8-苄氧基-5-(2-溴乙酰基)喹诺酮的合成

摘要

Kilogram scale synthesis of 8-Benzyloxy-5-(2-bromoacetyl) carbostyril,the intermediate of anti-asthma drugs,was studied from 8-hydroxyquinolin-N-oxide(Ⅱ) via isomerisation,Fries rearrangement,benzylation and bromination.Thus reflux reaction of Ⅱ (2.5 kg) and acetic anhydride(12 kg) for 4 h gave 8-acetoxyquinolone(Ⅲ).And then Ⅲ mixed with anhydrous AlCl3 (3.8 kg),acetylchloride(75 g) and dichloroethane(55 kg) into slurry and conducted Fries reaction at 75-85 ℃ for 4 h to produce 5-acetyl-8-hydroxylquinolone(Ⅳ).Subsequently,under the catalysis of KI/K2CO3,benzylation with benzylchloride (1.5 kg) in DMF was carried out to produce 8-benzyl-5-acetylquinolone (Ⅴ);Finally,BF3/Et2O catalyzed reaction of Ⅴ with bromine(1.9 kg) at 30-35 ℃ for 1 h to obtain 3.3 kg target product with purity of 98.4％ and the total yield of 56.5％.%研究了以8-羟基喹啉-N-氧化物为起始原料,经转位、Fries重排、苄基化和溴化等反应合成了抗哮喘药中间体8-苄氧基-5-(2-溴乙酰基)喹诺酮的千克级工艺.2.50 kg 8-羟基喹啉-N-氧化物和12 kg乙酰酐回流反应4h生成8-乙酰氧基喹诺酮,然后与3.8 kg无水AlCl3、75 g乙酰氯和55 kg二氯乙烷混合成浆状,加热到75～85℃进行Fries反应4h,得到5-乙酰基-8-羟基喹诺酮;5-乙酰基-8-羟基喹诺酮与1.5 kg氯化苄在DMF中,KI/K2 CO3催化下苄基化得到8-苄氧基-5-乙酰基喹诺酮,与1.9 kg液溴在30～35℃、BF3 /Et2O催化下反应1h,得到3.3 kg目标产物,质量分数98.4％,总收率56.5％.