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Synthesis of new heterocyclic resveratrol analogues in milli- and microreactors: intensification of the Wittig reaction

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Abstract

Resveratrol is a natural bioactive non-flavonoid polyphenol that protects from cardiovascular disease, neurodegenerative diseases and various cancers. Unfortunately, the amounts of resveratrol in plants are low and therefore, chemical synthesis is still the main way to obtain this valuable structure. In this work, Wittig reaction was chosen as the synthetic route for the study on technology influence in batch vs. micro- or milliflow reactors during the production of new resveratrol-like compounds. A series of reactions was carried out by batch synthesis, and intensified in a milli- and a microreactor, changing the reaction conditions to increase the efficiency and productivity of the process. Results were compared based on conversion, yield, productivity and trans/cis ratio. Similar yields and conversions were obtained in all reaction systems, but in much shorter time in the milli- and microscale compared to the batch reactor. On the other hand, higher productivities were obtained in the millireactor and microreactor, making them better systems for the proposed reactions of new heterocyclic resveratrol analogues synthesis.

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References

  1. Belwal T, Nabavi SM, Nabavi SF, Dehpour AR, Shirooie S (2020) Naturally occurring chemicals against Alzheimer’s Disease. Academic, London. https://doi.org/10.1016/C2018-0-03965-1

  2. Anekonda TS (2006) Brain Res Rev 52(2):316–326. https://doi.org/10.1016/j.brainresrev.2006.04.004

    Article  CAS  PubMed  Google Scholar 

  3. Anekonda TS, Wadsworth TL, Sabin R, Frahler K, Harris C, Petriko B, Ralle M, Woltjer R, Quinn JF (2011) J Alzheimers Dis 23:21–35. https://doi.org/10.3233/JAD-2010-101287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Li J, Qiu Z, Zhao GR (2022) Synth Syst Biotechnol 7:718–729. https://doi.org/10.1016/j.synbio.2022.03.001

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lopez-Hernandez J, Paseiro-Losada P, Sanches-Silva AT, Lage-Yusty MA (2007) Eur Food Res Technol 225:789–796. https://doi.org/10.1007/s00217-006-0483-x

    Article  CAS  Google Scholar 

  6. Montsko G, Nikfardjam MSP, Szabo Z, Boddi K, Lorand T, Ohmacht R, Mark L (2008) J Photochem Photobiol A 196:44–50. https://doi.org/10.1039/c2pp25239b

    Article  CAS  Google Scholar 

  7. Silva CG, Monteiro J, Marques RRN, Silva AMT, Martínez C, Canle M, Faria JL (2013) Photochem Photobiol Sci 12:638. https://doi.org/10.1039/c2pp25239b

    Article  CAS  PubMed  Google Scholar 

  8. Cottart CH, Nivet-Antoine C, Laguillier-Morizot C, Beaudeux JL (2010) Mol Nutr Food Res 54:7–16. https://doi.org/10.1002/mnfr.200900437

    Article  CAS  PubMed  Google Scholar 

  9. Klaus WL, Shiming L (2018) BioFactors 44:83–90. https://doi.org/10.1002/biof.1396

    Article  CAS  Google Scholar 

  10. Roupe KA, Remsberg CM, Yáñez JA, Davies NM (2006) Curr Clin Pharmacol 1:81–101. https://doi.org/10.2174/157488406775268246

    Article  CAS  PubMed  Google Scholar 

  11. Lin HS, Yue BD, Ho PC (2009) Biomed Chromatogr 23:1308–1315. https://doi.org/10.1002/bmc.1254

    Article  CAS  PubMed  Google Scholar 

  12. McCormack D, McFadden D (2013) Oxid Med Cell Longev 2013:575482. https://doi.org/10.1155/2013/575482

  13. Bertelli AAE, Giovanni L, Stradi R, Bertelli A, Tillement JP (1996) Int J Tissue React 18:67–71. https://doi.org/10.4172/2155-9880.1000216

    Article  CAS  PubMed  Google Scholar 

  14. Burns J, Yokota T, Ashihara H, Lean MEJ, Crozier A (2002) J Agric Food Chem 50:3337–3340. https://doi.org/10.1021/jf0112973

    Article  CAS  PubMed  Google Scholar 

  15. Ratola N, Faria JL, Alves A (2004) Food Technol Biotechnol 42:125–130

    CAS  Google Scholar 

  16. Šinkovec E, Krajnc M (2011) Org Process Res Dev 15:817–823. https://doi.org/10.1021/op200061j

    Article  CAS  Google Scholar 

  17. Okamoto H, Takahashi H, Takane T, Nishiyama Y, Kakiuchi K, Gohda S, Yamaji M (2017) Synthesis 49:2949–2957. https://doi.org/10.1055/s-0036-1588775

