醋丁洛尔的合成新工艺研究

New Process for the Synthesis of Acebutolol

以对氨基苯酚为原料,经氨基、羟基的乙酰化,Fries 重排,水解,氨基丁酰化,再与环氧氯丙烷反应,最后与异丙胺缩合,合成了具有内在活性的β1 肾上腺素受体阻断药醋丁洛尔,总收率达 51.5%。该路线简化了操作,将文献中报道的氨基、羟基的酰化反应合并为一步进行,水解,中和,氨基丁酰化也一锅法完成,避免了原工艺中存在的乙酰基和丁酰基的交换反应,从而避免了两个主要杂质的出现;并对其中关键步骤??Fries 重排反应进行了优化,确定了比较合理的反应条件:惰性无机盐氯化钠作为助溶剂,反应温度为 120℃,后处理用水量为 0.1mol 原料使用 80mL 水。

Acebutolol, which is a kind of β1-adrenoceptor blocking agent, was synthesized from 4-aminophenol via acetylation, Fries rearrangement, hydrolysis, butyrylation, reacting with epichlorohydrin and condensing with isopropyl amine. The new route simplified the process by carrying out the acetylation of the amino and the hydroxyl group in one step and finishing the hydrolysis N neutralization, butyrylation in one reactor. It avoids the exchanging reaction of the acetyl and the butyl group and then avoids the occurence of two main by-products. The key step (Fries rearrangement) was investigated, in which sodium chloride was added as cosolvent, suitable temperature found was 120°C, and quantity of water was selected with 800 mL per mol raw material. The new route simplifies the operations and cuts down two main impurities, the overall yield achieves 51.5%.