(1S,2S)-2-aminocyclohexan-1-ol

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

実験手順: The title compound was prepared by the procedure described for the synthesis of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide in Example 3, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol. The resultant solid gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 426.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24-8.19 (m, 2H), 7.99 (s, 1H), 7.87-7.84 (m, 1H), 7.62-7.55 (m, 2H), 7.39-7.36 (m, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.38 (s, 2H), 4.15-4.10 (m, 2H), 4.09-4.00 (m, 1H), 4.03 (s, 3H), 3.70-3.63 (m, 1H), 3.54-3.47 (m, 1H), 3.28-3.23 (m, 1H), 2.12-2.04 (m, 1H), 1.84-1.74 (m, 1H). The resultant solid gave a proton NMR spectra consistent with theory

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

実験手順: 1,5-Anhydro-3-(5-bromo-7-oxo-1,8-phenanthrolin-8(7H)-yl)-2,3-dideoxy-L-threo-pentitol was prepared by the procedure described for the synthesis of 5-bromo-8-[(1S,2S)-2-hydroxycyclohexyl]-1,8-phenanthrolin-7(8H)-one in Example 1, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol.

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

実験手順: To a solution of 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (600 mg, 2.10 mmol) in DMF (7 mL) at rt was added (1S,2S)-2-aminocyclohexanol (242 mg, 2.10 mmol), BOP (1.16 g, 2.63 mmol), and Et3N (0.59 mL, 4.21 mmol). The mixture was stirred at rt for 2 h. The resulting solution was quenched with 10% aqueous NaHCO3 and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated to afford 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxamide in pure form. The resulting solution was quenched with 10% aqueous NaHCO3 extracted with ethyl acetate The combined extracts were washed with water and brine dried (Na2SO4) concentrated

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

実験手順: To a solution of 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (600 mg, 2.10 mmol) in DMF (7 mL) at rt was added (1S,2S)-2-aminocyclohexanol (242 mg, 2.10 mmol), BOP (1.16 g, 2.63 mmol), and Et3N (0.59 mL, 4.21 mmol). The mixture was stirred at rt for 2 h. The resulting solution was quenched with 10% aqueous NaHCO3 and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated to afford 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxamide in pure form. The resulting solution was quenched with 10% aqueous NaHCO3 extracted with ethyl acetate The combined extracts were washed with water and brine dried (Na2SO4) concentrated

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

実験手順: To a solution of 8-amino-5-bromoquinoline-7-carboxylic acid (1.00 g, 3.74 mmol) in 20 mL of dichloromethane was added (1H-1,2,3-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (1.99 g, 4.49 mmol), (1S,2S)-2-aminocyclohexanol (0.517 g, 4.49 mmol), and triethylamine (1.04 mL, 7.49 mmol). After 3 h, a brown solid was collected and washed with dichloromethane and water to provide 8-amino-5-bromo-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-7-carboxamide that gave a mass ion (ES+) of 365.9 (81Br) for [M+H]+. a brown solid was collected washed with dichloromethane and water

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To (4-cyano-2-methyl-phenyl)boronic acid (1.75 g, 10.90 mmol), nickel iodide (0.10 g, 0.33 mmol), (1S,2S)-2-aminocyclohexan-1-ol (0.05 g, 0.33 mmol) and NaHMDS (2.01 g, 10.90 mmol) in isopropanol (10 mL) under an atmosphere of nitrogen was added 3-iodooxetane (1.00 g, 5.40 mmol) in isopropanol (1 mL) via cannula. The reaction mixture was heated at 90° C. for 2 hours, then cooled, diluted with ethanol (20 mL) and filtered over Celite®. The filtrate was concentrated in vacuo, then the residue was purified by silica gel column chromatography using 0-60% EtOAc/hexane as eluant to give 3-methyl-4-(oxetan-3-yl)benzonitrile (0.62 g, 65%) as a white solid. ESI-MS m/z calc. 173.1. found 174.3 (M+1)+; Retention time: 1.09 minutes (3 min run). cooled filtered over Celite® The filtrate was concentrated in vacuo the residue was purified by silica gel column chromatography

