A kind of preparation method of roflumilast intermediate
A technology for roflumilast and intermediates, which is applied in the field of preparation of roflumilast intermediate 3--4-benzoic acid, can solve the problems of difficult industrialized production, expensive reagents and high cost, and achieves feasible process and reaction Easy-to-control, simple-to-operate effects
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Embodiment 1
[0057] 117g of 3-bromo-4-hydroxybenzaldehyde and 20g of anhydrous potassium carbonate were added to 500ml of DMF. Stir for 30 min, then pass through difluorochloromethane at 60°C for 10 h, and then continue to react at the same temperature for 1 d. The solvent was evaporated under reduced pressure, 500ml of water was added, washed with dichloromethane (150ml×2), and about 100ml of concentrated hydrochloric acid was added to adjust the pH to 2. Extracted with ethyl acetate (200ml×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 194.9g of 3-bromo-4-(difluoromethoxy)benzaldehyde as a light yellow solid. The rate is 91%.
[0058] Add 100ml of hydrogen peroxide to a solution prepared from 52g of 3-bromo-4-(difluoromethoxy)benzaldehyde, 80ml of 50% potassium hydroxide solution, 13g of sodium chlorite and 500ml of methanol, and stir at 60°C for 2h. After the reaction was completed, 10% hydrochloric a...
Embodiment 2
[0062] 23g of 3-bromo-4-hydroxybenzaldehyde and 4.0g of anhydrous potassium carbonate were added to 100ml of dimethylsulfoxide. Stir for 60 min, then pass through difluorochloromethane at 60°C for 10 h, and then continue to react at the same temperature for 1 d. The solvent was evaporated under reduced pressure, 100ml of water was added, washed with dichloromethane (30ml×2), and about 20ml of concentrated hydrochloric acid was added to adjust the pH to 2. Extracted with ethyl acetate (40ml×2), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to dryness under reduced pressure to obtain 19g of light yellow solid 3-bromo-4-(difluoromethoxy)benzaldehyde, the yield 29%.
[0063] Add 20ml of hydrogen peroxide to a solution prepared from 10.4g of 3-bromo-4-(difluoromethoxy)benzaldehyde, 16ml of 50% potassium hydroxide solution, 3g of sodium chlorite and 100ml of methanol, and stir at 60°C for 2h. After the reaction was completed, 10% hydrochloric acid...
Embodiment 3
[0067] 58g of 3-bromo-4-hydroxybenzaldehyde and 10g of anhydrous potassium carbonate were added to 250ml of DMF. Stir for 30 min, then pass through difluorochloromethane at 60°C for 10 h, and then continue to react at the same temperature for 1 d. The solvent was evaporated under reduced pressure, 250ml of water was added, washed with dichloromethane (75ml×2), and about 50ml of concentrated hydrochloric acid was added to adjust the pH to 2. Extracted with ethyl acetate (100ml×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 97.9g of 3-bromo-4-(difluoromethoxy)benzaldehyde as a pale yellow solid. The rate is 91.1%.
[0068] Add 50ml of hydrogen peroxide to a solution prepared from 26g of 3-bromo-4-(difluoromethoxy)benzaldehyde, 40ml of 50% potassium hydroxide solution, 7g of sodium chlorite and 250ml of methanol, and stir at 60°C for 2h. After the reaction was completed, 10% hydrochloric acid w...
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