Substituted piperidines as modulators of dopamine neurotransmission
A kind of technology of propylpiperidine and ethylpiperidine, applied in the field of new regulators of dopamine neurotransmission
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Embodiment 1
[0237] 4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1-propylpiperidin-4-ol
[0238] To a solution of 3-bromo-2-fluorobenzotrifluoride (5.0 g, 20.5 mmol) in dry tetrahydrofuran (70 ml) under nitrogen at -78°C was added n-butyllithium (in hexane 2.5M, 9.0ml, 22.5mmol). The mixture was stirred for 1 hour, after which time a solution of freshly distilled 4-propyl-1-piperidone (2.6 g, 20.5 mmol) in dry tetrahydrofuran (30 mL) was added dropwise. The compound was stirred at -78°C for 30 minutes and then allowed to reach ambient temperature. Water (100ml) was added and the mixture was extracted with ethyl acetate (3x100ml). The combined organic phases were dried (MgSO 4 ), filtered and evaporated to dryness. The oily residue was purified by flash chromatography (ethyl acetate / methanol, 1:1) to give the title compound (2.8 g, 45%). The amine was converted to the hydrochloride and recrystallized from ethanol / ether: M.p. 175-177°C. MS m / z (relative intensity, 70 eV) 305 (M+, 5), 276 (bp...
Embodiment 2
[0240] 4-[4-Chloro-3-(trifluoromethyl)phenyl]-1-(2-methoxyethyl)piperidin-4-ol
[0241] To a mixture of 4-[chloro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.5g, 1.79mmol) and potassium carbonate (0.62g, 4.47mmol) in acetonitrile (40ml) was added 1-bromo-2-methoxyethane (0.17ml, 1.79mmol) and a small amount of sodium iodide crystals, and the mixture was heated under reflux for 15 hours. The mixture was cooled to ambient temperature, water (50ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 ml) and the combined organic phases were dried (MgSO 4 ) and evaporated under reduced pressure to give an oil. Purification by flash chromatography (ethyl acetate / methanol, 1:1) afforded the title compound (0.41 g, 70%). The amine was converted to the hydrochloride and recrystallized from ethanol / ether: M.p. 181-183°C. MS m / z (relative intensity, 70 eV) 337 (M+, 1), 294 (29), 292 (bp), 274 (72) 201 (29).
Embodiment 3
[0243] 4-[2-Fluoro-3-(trifluoromethyl)phenyl]-1-ethylpiperidin-4-ol
[0244] Prepared as in Example 1: 3-bromo-2-fluorobenzotrifluoride (5.0 g, 20.6 mmol), tetrahydrofuran (50 ml), n-butyllithium (2.5M in hexane, 9.0 ml, 22.5 mmol), 4 - Ethyl-1-piperidone (2.6 g, 20.6 mmol). Yield: 4.0 g. Conversion of amine to hydrochloride and recrystallization from ethanol / ether: M.p. 177-180°C. MS m / z (relative intensity, 70 eV) 291 (M+, 18), 277 (15), 276 (bp), 258 (37), 191 (27).
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