| 3.44 g |
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; |
A solution of sodium nitrite (1.56 g, 22.5 mmol) in water (4.5 mL) was added dropwise to a solution of 2-amino-5-hydroxybenzoic acid (2.30 g, 15.0 mmol) in a mixture of water (20 mL) and concentrated sulfuric acid (2.8 mL) at 0 C. After stirring for 5 min, a solution of potassium iodide (3.74 g, 22.5 mmol) in water (4.5 mL) was added dropwise to the mixture. The resulting solution was heated at 100 C with stirring for 1 h and then allowed to cool to room temperature. After stirring for 14 h,the mixture was cooled to 0 C. The precipitate was collected by filtration, washed with cold water, and dried in vacuo to give crude <strong>[57772-57-3]5-hydroxy-2-iodobenzoic acid</strong> (3.26 g) as a brown solid, which was dissolved in anhydrous DMF (65 mL). To this solution were added potassium carbonate (12.8 g, 92.7 mmol) and iodomethane (5.8 mL, 92.7 mmol) at room temperature under a nitrogen atmosphere. After stirring for 12 h, the mixture was filtered through a pad of celite and the pad was washed with Et2O. The filtrate was acidified with 10% HCl and then extracted with Et2O. The organic layer was washed with saturated aqueous NaHCO3, water, and brine, dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 4/1) to give methyl 2-iodo-5-methoxybenzoate [2] (3.44 g, 79% in 2 steps) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) delta 7.83(1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 2.9 Hz), 6.75 (1H, dd, J = 8.6, 2.9 Hz), 3.93 (3H, s), 3.82 (3H, s). To a solution of methyl 2-iodo-5-methoxybenzoate (1.21 g, 4.13 mmol) in a 3:1 mixture of MeOH and water (47 mL) was added lithium hydroxide hydrate (260 mg, 6.2 mmol) at room temperature. After stirring for 15 h, the resulting mixture was diluted with saturated aqueous NaHCO3 and washed with CH2Cl2. The aqueous layer was acidified with 10% HCl and then extraceted with CH2Cl2. The last organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in thionyl chloride (5.1 mL). After heating at reflux with stirring for2 h, the resulting solution was concentrated under reduced pressure. The remaining thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in anhydrous CH2Cl2 (13.5 mL). To the mixture were added isopropylamine (290 mg, 4.9 mmol) and triethylamine (1.24 g, 12.2 mmol) at 0 C under a nitrogen atmosphere. After stirring at room temperature for 6 h, the resulting solution was diluted with EtOAc. The mixture was washed with10% HCl, saturated aqueous NaHCO3, water, and brine; dried over Na2SO4; filtered; and concentrated under reduced pressure. The residue was purified by recrystallization from hexane and CHCl3 to give 17 (991 mg, 75% in 3 steps) as colorless needles. |
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