2-氨基环己醇盐酸盐

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (125 mg, 3.12 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). 2-Chloro-1-iodobenzene (152 μL, 1.25 mmol) and isopropyl alcohol (1.0 mL) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organics were washed with brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography using hexanes/ethyl acetate (60:40). The product was obtained as a yellow oil in 91% yield (212.7 mg). cap The septum cap lined cap The reaction mixture was transferred to a separatory funnel extracted with methylene chloride (3×10 mL) The organics were washed with brine dried over MgSO4 concentrated The crude material was purified by silica gel chromatography The product was obtained as a yellow oil in 91% yield (212.7 mg)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (125 mg, 3.12 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). 2-Chloro-1-iodobenzene (152 μL, 1.25 mmol) and isopropyl alcohol (1.0 mL) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organics were washed with brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography using hexanes/ethyl acetate (60:40). The product was obtained as a yellow oil in 91% yield (212.7 mg). cap The septum cap lined cap The reaction mixture was transferred to a separatory funnel extracted with methylene chloride (3×10 mL) The organics were washed with brine dried over MgSO4 concentrated The crude material was purified by silica gel chromatography The product was obtained as a yellow oil in 91% yield (212.7 mg)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (83.0 mg, 2.08 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). Iodobenzene (139 μL, 1.25 mmol), dimethyl sulfoxide (670 μL), and a stock solution of 9.45 M NaOH (330 μL, 3.12 mmol) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with diethyl ether (3×10 mL). The organic extracts were washed with 3 M HCl (3×10 mL). The acid extracts were then cooled in an ice bath and the solution was basified using a saturated NaOH solution. When the pH of the solution became basic, as indicated by pH paper, the solution became opaque. The mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organic extract was washed with brine, dried over MgSO4 and concentrated. A pale yellow oil was obtained and placed under high vacuum overnight. While under vacuum the oil solidified to give 182.5 mg (92% yield) of an off-white solid, mp 57-58° C. cap The septum cap lined cap The reaction mixture was transferred to a separatory funnel extracted with diethyl ether (3×10 mL) The organic extracts were washed with 3 M HCl (3×10 mL) The acid extracts were then cooled in an ice bath The mixture was transferred to a separatory funnel extracted with methylene chloride (3×10 mL) The organic extract was washed with brine dried over MgSO4 concentrated A pale yellow oil was obtained placed under high vacuum overnight

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of (4-chlorophenyl)dihydroxyborane (524.0 mg, 3.351 mmol), 2-aminocyclohexanol hydrochloride (42 mg, 0.28 mmol) and nickel iodide (87.3 mg, 0.279 mmol) in i-PrOH (10.00 mL) was added sodium hexamethyldisilazane (1.075 g, 5.864 mmol) at 0° C. Then the mixture was stirred at rt for 5 min before 2-bromomethyl-tetrahydro-furan (460.00 mg, 2.80 mmol) was added by syringe. The resulting mixture was then stirred at 60° C. for 5 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography(5% AcOEt in hexane). was added by syringe The solvent was then removed under reduced pressure the resulting residue was purified by a flash chromatography(5% AcOEt in hexane)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of (4-chlorophenyl)dihydroxyborane (524.0 mg, 3.351 mmol), 2-aminocyclohexanol hydrochloride (42 mg, 0.28 mmol) and nickel iodide (87.3 mg, 0.279 mmol) in i-PrOH (10.00 mL) was added sodium hexamethyldisilazane (1.075 g, 5.864 mmol) at 0° C. Then the mixture was stirred at rt for 5 min before, 2-(bromomethyl)tetrahydro-2-H-pyran (500.00 mg, 2.79 mmol) was added by syringe. The resulting mixture was then stirred at 60° C. for 5 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography(5% AcOEt in hexane). 1H NMR (400 MHz, MeOD) δ 1.20-1.34 (m, 1H), 1.43-1.62 (m, 4H), 1.75-1.85 (m, 1H), 2.61-2.80 (m, 2H), 3.36-3.54 (m, 2H), 3.85-3.95 (m, 1H), 7.12-7.32 (m, 4H). was added by syringe The solvent was then removed under reduced pressure the resulting residue was purified by a flash chromatography(5% AcOEt in hexane)

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of (4-chlorophenyl)dihydroxyborane (524.0 mg, 3.351 mmol), 2-aminocyclohexanol hydrochloride (42 mg, 0.28 mmol) and nickel iodide (87.3 mg, 0.279 mmol) in i-PrOH (10.00 mL) was added sodium hexamethyldisilazane (1.075 g, 5.864 mmol) at 0° C. Then the mixture was stirred at rt for 5 min before, 2-(bromomethyl)tetrahydro-2-H-pyran (500.00 mg, 2.79 mmol) was added by syringe. The resulting mixture was then stirred at 60° C. for 5 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography(5% AcOEt in hexane). 1H NMR (400 MHz, MeOD) δ 1.20-1.34 (m, 1H), 1.43-1.62 (m, 4H), 1.75-1.85 (m, 1H), 2.61-2.80 (m, 2H), 3.36-3.54 (m, 2H), 3.85-3.95 (m, 1H), 7.12-7.32 (m, 4H). was added by syringe The solvent was then removed under reduced pressure the resulting residue was purified by a flash chromatography(5% AcOEt in hexane)

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

实验步骤: In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (18 mg, 0.050 mmol) described in example 92, triethylamine (0.3 mL, 1.95 mmol), and 2-aminocyclohexanol hydrochloride (100 mg, 0.66 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxycyclohexyl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (8 mg, 38% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.29 (d, J=7.6 Hz, 1 H), 8.54 (s, 1 H), 7.37 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.12 (s, 2 H), 3.86 (m, 1 H), 3.56-3.47 (m, 4 H), 2.07 (m, 2 H), 1.75 (m, 2 H), 1.42-1.23 (m, 4 H); HRMS m/z calcd for C23H25N3O4F: 426.1829 Found: 426.1834.

