2-acetylbenzo[f][1]benzofuran-4,9-dione

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

実験手順: The synthetic process for preparing Crystal Form 3 is shown in FIGS. 6A-6D. The steps are outlined briefly herein. Step 1: 3-Butene-2-one (methyl vinyl ketone, MVK) is brominated using bromine No additional solvent is used. The intermediate 3,4-dibromobutan-2-one is dissolved in tetrahydrofuran (THF) and reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form a second intermediate, 3-bromo-3-buten-2-one. Once this reaction is complete, 2-hydroxy-1,4-naphthoquinone (HNQ) is added. A second portion of DBU is added, and the mixture is exposed to air. The reaction is quenched with water and the solids are collected by filtration. These solids are washed with aqueous sodium bicarbonate, aqueous acetic acid, water, and ethanol. The product is isolated by slurrying in ethanol and collecting the solids. Step 2: Residual amounts of the 2-acetyl-2,3-dihydronaphtho[2,3-b]furan-4,9-dione that accompany the desired 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (Compound 1) are oxidized to Compound 1 with activated manganese dioxide in toluene. The mixture is filtered through a cake of charcoal and Celite. The filtrate is concentrated to precipitate the product, which is filtered and dried. Step 3: The solids are slurried in ethyl acetate (25 mL/g purified Compound 1) at 75° C.-80° C. for about 5 hr, collected by filtration, and dried. Compound 1 produced with this method is Crystal Form 3. Compound 1 produced with this method without the slurry process yielded Crystal Form 1. The reaction is quenched with water the solids are collected by filtration These solids are washed with aqueous sodium bicarbonate, aqueous acetic acid, water, and ethanol The product is isolated collecting the solids The mixture is filtered through a cake of charcoal and Celite The filtrate is concentrated to precipitate the product, which is filtered dried collected by filtration dried

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

実験手順: In a 250 ml round-bottom flask, 2 grams (8.3 mmoles) of 2-acetyl-naphtho[2,3-b]furan-4,9-dione (prepared in example 2 or 3) was dissolved in 50 ml of DMF with heating. To the solution, added 3.5 ml of TEA, 2 grams of zinc powder, 0.3 gram of tetrabutylammonium bromide, 2.33 grams (13.3 mmoles) of [(tert-butoxycarbonyl)amino]acetic acid, 5.04 grams (13.3 mmoles) of N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) and 7.25 grams (41.7 mmoles) of sodium hydrosulfite. The mixture was sealed or isolated from air, and then had been stirred vigorously at room temperature overnight. After addition of 100 ml of ethyl acetate, the reaction mixture was filtered, and the solid was washed with 50 ml of ethyl acetate. The filtrates were combined, extracted with 100 ml of ice-cooled aqueous 3% citric acid solution twice, and dried with anhydrous sodium sulfate. The organic phase was evaporated to dryness. Product was purified by silica gel chromatograph using dichloromethane/ethyl acetate (4:1) as elution solvent. 1.64 gram (4.1 mmoles) of product was obtained with yield of 49.4% and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 1.44 (s, 9H), 2.59 (s, 3H), 4.28 (d, J=6, 2H), 7.49-7.65 (m, 3H), 7.97 (m, 1H), 8.20-8.35 (m, 2H), 11.4 (s, 1H). Mass (M+H) is 400, Mass [M-(tert-butyl)+2H] is 344. with heating The mixture was sealed isolated from air the reaction mixture was filtered the solid was washed with 50 ml of ethyl acetate extracted with 100 ml of ice- cooled aqueous 3% citric acid solution twice dried with anhydrous sodium sulfate The organic phase was evaporated to dryness Product was purified by silica gel chromatograph as elution solvent

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

実験手順: In a 500 ml round-bottom flask, 8 grams (33.3 mmoles) of 2-acetyl-naphtho[2,3-b]furan-4,9-dione (prepared in example 2 or 3) was dissolved in 150 ml of DMF with heating. To the solution, added 14 ml of TEA, 8 grams of zinc powder, 1 gram of tetrabutylammonium bromide and 29 grams (166.7 mmoles) of sodium hydrosulfite. The mixture was sealed or isolated from air. Then 17 grams (166.7 mmoles) of acetic anhydride was added with syringe, and the resulting mixture had been stirred vigorously at room temperature for 3 hours. After addition of 300 ml of ethyl acetate, the reaction mixture was filtered, and the solid was washed with 200 ml of ethyl acetate. The filtrates were combined, extracted with 300 ml of ice-cooled aqueous 3% citric acid solution twice, and dried with anhydrous sodium sulfate. The organic phase was evaporated to dryness. The residue was washed with 60 ml of ice-cooled ethanol, and then filtered solid was crystallized in 250 ml of ethanol. 5.5 grams (16.9 mmoles, yield 50.7%) of product was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in CDCl3) δ 2.59 (s, 3H), 2.62 (s, 3H), 2.66 (s, 3H), 7.50 (s, 1H), 7.53-7.62 (m, 2H), 8.00-8.03 (m, 2H). Mass (M+H) is 327, Mass (M+Na) is 349. with heating The mixture was sealed isolated from air the reaction mixture was filtered the solid was washed with 200 ml of ethyl acetate extracted with 300 ml of ice- cooled aqueous 3% citric acid solution twice dried with anhydrous sodium sulfate The organic phase was evaporated to dryness The residue was washed with 60 ml of ice- cooled ethanol filtered solid was crystallized in 250 ml of ethanol

