Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate

Pale Yellow Solid

Preparation of Ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate To a 3M solution of MeMgCl(55.86 g, 0.74 mol) in tetrahydrofuran was added a solution of diethyl 2-propyl imidazole- 4, 5-dicarboxylate (50 g, 0.19 mol) in tetrahydrofuran (200 ml) at -10 to 0°C under NMethyl bromide gas (35 g, 0.3686 mol) was passed through a dry solution of tetrahydrofuran (100 mL) and a small portion (5 to 10 mL) of this solution was added dropwise to a solution of magnesium strip (8 g, 0.33 mol) The solution of iodine (0.02g) and dry tetrahydrofuran (50mL) was stirred at room temperature. After the reaction was initiated, the solution of the remaining methyl bromide in THF was slowly added dropwise to keep the reaction slightly boiling. After the addition was complete, the reaction was continued for 3h until the magnesium strip disappeared. Get the corresponding Grignard reagent;The imidazole diesters of the compounds of the formula II 15g (0.059mol) was dissolved in dry dichloromethane (50mL), slowly added dropwise to the homemade format reagents, the dropping period, maintaining the temperature of the reaction system below 15 °C, after the addition was complete, the control The reaction was continued stirring at a temperature of 15 ~ 25 °C for 2h, after the reaction was cooled to 0 °C, further diluted with ethyl acetate (150mL), and then saturated amine chloride solution (100mL) was slowly added dropwise The process of maintaining the system temperature below 10 °C, dropping completed, the organic layer was collected by stratification, washed with saturated sodium chloride solution (30mLX3), and then dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent To give a residue. The resulting residue was recrystallized from isopropyl ether-n-hexane solvent, filtered and dried to give a white powdery solid 4- (1-hydroxy-1-methylethyl) -2-propyl- 1H-imidazole-5-carboxylate (13.8 g, yield: 97.5percent , HPLC: 99.7percent)100 g (4.16 mol) of magnesium powder was added to tetrahydrofuran (2 L)At 60 ° C into the methyl chloride gas to magnesium powder all disappeared (about 3 hours), And then reflux for 30 minutes, Cold to room temperature, A solution of gray magnesium chloride in methylmagnesium chloride in tetrahydrofuran was prepared.A solution of ethyl 2-propylimidazole-4, 5-dicarboxylate (2) (211.9 g, 0.83 mol) in 2.1 L tetrahydrofuran was added dropwise at 30 ° C.2 hours plus finished, Stirring was continued for 30 minutes.The solvent was removed under reduced pressure and the residue was added dropwise to a solid solution of saturated ammonium chloride solution. Add ethyl acetate 2.5L, the organic layer, the water layer and then ethyl acetate 500ml X 2 extraction, organic layer merger. Wash with saturated salt once. Dried over anhydrous magnesium sulfate. The solvent was evaporated to give pale yellow oil 1 (160.2 g, 80percent) with an APLC purity of 92.91percent, with ketone ethyl ester impurity 3 being 5.04percent.0 grams of 4, 4-dimethyl-2-propyl-4, 6-dihydrofuro [3, 4-d] imidazole (formula II) from Example 1, 30 ml of ethanol and 0.1 ml of concentrated sulfuric acid were added into 100 ml three-necked flask and stirred until completely dissolved, heated to 40-50°C and maintained at that temperature until the reaction completed. The reaction mixture was then allowed to cool to ambient temperature, the solvent was evaporated, 30 ml of ethyl acetate and 30 ml of water were added, and the mixture was adjusted to basic using sodium bicarbonate, The organic layer was separated and the aqueous layer was further extracted with 10 ml x 3 of ethyl acetate. The organic portion was washed once with saturated saline solution, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 3.4 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate, resulting in a yield of 92percent..3.0 grams of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid (formula III) from Example 4, 30 ml of ethanol, and 3.36 grams of thionyl chloride were added into 100 ml three-necked flask, and refluxed until the reaction completed. The reaction mixture was then allowed to cool to ambient temperature, the solvent was evaporated, 30 ml of ethyl acetate and 30 ml of water were added, and the mixture was adjusted to basic using sodium bicarbonate. The organic layer was separated and the aqueous layer was further extracted with 10 ml x 3 of ethyl acetate. The organic portion was washed once with saturated saline solution, dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated to give 2.9 grams of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate, resulting in a yield of 85percent.

Olmesartan (O550000) intermediate.