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

实验步骤: In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (18 mg, 0.050 mmol) described in example 92, triethylamine (0.3 mL, 1.95 mmol), and 2-aminocyclohexanol hydrochloride (100 mg, 0.66 mmol), was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxycyclohexyl)-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (8 mg, 38% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.29 (d, J=7.6 Hz, 1 H), 8.54 (s, 1 H), 7.37 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.12 (s, 2 H), 3.86 (m, 1 H), 3.56-3.47 (m, 4 H), 2.07 (m, 2 H), 1.75 (m, 2 H), 1.42-1.23 (m, 4 H); HRMS m/z calcd for C23H25N3O4F: 426.1829 Found: 426.1834.

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (125 mg, 3.12 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). 2-Chloro-1-iodobenzene (152 μL, 1.25 mmol) and isopropyl alcohol (1.0 mL) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organics were washed with brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography using hexanes/ethyl acetate (60:40). The product was obtained as a yellow oil in 91% yield (212.7 mg). cap The septum cap lined cap The reaction mixture was transferred to a separatory funnel extracted with methylene chloride (3×10 mL) The organics were washed with brine dried over MgSO4 concentrated The crude material was purified by silica gel chromatography The product was obtained as a yellow oil in 91% yield (212.7 mg)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (83.0 mg, 2.08 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). Iodobenzene (139 μL, 1.25 mmol), dimethyl sulfoxide (670 μL), and a stock solution of 9.45 M NaOH (330 μL, 3.12 mmol) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with diethyl ether (3×10 mL). The organic extracts were washed with 3 M HCl (3×10 mL). The acid extracts were then cooled in an ice bath and the solution was basified using a saturated NaOH solution. When the pH of the solution became basic, as indicated by pH paper, the solution became opaque. The mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organic extract was washed with brine, dried over MgSO4 and concentrated. A pale yellow oil was obtained and placed under high vacuum overnight. While under vacuum the oil solidified to give 182.5 mg (92% yield) of an off-white solid, mp 57-58° C. cap The septum cap lined cap The reaction mixture was transferred to a separatory funnel extracted with diethyl ether (3×10 mL) The organic extracts were washed with 3 M HCl (3×10 mL) The acid extracts were then cooled in an ice bath The mixture was transferred to a separatory funnel extracted with methylene chloride (3×10 mL) The organic extract was washed with brine dried over MgSO4 concentrated A pale yellow oil was obtained placed under high vacuum overnight

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (125 mg, 3.12 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). 2-Chloro-1-iodobenzene (152 μL, 1.25 mmol) and isopropyl alcohol (1.0 mL) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organics were washed with brine, dried over MgSO4 and concentrated. The crude material was purified by silica gel chromatography using hexanes/ethyl acetate (60:40). The product was obtained as a yellow oil in 91% yield (212.7 mg). cap The septum cap lined cap The reaction mixture was transferred to a separatory funnel extracted with methylene chloride (3×10 mL) The organics were washed with brine dried over MgSO4 concentrated The crude material was purified by silica gel chromatography The product was obtained as a yellow oil in 91% yield (212.7 mg)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 15 mL screw top test tube fitted with a PTFE septum cap was purged with argon before addition of CuI (5.0 mg, 0.026 mmol, 2.6 mol %), NaOH (83.0 mg, 2.08 mmol) and rac-2-amino-1-cyclohexanol HCl (158 mg, 1.04 mmol). Iodobenzene (139 μL, 1.25 mmol), dimethyl sulfoxide (670 μL), and a stock solution of 9.45 M NaOH (330 μL, 3.12 mmol) were added, via syringe, under argon. The septum cap was replaced with a solid, Teflon-lined cap and the reaction was stirred magnetically at 90° C. for 48 h. The resulting homogeneous solution was allowed to cool before dilution with 10 mL brine. The reaction mixture was transferred to a separatory funnel and extracted with diethyl ether (3×10 mL). The organic extracts were washed with 3 M HCl (3×10 mL). The acid extracts were then cooled in an ice bath and the solution was basified using a saturated NaOH solution. When the pH of the solution became basic, as indicated by pH paper, the solution became opaque. The mixture was transferred to a separatory funnel and extracted with methylene chloride (3×10 mL). The organic extract was washed with brine, dried over MgSO4 and concentrated. A pale yellow oil was obtained and placed under high vacuum overnight. While under vacuum the oil solidified to give 182.5 mg (92% yield) of an off-white solid, mp 57-58° C. cap The septum cap lined cap The reaction mixture was transferred to a separatory funnel extracted with diethyl ether (3×10 mL) The organic extracts were washed with 3 M HCl (3×10 mL) The acid extracts were then cooled in an ice bath The mixture was transferred to a separatory funnel extracted with methylene chloride (3×10 mL) The organic extract was washed with brine dried over MgSO4 concentrated A pale yellow oil was obtained placed under high vacuum overnight