    Article  CAS  Google Scholar 

  18. Gerardy R, Emmanuel N, Toupy T, Kassin V-E, Tshibalzona NN, Schmitz M, Monbaliu J-CM (2018) Eur J Org Chem 2018:2301–2351. https://doi.org/10.1002/ejoc.201800149

  19. Baumann M, Moody TS, Smyth M, Wharry S (2020) Org Process Res Dev 24:1802–1813. https://doi.org/10.1021/acs.oprd.9b00524

  20. Bloemendal VRLJ, Janssen MACH, van Hest JCM, Rutjes FPJT (2020) React Chem Eng 5:1186–1197. https://doi.org/10.1039/D0RE00087F

  21. Plutschack MB, Pieber B, Gilmore K, Seeberger PH (2017) Chem Rev 117:11796–11893. https://doi.org/10.1021/asc.chemrev.7b00183

    Article  CAS  PubMed  Google Scholar 

  22. Wegner J, Ceylan S, Kirschning A (2011) Chem Commun 47:4583–4592. https://doi.org/10.1039/C0CC05060A

    Article  CAS  Google Scholar 

  23. Geyer K, Codee JDC, Seeberger PH (2006) Chem Eur J 12:8434. https://doi.org/10.1002/chem.200600596

    Article  CAS  PubMed  Google Scholar 

  24. Mlakić M, Šalić A, Bačić M, Zelić B, Šagud I, Horváth O, Škorić I (2021) Catalysts 11:395. https://doi.org/10.3390/catal11030395

    Article  CAS  Google Scholar 

  25. Horspool WM, Song PS (1995) CRC Handbook of Organic Photochemistry and Photobiology, Boca Raton

  26. Griesbeck A, Oelgemӧller M, Ghetti F (2012) CRC Handbook of Organic Photochemistry and Photobiology, Boca Raton

  27. Gingerich SB, Jennings PW (1983) J Org Chem 48:2606. https://doi.org/10.1021/jo00163a039

    Article  CAS  Google Scholar 

  28. Gülçin I (2010) Innov Food Sci Emerg Technol 11:210–218. https://doi.org/10.1016/j.ifset.2009.07.002

    Article  CAS  Google Scholar 

  29. Fauconneau B, Waffo-Teguo P, Huguet F, Barrier L, Decendit A, Merillon JM (1997) Life Sci 61:2103–2110. https://doi.org/10.1016/s0024-3205(97)00883-7

    Article  CAS  PubMed  Google Scholar 

  30. Orallo F (2006) Curr Med Chem 13:87–98

    Article  CAS  PubMed  Google Scholar 

  31. Francioso A, Mastromarino P, Masci A, d’Erme M, Mosca L (2014) Med Chem 10:237–245. https://doi.org/10.2174/15734064113096660053

    Article  CAS  PubMed  Google Scholar 

  32. Kulkarni SS, Canto C (2015) Biochim Biophys Acta 1852:1114–1123. https://doi.org/10.1016/j.bbadis.2014.10.005

    Article  CAS  PubMed  Google Scholar 

  33. Brand-Williams W, Cuvelier ME, Berset C (1995) LWT - Food Sci Technol 28:25–30. https://doi.org/10.1016/S0023-6438(95)80008-5

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the University of Zagreb short term scientific support for 2021 under the title Synthesis and photochemistry of various new heterostilbene derivatives. We acknowledge the NMR Centre at Ruđer Bošković Institute and the competent help by Željko Marinić for recording all the NMR spectra.

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Author notes

  1. Milena Mlakić and Lucija Rajič contributed equally.

Authors and Affiliations

  1. Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10 000, Zagreb, Croatia

    Milena Mlakić, Lucija Rajič & Irena Škorić

  2. Pliva R&D, Teva Pharmaceutical Industries Ltd, Prilaz baruna Filipovića 29, HR-10 000, Zagreb, Croatia

    Lucija Rajič, Anabela Ljubić, Vitomir Vušak & Ivana Šagud

  3. Department of Reaction Engineering and Catalysis, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10 000, Zagreb, Croatia

    Bruno Zelić, Martin Gojun & Anita Šalić

  4. Department of Packaging, Recycling and Environmental Protection, University North, Trg dr. Žarka Dolinara 1, HR-48 000, Koprivnica, Croatia

    Bruno Zelić

  5. Department of Chemistry, Faculty of Science and Education, University of Mostar, Matice hrvatske bb, 88 000, Mostar, Bosnia and Herzegovina

    Ilijana Odak & Ivona Čule

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  1. Milena Mlakić
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Correspondence to Anita Šalić or Irena Škorić.

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Mlakić, M., Rajič, L., Ljubić, A. et al. Synthesis of new heterocyclic resveratrol analogues in milli- and microreactors: intensification of the Wittig reaction. J Flow Chem 12, 429–440 (2022). https://doi.org/10.1007/s41981-022-00239-9

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