75% |
With potassium carbonate In N,N-dimethyl-formamide at 0 - 60℃; for 12.5h; |
10 Example 10 5-methoxybenzofuran-2-carboxylic acid phosphonoethyl ester (Compound 10)
Under ice-cooling,2-hydroxy-5-methoxybenzaldehyde (3.0g, 20mmol) and anhydrous K2CO3 (3.3g,23.4mmol) (50ml) was dissolved in DMF, was slowly added dropwise ethylbromoacetate (3.3g, 20mmol). After dropping Bi, 0 ° C was stirred for 30min,then at 60 ° C in an oil bath, the reaction 12h. The reaction solution waspoured into ice water, over Filtered, the solid was dissolved in chloroform,dried over anhydrous Na2SO4, filtered, and spin dry the solvent, by silica gelcolumn chromatography, To give 3.24 g of a yellow solid (75% yield), which was dissolved indioxane (30ml) was added 1N hydrogen Sodium hydroxide solution (15ml), stirredat room temperature 2h, the dioxane was evaporated to dryness, the residualliquid was poured into ice water, washed with diethyl Washed with methylenechloride, adjusting the PH value to 2, the solid was collected by filtration 2.68g (92% yield), whichwas dissolved in methylene Dioxane (50ml), was added DIC (1.51g, 11.98mmol),after stirring at room temperature 1h, was added DMAP (0.24g, 1.96 mmol) anddimethyl hydroxyethyl phosphonate (1.84g, 10.95mmol), heated to reflux after6h, water and saturated brine The reaction solution was washed with water,dried over anhydrous magnesium sulfate, filtered and evaporated to dryness,ethyl acetate - petroleum ether system recrystallized To (dimethoxyphosphoryl)ethyl 5-methoxybenzofuran-2-carboxylate 3.67g (77% yield), which was Was dissolved indichloromethane (50ml), was added trimethylsilyl bromide (9.85g, 64.8mmol) atroom temperature was stirred for 3h, with Quench with methanol, evaporated todryness to give the product 5-methoxy-benzofuran-2-carboxylic acid ethyl esterphosphono 2.38 g (yield, 74%). |
72.2% |
With potassium carbonate In N,N-dimethyl-formamide |
5 Step 5
A compound 8 (24.95 g, available from Tokyo Chemical Industry Co., Ltd.) was caused to react with ethyl bromoacetate and K2CO3 under N,N-dimethylformamide (DMF) to obtain a compound 9 in the form of white solid (yield amount: 26.07 g, yield percentage: 72.2%). |
72.2% |
With potassium carbonate In N,N-dimethyl-formamide |
5 Step 5
A compound 8 (24.95 g, available from Tokyo Chemical Industry Co., Ltd.) was caused to react with ethyl bromoacetate and K2CO3 under N,N-dimethylformamide (DMF) to obtain a compound 9 in the form of white solid (yield amount: 26.07 g, yield percentage: 72.2%). |
62% |
With potassium carbonate In N,N-dimethyl-formamide for 2h; Reflux; Inert atmosphere; |
85 Synthesis of Compound 3
The mixture of compound 1 (15.2 g, 0.1 mol), compound 2 (16.6 g, 0.1 mol) and K2CO3(27.6 g, 0.2 mol) in DMF (150 mL) was heated to reflux under n2 for 2 h. After cooled to RT, the reaction mixture was concentrated and dissolved in DCM (100 mL), the solution washed with sat.NaHCO3, brine, dried over Na2SO4, concentrated. The residue was purified by silica gel column to give compound 3 (11.8 g, 62% yield) as white solid. |
58% |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; |
103.1
(1) ethyl 5-methoxy-1-benzofuran-2-carboxylate A suspension (100 mL) of 2-hydroxy-5-methoxybenzaldehyde (10 g), ethyl bromoacetate (8.02 mL) and potassium carbonate (18.2 g) in N,N-dimethylformamide was stirred at 80° C. overnight. After cooling to room temperature, ethyl acetate was added, and the mixture was washed 3 times with saturated aqueous sodium carbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate/hexane to give the object product (8.37 g, 58%). 1H NMR (200 MHz, CDCl3) δ ppm 1.43 (t, J=7.0 Hz, 3H) 3.85 (s, 3H) 4.44 (q, J=7.0 Hz, 2H) 7.02-7.10 (m, 2H) 7.45-7.51 (m, 2H) |
58% |
With potassium carbonate In N,N-dimethyl-formamide at 60 - 100℃; |
|
50% |
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 15h; |
3 Preparation Example 3: Ethyl 5-methoxybenzofuran-2-carboxylate
After dissolving 2-hydroxy-5-methoxybenzaldehyde (1.25 mL, 10.0 mmol) in DMF (30 mL), K2CO3 (6.91 g, 50.0 mmol) and ethyl bromoacetate (1.33 mL, 12.0 mmol) were added thereto. And reacted at 70°C for 15 hours. The reaction solution was diluted with water and extracted with EA. The organic layer was dried over MgSO4, filtered, and distilled under reduced pressure. The residue was separated by column chromatography (n-Hex:EA=3:1) to give 1.1 g (yield 50%, white solid) of the title compound. |
33% |
With potassium carbonate In N,N-dimethyl-formamide at 80℃; |
|
|
With potassium carbonate In N,N-dimethyl-formamide for 1.5h; Reflux; Molecular sieve; |
|