3,3,3-三氟丙胺盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,3-dimethylbutanal (0.64 g, 6.0 mmol), 3,3,3-trifluoropropan-1-amine hydrochloride (Oakwood) (0.9 g, 6.0 mmol), 2 g of 4 Å (8-12 mesh beads) molecular sieves, and triethylamine (0.84 mL, 6.0 mmol) in 9 mL of dry acetonitrile was stirred for 20 hours at ambient temperature. The mixture was filtered through Celite and washed with 8 mL of acetonitrile. Potassium thiocyanate (0.78 g, 8.0 mmol) was added and the mixture warmed to 50° C. Iodine (1.5 g, 6.0 mmol) was added and the reaction stirred at 50° C. for 6 hours. To the mixture 10 mL of 20% Na2S2O5 was added, and stirring continued for 30 minutes. The organic layer was separated, dried with Na2SO4, filtered, and the solvent removed under reduced pressure. The resulting solid was used without further purification. 1H NMR (500 MHz, ACETONITRILE-D3) δ ppm 1.30 (s, 9H), 2.72-2.84 (m, 2H), 4.28 (t, J=6.87 Hz, 2H), 6.92 (s, 1H). MS (DCI/NH3) m/z 253.0 (M+H)+. The mixture was filtered through Celite washed with 8 mL of acetonitrile the mixture warmed to 50° C the reaction stirred at 50° C. for 6 hours stirring continued for 30 minutes The organic layer was separated dried with Na2SO4 filtered the solvent removed under reduced pressure The resulting solid was used without further purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-(methoxycarbonyl)pyridine-2-carboxylic acid (100 mg, 0.55 mmol) was dissolved in acetonitrile (1 mL). Triethylamine (0.230 mL, 1.66 mmol) and O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (314 mg, 0.83 mmol) were added. The reaction mixture was stirred at rt for 5 min. 3,3,3-trifluoropropylamine hydrochloride (83 mg, 0.55 mmol) was added and the reaction mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the crude was pardoned between ethyl acetate and 1M sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude was purified by column chromatography using a gradient of ethyl acetate in heptane yielded 38 mg (25%) of the title compound as a white solid; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.17 (t, 1 H), 9.11 (d, 1 H), 8.48 (dd, 1 H), 8.18 (d, 1 H), 3.92 (s, 3 H), 3.53-3.60 (m, 2 H), 2.54-2.66 (m, 2 H); MS (ESI) m/z 277[M+H+], m/z 275[M−H+]; the reaction mixture was stirred at ambient temperature for 2 h The solvent was removed in vacuo The organic layer was dried over magnesium sulfate concentrated in vacuo The crude was purified by column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from the product of Example 45A and commercially available 3,3,3-trifluoropropylamine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz), 1.43 (s, 6H), 1.48 (s, 6H), 2.39-3.50 (m, 2H), 3.35-3.42 (m, 2H), 7.68-7.81 (m, 3H), 8.31 (t, J=5.4 Hz, 1H), 11.53 (br s, 1H). MS (ESI+) m/z 527 (M+H)+. Anal. calcd. for C22H21F7N2O3S: C, 50.19; H, 4.02; N, 5.32. Found: C, 50.30; H, 4.13; N, 5.00.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Heat a mixture of prop-1-en-2-yl(5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (0.20 g, 0.518 mmol), 3,3,3-trifluoropropylamine hydrochloride (0.093 g, 0.622 mmol) and 1-methylpyrrolidine (0.068 mL, 0.648 mmol) in THF (5 mL) at 55° C. overnight. Cool to RT, add H2O, extract with EtOAc (2×), wash the combined organics with brine (2×), dry over MgSO4 and concentrate to dryness to afford the title compound (220 mg, 96%). 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 3.58-3.02 (m, 2H), 2.42 (m, 2H), 2.41 (s, 3H), 1.95 (s, 3H). Heat extract with EtOAc (2×) wash the combined organics with brine (2×) dry over MgSO4 concentrate to dryness

