(1R)-2,2,2-trifluoro-1-phenylethanamine

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

実験手順: N,N-Diisopropylethylamine (0.087 mL, 0.495 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.045 g, 0.215 mmol), and propylphosphonic anhydride (0.126 mL of a 50% solution in ethyl acetate, 0.215 mmol) were added to a suspension of 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.165 mmol) in dichloromethane (2.54 mL). The mixture was stirred for 15 h, diluted with 10% Na2CO3 (2 mL) and methylene chloride (5 mL), and poured into a hydrophobic frit to separate the phases. The organic phase was absorbed onto florisil and purified via column chromatography (ISCO, 1-10% methanol/methylene chloride). The material was dissolved in methylene chloride, and the organic phase was washed with 10% Na2CO3 (2×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide as a light orange solid (0.068 g, 51% yield). MS (m/z) 763.2 (M+H+). poured into a hydrophobic frit to separate the phases The organic phase was absorbed onto florisil purified via column chromatography (ISCO, 1-10% methanol/methylene chloride) The material was dissolved in methylene chloride the organic phase was washed with 10% Na2CO3 (2×10 mL) dried over MgSO4 filtered concentrated in vacuo

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

実験手順: N,N-Diisopropylethylamine (0.087 mL, 0.495 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.045 g, 0.215 mmol), and propylphosphonic anhydride (0.126 mL of a 50% solution in ethyl acetate, 0.215 mmol) were added to a suspension of 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.165 mmol) in dichloromethane (2.54 mL). The mixture was stirred for 15 h, diluted with 10% Na2CO3 (2 mL) and methylene chloride (5 mL), and poured into a hydrophobic frit to separate the phases. The organic phase was absorbed onto florisil and purified via column chromatography (ISCO, 1-10% methanol/methylene chloride). The material was dissolved in methylene chloride, and the organic phase was washed with 10% Na2CO3 (2×10 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford 6-(ethylsulfonyl)-7-(methyloxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide as a light orange solid (0.068 g, 51% yield). MS (m/z) 763.2 (M+H+). poured into a hydrophobic frit to separate the phases The organic phase was absorbed onto florisil purified via column chromatography (ISCO, 1-10% methanol/methylene chloride) The material was dissolved in methylene chloride the organic phase was washed with 10% Na2CO3 (2×10 mL) dried over MgSO4 filtered concentrated in vacuo

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

実験手順: A mixture of 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.977 g, 1.929 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.449 g, 2.12 mmol), N,N-diisopropylethylamine (0.404 mL, 2.315 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (1.705 mL of a 50% solution in ethyl acetate, 2.89 mmol) in dichloromethane (19.29 mL) was stirred at 0° C. for 2 h, warmed to room temperature, and stirred at room temperature overnight. The mixture was diluted with 10% Na2CO3, and extracted with methylene chloride (four times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate hexanes) to afford 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.570 g, 31% yield). MS (m/z) 664.1 (M+H+). warmed to room temperature stirred at room temperature overnight extracted with methylene chloride (four times) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate hexanes)

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

実験手順: A mixture of 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.977 g, 1.929 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.449 g, 2.12 mmol), N,N-diisopropylethylamine (0.404 mL, 2.315 mmol), and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (1.705 mL of a 50% solution in ethyl acetate, 2.89 mmol) in dichloromethane (19.29 mL) was stirred at 0° C. for 2 h, warmed to room temperature, and stirred at room temperature overnight. The mixture was diluted with 10% Na2CO3, and extracted with methylene chloride (four times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate hexanes) to afford 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.570 g, 31% yield). MS (m/z) 664.1 (M+H+). warmed to room temperature stirred at room temperature overnight extracted with methylene chloride (four times) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate hexanes)

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

実験手順: A mixture of 2-(3-bromophenyl)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-4-quinolinecarboxylic acid (0.250 g, 0.398 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.093 g, 0.438 mmol), and N,N-diisopropylethylamine (77 μL, 0.438 mmol) in dichloromethane (3.98 mL) was cooled to 0° C., and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.356 mL of 50% solution in ethyl acetate, 0.597 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The mixture was diluted with water (2 mL) and saturated aqueous NaHCO3 (1 mL) was added. After stirring for 30 min, the organic phase was removed, passed over a phase separator, and concentrated in vacuo. The residue was dissolved in acetonitrile, and water was added slowly until the mixture became cloudy. The solid precipitate was collected by filtration, washed with water, and dried to afford 2-(3-bromophenyl)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.260 g, 88% yield). MS (m/z) 747.1 (M+H+). warmed to room temperature stirred overnight was added After stirring for 30 min the organic phase was removed concentrated in vacuo The residue was dissolved in acetonitrile water was added slowly until the mixture The solid precipitate was collected by filtration washed with water dried

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

実験手順: A mixture of 2-(3-bromophenyl)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-4-quinolinecarboxylic acid (0.250 g, 0.398 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.093 g, 0.438 mmol), and N,N-diisopropylethylamine (77 μL, 0.438 mmol) in dichloromethane (3.98 mL) was cooled to 0° C., and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.356 mL of 50% solution in ethyl acetate, 0.597 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The mixture was diluted with water (2 mL) and saturated aqueous NaHCO3 (1 mL) was added. After stirring for 30 min, the organic phase was removed, passed over a phase separator, and concentrated in vacuo. The residue was dissolved in acetonitrile, and water was added slowly until the mixture became cloudy. The solid precipitate was collected by filtration, washed with water, and dried to afford 2-(3-bromophenyl)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.260 g, 88% yield). MS (m/z) 747.1 (M+H+). warmed to room temperature stirred overnight was added After stirring for 30 min the organic phase was removed concentrated in vacuo The residue was dissolved in acetonitrile water was added slowly until the mixture The solid precipitate was collected by filtration washed with water dried