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

実験手順: In a 250 ml beaker, 2 grams (8.3 mmoles) of 2-acetyl-naphtho[2,3-b]furan-4,9-dione (prepared in example 2 or 3) was dissolved in 40 ml of DMF with heating. To the solution with stirring, 1 gram (26.4 mmoles) of sodium borohydride in 10 ml of water was added. The mixture was stirred in open air for 30 minutes, then diluted by adding 250 ml of water. The resulting mixture was extracted with 100 ml of dichloromethane twice. The combined organic phase was washed with 200 ml of water, dried with anhydrous sodium sulfate, and evaporated to dryness. The residue was crystallized in ethyl acetate to yield 1.6 gram (6.6 mmoles) of pure product with overall yield 80%. Pure product was characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 1.47 (d, J=7, 3H), 4.88 (m, 1H), 5.83 (d, J=5, 1H), 6.91 (s, 1H), 7.84-7.90 (m, 2H), 8.06-8.11 (m, 2H). Mass (M+H) is 243. with heating The mixture was stirred in open air for 30 minutes diluted The resulting mixture was extracted with 100 ml of dichloromethane twice The combined organic phase was washed with 200 ml of water dried with anhydrous sodium sulfate evaporated to dryness The residue was crystallized in ethyl acetate

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

実験手順: The synthetic process for preparing Crystal Form 3 is shown in FIGS. 6A-6D. The steps are outlined briefly herein. Step 1: 3-Butene-2-one (methyl vinyl ketone, MVK) is brominated using bromine. No additional solvent is used. The intermediate 3,4-dibromobutan-2-one is dissolved in tetrahydrofuran (THF) and reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form a second intermediate, 3-bromo-3-buten-2-one. Once this reaction is complete, 2-hydroxy-1,4-naphthoquinone (HNQ) is added. A second portion of DBU is added, and the mixture is exposed to air. The reaction is quenched with water and the solids are collected by filtration. These solids are washed with aqueous sodium bicarbonate, aqueous acetic acid, water, and ethanol. The product is isolated by slurrying in ethanol and collecting the solids. Step 2: Residual amounts of the 2-acetyl-2,3-dihydronaphtho[2,3-b]furan-4,9-dione that accompany the desired 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (Compound 1) are oxidized to Compound 1 with activated manganese dioxide in toluene. The mixture is filtered through a cake of charcoal and Celite. The filtrate is concentrated to precipitate the product, which is filtered and dried. Step 3: The solids are slurried in ethyl acetate (25 mL/g purified Compound 1) at 75° C.-80° C. for about 5 hr, collected by filtration, and dried. Compound 1 produced with this method is Crystal Form 3. Compound 1 produced with this method without the slurry process yielded Crystal Form 1. The reaction is quenched with water the solids are collected by filtration These solids are washed with aqueous sodium bicarbonate, aqueous acetic acid, water, and ethanol The product is isolated collecting the solids The mixture is filtered through a cake of charcoal and Celite The filtrate is concentrated to precipitate the product, which is filtered dried collected by filtration dried

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

実験手順: The synthetic process for preparing Crystal Form 3 is shown in FIGS. 6A-6D. The steps are outlined briefly herein. Step 1: 3-Butene-2-one (methyl vinyl ketone, MVK) is brominated using bromine No additional solvent is used. The intermediate 3,4-dibromobutan-2-one is dissolved in tetrahydrofuran (THF) and reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to form a second intermediate, 3-bromo-3-buten-2-one. Once this reaction is complete, 2-hydroxy-1,4-naphthoquinone (HNQ) is added. A second portion of DBU is added, and the mixture is exposed to air. The reaction is quenched with water and the solids are collected by filtration. These solids are washed with aqueous sodium bicarbonate, aqueous acetic acid, water, and ethanol. The product is isolated by slurrying in ethanol and collecting the solids. Step 2: Residual amounts of the 2-acetyl-2,3-dihydronaphtho[2,3-b]furan-4,9-dione that accompany the desired 2-acetyl-4H,9H-naphtho[2,3-b]furan-4,9-dione (Compound 1) are oxidized to Compound 1 with activated manganese dioxide in toluene. The mixture is filtered through a cake of charcoal and Celite. The filtrate is concentrated to precipitate the product, which is filtered and dried. Step 3: The solids are slurried in ethyl acetate (25 mL/g purified Compound 1) at 75° C.-80° C. for about 5 hr, collected by filtration, and dried. Compound 1 produced with this method is Crystal Form 3. Compound 1 produced with this method without the slurry process yielded Crystal Form 1. The reaction is quenched with water the solids are collected by filtration These solids are washed with aqueous sodium bicarbonate, aqueous acetic acid, water, and ethanol The product is isolated collecting the solids The mixture is filtered through a cake of charcoal and Celite The filtrate is concentrated to precipitate the product, which is filtered dried collected by filtration dried