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Practical synthesis of tetrahydrofolate by highly efficient catalytic hydrogenation in continuous flow

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Abstract

Hundred-gram scale of highly selective catalytic hydrogenation of folic acid has been developed, which is adopted continuous-flow technology with Raney Ni as a catalyst. Through optimization of the reaction condition, a high conversion rate of folic acid (> 99%) and a high selectivity (99%) of tetrahydrofolate have been achieved. Additionally, a high-purity calcium-6S-5-methyltetrahydrofolate (6S-5-MTHF.Ca) has been synthesized from tetrahydrofolate obtained by continuous hydrogenation through chiral resolution, methylation, salting and recrystallization (purity: 99.5%, de: 97.6%). Compared to known methods, this method provides a feasible procedure using simple, inexpensive, and readily available reagents, making it a step-economical and cost-effective alternative strategy for production of tetrahydrofolate and its active derivatives.

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Acknowledgements

We gratefully acknowledge the supports of Shenzhen Science and Technology Research Fund (No. JSGG20201103153807021; KCXFZ20230731094904009; GXWD20220811173736002), Natural Science Foundation of Guangdong Province (No.2021A1515110366), National Natural Science Foundation of China (No. 22302048; No. 82204231) and Shenzhen Key Laboratory of Advanced Functional Carbon Materials Research on this work.

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Author notes

  1. Heng Pang and Junrong Huang contributed equally to this work.

Authors and Affiliations

  1. School of Science, Harbin Institute of Technology (Shenzhen), Taoyuan Street, Nanshan District, Shenzhen, 518055, China

    Heng Pang, Junrong Huang, Juntao Wang, Gang Wang, Ana Xu, Hengzhi You & Fen-Er Chen

  2. Green Pharmaceutical Engineering Research Center, Harbin Institute of Technology (Shenzhen), Taoyuan Street, Nanshan District, Shenzhen, 518055, China

    Junrong Huang, Hengzhi You & Fen-Er Chen

  3. Shenzhen Key Laboratory of Flexible Printed Electronics Technology, also School of Materials Science and Engineering, Harbin Institute of Technology (Shenzhen), Taoyuan Street, Nanshan District, Shenzhen, 518055, China

    Lei Luo & Qunhui Yuan

  4. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai, 200433, China

    Fen-Er Chen

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  1. Heng Pang
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The Supporting Information is available free of charge at Experimental procedures for other compounds and copies of 1H NMR for all compounds, HPLC of 6S-5-methyltetrahydrofolate and calcium-6S-5-methyltetrahydrofolate, and the selectivity tetrahydrofolate and dihydrofolate.

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Pang, H., Huang, J., Wang, J. et al. Practical synthesis of tetrahydrofolate by highly efficient catalytic hydrogenation in continuous flow. J Flow Chem (2024). https://doi.org/10.1007/s41981-024-00310-7

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