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

実験手順: A suspension of 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.167 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.046 g, 0.218 mmol), N,N-diisopropylethylamine (0.088 mL, 0.502 mmol), and propylphosphonic anhydride (0.128 mL of a 50% solution in ethyl acetate, 0.218 mmol) in dichloromethane (2.57 mL) was stirred at room temperature for 30 min. Water (2 mL) was added, and the mixture was poured into a hydrophobic frit to separate the layers. The organic phase was concentrated in vacuo, and the residue was loaded onto florisil and purified via column chromatography (ISCO, 4 g silica, 0-10% methanol/methylene chloride) to afford 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.110 g, 83% yield). MS (m/z) 755.2 (M+H+). the mixture was poured into a hydrophobic frit to separate the layers The organic phase was concentrated in vacuo purified via column chromatography (ISCO, 4 g silica, 0-10% methanol/methylene chloride)

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

実験手順: A suspension of 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.100 g, 0.167 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.046 g, 0.218 mmol), N,N-diisopropylethylamine (0.088 mL, 0.502 mmol), and propylphosphonic anhydride (0.128 mL of a 50% solution in ethyl acetate, 0.218 mmol) in dichloromethane (2.57 mL) was stirred at room temperature for 30 min. Water (2 mL) was added, and the mixture was poured into a hydrophobic frit to separate the layers. The organic phase was concentrated in vacuo, and the residue was loaded onto florisil and purified via column chromatography (ISCO, 4 g silica, 0-10% methanol/methylene chloride) to afford 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.110 g, 83% yield). MS (m/z) 755.2 (M+H+). the mixture was poured into a hydrophobic frit to separate the layers The organic phase was concentrated in vacuo purified via column chromatography (ISCO, 4 g silica, 0-10% methanol/methylene chloride)

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

実験手順: 6-(Methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (100 mg, 0.162 mmol), dichloromethane (1621 μL), DIEA (31.2 μL, 0.178 mmol), and [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (37.7 mg, 0.178 mmol) were combined in a round bottom flask. The mixture was cooled to 0° C. and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (145 μL, 0.243 mmol) (50% in EtOAc) was added dropwise. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The next day 0.1 mL of water and 2 mL of CH3CN were added, and the solution was concentrated to afford a yellow residue. The residue was dissolved in MeOH/DMSO and purified by reverse phase HPLC to afford the title compound as a white solid (32 mg, 27%). MS (m/z) 735.3 (M+H+). warmed to room temperature stirred overnight the solution was concentrated to afford a yellow residue purified by reverse phase HPLC

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

実験手順: 6-(Methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (100 mg, 0.162 mmol), dichloromethane (1621 μL), DIEA (31.2 μL, 0.178 mmol), and [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (37.7 mg, 0.178 mmol) were combined in a round bottom flask. The mixture was cooled to 0° C. and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (145 μL, 0.243 mmol) (50% in EtOAc) was added dropwise. The mixture was stirred at 0° C. for 2 h, warmed to room temperature, and stirred overnight. The next day 0.1 mL of water and 2 mL of CH3CN were added, and the solution was concentrated to afford a yellow residue. The residue was dissolved in MeOH/DMSO and purified by reverse phase HPLC to afford the title compound as a white solid (32 mg, 27%). MS (m/z) 735.3 (M+H+). warmed to room temperature stirred overnight the solution was concentrated to afford a yellow residue purified by reverse phase HPLC

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

実験手順: A suspension of 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.125 g, 0.223 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.061 g, 0.289 mmol), N,N-diisopropylethylamine (0.117 mL, 0.668 mmol), and T3P (propylphosphonic anhydride, 0.170 mL of a 50% w/v solution in ethyl acetate, 0.289 mmol) in dichloromethane (3.42 mL) was stirred at room temperature for 20 h. Additional portions of [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.031 g, 0.145 mmol) and T3P (propylphosphonic anhydride, 0.085 mL of a 50% w/v solution in ethyl acetate, 0.145 mmol) were added, and the mixture stirred for 2 h. Water (2 mL) was added, and the mixture was poured through a hydrophobic frit. The isolated organic phase was absorbed onto florisil and purified via column chromatography (ISCO, 4 g silica, 1-6% methanol/methylene chloride) to afford 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.048 g, 28% yield). MS (m/z) 719.2 (M+H+). the mixture was poured through a hydrophobic frit The isolated organic phase was absorbed onto florisil purified via column chromatography (ISCO, 4 g silica, 1-6% methanol/methylene chloride)

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

実験手順: A suspension of 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.125 g, 0.223 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.061 g, 0.289 mmol), N,N-diisopropylethylamine (0.117 mL, 0.668 mmol), and T3P (propylphosphonic anhydride, 0.170 mL of a 50% w/v solution in ethyl acetate, 0.289 mmol) in dichloromethane (3.42 mL) was stirred at room temperature for 20 h. Additional portions of [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.031 g, 0.145 mmol) and T3P (propylphosphonic anhydride, 0.085 mL of a 50% w/v solution in ethyl acetate, 0.145 mmol) were added, and the mixture stirred for 2 h. Water (2 mL) was added, and the mixture was poured through a hydrophobic frit. The isolated organic phase was absorbed onto florisil and purified via column chromatography (ISCO, 4 g silica, 1-6% methanol/methylene chloride) to afford 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.048 g, 28% yield). MS (m/z) 719.2 (M+H+). the mixture was poured through a hydrophobic frit The isolated organic phase was absorbed onto florisil purified via column chromatography (ISCO, 4 g silica, 1-6% methanol/methylene chloride)