| 90% |
Stage #1: With 2-(methylsulfonyl)ethyl alcohol; sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 2 h;
Stage #2: With hydrogenchloride; water In DMF (N,N-dimethyl-formamide) |
To a solution of 2-fluoro-4-hydroxybenzonitrile g (1 g, 7.2 mmol) in acetone (50 ml) was added methyliodide (2 g, 14.4 mmol, 2 equiv. ) and potassium carbonate (2 g, 14 mmol, 2 equiv. ). The mixture was heated under reflux for 2 h, cooled to room temperature, filtered and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried with MgS04, filtered and concentrated to give 1.1 g of the product h as yellow crystals. To a mixture of 2-fluoro-4-methoxybenzonitrile h (1 g, 7 mmol) and 2-methane- sulfonylethanol (1 g, 11 mmol, 1.5 equiv. ), in dry DMF, at 0°C, was added sodium hydride (3 equiv. , 20 mmol, 0.8 g of a dispersion of 60percent NaH in mineral oil). The reaction mixture was allowed to warm to room temperature and, after 2h, was quenched by addition of a IN hydrochloric acid. The resulting solution was diluted with water and extracted with ethyl acetate (2x). The organic layers were combined, washed with brine, dried with MgS04, filtered and concentrated to afford 1 g (90percent) of product i as a yellow solid. Phenol i (1 g, 7 mmol), chloroacetone (0.7 g, 8.4 mmol, 1.2 equiv. ), potassium iodide (1 g, 8.4 mmos, 1.2 equiv. ) and potassium carbonate (2 g, 14 mmol, 2 equiv. ) were mixed in acetone and refluxed for 1 h. The reaction mixture was filtered and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried with MgS04, filtered and concentrated to give 1.6 g (100percent) of product j as a white/brown solid To a solution of compound j (0.2 g, 1 mmol) in methanol (10 ml) was added sodium methoxide (0.06 g, 1.1 mmol, 1.1 equiv.). After stirring at room temperature for 1 h, the reaction mixture was diluted with water, most methanol was stripped off by evaporation under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with MgS04, filtered and concentrated to give 175 mg (90percent) of the product k as a yellow powder. To a solution of compound k (0.500 g, 2.4 mmol) in dichloromethane (20 ml) were successively added cyanoacetic acid (1.2 equiv. , 2.92 mmol, 249 mg), 1-(3-dimethyl- aminopropyl) -3-ethylcarbodiimide hydrochloride (1.1 equiv, 2.68 mmol, 514 mg) and catalytic amount of 1-hydroxybenzotriazole. The reaction mixture was stirred at room temperature during 16 h. More dichlormethane was added and the resulting solution was washed with water, a saturated aqueous solution of sodium bicarbonate and brine, The organic layer was dried with MgS04, filtered and concentrated to give 700 mg (100percent) of compound I as an orange powder. Intermediate 1 (0.660 g, 2.42 mmol) and triethylamine (0.368 g, 3.64 mmol, 1.5 equiv.) were heated to reflux in ethanol during 24 h. The reaction mixture was concentrated to give 0.580 g (yield = 94percent) of the product m as a yellow solid. The crude material was used as such in the next step. To a suspension of intermediate m (0.23 g, 0.9 mmol) in dichloromethane were added successively powdered molecular sieves, 4-nitrophenylboronic acid (0.31 g, 1.8 mmol, 2 equiv. ), pyridine (0.145 g, 1.8 mmol, 2 equiv. ), copper acetate (0.33 g, 1.8 mmole, 2 equiv. ) and triethylamine (0.185 g, 1.8 mmole, 2 equiv. ). The reaction mixture was stirred at room temperature with a CaCl2 tube during 22 h. The mixture was filtered over decalite and rinsed thoroughly with multiple portions of dichloromethane. The combined filtrates were washed with a saturated solution of sodium bicarbonate and brine, dried with MgS04, filtered and concentrated. Purification by flash chromatography on silica gel (eluent: 5percent methanol in dichloromethane) followed by purification by preparative TLC (eluent: 5percent methanol in dichloromethane) gave 10 mg of product 5 as a yellow powder. Compound 5 (170 mg, 0.45 mmol) was dissolved in dichloromethane (10 ml) under N2-atmosphere, and the reaction mixture was cooled to 0°C. A solution of boron tribromide (20 equiv. , 9 mmol, 9 ml of a solution of 1M BBr3 in dichloromethane) was added and the reaction mixture was allowed to warm to room temperature. After 4 h, the reaction contents was poured into a mixture of ice and a saturated solution of sodium bicarbonate under vigorous stirring. The precipitate was isolated by filtration, washed with water, isopropanol and diisopropyl ether to give 46 mg (yield = 28percent, purity = 90percent) of the desired phenol 6 as an orange powder. |
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