Hydrochloric Acid → 1-[1-(4-Chlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

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Reaction Steps

A solution of 1-(4-chlorophenyl)cyclobutanecarbonyl chloride (22.9 g) in ether (200 ml) was added to a stirred mixture of 3,4-dimethoxyphenethylamine (18.1 g), triethylamine (13.9 ml) and ether (300 ml). The mixture was stirred for 1.5 hours and then water was added. The ether layer yielded a residue which was dissolved in dichloromethane (100 ml) and added to polyphosphate ester (195 g) under nitrogen. The mixture was kept at 75°-82° C. for 16 hours and then added to water (1,200 ml). The organic phase was washed with water and basified with excess aqueous ammonia solution. The basic aqueous solution was extracted with ether. The ether extract yielded an oil which was dissolved in methanol (200 ml). Twelve portions of sodium borohydride (12 g in total) were added over twenty minutes. The mixture was stirred for 16 hours and acidified by the careful addition of 5N hydrochloric acid. The mixture was allowed to stand for 16 hours and the resulting solid was separated by filtration. Water was added to the filtrate which was then basified and extracted with ethyl acetate. The extract gave a residue which was dried by azeotropic distillation with propan-2-ol to give 1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, a sample (8.8 g) of which was heated at 90°-95° C. with formic acid (5 ml) and 37-40% aqueous formaldehyde solution (6.2 ml) for 16 hours. Water was added and the mixture basified with aqueous sodium hydroxide solution and extracted with ether. The extract yielded a gum which was heated under reflux with 48% aqueous hydrobromic acid (100 ml) for 31/2 hours. Charcoal and industrial methylated spirits (100 ml) were added and the mixture filtered. Removal of the solvent from the filtrate gave a residue which was dried by azeotropic distillation with propan-2-ol. The residue was taken up in a 1:1 mixture of propan-2-ol and ethanol and the solvent removed by evaporation. The residue was heated under reflux with ethanol for 30 minutes and then cooled. The solid was collected by filtration and washed with a small amount of cold ethanol to give 1-[1-(4-chlorophenyl)cyclobutyl]-6,7-dihydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 220° C.

Provenance & Evidence