Chin. J. Org. Chem. ›› 2012, Vol. 32 ›› Issue (12): 2368-2372.DOI: 10.6023/cjoc201207023 Previous Articles     Next Articles



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
  • 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).

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