METHYL 3-METHYLTHIOPHENE-2-CARBOXYLATE

Step 1 : Methyl 3-methylthiophene-2-carboxylate: To a solution of 3-Methylthiophene-2- carboxylic acid (15 g, 105 mmol, 1.0 eq) in methanol (150 mL) was added cone sulfuric acid (7.5 mL) drop wise and refluxed for 12 h. The solvent was evaporated under vacuum and the residue was taken into ethyl acetate (200 mL), washed with water (2x50 mL), saturated aqueous sodium bicarbonate solution (2x50 mL), brine (50 mL), dried (NaIn a 1 L round-bottomed flask, 3-methylthiophene-2-carboxylic acid (15 g, 106 mmol) was combined with methanol (211 mL) to give an off-white suspension. This mixture was cooled to 0 °C in an ice- water bath. Concentrated sulfuric acid (6 ml, 113 mmol) was added dropwise to the cold suspension. The reaction mixture was stirred with gradual warming to room temperature. The reaction mixture was stirred at room temperature over three days. After this time, TLC showed complete conversion of the starting material to a less polar product. The reaction mixture was concentrated to remove methanol. The remaining light brown oil was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over NaA suspension of 3-methylthiophene-2-carboxylic acid (available from Aldrich; 15 g, 106 mmol) in MeOH (211 mL) was cooled to 0 °C. Concentrated sulfuric acid (6 ml, 113 mmol) was added drop wise and the mixture was stirred at room temperature for 3 days. The reaction mixture as concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHC0To a stirred solution of 100 g (0.7023 mol) of 3-methyl-2-thiophene carboxylic acid in 1000 ml of acetone was added 122.0 g (0.8827 mol) of potassium carbonate in 500 ml of acetone and was added drop wise of 89.0 g (0.7056 mol) of dimethyl sulfate, whilemaintaining the temperature of the reaction mixture at 25-30°C. When the addition was complete, the solution was stirred at 25-30°C for 4 hr. The acetone was removed by distillation under vacuum and the reaction mixture was diluted with 3000 ml of water while maintaining at 25-30°C by cooling and extracted with three 1000 ml portions of ethyl acetate. The ethyl aceiate extracts were combined, washed two times with 1000 mlportions of water, and dried over anhydrous sodium sulfate. The ethyl acetate was removed by distillation under vacuum at 60°C to give 105.2 g (95.6 percent) as a light yellow oily mass with 99.8 percent purity by HPLC.Methyl 3-Methylthiophene-2-carboxylate 101a3-Methylthiophene-2-carbonyl chloride (1) (10 mL, 18mmol) in 30 mL of meth-nol was heated to boiling under reflux for 18 hours, then concentrated in vacuo. The residue was partitioned between diethyl ether and water. The organic layer was dried with NaExample 102Methyl 3-Methylthiophene-2-carboxylate 102aCGIPHARM60WO3-Methylthiophene-2-carbonyl chloride (1) (10 mL, 18mmol) in 30 mL of methanol was heated to boiling under reflux for 18 hours, then concentrated in vaculo. The residue was partitioned between diethyl ether and water. The organic layer was dried with NaEXAMPLE 6