8-氯-5,6-二氢-11H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-酮的新合成方法  

Novel Synthesis of 8-Chloro-5,6-dihydro-11Hbenzo[5,6]cyclohepten[1,2-b]pyridine-11-one

作　　者：王宏博[1] 张柯华[1] 周后元[1] 

机构地区：[1]中国医药工业研究总院上海医药工业研究院创新药物与制药工艺国家重点实验室,上海201203

出　　处：《中国医药工业杂志》2016年第7期843-847,共5页Chinese Journal of Pharmaceuticals

基　　金：中国医药集团新产品开发基金(2012YS01)

摘　　要：8-氯-5,6-二氢-11H-苯并[5,6]环庚烷并[1,2-b]吡啶-11-酮(1)是氯雷他定的重要中间体。本研究以间二氯苯和环氧乙烷为起始原料,经格氏反应和溴化得2-(3-氯苯基)乙基溴(3)、先后与丙二酸二乙酯和2-(2-溴乙基)-1,3-二氧戊环(5)发生亲核取代反应得到2-[2-(3-氯苯基)乙基]-2-[2-(1,3-二氧戊环-2-基)乙基]丙二酸二乙酯(6),6经水解脱羧得2-[2-(1,3-二氧戊环-2-基)乙基]-4-(3-氯苯基)丁酸(7),7与甲基锂反应得到3-[2-(1,3-二氧戊环-2-基)-乙基]-5-(3-氯苯基)戊-2-酮(8),8与盐酸羟胺反应、环合得到3-[2-(3-氯苯基)乙基]-2-甲基吡啶(9),9经二氧化硒氧化得到3-[2-(3-氯苯基)乙基]-2-吡啶甲酸(10),10经分子内傅-克环合反应制得1。新路线未见文献报道,具产业化前景。A novel synthetic route of 8-chloro-5,6-dihydro- 11H-benzo [5,6] cyclohepten [ 1,2-b] pyridine- 11-one （1）, an important intermediate of loratadine was described. Diethyl 2- [2- （3-chlorophenyl） ethyl]-2- [2- （1,3- dioxolan-2-yl） ethyl] malonate （6） was synthesized from 1,3-diehlorobenzene and epoxyethane via Grignard reaction and bromination, followed by the nucleophilic substitutions successively with diethyl malonate and 2-（2-bromoethyl）- 1,3-dioxolane. Then compound 6 was converted to 2-[2-（1,3-dioxolan-2-yl）ethyl]-4-（3-chlorophenyl） butanic acid （7） by hydrolysis and decarboxylation. 3-[2-（3-Chlorophenyl）ethyl]-2-methylpyridine （9） was obtained by methylation of 7 with lithium methide, followed by condensation with hydroxylamine hydrochloride and eyclization. Finally, 1 was prepared by oxidation of 9 with SeO2 and Friedel-Craft eyelization. The new route was unprecedentedly reported and showed a potency for manufacture in industrial scale.

关 键 词：氯雷他定 中间体 8-氯-5 6-二氢-11H-苯并[5 6]环庚烷并[1 2-b]吡啶-11-酮 合成方法 

分 类 号：R914.5[医药卫生—药物化学]