Synthesis of [(3S,5R)-3-Hydroxy-5-methylpiperidin-1-yl](2-methylpyridin-3-yl)methanone

Abstract

There remain challenges for effectively synthesizing heterocycles containing both piperidine and pyridine rings, mainly due to the inefficient synthetic process mostly requiring long reaction times. This paper reports a simple and efficient method for the synthesis of [(3S,5R)-3-hydroxy-5-methylpiperidin-1-yl](2-methylpyridin-3-yl)methanone through six steps starting from D-pyroglutaminol. The key step involved the introduction of a chiral methyl group by alkylation of lithiated (3S,7aR)-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one with methyl iodide, followed by reduction and rearrangement to generate a benzyl-protected piperidine intermediate. After deprotection and amide formation, the final product was obtained with an overall yield of 32% in a total time of ~80 h). With readily available and inexpensive starting material through an operationally simple process, the method holds potential for applications in organic synthesis of other piperidine- and pyridine-containing heterocycles.

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ACKNOWLEDGMENTS

The authors gratefully acknowledge support from the Key Research and Development Program of Shaanxi Province (2018ZDXM-GY-159 and 2020ZDLSF03-07), the Graduate Innovation and Practice Skills Foundation of Xi’an Shiyou University (YCS20211019), and Collaborative Innovation Center for Unconventional Oil and Gas Exploration and Development (17JF033).

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Correspondence to Qun-Zheng Zhang or Xun-Li Zhang.

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Zhang, QZ., Li, ZY., Zhang, L. et al. Synthesis of [(3S,5R)-3-Hydroxy-5-methylpiperidin-1-yl](2-methylpyridin-3-yl)methanone. Russ J Org Chem 56, 2201–2206 (2020). https://doi.org/10.1134/S1070428020120246

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Keywords:

  • organic synthesis
  • piperidine- and pyridine-containing heterocycle
  • [(3S,5R)-3-hydroxy-5-methylpiperidin-1-yl](2-methylpyridin-3-yl)methanone