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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。
Chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-one (1) is an important intermediate for loratadine. In this study, m-dichlorobenzene and ethylene oxide as starting materials, the Grignard reaction and bromination of 2- (3-chlorophenyl) ethyl bromide (3), followed by diethyl malonate and Nucleophilic substitution reaction of 2- (2-bromoethyl) -1,3-dioxolane (5) gives 2- [2- (3- chlorophenyl) ethyl] -2- [2- Dioxolan-2-yl) ethyl] propanedioic acid diethyl ester (6), 6 is hydrolytically decarboxylated to give 2- [2- (7) is reacted with methyllithium to give 3- [2- (1,3-dioxolan-2-yl) -ethyl] -5 (8) is reacted with hydroxylamine hydrochloride to give 3- [2- (3-chlorophenyl) ethyl] -2-methylpyridine , 9 is oxidized by selenium dioxide to give 3- [2- (3-chlorophenyl) ethyl] -2-pyridinecarboxylic acid (10), 10 by intramolecular Friedel-Crafts reaction. No new route reported in the literature, with industrialization prospects.