1- 溴-7- 甲氧基萘先和镁屑反应制备格氏试剂，再和环氧乙烷经格氏反应得7- 甲氧基-1- 萘乙醇，和苯磺酰氯经酯化反应得(7- 甲氧基-1- 萘乙基) 苯磺酸酯，然后与邻苯二甲酰亚胺钾盐在DMF 中反应得N-[2-(7- 甲氧基-1- 萘基) 乙基]- 邻苯二甲酰亚胺。然后在水合肼中水解得2-(7- 甲氧基-1- 萘基) 乙胺盐酸盐，最后和乙酸酐反应得阿戈美拉汀，总收率 43.5％。本工艺路线短，操作简便，无需高温高压等特殊条件，已应用于放大生产。本工艺已于2008 年申请专利并获得授权。
Abstract
A new synthetic route for agomelatine was developed. 1-Bromo-7-methoxynaphthalene reacted with magnesium to prepare Grignard reagent, and then ethylene oxide was subjected to a Grignard reaction to afford 7-methoxy-1-naphthylethanol, which was subjected to a esterification with benzenesulfonyl chloride to give (7-methoxy- 1-naphthalenyl)benzenesulfonate. Then the latter reacted with potassium phthalimide in DMF to prepare N-[2-(7- methoxy-1-naphthyl)ethyl]phthalimide. After a hydrolysis in hydrazine hydrate and a acetylation with acetic anhydride, the target compound was obtained with a total yield of 43.5％. The process has the advantages of short route, simple operation and no need of special conditions such as high temperature and high pressure, and it has been applied in largescale production. The process has been patented and authorized in 2008.
关键词
阿戈美拉汀 /
抗抑郁 /
格氏反应 /
工艺改进
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Key words
agomelatine /
antidepressant /
Grignard reaction /
process improvement
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参考文献
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