. 50 minutes at ambient temperature, reaction mixture the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL) was dried over Na2SO4 The solution was concentrated in vacuo affording an viscous oil The crude product was further purified by flash chromatography (60% EtOAc in hexane)