(5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone CAS 461432-22-4

The preparation method of 5-bromo-2-chloro-4′-ethoxybenzophenone, adding 24g (0.2mol) of thionyl chloride, 0.1ml of DMF, 5-bromo-2-chlorobenzoic acid to the flask successively 23.5g (0.1mol), stirred and heated to reflux for 4h, after the reaction, thionyl chloride was removed by distillation under reduced pressure at 60°C to obtain 25.1g of a yellow solid 5-bromo-2-chlorobenzoyl chloride crude product (yield 99%);

Directly add 100ml of dichloromethane, stir to dissolve, cool down to -20℃～-25℃, add 66g of aluminum trichloride supported by silica gel (the load is 1.6mmol/g, a total of 0.105mol), and control the vacuum degree of the system to -0.05MPa 13.4g (0.11mol) of phenethyl ether was added dropwise to react for 2h, filtered, soaked and washed with 40ml of dichloromethane, the filter cake was combined into the filtrate, washed with 5% sodium bicarbonate solution and water in turn, and the solvent was evaporated. Gained solid carries out recrystallization with the mixed solvent (ethanol and water volume ratio is 3:2) of 4 times of volumes of ethanol and water, and obtains 5-bromo-2-chloro-4′-ethoxybenzophenone after drying 31.1 g (total yield 91.8%, HPLC purity 99.88%).

15g of 5-bromo-2-chlorobenzoic acid (0.064mol), 100mL of dichloromethane and 0.5mL of N,N-dimethylformamide were sequentially added to a 250mL three-neck flask, and the mixture was stirred and mixed. 8.1 g of oxalyl chloride (0.064 mol, 1.0 eq) was added dropwise to the uniformly stirred mixture at 20-30° C., and the resulting mixture was stirred at room temperature overnight. The reaction solution was transferred to a 250 mL round-bottomed flask, concentrated to dryness under reduced pressure at 35-45 °C, and 50 mL of dichloromethane was added to dissolve and concentrate the resulting slurry, and the clear solution was 5-bromo-2-chlorobenzoyl chloride solution, spare.

7.8 g of phenethyl ether (0.064 mol, 1.0 eq) and 50 mL of dichloromethane were sequentially added to a 250 mL three-necked flask, stirred and mixed, and the mixture was cooled to -5°C. To the cooled mixed solution, 8.9 g of aluminum trichloride (0.067 mol, 1.05 eq) was added in three batches, and the mixture was stirred at -5°C for 0.5 hour. Then, the above-mentioned ready-to-use solution was added dropwise to the reaction mixture, and the obtained mixture was heated to 0-10° C. and stirred for 1 hour. A small amount of the reaction solution was quenched with water and then tested by HPLC. The detection result showed that the ratios of compound 3 and compound 4 in the reaction solution were 86.3% and 12.8%, respectively.

HPLC results showed that after the completion of the reaction of 5-bromo-2-chlorobenzoic acid, 50 mL of drinking water was added dropwise to the reaction solution to quench the reaction. The aqueous layer was separated, and the aqueous layer was back-extracted twice with 100 mL×2 dichloromethane. Combine the dichloromethane layers, successively wash the dichloromethane layer twice with 100 mL of 1N hydrochloric acid solution, wash the dichloromethane layer twice with 100 mL of 1N sodium hydroxide solution, wash the dichloromethane layer once with 100 mL of drinking water, and wash the dichloromethane layer with 100 mL of saturated brine. methane layer once.

The washed dichloromethane layer was dried over anhydrous sodium sulfate, transferred to a 500 mL round-bottomed flask, and concentrated to dryness under reduced pressure at 35-45°C. 100 mL of ethanol was added to the concentrate, the temperature was raised to 50-60° C. and stirred for 1 hour, then cooled to room temperature and stirred for 1 hour, and then cooled to 0-10° C. and stirred for 1 hour. Filter and wash the filter cake with 10 mL of pre-chilled ethanol. The filter cake was dried under reduced pressure at 50-60°C to obtain a white powder, namely compound 3, namely (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone, totaling 13.1 g, with a molar yield of 60.4% (The yield reported by the patent is 58%), and the HPLC purity is 96.9%.