4-Substituted piperidine compound
a piperidine compound and substitute technology, applied in the field of compounds, can solve the problems of not finding clinically useful acetylcholinesterase inhibitors, and achieve the effect of superior acetylcholinesterase inhibitory action
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example 1
4-[(5,6-Dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine hydrochloride
In 5 ml of 1,2-dichloroethane was dissolved 0.25 g (0.63 mmol) of 1-benzyl-4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine, followed by adding 0.81 ml (0.77 mmol) of 1-chloroethylchloroformate. After heating under reflux for one hour, it was evaporated. 5 ml of methanol was added thereto, followed by heating under reflux for further 40 minutes. It was evaporated, and the resulting residue was recrystallized from methanol-diethyl ether, to obtain 0.19 g of the title compound (free form) as pale yellowish white crystals (yield; 98%). The physicochemical data of the free form of the title compound are shown below.
Melting point: 234-238° C. (decomposition) 1H-NMR (400 Mz: CD3OD) δ 1.45-1.60 (2H,m), 1.77(1H,ddd,J=6 Hz, J=14.8 Hz,J=30 Hz), 1.94-2.14(4H,m), 2.94-3.06(2H,m), 3.22-3.48(4H,m), 3.86(3H,s), 3.95(3H,s), 7.07(1H,s), 7.18(1H,s).
The product was converted into hydrochloride in a conventional...
example 2
4-[(5,6-Dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-methylpiperidine hydrochloride
To 68 mg (0.20 mmol) of 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine hydrochloride were added 0.052 ml (1.39 mmol) of formic acid and 0.10 ml (1.38 mmol) of 37% formaldehyde. After heating at 80° C. for 3 hours, it was allowed to be cooled to room temperature and 30 ml of ethyl acetate was added thereto. It was washed with 30 ml of aqueous 1N sodium hydroxide and 30 ml of brine, dried (MgSO4) and then evaporated. The resulting residue was purified by using fractionating thin layer chromatography (methylene chloride / methanol), to give 34 mg of the title compound (free form) as a pale yellow oil (yield; 53%). The product was converted into hydrochloride in a conventional method and recrystallized from ethanol / tert-butylmethyl ether, to give the title compound as pale yellowish white crystals. The physicochemical data of the title compound (hydrochloride) are shown below.
example 3
4-[(5,6-Dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(1-methylethyl)piperidine hydrochloride
In 3 ml of DMF was dissolved 50 mg (0.15 mmol) of 4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methylpiperidine hydrochloride, followed by adding 0.049 ml (0.35 mmol) of triethylamine and 0.016 ml (0.17 mmol) of 2-bromopropane. After heating at 70° C. for 6 hours, it was allowed to be cooled to room temperature and 30 ml of ethyl acetate was added thereto. It was washed with 30 ml of water and 30 ml of brine, dried (MgSO4) and then evaporated. The resulting residue was purified by a fractionating thin layer chromatography (methylene chloride / methanol), to give 13 mg of the title compound (free form) as a pale yellow oil (yield; 26%). The product was converted into hydrochloride in a conventional method and solidified by using diethyl ether, to give the title compound as a pale yellowish white amorphous. The physicochemical data of the title compound (hydrochloride) are shown below.
1H-NMR (4...
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