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Heat a mixture of prop-1-en-2-yl(5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (0.20 g, 0.518 mmol), 3,3,3-trifluoropropylamine hydrochloride (0.093 g, 0.622 mmol) and 1-methylpyrrolidine (0.068 mL, 0.648 mmol) in THF (5 mL) at 55° C. overnight. Cool to RT, add H2O, extract with EtOAc (2×), wash the combined organics with brine (2×), dry over MgSO4 and concentrate to dryness to afford the title compound (220 mg, 96%). 1H NMR (400 MHz, DMSO-d6): δ 9.23 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.23 (d, J=12.3 Hz, 1H), 6.75 (t, J=5.9 Hz, 1H), 3.58-3.02 (m, 2H), 2.42 (m, 2H), 2.41 (s, 3H), 1.95 (s, 3H). Heat extract with EtOAc (2×) wash the combined organics with brine (2×) dry over MgSO4 concentrate to dryness

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3,3,3-trifluoropropan-1-amine hydrochloride (0.165 g) in methanol (3 mL) was added 2,2-dimethoxyacetaldehyde (60% in water, 0.17 mL) followed by sodium bicarbonate (0.093 g) and the mixture was stirred at ambient temperature overnight. A slurry of palladium on carbon 10% (50 mg) in methanol (1 mL) was added and the mixture was hydrogenated at 5 bar pressure for 4 hours. The mixture was filtered and concentrated in vacuo. The resulting gummy solid was suspended in DCM (5 mL) and dried over sodium sulphate, filtered and evaporated to give the titled compound as a yellow gum. Yield 0.152 g. the mixture was hydrogenated at 5 bar pressure for 4 hours The mixture was filtered concentrated in vacuo dried over sodium sulphate filtered evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3,3,3-trifluoropropan-1-amine hydrochloride (0.165 g) in methanol (3 mL) was added 2,2-dimethoxyacetaldehyde (60% in water, 0.17 mL) followed by sodium bicarbonate (0.093 g) and the mixture was stirred at ambient temperature overnight. A slurry of palladium on carbon 10% (50 mg) in methanol (1 mL) was added and the mixture was hydrogenated at 5 bar pressure for 4 hours. The mixture was filtered and concentrated in vacuo. The resulting gummy solid was suspended in DCM (5 mL) and dried over sodium sulphate, filtered and evaporated to give the titled compound as a yellow gum. Yield 0.152 g. the mixture was hydrogenated at 5 bar pressure for 4 hours The mixture was filtered concentrated in vacuo dried over sodium sulphate filtered evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,3-dimethylbutanal (0.64 g, 6.0 mmol), 3,3,3-trifluoropropan-1-amine hydrochloride (Oakwood) (0.9 g, 6.0 mmol), 2 g of 4 Å (8-12 mesh beads) molecular sieves, and triethylamine (0.84 mL, 6.0 mmol) in 9 mL of dry acetonitrile was stirred for 20 hours at ambient temperature. The mixture was filtered through Celite and washed with 8 mL of acetonitrile. Potassium thiocyanate (0.78 g, 8.0 mmol) was added and the mixture warmed to 50° C. Iodine (1.5 g, 6.0 mmol) was added and the reaction stirred at 50° C. for 6 hours. To the mixture 10 mL of 20% Na2S2O5 was added, and stirring continued for 30 minutes. The organic layer was separated, dried with Na2SO4, filtered, and the solvent removed under reduced pressure. The resulting solid was used without further purification. 1H NMR (500 MHz, ACETONITRILE-D3) δ ppm 1.30 (s, 9H), 2.72-2.84 (m, 2H), 4.28 (t, J=6.87 Hz, 2H), 6.92 (s, 1H). MS (DCI/NH3) m/z 253.0 (M+H)+. The mixture was filtered through Celite washed with 8 mL of acetonitrile the mixture warmed to 50° C the reaction stirred at 50° C. for 6 hours stirring continued for 30 minutes The organic layer was separated dried with Na2SO4 filtered the solvent removed under reduced pressure The resulting solid was used without further purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,3-dimethylbutanal (0.64 g, 6.0 mmol), 3,3,3-trifluoropropan-1-amine hydrochloride (Oakwood) (0.9 g, 6.0 mmol), 2 g of 4 Å (8-12 mesh beads) molecular sieves, and triethylamine (0.84 mL, 6.0 mmol) in 9 mL of dry acetonitrile was stirred for 20 hours at ambient temperature. The mixture was filtered through Celite and washed with 8 mL of acetonitrile. Potassium thiocyanate (0.78 g, 8.0 mmol) was added and the mixture warmed to 50° C. Iodine (1.5 g, 6.0 mmol) was added and the reaction stirred at 50° C. for 6 hours. To the mixture 10 mL of 20% Na2S2O5 was added, and stirring continued for 30 minutes. The organic layer was separated, dried with Na2SO4, filtered, and the solvent removed under reduced pressure. The resulting solid was used without further purification. 