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With triethylamine;dmap; In dichloromethane; at 0 - 25℃; for 3h; |
To a solution of aminobromonaphthlene (1.81 g, 8.2 mmol) in 80 mL of dichloromethane at 0 0C were added acetic anhydride (1.15 mL, 12.2 mmol), and tpiethylamine (2.86 mL, 20 mmol) and a small amount of DMAP. The solution was warmed to RT and stirred for 3 h. The solvent was removed and the residue was dissolved in ethyl acetate, washed with water, 1N HCl, water, 1N NaOH, saturated sodium bicarbonate solution and brine successively. The organic layer was then dried with sodium sulfate and concentrated m vacuo to give the acetamide as a pmk solid. This bromide intermediate was subjected to the same Heck reaction and hydrogenation procedures as descnbed earlier, and shown in Scheme 25, to provide the product as a sticky oil. To a solution of this intermediate (86 mg, 0.22 mmol) in 15 mL of chloroform at 0 0C, was added dropwise a solution of bromine (14 uL, 42 mg, 0.26 mmol) in 1.5 mL of chloroform. The mixture was stirred at 0 0C for 5 mm and quenched with 1percent sodium sulfite. Two batches of this intermediate were combined and the aqueous phase was extracted with chloroform three times. The organic phase was washed with saturated sodium bicarbonate solution, and dried over sodium sulfate. A mixture of this bromide intermediate (0.56 g, 1.19 mmol), methyl boronic acid (93 mg, 1.55 mmol), potassium carbonate (494 mg, 3.58 mmol), palladium tetrakistriphenylphosphme (138 mg, 0.12 mmol), 2 mL of water and 20 mL of dioxane, was degassed with argon and heated at 100 0C overnight. After concentration, the residue was pupified by Biotage to give a white solid. To a solution of this methylated intermediate (89 mg, 0.22 mmol) in 5 mL of chloroform, were added potassium acetate (44 mg, 0.44 mmol), acetic acid (26 mg, 0.44 mmol), acetic anhydpide (45 mg, 0.44 mmol), 18- crown-6 (10 mg), and amylnitrite (74 uL, 0 63 mmol) The mixture was heated at 700C overnight. The reaction mixture was then purified by Biotage to give a white solid. To a suspension of this tricyclic acetamide intermediate (58 mg, 0.14 mmol) in 40 mL of methanol, were added sodium ethoxide (226 uL, 21percent in methanol). After 5 mm, to the mixture was added 10 mL of aqueous 1N lithium hydroxide solution, and the mixture was stirred for 30 mm The solvent was evaporated and the aqueous residue was acidified and extracted with 30percent isopropanol in chloroform. After removing the solvent, the residue was purified by RP-HPLC to give the desired product as a white solid 1H NMR (DMSO-d6, 500 MHz) delta 11.2 (1H, s), 8.55 (1H, s), 8.47 (1H, d), 8 24 (1H, d), 7.95 (1H, d), 7.84 (1H, s), 7 67 (1H, d), 7 59 (3H, m), 7.12 (1H, t), 3.12 (2H, t), 2.83 (2H, t); LCMS m/z 360 (M++1). |
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