富马酸卢帕他定的合成  

Synthesis of Rupatadine Fumarate

作　　者：韩英昂 滕大为[1] 龙中柱 蔡畅 蔡水洪 HAN Ying'ang;TENG Dawei;LONG Zhongzhu;CAI Chang;CAI Shuihong(College of Chemistry Engineering,Qingdao University of Science and Technology,Qingdao 266042;Qidong Dongyue Pharmaceutical Co.,Ltd.,Nantong 226251)

机构地区：[1]青岛科技大学化工学院,山东青岛266042 [2]启东东岳药业有限公司,江苏南通226251

出　　处：《中国医药工业杂志》2024年第1期48-52,共5页Chinese Journal of Pharmaceuticals

摘　　要：以烟酸乙酯(4)和间氯苯乙腈(5)为原料,经克莱森缩合、酸水解脱羧反应,得2-(3-氯苯基)-1-(吡啶-3-基)-1-乙酮(6)。6与水合肼经黄鸣龙还原反应,得3-(3-氯苯乙基)吡啶(7),7在钨酸钠催化下经过氧化氢氧化后,再经Reissert-Henze吡啶氰基化反应,得3-(3-氯苯乙基)-2-氰基吡啶(8),水解后闭环得8-氯-10,11-二氢-4-氮杂-5H-二苯并[a,d]-5-环庚酮(3),再与1-[(5-甲基吡啶-3-基)甲基]-4-哌啶酮(12)经McMurry偶联反应,并与富马酸成盐,得到富马酸卢帕他定(1),总收率28.0%(以4计),纯度99.7%。该路线避免格氏试剂的使用,且环合反应使用“一锅法”,操作方便,适合工业化生产。Starting with ethyl nicotinate(4)and 3-chlorobenzyl cyanide(5)as raw materials,through the Claisen condensation,acid hydrolysis and decarboxylation,2-(3-chlorophenyl)-1-(pyridin-3-yl)-1-ethanone(6)was obtained.Compound 3-(3-chlorophenethyl)pyridine(7)was generated by Huang Minglong reduction with hydrazine hydrate.After sodium tungstate catalysis and subsequent oxidation with hydrogen peroxide,followed by the Reissert-Henze pyridine cyanation reaction,3-(3-chlorophenethyl)-2-cyanopyridine(8)was obtained.After hydrolysis and ring closure,8-chloro-10,11-dihydro-4-aza-5H-dibenzo[a,d]cyclohept-5-one(3)was obtained.Then compound 3 reacted with 1-[(5-methylpyridin-3-yl)methyl]-4-piperidone(12)by McMurry coupling reaction and salted with fumaric acid,resulting in rupatadine fumarate(1).The overall yield was 28.0%(based on 4),with a purity of 99.7%.This synthetic route avoids the use of Grignard reagents.Additionally,the cyclization employs a one-pot"method,providing convenient operation and suitability for industrial production.

关 键 词：富马酸卢帕他定 抗组胺药 合成 

分 类 号：R976[医药卫生—药品]