反应详情

温度

100 °C

2-(3-Methyl-butyl)-6-thiophen-2-yl-2H-pyridazine-3,5-dione (0.215 g, 0.814 mmol) and (bis-methylsulfanyl-methylene)-methyl-sulfonium tetrafluoro borate salt (prepared as described in WO 2008/011337; 0.79 g, 3.26 mmol) were combined. 1,4-Dioxane (1.06 mL) and pyridine (0.15 mL) were added. The mixture was heated at 100° C. for 1 h while stirring. Upon cooling, the mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL), saturated aqueous brine solution (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was passed through a plug of silica gel (Merck silica gel 60, 40-63 μm; eluting with 25% ethyl acetate in hexanes). Upon concentrating, 4-(bis-methylsulfanyl-methylene)-2-(3-methyl-butyl)-6-thiophen-2-yl-2H-pyridazine-3,5-dione (0.06 g, 0.163 mmol) was obtained as an orange solid. The solid was combined with 2-amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide (0.07 g, 0.245 mmol). Toluene (5 mL) and 1,4-dioxane (10 mL) were added and the mixture stirred at 100° C. in a sealed vial for 2 h. Upon cooling, the mixture was concentrated in vacuo to afford a thick oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 5-100% ethyl acetate in hexanes) afford the desired product, N-{3-[5-hydroxy-2-(3-methyl-butyl)-3-oxo-6-thiophen-2-yl-2,3-dihydro-pyridazin-4-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.018 g, 0.032 mmol, 10%) as a light orange powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.95 (6H, d, J=6.2 Hz), 1.57-1.69 (3H, m), 2.97 (3H, s), 4.13 (2H, t, J=7.1 Hz), 4.27 (2H, d, J=5.5 Hz), 7.13-7.16 (1H, m), 7.31 (1H, s), 7.64-7.69 (2H, m), 7.89 (1H, d, J=4.0 Hz). LC-MS (ESI) calculated for C20H23N5O6S4 557.05. found 558.0 [M+H+].

1. temperatureUpon cooling
2. washwashed with water (15 mL), saturated aqueous brine solution (15 mL)
3. dry with materialdried over sodium sulfate
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. concentrationUpon concentrating