有机化学 ›› 2012, Vol. 32 ›› Issue (12): 2368-2372.DOI: 10.6023/cjoc201207023 上一篇    下一篇

研究简报

1,2,6,7-四氢-8H-茚并[5,4-b]呋喃-8-酮的合成新方法

黄志雄a, 吴成龙a, 桑志培a, 邓勇a,b   

  1. a 四川大学华西药学院 药物化学系 成都 610041;
    b 四川大学华西药学院 靶向药物及释药系统教育部重点实验室 成都 610041
  • 收稿日期:2012-07-18 修回日期:2012-08-08 发布日期:2012-08-21
  • 通讯作者: 邓勇 E-mail:dengyongy@sohu.com
  • 基金资助:
    国家自然科学基金(Nos. 20672077, 20872099)资助项目.

An Improved Synthesis of 1,2,6,7-Tetrahydro-8H-indeno[5,4-b]furan-8-one

Huang Zhixionga, Wu Chenglonga, Shang Zhipeia, Deng Yonga,b   

  1. a Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 61004;
    b Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041
  • Received:2012-07-18 Revised:2012-08-08 Published:2012-08-21
  • Supported by:
    Project supported by the National Natural Science Foundation of China (Nos. 20672077, 20872099).

发展了一条1,2,6,7-四氢-8H-茚并[5,4-b]呋喃-8-酮的新合成方法, 以价廉、易得的对溴苯酚为原料, 在无水碳酸钾作用下与2-溴乙醛缩二乙醇缩合后用多聚磷酸(PPA)环合得5-溴苯并呋喃, 该中间体与丙烯酸甲酯在Pd(OAc)2催化下, 经Heck偶合反应得3-(苯并呋喃-5-基)丙酸甲酯, 在氢氧化钠水溶液中经Raney Ni催化氢化和水解一锅反应得3-(2,3-二氢苯并呋喃-5-基)丙酸, 再经二溴代、Friedel-Crafts酰化反应和氢解脱溴, 得1,2,6,7-四氢-8H-茚并[5,4-b]呋喃- 8-酮, 7步反应总收率49.9%. 该方法原料易得、反应条件温和、操作简便、产物分离纯化容易, 收率良好, 适合大规模制备1,2,6,7-四氢-8H-茚并[5,4-b]呋喃-8-酮.

关键词: 3-(2,3-二氢苯并呋喃-5-基)丙酸, 1,2,6,7-四氢-8H-茚并[5,4-b]呋喃-8-酮, 雷美替胺, 褪黑素受体激动剂, 中间体, 合成

A novel process for synthesis of 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, a key intermediate for preparation of ramelteon, a MT1 and MT2 melatonin receptor selective agonist, was developed. The key intermediate 3-(2,3-dihydrobenzofuran-5-yl)propanoic acid was synthesized by condensation of p-bromophenol with bromoacetaldehyde diethyl acetal in the presence of K2CO3 and Friedel-Crafts reaction to give 5-bromobenzofuran, which was subsequently subjected to Heck coupling reaction with methyl acrylate in the presence of palladium acetate, then catalytic hydrogenation and hydrolysis in one pot reaction. Subsequently, 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one was synthesized from 3-(2,3-dihydrobenzo- furan-5-yl)propanoic acid through bromination, Friedel-Crafts acylation and catalytic hydrogenolysis debromination. The overall yield was about 49.9%. The structures of intermediates and final product were determined by 1H NMR, 13C NMR and HRMS techniques. This method has the advantages of easily available starting materials, simply conducted procedures, relatively high yield and easy purification, and is more suitable for scale-up production.

Key words: 3-(2,3-dihydrobenzofuran-5-yl)propanoic acid, 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, ramelteom, melatonin receptor agonist, intermediate, synthesis