N-ethyl-N-propan-2-ylpropan-2-amine;trihydrofluoride

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

実験手順: To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (440 mg, 0.694 mmol) in ACETONITRILE (0.1 mL, 1.915 mmol) at room temperature was added diisopropylethylamine (0.545 mL, 3.12 mmol), Diisopropylethylamine trihydrofluoride (197 mg, 1.041 mmol), and perfluoro-1-butanesulfonyl fluoride (0.249 mL, 1.387 mmol). The reaction was stirred at room temperature overnight. It was then poured into sat'd NaHCO3 and diluted with ether. The ether layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (15%-20% EtOAc/Hex) to give title compound (420 mg, 0.660 mmol, 95% yield) as a colorless film. LC/MS (HPLC method 3): tR=4.33 min, 636.3(MH)+. The ether layer was washed with water and brine dried over MgSO4 filtered concentrated The crude product was purified by silica gel column chromatography (15%-20% EtOAc/Hex)

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

実験手順: To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (440 mg, 0.694 mmol) in ACETONITRILE (0.1 mL, 1.915 mmol) at room temperature was added diisopropylethylamine (0.545 mL, 3.12 mmol), Diisopropylethylamine trihydrofluoride (197 mg, 1.041 mmol), and perfluoro-1-butanesulfonyl fluoride (0.249 mL, 1.387 mmol). The reaction was stirred at room temperature overnight. It was then poured into sat'd NaHCO3 and diluted with ether. The ether layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (15%-20% EtOAc/Hex) to give title compound (420 mg, 0.660 mmol, 95% yield) as a colorless film. LC/MS (HPLC method 3): tR=4.33 min, 636.3(MH)+. The ether layer was washed with water and brine dried over MgSO4 filtered concentrated The crude product was purified by silica gel column chromatography (15%-20% EtOAc/Hex)

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

実験手順: To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (50 mg, 0.079 mmol) in acetonitrile (0.1 mL) at room temperature was added diisopropylethylamine (0.062 mL, 0.355 mmol), diisopropylethylamine trihydrofluoride (22.4 mg, 0.118 mmol), and perfluoro-1-butanesulfonyl fluoride (0.028 mL, 0.16 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into saturated sodium bicarbonate, and diluted with diethyl ether. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→20% ethyl acetate/n-hexane) gave 40 mg (80%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.33 (dd, J=9.2, 5.5 Hz, 2H), 7.03 (dd, J=8.9, 8.5 Hz, 2H), 6.73 (bs, 1H), 5.66 (d, J=10.7 Hz, 1H), 5.63 (d, J=10.7 Hz, 1H), 5.16 (m, 1H), 4.62 (ddd, J=46.7, 9.5, 2.4 Hz, 1H), 4.42 (ddd, J=48.2, 9.8, 7.3 Hz, 1H), 3.75 (bs, 2H), 3.60 (m, 2H), 3.52 (d, J=9.2 Hz, 1H), 3.45 (d, J=9.2 Hz, 1H), 3.10 (bs, 1H), 3.03 (m, 1H), 2.27 (m, 1H), 2.07 (m, 1H), 1.99 (m, 1H), 1.87 (m, 1H), 1.44 (s, 9H), 0.92 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 155.1, 145.4, 138.5, 128.9 (d, J=7.7 Hz), 128.2, 128.11, 128.07, 124.9, 122.7, 122.6, 118.9, 115.3 (d, J=21 Hz), 85.9, 84.4, 81.9, 79.5, 78.8, 77.3, 77.1, 67.8, 41.5, 40.5, 39.7, 32.2, 31.8, 28.6, 17.9, −1.4. Mass spec.: 636.43 (MH)+. The ethereal was washed with water brine, dried over magnesium sulfate concentrated Column chromatography (15%→20% ethyl acetate/n-hexane) gave 40 mg (80%) as a colorless film

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 0.02 g (0.04 mmol) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-hydroxy-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide in 0.20 ml CH3CN at rt was added 0.02 ml (0.13 mmol) DIEA, 0.009 ml (0.05 mmol) N,N-diisopropylethylamine trihydrofluoride, and 0.007 ml (0.04 mmol) perfluoro-1-butanesulfonyl fluoride (PBSF). After 2 h at room temperature, 0.007 ml (0.04 mmol) PBSF was added to the reaction mixture and the reaction was heated to 45° C. After 18 h at 45° C., the reaction temperature was increased to 60° C. After 4 h at 60° C., add 0.009 ml (0.05 mmol) N,N,-diisopropylethylamine trihydrofluoride and 0.007 ml (0.04 mmol) PBSF and continue heating. After 24 h, the reaction is still incomplete. At this point, the reaction mixture was quenched with water, filtered through a plug of silica and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.003 g (16%) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-fluoro-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide. ES-MS [M+1]+=522.3. 1H NMR (CDCl3, 400 MHz) 8.24 (d, 1H, J=2.65 Hz); 7.57 (s, 1H); 7.40-7.30 (m, 3H); 7.31-7.22 (m, 3H); 4.57-4.46 (d, 1H, J=47.2 Hz); 4.41 (q, 2H, J=8.06 Hz); 3.63 (s, 2H); 1.63 (s, 6H); 1.32 (s, 9H). After 18 h at 45° C. the reaction temperature was increased to 60° C After 4 h at 60° C. continue heating After 24 h At this point, the reaction mixture was quenched with water filtered through a plug of silica concentrated in vacuo Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18)

