A kind of method for preparing roflumilast intermediate
A technology for roflumilast and intermediates, which is applied in the field of preparing roflumilast intermediates, can solve the problems of complex operation, high cost, and unsuitability for industrial production, and achieve simple synthesis process, easy operation, and high synthesis yield. The effect of high purity
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Embodiment 1
[0026] Embodiment 1, the preparation of roflumilast intermediate
[0027] 33.2 g of 3-bromo-4-hydroxybenzaldehyde, CHF 2 21.8 g of Br, 15.6 g of 60% sodium hydroxide, 81.4 g of tetrabutylphosphine bromide, and 300 mL of DMF were added to the reactor, heated at 110° C., stirred and reacted for 6 hours, and the solvent was evaporated. Water was added, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 40.2 g of product with a yield of 96.9%.
[0028] 25 g of the above-obtained product, 30 g of cyclopropyl methanol, 69 g of potassium carbonate, 170 g of tetrabutylphosphine bromide, and 500 mL of DMF were heated at 90° C., reacted for 12 hours, and the solvent was evaporated. Extract with ethyl acetate, dry with magnesium sulfate, filter and evaporate the solvent to obtain 23 g of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde with a yield of 95.0%.
[0029] ESI-MS: m / z243[M+H]+;
[0030] 1 HNMR (400MHZDMSO): δ0.58-0.60...
Embodiment 2
[0031] Embodiment 2, the preparation of roflumilast intermediate
[0032] 830 g of 3-bromo-4-hydroxybenzaldehyde, CHF 2 545g of Br, 390g of 60% sodium hydroxide, 2.035kg of tetrabutylphosphine bromide, and 7.5L of DMF were added to the reactor, heated at 110° C., stirred and reacted for 6 hours, and the solvent was evaporated. Water was added, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 99.56 g of product with a yield of 96.0%.
[0033] 0.5 kg of the product obtained above, 0.6 kg of cyclopropyl methanol, 1.38 kg of potassium carbonate, 3.4 kg of tetrabutylphosphine bromide, and 20 L of DMF were heated at 90° C., reacted for 12 hours, and evaporated to remove the solvent. It was extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 451.3 g of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde with a yield of 93.2%.
Embodiment 3
[0034] Embodiment 3, the preparation of roflumilast intermediate
[0035] 33.2 g of 3-bromo-4-hydroxybenzaldehyde, CHF 2 21.8 g of Br, 15.6 g of 60% sodium hydroxide, 81.4 g of tetrabutylphosphine bromide, and 300 mL of DMF were added to the reactor, heated at 120° C., stirred and reacted for 2 hours, and the solvent was evaporated. Water was added, extracted with ethyl acetate, dried over magnesium sulfate, filtered and evaporated to dryness to obtain 38.5 g of product with a yield of 92.0%.
[0036] 25 g of the above-obtained product, 30 g of cyclopropyl methanol, 106 g of potassium phosphate, 170 g of tetrabutylphosphine bromide, and 500 mL of DMA were heated at 85° C., reacted for 11 hours, and the solvent was evaporated. Extract with ethyl acetate, dry with magnesium sulfate, filter and evaporate the solvent to obtain 22 g of 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde with a yield of 90.9%.
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