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With sodium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
A mixture of 1.7 g (lOmmol) of <strong>[4066-41-5]5-acetyl-thiophene-2-carboxylic acid</strong>, 0. 75 mL MeI (12 mmol), 4.3 g of Na2C03 (35mmol) in DMF 10 mL was allowed to stir at room temperature overnight. Quench with water with some addition of sat. NH4Cl sol. Precipitate formed and was collected to yield 1.48g of <strong>[4066-41-5]5-acetyl-thiophene-2-carboxylic acid</strong> methyl ester as a white solid. Yield 80%. A mixture of 5.1 g of <strong>[4066-41-5]5-acetyl-thiophene-2-carboxylic acid</strong> methyl ester, 11 g of CuBr2 in 50 mL of EtOAc was refluxed for 6 hrs. The reaction mixture was cooled to rt and filtered through diatomaceous earth and purified by combiflash to yield 5 g of 5- (2- bromo-acetyl) -thiophene-2-carboxylic acid methyl ester.. Yield 69%. A mixture of 263 mg (lmmol) of the above ester and 0.4 mL of formamide was heated to 120C. Then a mixture of 0.2 mL and 0.1 g of concentrated H2S04 was added. The reaction mixture was heated at 120C for 1 h. The reaciton mixture was cooled down to room temperature and poured into water, and extracted with ether. The ethereal extract was dried over MgS04, and concentrated in vacuo. The residue was purified by combiflash to yield 60 mg of 5-oxazol-4-yl-thiophene-2-carboxylic acid methyl ester as light yellow solid. Yield 30%. The above ester was dissolved in 3 mL THF, 1 mL MeOH and 1 mL 1N LiOH solution and stirred overnight. The solvent was removed. Acetic acid was added and a light yellow precipitate formed which was collected by filtration to yield 20 mg of the title compound. Yield 33%.
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 23℃; for 72h;
i) To a solution of <strong>[4066-41-5]5-acetylthiophene-2-carboxylic acid</strong> (5.00 g, 29.4 mmol) in dry DMF (24 mL) were added K2C03 (12.2 g, 88.0 mmol) and iodomethane (5.00 g, 35.3 mmol, 2.20 ml) and the RM was stirredat RT for 72 h. Upon completion the RM was acidified with 1M HCI (50 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with aqueous saturated solution of NaHCO3 (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. Trituration with diethyl ether and filtration afforded INT-7A (4.11 g, 21.2 mmol 72%) as a brown solid. LCMS: calc. for [M+H]1 85.02, found 185.2.
72%
With potassium carbonate; In N,N-dimethyl-formamide; at 23℃;
To a solution of <strong>[4066-41-5]5-acetylthiophene-2-carboxylic acid</strong> (5.00 g, 29.4 mmol) in dry DMF (24 mL) were addedK2C03 (12.2 g, 88 mmol) and iodomethane (5.00 g, 35.3 mmol, 2.20 ml) and the mixture was stirred at rtover the weekend. Upon completion the mixture was acidified with I M HCI (50 rnL) and extracted withEtOAc (3x 20 mL). The combined organic layers were washed with aqueous saturated solution ofNaHCO3 (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. Trituration with Et20 and filtration afforded methyl 5-acetylthiophene-2-carboxylate (4.11 g, 21.2 mmol, 72%) as a brown solid. LCMS: cal for [M+HJ 185.02, fd 185.2.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 60h;
A solution of <strong>[4066-41-5]5-acetyl-thiophene-2-carboxylic acid</strong> (1 g, 5.88 mmol) in DMF (24 mL) is treated with potassium carbonate (813 mg, 5.88 mmol), then iodomethane (0.368 mL, 5.88 mmol), and stirred for 60 h at rt. The reaction mixture is acidified and extracted into ethyl acetate twice. The combined organic layers are washed with brine, dried, filtered, and concentrated, then taken up in ethyl acetate, washed with saturated aqueous potassium carbonate, dried, filtered and concentrated to give <strong>[4066-41-5]5-acetyl-thiophene-2-carboxylic acid</strong> methyl ester (653 mg)
With sodium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step 1 : methyl 5-acetylthiophene-2-carboxylate A mixture of <strong>[4066-41-5]5-acetylthiophene-2-carboxylic acid</strong> (0.85 g, 5 mmol), iodomethane (0.38 ml, 6.00 mmol) and sodium carbonate (1.86 g, 17.50 mmol) in DMF (10 ml) was stirred at RT overnight. The mixture was concentrated under reduced pressure and the residue was taken up in EtOAc. The mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated and the residue was purified by flash chromatography on a silica gel column with 0-30% EtOAc/hexane to give the title compound. MS (ESI) m/z 185.07 (M+H).
Step 1: methyl 5-acetylthiophene-2-carboxylateTo a solution of <strong>[4066-41-5]5-acetylthiophene-2-carboxylic acid</strong> (3.24 g, 19.0 mmol) dissolved in a mixture of toluene (50 mL) and methanol (50 mL) cooled to 0 C. was added 2.0 M trimethylsilyldiazomethane in ether (19.0 mL, 38.1 mmol) dropwise. Upon complete addition, the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with the addition of acetic acid and the solvent was removed. The residue thus obtained was partitioned between ethyl acetate and saturated aqueous NaHCO3 and upon separation, the organic layer was dried over anhydrous magnesium sulfate and concentrated to afford the desired product (3.49 g, 100%). LC-MS: (FA) ES+ 185)
11%
With tetrafluoroboric acid; In dichloromethane; water; at 0℃; for 2h;
To a solution of 4-acethylthiopene-3-carboxylic acid (1 g, 5.52 mmol) in DCM (17 ml),40% aqueous tetrafluoroboric acid (0.49 g, 5.52 mmol) was added at 0C. Thereafter, 4 portions of trimethylsilyldiazomethane (altogether 1.76 ml, 1.26 g, 11.04 mmol) were added dropwise under stirring at 0C. The first portion was directly added after cooling to 0C and the other 3 portions were adjoined in intervals of 30 minutes. Stirring was continued for 30 minutes after the last addition. The reaction mixture was then extracted with DCM/H2O, driedover MgSO4, and evaporated to dryness prior to purification by column chromatography (silica gel 60, petrol ether/ethyl acetate 8:2) to give product 7as yellow crystals. Yield: 0.21 g (11%), light yellow crystals, mp. 127-128C. Analytical data arein complete accordance with literature values.2
With thionyl chloride; In N,N-dimethyl-formamide; for 5h;Reflux;
In a 250-ml three-necked flask, add <strong>[4066-41-5]5-acetyl-2-thiophenecarboxylic acid</strong> (5 g, 29.4 mmol), 120 ml of methanol, and 1.5 ml of N, N-dimethylformamide (DMF). Slowly add subchlorite at room temperature. Sulfone (12.24 g, 102.9 mmol), refluxed for 5 h after completion of dropwise addition.After the reaction is completed, cool down, adjust the pH to neutral with saturated sodium bicarbonate, and dilute with water to precipitate a large amount of solids. Add water until the solids no longer increase. The crude 5-acetyl-2-thiophene methyl ester is obtained by suction filtration. After weighing, 4.75g was weighed, and the yield was 87.4%.
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