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

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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.

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Acknowledgements

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

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  1. Wei Peng and Jian Chen contributed equally to this work.

Authors and Affiliations

  1. College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, Hunan, People’s Republic of China

    Wei Peng, Jian Chen, Hui Liu, Xiufang Li, Zhiwei Deng, Jing Yuan, Yizhou Peng, Yanjing Yang & Shian Zhong

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  1. Wei Peng
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  2. Jian Chen
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  3. Hui Liu
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  7. Yizhou Peng
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Correspondence to Yanjing Yang or Shian Zhong.

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Peng, W., Chen, J., Liu, H. et al. An improved synthesis of the 5-HT1A receptor agonist Eptapirone free base. Chem. Pap. 73, 1321–1331 (2019). https://doi.org/10.1007/s11696-019-00685-1

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