Substituted thienobenzoquinoneisoxazole compounds, preparation method and application thereof
An isoxazole and compound technology, applied in the application as an antifungal drug, substituted tricyclic benzoquinone compounds and the field of preparation thereof, can solve the problems of low bioavailability, limited clinical application, large toxic and side effects and the like
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Embodiment 1
[0118] Example 1: Preparation of 5,5-dibromo-6,7-dihydrobenzo[b]thiophene-4(5H)-one (Ⅱ)
[0119] Add CuBr to a 500 mL round bottom flask 2 (28.2g, 126mmol, 4eq) and 80mL ethyl acetate. Heat this suspension to 80°C for a few minutes. Then 80 mL of a chloroform solution in which 6,7-dihydrobenzo[b]thiophen-4(5H)-one VIII (4.78 g, 31.45 mmol) was dissolved was added. After the addition was complete, the mixture was stirred overnight at this temperature. After the reaction of starting materials was complete the mixture was concentrated to dryness in vacuo. The residue was diluted with ethyl acetate and filtered through alumina. Filtrate with saturated NaHCO 3 After washing, the organic phase was dried over sodium sulfate and concentrated after filtration to obtain 9.5 g of white crystal product with a yield of 97%. 1 H NMR (400MHz, CDCl 3 )δppm: 7.51(d, J=5.2Hz, 1H), 7.20(d, J=5.2Hz, 1H), 3.18(s, 4H).
Embodiment 2
[0120] Example 2: Preparation of 5-bromobenzo[b]thiophene-4-ol (Ⅲ)
[0121] Compound 5,5-dibromo-6,7-dihydrobenzo[b]thiophen-4(5H)-one (9.6 g, 31 mmol) and DMF (100 mL) were added into a 250 mL round bottom flask. To this solution was added lithium carbonate (14 g, 186. mmol, 6 eq). The reaction mixture was heated to 100°C under nitrogen for 6 hours. The reaction solution was then cooled to room temperature and filtered. The filtrate was diluted with water, acidified to pH = 1 with HCl, and extracted with ethyl acetate. The organic phase was washed with water and brine, concentrated and purified by column chromatography (eluent: ethyl acetate:petroleum ether=1:50) to obtain 6.82 g of white solid with a yield of 95.8%. 1 H NMR (400MHz, CDCl 3 )δppm: 7.52 (d, J = 5.2Hz, 1H), 7.41 (d, J = 5.2Hz, 1H), 7.40 (d, J = 8.4, 1H), 7.35 (d, J = 8.4, 1H), 5.89 (br s,4H).
Embodiment 3
[0122] Example 3: Preparation of 5-bromobenzo[b]thiophene-4,7-dione (IV)
[0123] Into a 500 mL round bottom flask was added phenol 5-bromobenzo[b]thiophen-4-ol (4.6 g, 20 mmol), 80 mL acetic acid, 120 mL trifluoroacetic acid and a few drops of water. The reaction mixture was cooled to zero degree with an ice-water bath, and then iodobenzene diacetate (19.3 g, 60 mmol, 3 eq) was added in portions. After the addition was complete, the mixture was stirred for an additional 10 minutes and at room temperature for 20 minutes. Then 100 mL of methanol was added, and after stirring for 10 minutes, water and dichloromethane were added. The organic phase was separated and concentrated. The concentrated residue was purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether=1:50) to obtain 3.91 g of a yellow solid with a yield of 80.5%. 1 H NMR (400MHz, CDCl 3 )δppm: 7.73(d, J=5.2Hz, 1H), 7.66(d, J=5.2Hz, 1H), 7.42(s, 1H); 13 C NMR (100MHz, CDCl 3 )δppm: 177...
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