Benzisoxazole derivative salt
A technology of benzisoxazole and ray diffraction, applied in the field of hydrochloride, hydrobromide, preparation of the salt, p-toluenesulfonate and ethanedisulfonate
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Embodiment 1
[0257] 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)guanidine according to conventional methods Preparation of pyridin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid
[0258] At 70°C, 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl A slurry of )piperidin-1-yl]-methyl}tetrahydro-2H-pyran-4-carboxylic acid (1.326 kg, 2.807 mol, white solid) was dissolved in ethyl acetate (18.564 L). The solution was cooled to 64°C during 35 minutes and 200 mg of seeds (0.423 mmol) were inoculated into the mixture. The mixture was cooled to 40 °C during 5 h and stirred at this temperature for 14.5 h. The slurry was gradually cooled to 19 °C over a period of 6 h, and the mixture was stirred at this temperature for 46 h. The formed precipitate was collected by filtration, and the filter cake was washed with 2.0 L of ethyl acetate. Dry the filter cake at 50°C under reduced pressure to obtain 1.140kg of the desired 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1...
Embodiment 2
[0268] 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidine-1- Preparation of hydrochloride (HCl salt) of methyl]tetrahydro-2H-pyran-4-carboxylic acid
[0269] At 70°C, 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl )piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid (244 mg, 0.516 mmol) was dissolved in n-BuOH (4.5 mL), and concentrated HCl (37 wt%, 35.5 μL , 0.425mmol). After stirring the mixture overnight at 70°C, it was gradually cooled to room temperature.
[0270] After the resulting precipitate was collected by filtration, washed with EtOH and dried in vacuo, 178 mg (0.350 mmol) of 4-{[4-({[4-(2 ,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran- 4-Carboxylic acid hydrochloride (HCl salt).
[0271] 1 H-NMR delta: 7.61 (t, 1H, J=8.4Hz), 7.27 (d, 1H, J=8.8Hz), 6.96 (d, 1H, J=8.0Hz), 4.96 (q, 2H, J=8.5 Hz), 4.35-4.15(m, 2H), 3.80-3.65(m, 2H), 3.65-3.30(m, 4H), 3.41(...
Embodiment 3
[0278] 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidine-1- Preparation of hydrobromide (HBr salt) of base]methyl}tetrahydro-2H-pyran-4-carboxylic acid
[0279] At 65°C, 4-{[4-({[4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl )piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid (351 mg, 0.744 mmol) was dissolved in n-BuOH (14 mL), and HBr (0.5 M, 1.51 mL, 0.759 mmol) in EtOH. After stirring the mixture overnight at 65°C, it was gradually cooled to room temperature.
[0280] After the resulting precipitate was collected by filtration, washed with EtOH and dried in vacuo, 254 mg (0.459 mmol) of 4-{[4-({[4-(2 ,2,2-trifluoroethoxy)-1,2-benzisoxazol-3-yl]oxy}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran- 4-Carboxylic acid hydrobromide (HBr salt).
[0281] 1 H-NMR delta: 7.61 (t, 1H, J = 8.1Hz), 7.27 (d, 1H, J = 8.8Hz), 6.97 (d, 1H, J = 8.0Hz), 4.96 (q, 2H, J = 8.8 Hz), 4.40-4.15(m, 2H), 3.80-3.65(m, 2H), 3.65-3.30(m, 4H), 3...
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