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

実験手順: To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (440 mg, 0.694 mmol) in ACETONITRILE (0.1 mL, 1.915 mmol) at room temperature was added diisopropylethylamine (0.545 mL, 3.12 mmol), Diisopropylethylamine trihydrofluoride (197 mg, 1.041 mmol), and perfluoro-1-butanesulfonyl fluoride (0.249 mL, 1.387 mmol). The reaction was stirred at room temperature overnight. It was then poured into sat'd NaHCO3 and diluted with ether. The ether layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (15%-20% EtOAc/Hex) to give title compound (420 mg, 0.660 mmol, 95% yield) as a colorless film. LC/MS (HPLC method 3): tR=4.33 min, 636.3(MH)+. The ether layer was washed with water and brine dried over MgSO4 filtered concentrated The crude product was purified by silica gel column chromatography (15%-20% EtOAc/Hex)

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

実験手順: To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (50 mg, 0.079 mmol) in acetonitrile (0.1 mL) at room temperature was added diisopropylethylamine (0.062 mL, 0.355 mmol), diisopropylethylamine trihydrofluoride (22.4 mg, 0.118 mmol), and perfluoro-1-butanesulfonyl fluoride (0.028 mL, 0.16 mmol). The reaction was stirred at room temperature overnight. The reaction was poured into saturated sodium bicarbonate, and diluted with diethyl ether. The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→20% ethyl acetate/n-hexane) gave 40 mg (80%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.33 (dd, J=9.2, 5.5 Hz, 2H), 7.03 (dd, J=8.9, 8.5 Hz, 2H), 6.73 (bs, 1H), 5.66 (d, J=10.7 Hz, 1H), 5.63 (d, J=10.7 Hz, 1H), 5.16 (m, 1H), 4.62 (ddd, J=46.7, 9.5, 2.4 Hz, 1H), 4.42 (ddd, J=48.2, 9.8, 7.3 Hz, 1H), 3.75 (bs, 2H), 3.60 (m, 2H), 3.52 (d, J=9.2 Hz, 1H), 3.45 (d, J=9.2 Hz, 1H), 3.10 (bs, 1H), 3.03 (m, 1H), 2.27 (m, 1H), 2.07 (m, 1H), 1.99 (m, 1H), 1.87 (m, 1H), 1.44 (s, 9H), 0.92 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 155.1, 145.4, 138.5, 128.9 (d, J=7.7 Hz), 128.2, 128.11, 128.07, 124.9, 122.7, 122.6, 118.9, 115.3 (d, J=21 Hz), 85.9, 84.4, 81.9, 79.5, 78.8, 77.3, 77.1, 67.8, 41.5, 40.5, 39.7, 32.2, 31.8, 28.6, 17.9, −1.4. Mass spec.: 636.43 (MH)+. The ethereal was washed with water brine, dried over magnesium sulfate concentrated Column chromatography (15%→20% ethyl acetate/n-hexane) gave 40 mg (80%) as a colorless film

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 0.02 g (0.04 mmol) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-hydroxy-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide in 0.20 ml CH3CN at rt was added 0.02 ml (0.13 mmol) DIEA, 0.009 ml (0.05 mmol) N,N-diisopropylethylamine trihydrofluoride, and 0.007 ml (0.04 mmol) perfluoro-1-butanesulfonyl fluoride (PBSF). After 2 h at room temperature, 0.007 ml (0.04 mmol) PBSF was added to the reaction mixture and the reaction was heated to 45° C. After 18 h at 45° C., the reaction temperature was increased to 60° C. After 4 h at 60° C., add 0.009 ml (0.05 mmol) N,N,-diisopropylethylamine trihydrofluoride and 0.007 ml (0.04 mmol) PBSF and continue heating. After 24 h, the reaction is still incomplete. At this point, the reaction mixture was quenched with water, filtered through a plug of silica and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) afforded 0.003 g (16%) 2-(4-tert-butylphenyl)-N-{(S)-[1-(2-fluoro-1,1-dimethylethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide. ES-MS [M+1]+=522.3. 1H NMR (CDCl3, 400 MHz) 8.24 (d, 1H, J=2.65 Hz); 7.57 (s, 1H); 7.40-7.30 (m, 3H); 7.31-7.22 (m, 3H); 4.57-4.46 (d, 1H, J=47.2 Hz); 4.41 (q, 2H, J=8.06 Hz); 3.63 (s, 2H); 1.63 (s, 6H); 1.32 (s, 9H). After 18 h at 45° C. the reaction temperature was increased to 60° C After 4 h at 60° C. continue heating After 24 h At this point, the reaction mixture was quenched with water filtered through a plug of silica concentrated in vacuo Purification by preparative HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18)