8-苄氧基-5-(2-溴乙酰基)喹诺酮的合成  

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

作　　者：李树安 谭超兰[1] 张丹丹 黄文静 占垚 张珍明 Li Shu＇an;Tan Chaolan;Zhang Dandan;Huang Wenjing;Zhan Yao;Zhang Zhenming(School of Pharmacy, Huaihai Institute of Technology, Lianyungang 222005, Jiangsu, China;Jiangsu Province Institute of Marine Resources, Huaihai Institute of Technology, Lianyungang 222005, Jiangsu, China)

机构地区：[1]淮海工学院药学院,江苏连云港222005 [2]江苏省海洋资源开发研究院,江苏连云港222005

出　　处：《精细石油化工》2018年第2期40-43,共4页Speciality Petrochemicals

基　　金：国家海洋公益性行业科研专项(201305007);江苏省六大人才高峰资助项目(2013);江苏省连云港市产业前瞻与共性关键技术项目(CG1508;CG1613)

摘　　要：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%.

关 键 词：8-苄氧基-5-(2-溴乙酰基)喹诺酮 抗哮喘药 中间体 千克级合成 

分 类 号：O626[理学—有机化学] TQ460.1[理学—化学]