Preparation of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid
2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is a key intermediate for the synthesis of flecainide, a cardiovascular drug. The prior art is mainly obtained by the condensation of gentisic acid and trifluoroethyl trifluoromethanesulfonate. Due to the high price of gentisic acid and trifluoroethyl trifluoromethanesulfonate, 2,5-bis(2,2 , The cost of 2-trifluoroethoxy) benzoic acid is relatively high.
2,5-bis(2,2,2-trifluoroethoxy)benzoic acid
The production method of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid includes the following steps in sequence:
(1) Put 100ml of DMF, 47.2g of p-dibromobenzene, 24g of sodium hydride, 150 of trifluoroethanol and 25g of ketone iodide into the reaction flask, and react at 120°C for 12h. After the reaction, pour into cooling water and add Activated carbon is decolorized, filtered, the mother liquor is extracted with dichloromethane, dichloromethane is recovered, and recrystallized with methanol to obtain white flaky crystals, 48.5g of 1,4-bis(2,2,2-trifluoroethoxy)benzene. The calculated yield is 88.5%.
(2) Add 1,4-bis(2,2,2-trifluoroethoxy)benzene 27.4g (0.1mol), dichloromethane 100ml, anhydrous aluminum trichloride 26.7g (0.2 mol), cool to 10°C, add 9.4g (0.12mol) of acetyl chloride dropwise, after the titration, it will naturally rise to room temperature and react for 4h. After completion, pour into 100g ice and 30ml HCl (30%), separate into layers, and collect the lower organic layer , The aqueous layer was extracted with dichloromethane (50ml*3), the organic layers were combined, washed with water until neutral, dried with sodium sulfate, filtered, and recovered dichloromethane to obtain 2,5-bis(2,2,2-trifluoroethane) (Oxy) acetophenone crude product. The crude product was recrystallized with methanol to obtain 24.6 g of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone, with a calculated yield of 78%.
(3) Add 31.6g (0.1mol) of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone, 150g of water and 4.2g of sodium hydroxide to the reaction flask, and raise the temperature to 80°C , Start to add 65g of sodium hypochlorite (10% concentration) dropwise, drop the reaction for 4 hours, after completion, add activated carbon to decolorize for 0.5h, filter, cool the filtrate to room temperature, adjust the pH of the filtrate to 2~3 with 30% hydrochloric acid, precipitate a white solid, filter, and collect The solid was recrystallized with ethanol to obtain 23.8 g of a white crystalline solid. The purity measured by HPLC was 99.60%, and the calculated yield was 74.8%.
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