Background and overview[1]
2,5-Bis(2,2,2-trifluoroethoxy)benzoic acid is a key intermediate in the synthesis of the cardiovascular drug flecainide. The existing technology is mainly obtained by the condensation of gentisic acid and trifluoroethyl trifluoromethanesulfonate. Since gentisic acid and trifluoroethyl trifluoromethanesulfonate are expensive, 2,5-bis(2,2 , 2-trifluoroethoxy)benzoic acid has a higher cost.
Structure
Preparation[1]
A method for preparing 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 suboxone iodide into the reaction bottle in sequence, and react at 120°C for 12 hours. After the reaction is completed, pour it into cooling In water, add activated carbon to decolorize, filter, extract the mother liquor with dichloromethane, recover dichloromethane, add methanol to recrystallize to obtain white flake crystals, which is 1,4-bis(2,2,2-trifluoroethoxy)benzene. 48.5g, calculated yield 88.5%.
(2). Add 27.4g (0.1mol) of 1,4-bis(2,2,2-trifluoroethoxy)benzene, 100ml of dichloromethane, and 26.7 anhydrous aluminum trichloride into the reaction bottle. g (0.2mol), cool to 10°C, add 9.4g (0.12mol) acetyl chloride dropwise, and after titration, naturally rise to room temperature and react for 4 hours. After completion, pour into 100g ice and 30ml HCl (30%), separate layers, collect The lower organic layer and the aqueous layer were extracted with dichloromethane (50ml*3). The organic layers were combined, washed with water until neutral, dried with sodium sulfate, filtered, and the dichloromethane was recovered to obtain 2,5-bis(2,2,2- Trifluoroethoxy)acetophenone crude product. The crude product was recrystallized from 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 into the reaction bottle, and raise the temperature. to 80°C, start adding 65g of sodium hypochlorite (10% concentration) dropwise, and finish the reaction for 4 hours. At the end, add activated carbon for decolorization for 0.5h, filter, cool the filtrate to room temperature, adjust the pH of the filtrate to 2~3 with 30% hydrochloric acid, and precipitate a white solid. Filter, collect the solid, and recrystallize with ethanol to obtain 23.8 g of white crystalline solid. The purity is 99.60% as measured by HPLC, and the calculated yield is 74.8%.
Main reference materials
[1] CN200910115069.8 Preparation method of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid
