3,3-Difluorocyclobutanecarboxylic acid

100ml eggplant bottle inside the addition of 15ml of water and 2g sodium hydroxide, stirring dissolved, add 35ml of ethanol, Then 5 g of 2-chloro-3, 3-difluoro-1-encyclobutanoic acid (6) was added and the system was purged with nitrogen three times, 100 mg of 10percent palladium on carbon was added. System with hydrogen replacement 3 times, the reaction heated to 40 , The mixture was stirred for 12 hours under a hydrogen atmosphere. The HPLC product was completely disappeared and the reaction was terminated.The temperature was reduced to room temperature, filtered to remove palladium on carbon, and the filter cake was rinsed twice with 10 ml of ethanol.The filtrate was distilled off under reduced pressure at 35 ° C to remove ethanol. The remaining water phase by adding 15ml ice water diluted to about 0-5 , With 5percent hydrochloric acid to adjust PH = 1-2, ethyl acetate extraction twice (30mlX2), combined organic phase, Dried over anhydrous sodium sulfate and distilled under reduced pressure at 35 ° C to give 4 g of crude product, crude product n-heptane beating, Filtered and dried to give 3.9 g of 3, 3-difluorocyclobutanoic acid (1) as a white product, yield 98percent.2-Chloro-3, 3-difluoro-1-encyclobutanecarboxylic acid (56.9 g, 0.34 mol), Triethylamine (68 g, 0.68 mol), 10percent wet palladium on carbon (5.7 g) was added to methanol (570 mL). Hydrogen pressure 45-50 psi, temperature 45-50 ° C, and reaction 18-20 hours. The reaction was terminated, the temperature was lowered to 20-25 ° C, and the catalyst was removed by filtration. The filtered organic phase was added to a 5percent aqueous solution of sodium hydrogencarbonate (270 mL), concentrated to 350-400 mL under reduced pressure, and then adjusted to pH 1-2 with concentrated hydrochloric acid. The organic layer was washed with dichloromethane 200 mL * 3). The organic phase was concentrated to dryness to give 42 g of product (yield 90-95percent).Benzyl 3, 3-difluorocyclobutanecarboxylate (0.84 g, 3.72 mmol) was dissolved in ethanol (40 mL), and approximately 0.02 g palladium on activated carbon was added. The mixture was stirred at room temperature for 12 h under the atmosphere of HTo solution of benzyl 3, 3-difluorocyclobutane carboxylate(450 mg, 2.0 mmol) dissolved in ethanol (10 mL), was added Pd/C(10percent, 40 mg). To a solution of benzyl 3, 3-difluorocyclobutanecarboxylate (1.4 g, 6.2 mmol) in ethanol (50 mL) was added palladium on activated carbon (500 mg) and the reaction mixture was stirred at RT under an atmosphere of hydrogen (1 atm) for 12 h. Example 37d

3,3-Difluorocyclobutane carboxylic acid is used as an organic and pharmaceutical intermediate.