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An improved synthesis of the 5-HT1A receptor agonist Eptapirone free base

  • Wei Peng
  • Jian Chen
  • Hui Liu
  • Xiufang Li
  • Zhiwei Deng
  • Jing Yuan
  • Yizhou Peng
  • Yanjing YangEmail author
  • Shian ZhongEmail author
Original Paper
  • 9 Downloads

Abstract

Eptapirone free base, F11440,4-methyl-2-(4-(4-(pyrimidin-2-yl)piperazin-1-yl)butyl)-1,2,4-triazine-3,5(2H,4H)-dione, represents a potent and selective 5-HT1A receptor agonist with high efficacy and the potential to regulate anxiety disorders. Herein, we report a method to retro-synthesize eptapirone free base. The compound consists of heterocyclic aromatic portion and aliphatic portion, and the synthetic route consisted of a total of nine steps with an overall yield of 8.8% starting from the commercially available materials. The key steps in the synthetic method involved: (1) using sodium hydroxide and ethylene glycol as solvent resulted in a better cyclization and yield (61.6%) of 1,2,4-triazine-3,5(2H,4H)-dione; (2) an acceptable yield (63.1%) of 4-tert-butyl(pyrimidin-2-yl)piperazine-1-carboxylate was obtained under an optimized conditions of using triethylamine as a base, ethanol as a solvent, and a reaction temperature of 50 °C for 16 h with non-metal catalysis and less byproducts; (3) the reaction step of eptapirone could get a better yield (49.6%) with an optimized condition of potassium carbonate as a base, acetonitrile as a solvent, NaI as a catalyst, and a reaction temperature of 50 °C for 12 h by nucleophilic substitution reaction. The main advantages of this route were an acceptable product purity, the commercial availability of all starting materials and the absence of high temperature, high pressure and noble metal catalysts, which could result in more feasible commercial applications.

Keywords

Eptapirone free base Anxiety disorder High purity Commercial applications 

Notes

Acknowledgements

This work was financially supported by the National Science Foundation of China (No. 21576295).

Supplementary material

11696_2019_685_MOESM1_ESM.docx (54.3 mb)
Supplementary material 1 (DOCX 55590 kb)

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Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2019

Authors and Affiliations

  • Wei Peng
    • 1
  • Jian Chen
    • 1
  • Hui Liu
    • 1
  • Xiufang Li
    • 1
  • Zhiwei Deng
    • 1
  • Jing Yuan
    • 1
  • Yizhou Peng
    • 1
  • Yanjing Yang
    • 1
    Email author
  • Shian Zhong
    • 1
    Email author
  1. 1.College of Chemistry and Chemical EngineeringCentral South UniversityChangshaPeople’s Republic of China

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