反应详情

6,7,8,9-Tetrahydro-1H-benz[g]indole-2,3-dione The benz[g]isatin was prepared in two steps from 5,6,7,8-tetrahydro-1-naphthylamine using the methods described for 1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione (G. W. Rewcastle et. al., J. Med. Chem., 1991, 34, 217). The product (54% yield from N-[1-(5,6,7,8-tetrahydronaphthalenyl)]-2-(hydroximino)acetamide) was obtained as an orange solid: mp. 234–235° C. (lit. [U.S. Pat. No. 1,856,210, 1929] 232° C.); NMR δH (400 MHz; DMSO-d6) 1.73 (4H, m), 2.49 (2H, m), 2.73 (2H, m), 6.78 (1H, d, J 7.7 Hz), 7.21 (1H, d, J 7.7 Hz) and 10.92 (1H, s). 6,7,8,9-Tetrahydro-1H-benz[g]indole To a suspension of lithium aluminium hydride (2.85 g, 75.0 mmol) in dry tetrahydrofuran (150 mL) was added 6,7,8,9-tetrahydro-1H-benz[g]indole-2,3-dione (3.018 g, 15.0 mmol) portionwise over 30 min. The green suspension was heated under reflux for 18 h and then cooled to 0° C. The suspension was treated with water (2.8 mL), 5 N aqueous sodium hydroxide (2.1 mL), and water (9.2 mL), and was stirred for an additional 1 h. The suspension was then filtered, the residue was washed with tetrahydrofuran, and the filtrate then concentrated in vacuo. The residue obtained was purified by column chromatography [SiO2; ethyl acetate-heptane (1:19)] and triturated with hexane to give the title indole (1.58 g, 62%) as a white solid: mp. 93–94° C. (lit. [Khim. Geterotsikl. Soedin., 1978, 14, 634] 89–90° C.); Found: C, 84.25; H, 7.65; N, 8.16%. C12H13N requires C, 84.17; H, 7.65; N, 8.18%. (S)-1-[2-(tert-Butoxycarbonylamino)]-6,7,8,9-tetrahydro-1H-benz[g]indole To a suspension of powdered potassium hydroxide (85%; 2.11 g, 32.0 mmol) in methyl sulfoxide (30 mL) at 40° C. was added 6,7,8,9-tetrahydro-1H-benz[g]indole (1.37 g, 8.0 mmol). The green suspension was stirred at 40° C. for 1 h, and then a solution of (S)-2-(tert-butoxycarbonylamino)propane methanesulfonate (5.07 g, 20.0 mmol) in methyl sulfoxide (10 mL) was added dropwise over 1 h. The suspension was heated at 40° C. for 66 h, poured onto a mixture of ice (150 g) and water (50 mL) and extracted with isopropyl ether (2×50 mL). The combined organic extracts were washed with water (50 mL), dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] and triturated with hexane to give the title carbamate (1.49 g, 57%), as a white solid: mp. 118–119° C.; Found: C, 72.65; H, 8.75; N, 8.45%. C20H28N2O2 requires C, 73.14; H, 8.59; N, 8.52%; NMR δH (400 MHz; CDCl3) 7.34 (1H, d, J 8.0 Hz), 6.92 (1H, m), 6.82 (1H, d, J 8.0 Hz), 6.40 (1H, m), 4.4 (1H, br), 4.28 (1H, m, J 6.5 Hz), 3.96 (1H, m, J 6.8 Hz), 3.16 (2H, m), 2.91 (2H, m), 1.89 (2H, m), 1.83 (2H, m), 1.45 (9H, br s) and 1.07 (3H, d, J 6.8 Hz). (S)-1-[2-(tert-Butoxycarbonylamino)]-2,3,6,7,8,9-hexahydro-1H-benz[g]indole To a solution of (S)-1-[2-(tert-butoxycarbonylamino)]-6,7,8,9-tetrahydro-1H-benz[g]indole (0.985 g, 3.0 mmol) in acetic acid (50 mL) cooled in ice was added sodium cyanoborohydride (0.60 g, 9.55 mmol) in one portion. The solution was stirred for 18 h and was poured onto a mixture of ice (150 g) and water (50 mL). The suspension was stirred for 15 min and more ice was added. The suspension was basified with ammonium hydroxide (140 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), dried (magnesium sulfate) and concentrated in vacuo. The residue obtained was purified by column chromatography [SiO2; ethyl acetate:heptane (1:4)] to give the title carbomate (0.935 g, 94%) as a pale purple solid: mp. 91–91.5° C.; Found: C, 72.7; H, 9.2; N, 8.4%. C20H30N2O2 requires C, 72.7; H, 9.15; N, 8.5%; NMR (400 MHz, CDCl3) δH 6.90 (1H, d, J 7.5 Hz), 6.58 (1H, d, J 7.5 Hz), 4.69 (1H, br s), 3.84 (1H, m), 3.42 (2H, m), 3.14 (1H, m), 2.99 (3H, m), 2.77 (2H, m), 2.66 (2H, m), 1.75 (4H, m), 1.44 (9H, s) and 1.26 (3H, d, J 6.6 Hz). (S)-1-(2,3,6,7,8,9-Hexahydro-1H-benz[g]indol-1yl)]-2-propylamine fumarate To a stirred solution of (S)-1-[2-(tert-butoxycarbonylamino)]-2,3,6,7,8,9-hexahydro-1H-benz[g]indole (0.859 g, 2.60 mmol) in methanol (8.6 mL) was added hydrogen chloride (4 M in dioxan; 6.5 mL, 26 mmol). The solution was stirred for 3 h and was concentrated in vacuo. The oil was partitioned between dichloromethane (25 mL) and 0.5 N aqueous sodium hydroxide (25 mL), and the aqueous phase was extracted with dichloromethane (25 mL). The combined organic phases were washed with water (25 mL), dried (sodium sulfate) and concentrated in vacuo to give an oil which was dissolved in 2-propanol (7 mL) at 40° C. The solution was added dropwise to a solution of fumaric acid (0.377 g, 3.25 mmol) in 2-propanol (7 mL) at 0° C. The white suspension was cooled to 0° C. and filtered. The filter-cake was washed with 2-propanol and ether and dried to give the title compound (0.789 g, 79%) as a white solid: mp. 178–182° C.; Found: C, 65.6; H, 7.6; N, 8.05%. C15H22N2.C4H4O4 requires C, 65.9; H, 7.6; N, 8.1%; NMR (400 MHz; DMSO-d6) δH 6.84 (1H, d, J 7.5 Hz), 6.52 (1H, d, J 7.5 Hz), 6.44 (2H, s), 3.37 (2H, m), 3.23 (2H, m), 3.00 (1H, m), 2.89 (2h, m), 2.64 (4H, m), 1.65 (4H, m) and 1.26 (3H, d, J 6.5 Hz).