Method for preparing roflumilast intermediate
A technology for roflumilast and intermediates, applied in the field of preparation of roflumilast intermediate 3--4-benzoic acid, can solve the problems of difficult industrial production, expensive reagents, high cost, etc. Easy to control, overcome the effect of poor selectivity
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Embodiment 1
[0060] 117 g of 3-bromo-4-hydroxybenzaldehyde and 20 g of anhydrous potassium carbonate were added to 500 ml 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 1d. The solvent was evaporated under reduced pressure, 500 ml of water was added, washed with dichloromethane (150 ml×2), and about 100 ml of concentrated hydrochloric acid was added to adjust the pH to 2. Extracted with ethyl acetate (200 ml×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 194.9 g of light yellow solid 3-bromo-4-(difluoromethoxy)benzaldehyde, Yield 91%.
[0061] 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 500 ml of methanol, and stir at 60°C for 2 h. After the reaction was completed, 10% hydrochloric aci...
Embodiment 2
[0065] 23 g of 3-bromo-4-hydroxybenzaldehyde and 4.0 g of anhydrous potassium carbonate were added to 100 ml 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 1d. The solvent was evaporated under reduced pressure, 100 ml of water was added, washed with dichloromethane (30 ml×2), and about 20 ml of concentrated hydrochloric acid was added to adjust the pH to 2. Extracted with ethyl acetate (40 ml×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 19 g of light yellow solid 3-bromo-4-(difluoromethoxy)benzaldehyde. rate 29%.
[0066] 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 100 ml of methanol, and stir at 60°C for 2 h . After the reaction was completed, 10% hydroch...
Embodiment 3
[0070] 58 g of 3-bromo-4-hydroxybenzaldehyde and 10 g of anhydrous potassium carbonate were added to 250 ml 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 1d. The solvent was evaporated under reduced pressure, 250 ml of water was added, washed with dichloromethane (75 ml×2), and about 50 ml of concentrated hydrochloric acid was added to adjust the pH to 2. Extracted with ethyl acetate (100 ml×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 97.9 g of light yellow solid 3-bromo-4-(difluoromethoxy)benzaldehyde, Yield 91.1%.
[0071] 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 250 ml of methanol, and stir at 60°C for 2 h. After the reaction was completed, 10% hydrochloric acid wa...
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