8-苄氧基-5-(2-溴乙酰基)喹诺酮的合成

SYNTHESIS OF 8-BENZYLOXY-5-(2-BROMOACETYL)CARBOSTYRIL

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。2.50kg 8-羟基喹啉-N-氧化物和12kg乙酰酐回流反应4h生成8-乙酰氧基喹诺酮,然后与3.8kg无水AlCl_3、75g乙酰氯和55kg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1.5kg氯化苄在DMF中,KI/K_2CO_3催化下苄基化得到8-苄氧基-5-乙酰基喹诺酮,与1.9kg液溴在30~35℃、BF_3/Et_2O催化下反应1h,得到3.3kg目标产物,质量分数98.4%,总收率56.5%。

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 ofⅡ（2.5 kg）and acetic anhydride（12 kg）for 4 hgave 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 hto obtain3.3 kg target product with purity of 98.4% and the total yield of 56.5%.