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发明授权
CN105523922B 一种罗氟司特中间体的制备方法 失效 - 权利终止 转让

一种罗氟司特中间体的制备方法
摘要：
本发明公开了一种罗氟司特中间体的制备方法，包括：1)在羟胺存在下，将3,4‑二羟基苯甲醛与二氟溴乙酸甲酯在乙腈中30‑45℃下进行接触反应，反应结束加入水，二氯甲烷萃取，浓缩，石油醚重结晶得3‑羟基‑4‑二氟甲氧基苯甲醛；2)将3‑羟基‑4‑二氟甲氧基苯甲醛与溴甲基环丙烷在N‑甲基吗啉和锌盐存在下在乙腈中进行混合反应，混合反应的温度为55‑60℃，得3‑环丙基甲氧基‑4‑二氟甲氧基苯甲醛；3)将3‑环丙基甲氧基‑4‑二氟甲氧基苯甲醛与氧化剂进行氧化反应，氧化反应的温度为45‑50℃，得3‑环丙基甲氧基‑4‑二氟甲氧基苯甲酸，其中，所述氧化剂由MnO2和HClO组成。本发明的方法选择性好，提高收率；条件更加温和，不会对其他基团产生影响，副产物更少。
摘要（英）：

The invention discloses a preparation method for roflumilast intermediates. The preparation method includes: 1), adding 3, 4-dihydroxybenzaldehyde and methyl bromodifluoroacetate into acetonitrile for contact reaction at the temperature of 30-45 DEG C in the presence of hydroxylamine, adding water after reaction completion, extracting and concentrating dichloromethane, and performing petroleum ether recrystallization to obtain 3-hydroxy-4-diflouromethylbenzaldehyde; 2), adding the 3-hydroxy-4-diflouromethylbenzaldehyde and bromomethyl cyclopropane into the acetonitrile for hybrid reaction in the presence of N-methylmorpholine and zinc salt at the temperature of 55-60 DEG C to obtain 3-cyclopropylmethoxy-4-(difluoromethoxy) benzaldehyde; 3), subjecting the 3-cyclopropylmethoxy-4-(difluoromethoxy) benzaldehyde and oxidizing agent comprising MnO2 and HClO to oxidation reaction at the temperature of 45-50 DEG C to obtain 3-cyclopropylmethoxy-4-(difluoromethoxy) benzoic acid. The preparation method has the advantages that selectivity is high and yield is increased; conditions are milder, influences on other groups are avoided and by-products are fewer.

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