p-Toluenesulfonic acid → 4-Aminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine

Beteiligte Stoffe

Reaktionsschritte

A mixture of 4-aminomethylpiperidine (3.58 g) and 4'-chloroacetophenone (4.85 g) in toluene (100 ml) was boiled under reflux with a catalytic amount of p-toluenesulphonic acid for 5 hours, removing the water formed by means of a Dean and Stark apparatus, to give a solution. The solution was cooled and 2-bromoethyl 4-methylphenyl ether (6.68 g) was added, followed by triethylamine (4.4 ml). This mixture was boiled under reflux for 6 hours then evaporated to dryness. 6M Hydrochloric acid (50 ml) was added to the residue and the mixture heated on a steam bath for 16 hours. The mixture was evaporated to near dryness, water (50 ml) was added and the mixture was washed with ether. The aqueous layer was basified with 2M sodium hydroxide solution and extracted with dichloromethane to give 4-aminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine as an oil. The oil was cooled in ice and 98% formic acid (5.0 ml) and formaldehyde (5.0 ml, 38% aqueous solution) were added. The mixture was heated on a steam bath for 4 hours then evaporated to near dryness and the residue treated with 2M hydrochloric acid (50 ml). The solution obtained was washed with dichloromethane, basified with 2M sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled at 150° C. at 0.13 mbar. This distillate was dissolved in ether and the solution acidified with ethereal hydrogen chloride. The precipitate was collected by filtration, washed with ether and recrystallised from absolute ethanol to give 4-dimethylaminomethyl-1-[2-(4-methylphenoxy)ethyl]piperidine dihydrochloride, m.p. 278°-280° C.

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