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To (4-cyano-2-methyl-phenyl)boronic acid (1.75 g, 10.90 mmol), nickel iodide (0.10 g, 0.33 mmol), (1S,2S)-2-aminocyclohexan-1-ol (0.05 g, 0.33 mmol) and NaHMDS (2.01 g, 10.90 mmol) in isopropanol (10 mL) under an atmosphere of nitrogen was added 3-iodooxetane (1.00 g, 5.40 mmol) in isopropanol (1 mL) via cannula. The reaction mixture was heated at 90° C. for 2 hours, then cooled, diluted with ethanol (20 mL) and filtered over Celite®. The filtrate was concentrated in vacuo, then the residue was purified by silica gel column chromatography using 0-60% EtOAc/hexane as eluant to give 3-methyl-4-(oxetan-3-yl)benzonitrile (0.62 g, 65%) as a white solid. ESI-MS m/z calc. 173.1. found 174.3 (M+1)+; Retention time: 1.09 minutes (3 min run). cooled filtered over Celite® The filtrate was concentrated in vacuo the residue was purified by silica gel column chromatography

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

実験手順: The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid and (1S,2S)-2-amino-cyclohexanol as starting materials, MS (ISP) 465.1, 467.1 (M+H)+.

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

実験手順: The title compound was prepared by the procedure described for the synthesis of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide in Example 3, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol. The resultant solid gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 426.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24-8.19 (m, 2H), 7.99 (s, 1H), 7.87-7.84 (m, 1H), 7.62-7.55 (m, 2H), 7.39-7.36 (m, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.38 (s, 2H), 4.15-4.10 (m, 2H), 4.09-4.00 (m, 1H), 4.03 (s, 3H), 3.70-3.63 (m, 1H), 3.54-3.47 (m, 1H), 3.28-3.23 (m, 1H), 2.12-2.04 (m, 1H), 1.84-1.74 (m, 1H). The resultant solid gave a proton NMR spectra consistent with theory

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

実験手順: The title compound was prepared by the procedure described for the synthesis of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide in Example 3, substituting (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol for (1S,2S)-2-aminocyclohexanol. The resultant solid gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 426.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.24-8.19 (m, 2H), 7.99 (s, 1H), 7.87-7.84 (m, 1H), 7.62-7.55 (m, 2H), 7.39-7.36 (m, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.38 (s, 2H), 4.15-4.10 (m, 2H), 4.09-4.00 (m, 1H), 4.03 (s, 3H), 3.70-3.63 (m, 1H), 3.54-3.47 (m, 1H), 3.28-3.23 (m, 1H), 2.12-2.04 (m, 1H), 1.84-1.74 (m, 1H). The resultant solid gave a proton NMR spectra consistent with theory

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

実験手順: To the solution of A4 (100 mg, 0.24 mmol) and DIEA (140 mg, 0.96 mmol) in 10 mL of DMF, was added (1S,2S)-2-Amino-cyclohexanol (45 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol), dried under vacuum to provide to provide title compound (70 mg, 74% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.62 (s, 1H), 10.88 (s, 1H), 7.71-7.77 (m, 2H), 7.36-7.39 (d, 1H), 6.81-6.95 (m, 2H), 4.58-4.60 (d, 1H), 3.48-3.60 (m, 1H), 3.30-3.35 (m, 1H), 2.41-2.44 (ds, 6H), 1.88-1.90 (t, 2H), 1.62 (S, 2h), 1.23 (s, 4H). LC/MS: 398.1 [M+H]+. completion of the reaction DMF was evaporated under reduced pressure the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication The solid was collected by filtration washed with methanol), dried under vacuum to provide

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

実験手順: To the solution of A4 (100 mg, 0.24 mmol) and DIEA (140 mg, 0.96 mmol) in 10 mL of DMF, was added (1S,2S)-2-Amino-cyclohexanol (45 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for several hours. LC/MS was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication. The solid was collected by filtration and washed with methanol), dried under vacuum to provide to provide title compound (70 mg, 74% yield) as orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.62 (s, 1H), 10.88 (s, 1H), 7.71-7.77 (m, 2H), 7.36-7.39 (d, 1H), 6.81-6.95 (m, 2H), 4.58-4.60 (d, 1H), 3.48-3.60 (m, 1H), 3.30-3.35 (m, 1H), 2.41-2.44 (ds, 6H), 1.88-1.90 (t, 2H), 1.62 (S, 2h), 1.23 (s, 4H). LC/MS: 398.1 [M+H]+. completion of the reaction DMF was evaporated under reduced pressure the residue was precipitated with 5% diethylamine/methanol (25 mL) under sonication The solid was collected by filtration washed with methanol), dried under vacuum to provide