1H NMR (500 MHz, ACETONITRILE-D3) δ ppm 1.30 (s, 9H), 2.72-2.84 (m, 2H), 4.28 (t, J=6.87 Hz, 2H), 6.92 (s, 1H). MS (DCI/NH3) m/z 253.0 (M+H)+. The mixture was filtered through Celite washed with 8 mL of acetonitrile the mixture warmed to 50° C the reaction stirred at 50° C. for 6 hours stirring continued for 30 minutes The organic layer was separated dried with Na2SO4 filtered the solvent removed under reduced pressure The resulting solid was used without further purification

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 30 mg of 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde in 1.5 mL of methanol were added 0.018 mL of triethylamine, 10 mg of 3,3,3-trifluoro-propylamine hydrochloride and 0.5 g of 4 Å powdered molecular sieves. The resulting mixture was stirred at room temperature for 1 h then 2.4 mg of sodium borohydride was added. After stirring at room temperature for 45 minutes, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by azeotropal removal of traces of acetic acid with cyclohexane to give 6.5 mg of 3-(2-methoxy-4-{2-(4-trifluoromethyl-phenyl)-4-[(3,3,3-trifluoro-propylamino)-methyl]-thiazol-5-ylmethoxy}-phenyl)-4H-[1,2,4]oxadiazol-5-one as a white solid. After stirring at room temperature for 45 minutes the reaction mixture was concentrated under reduced pressure The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by azeotropal removal of traces of acetic acid with cyclohexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 30 mg of 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde in 1.5 mL of methanol were added 0.018 mL of triethylamine, 10 mg of 3,3,3-trifluoro-propylamine hydrochloride and 0.5 g of 4 Å powdered molecular sieves. The resulting mixture was stirred at room temperature for 1 h then 2.4 mg of sodium borohydride was added. After stirring at room temperature for 45 minutes, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by azeotropal removal of traces of acetic acid with cyclohexane to give 6.5 mg of 3-(2-methoxy-4-{2-(4-trifluoromethyl-phenyl)-4-[(3,3,3-trifluoro-propylamino)-methyl]-thiazol-5-ylmethoxy}-phenyl)-4H-[1,2,4]oxadiazol-5-one as a white solid. After stirring at room temperature for 45 minutes the reaction mixture was concentrated under reduced pressure The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by azeotropal removal of traces of acetic acid with cyclohexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 30 mg of 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde in 1.5 mL of methanol were added 0.018 mL of triethylamine, 10 mg of 3,3,3-trifluoro-propylamine hydrochloride and 0.5 g of 4 Å powdered molecular sieves. The resulting mixture was stirred at room temperature for 1 h then 2.4 mg of sodium borohydride was added. After stirring at room temperature for 45 minutes, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by azeotropal removal of traces of acetic acid with cyclohexane to give 6.5 mg of 3-(2-methoxy-4-{2-(4-trifluoromethyl-phenyl)-4-[(3,3,3-trifluoro-propylamino)-methyl]-thiazol-5-ylmethoxy}-phenyl)-4H-[1,2,4]oxadiazol-5-one as a white solid. After stirring at room temperature for 45 minutes the reaction mixture was concentrated under reduced pressure The crude product was purified by preparative thin layer chromatography on silica gel (dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by azeotropal removal of traces of acetic acid with cyclohexane