六氢-1H-氮杂卓-4-醇盐酸盐

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

实验步骤: Intermediate 55A (0.10 g, 0.26 mmol), azepan-4-ol hydrochloride (0.052 g, 0.34 mmol, see WO 2011019090) and TEA (0.146 mL, 1.05 mmol) were mixed in dichloromethane (4 mL). The mixture was stirred at RT for 1 h and then sodium triacetoxyhydroborate (0.112 g, 0.53 mmol) was added and the mixture was stirred at RT overnight. Aqueous NaHCO3 (sat., 3 mL) and dichloromethane (3 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by preparative reverse-phase HPLC at pH 10 to give 88 mg (70%). 1H NMR (600 MHz, DMSO) δ 1.38-1.85 (m, 7H), 2.37-2.65 (m, 3H), 3.53 (s, 2H), 3.71-3.77 (m, 1H), 3.88 (s, 3H), 4.05-4.14 (m, 1H), 4.31-4.46 (m, 1H), 4.5-4.67 (m, 2H), 5.05-5.2 (m, 2H), 6.85 (d, 2H), 7.17-7.29 (m, 4H), 8-8.05 (m, 2H), LC purity: 94%. the mixture was stirred at RT overnight the mixture was filtered through a phase separator the solvent was removed by evaporation The product was purified by preparative reverse-phase HPLC at pH 10 to give 88 mg (70%)

反应条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of azepan-4-ol hydrochloride (300 mg, 1.98 mmol) and 4-fluorobenzonitrile (311 mg, 2.57 mmol) in dimethyl sulfoxide (3.00 ml) was added potassium carbonate (821 mg, 5.94 mmol). The mixture was stirred at 120° C. for 6 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/4) to afford 4-(4-hydroxyazepan-1-yl)benzonitrile as a yellow solid (306 mg, 1.41 mmol, 71%). The mixture was partitioned between water and ethyl acetate The organic layer was washed with water (three times) dried over sodium sulfate concentrated in vacuo The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=1/4)

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

实验步骤: To a solution of tert-butyl 4-hydroxyazepane-1-carboxylate (1.00 g, 4.65 mmol) in ethyl acetate (23 ml) was added 4N hydrogen chloride in ethyl acetate (23 ml, 92.0 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo to afford azepan-4-ol hydrochloride as a pale yellow oil (710 mg, 4.65 mmol, >99%). This compound was used for the next reaction without further purification. The mixture was concentrated in vacuo

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

实验步骤: Intermediate 55A (0.10 g, 0.26 mmol), azepan-4-ol hydrochloride (0.052 g, 0.34 mmol, see WO 2011019090) and TEA (0.146 mL, 1.05 mmol) were mixed in dichloromethane (4 mL). The mixture was stirred at RT for 1 h and then sodium triacetoxyhydroborate (0.112 g, 0.53 mmol) was added and the mixture was stirred at RT overnight. Aqueous NaHCO3 (sat., 3 mL) and dichloromethane (3 mL) were added and the mixture was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by preparative reverse-phase HPLC at pH 10 to give 88 mg (70%). 1H NMR (600 MHz, DMSO) δ 1.38-1.85 (m, 7H), 2.37-2.65 (m, 3H), 3.53 (s, 2H), 3.71-3.77 (m, 1H), 3.88 (s, 3H), 4.05-4.14 (m, 1H), 4.31-4.46 (m, 1H), 4.5-4.67 (m, 2H), 5.05-5.2 (m, 2H), 6.85 (d, 2H), 7.17-7.29 (m, 4H), 8-8.05 (m, 2H), LC purity: 94%. the mixture was stirred at RT overnight the mixture was filtered through a phase separator the solvent was removed by evaporation The product was purified by preparative reverse-phase HPLC at pH 10 to give 88 mg (70%)