2-bromo-1-piperidin-1-ylethanone

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following General Procedure: Method B using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and 2-bromo-1-(piperidin-1-yl)ethanone (31 mg, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(2-oxo-2-(piperidin-1-yl)ethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (31 mg, 75%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.17 (s, 1H), 8.28 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.87 (s, 1H), 5.82 (d, J=7.3 Hz, 1H), 4.95 (s, 1H), 4.68 (d, J=8.6 Hz, 1H), 4.59-4.50 (m, 2H), 4.00-3.74 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.69 (s, 1H), 3.60 (s, 6H), 3.40 (s, 3H), 3.35-3.25 (m, 4H), 3.12 (t, J=9.2 Hz, 1H), 2.54 (br s, 1H), 2.16 (s, 3H), 1.68 (br s, 2H), 1.62 (br s, 4H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 823 (M+H); HPLC 98.7% (AUC), tR 16.81 min. the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following General Procedure: Method B using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and 2-bromo-1-(piperidin-1-yl)ethanone (31 mg, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(2-oxo-2-(piperidin-1-yl)ethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (31 mg, 75%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.17 (s, 1H), 8.28 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.87 (s, 1H), 5.82 (d, J=7.3 Hz, 1H), 4.95 (s, 1H), 4.68 (d, J=8.6 Hz, 1H), 4.59-4.50 (m, 2H), 4.00-3.74 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.69 (s, 1H), 3.60 (s, 6H), 3.40 (s, 3H), 3.35-3.25 (m, 4H), 3.12 (t, J=9.2 Hz, 1H), 2.54 (br s, 1H), 2.16 (s, 3H), 1.68 (br s, 2H), 1.62 (br s, 4H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 823 (M+H); HPLC 98.7% (AUC), tR 16.81 min. the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following General Procedure: Method B using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and 2-bromo-1-(piperidin-1-yl)ethanone (31 mg, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(2-oxo-2-(piperidin-1-yl)ethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (31 mg, 75%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.17 (s, 1H), 8.28 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.87 (s, 1H), 5.82 (d, J=7.3 Hz, 1H), 4.95 (s, 1H), 4.68 (d, J=8.6 Hz, 1H), 4.59-4.50 (m, 2H), 4.00-3.74 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.69 (s, 1H), 3.60 (s, 6H), 3.40 (s, 3H), 3.35-3.25 (m, 4H), 3.12 (t, J=9.2 Hz, 1H), 2.54 (br s, 1H), 2.16 (s, 3H), 1.68 (br s, 2H), 1.62 (br s, 4H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 823 (M+H); HPLC 98.7% (AUC), tR 16.81 min. the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-(1-Methyl-1H-indol-3-yl)-1,2,4-triazole (0.190 g, 0.960 mmol) was dissolved with stirring in dry THF (5 ml) and was treated with sodium hydride (80%) (0.032 g, 1.05 mmol), followed by 1-(bromoacetyl)piperidine (Bull. Soc, Chim. Fr. 1964, 5, 1063-9) (0.232 g, 1.05 mmol) in dry THF (1 ml). After 4 h, the reaction mixture was evaporated under reduced pressure and partitioned between EtOAc and water. The organic layer was then dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil, which was purified by silica-gel chromatography (EtOAc→EtOAc:MeOH 100:1 as eluant) to give the title compound (D5b) as a white solid (0.080 g, 26%). the reaction mixture was evaporated under reduced pressure partitioned between EtOAc and water The organic layer was then dried (Na2SO4) evaporated under reduced pressure to give a yellow oil, which was purified by silica-gel chromatography (EtOAc→EtOAc:MeOH 100:1 as eluant)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5-(1-Methyl-1H-indol-3-yl)tetrazole (0.080 g, 0.402 mmol) was dissolved in dry THF (5 ml) and treated with sodium hydride (80%) (0.014 g, 0.441 mmol). When effervescence had ceased, 1-(bromoacetyl)piperidine (Bull. Soc. Chim. France 1964 5, 1063) (0.093 g, 0.422 mmol) in dry THF (2 ml) was added. After 1 h, a further amound of 1-(bromoacetyl)piperidine (0.047 g, 0.211 mmol) in dry THF (1 ml) was added. After a further 2 h, the reaction mixture was evaporated under reduced pressure to give a brown solid which was partitioned between CHCl3 and water. The organic layer was washed with NaHCO3 solution, and the combined aqueous layers were extracted with CHCl3. The combined organic layers were then dried (Na2SO4) and evaporated to give an off white foam which was dried in vacuo and then purified by silica-gel chromatography (pentane: EtOAc 1:1 as eluant) to give the title compound (D3 ) as a white solid (0.080 g, 61%) After a further 2 h the reaction mixture was evaporated under reduced pressure to give a brown solid which was partitioned between CHCl3 and water The organic layer was washed with NaHCO3 solution the combined aqueous layers were extracted with CHCl3 The combined organic layers were then dried (Na2SO4) evaporated to give an off white foam which was dried in vacuo purified by silica-gel chromatography (pentane: EtOAc 1:1 as eluant)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5-(1-Methyl-1H-indol-3-yl)tetrazole (0.080 g, 0.402 mmol) was dissolved in dry THF (5 ml) and treated with sodium hydride (80%) (0.014 g, 0.441 mmol). When effervescence had ceased, 1-(bromoacetyl)piperidine (Bull. Soc. Chim. France 1964 5, 1063) (0.093 g, 0.422 mmol) in dry THF (2 ml) was added. After 1 h, a further amound of 1-(bromoacetyl)piperidine (0.047 g, 0.211 mmol) in dry THF (1 ml) was added. After a further 2 h, the reaction mixture was evaporated under reduced pressure to give a brown solid which was partitioned between CHCl3 and water. The organic layer was washed with NaHCO3 solution, and the combined aqueous layers were extracted with CHCl3. The combined organic layers were then dried (Na2SO4) and evaporated to give an off white foam which was dried in vacuo and then purified by silica-gel chromatography (pentane: EtOAc 1:1 as eluant) to give the title compound (D3 ) as a white solid (0.080 g, 61%) After a further 2 h the reaction mixture was evaporated under reduced pressure to give a brown solid which was partitioned between CHCl3 and water The organic layer was washed with NaHCO3 solution the combined aqueous layers were extracted with CHCl3 The combined organic layers were then dried (Na2SO4) evaporated to give an off white foam which was dried in vacuo purified by silica-gel chromatography (pentane: EtOAc 1:1 as eluant)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following General Procedure: Method B using (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (35 mg, 0.050 mmol), potassium carbonate (21 mg, 0.15 mmol) and 2-bromo-1-(piperidin-1-yl)ethanone (31 mg, 0.15 mmol), the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol) to afford (6R,6aS,14aR)-methyl 6,8,14a-trihydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-1-(2-oxo-2-(piperidin-1-yl)ethoxy)-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (31 mg, 75%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 14.17 (s, 1H), 8.28 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 5.87 (s, 1H), 5.82 (d, J=7.3 Hz, 1H), 4.95 (s, 1H), 4.68 (d, J=8.6 Hz, 1H), 4.59-4.50 (m, 2H), 4.00-3.74 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.69 (s, 1H), 3.60 (s, 6H), 3.40 (s, 3H), 3.35-3.25 (m, 4H), 3.12 (t, J=9.2 Hz, 1H), 2.54 (br s, 1H), 2.16 (s, 3H), 1.68 (br s, 2H), 1.62 (br s, 4H), 1.36 (d, J=6.1 Hz, 3H); MS (ESI+) m/z 823 (M+H); HPLC 98.7% (AUC), tR 16.81 min. the product was purified by preparative TLC (silica gel, 95:5 dichloromethane/methanol)