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A multi-step continuous flow synthesis of pomalidomide

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Abstract

The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide are widely used to treat multiple myeloma. The permanent need of IMiDs analogues in clinical screening and practice has created the demand to find a reliable and robust method for their preparation. To reach this goal, the use of flow chemistry is quite appealing, allowing a safe operation, an excellent reproducibility and an efficient process. Herein, we describe a continuous 3–4 step flow approach for the synthesis of the pomalidomide (38–47% overall yield) and a few analogues.

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References

  1. Lenz W (1988) A short history of thalidomide Embryopathy. Teratology 38:203–215

    Article  CAS  PubMed  Google Scholar 

  2. Eriksson T, Björkman S, Höglund P (2001) Clinical pharmacology of thalidomide. Eur J Clin Pharmacol 57:365–376

    Article  CAS  PubMed  Google Scholar 

  3. Mcbride WG (1961) Thalidomide and congenital abnormalities. The Lancet 278:1358

    Article  Google Scholar 

  4. Speirs AL (1962) Thalidomide and congenital abnormalities. The Lancet 279:303–305

    Article  Google Scholar 

  5. Wnendt S, Finkam M, Winter W, Ossig J, Raabe G, Zwingenberger K (1996) Enantioselective inhibition of TNF-α release by thalidomide and thalidomide-analogues. Chirality 8:390–396

    Article  CAS  PubMed  Google Scholar 

  6. Eriksson T, Bjöurkman S, Roth B, Fyge Å, Höuglund P (1995) Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality 7:44–52

    Article  CAS  PubMed  Google Scholar 

  7. Muller GW, Chen R, Huang S-Y, Corral LG, Wong LM, Patterson RT, Chen Y, Kaplan G, Stirling DI (1999) Amino-substituted thalidomide analogs: potent inhibitors of TNF-α production. Bioorg Med Chem Lett 9:1625–1630

    Article  CAS  PubMed  Google Scholar 

  8. Wiles C, Watts P (2012) Continuous flow reactors: a perspective. Green Chem 14:38–54

    Article  CAS  Google Scholar 

  9. Malet-Sanz L, Susanne F (2012) Continuous flow synthesis. A pharma perspective. J Med Chem 55:4062–4098. https://doi.org/10.1021/jm2006029

    Article  CAS  PubMed  Google Scholar 

  10. De Angelis S, Celestini P, Purgatorio R, Degennaro L, Rebuzzini G, Luisi R, Carlucci C (2019) Development of a continuous flow synthesis of propranolol: tackling a competitive side reaction. J Flow Chem 9(4):231–236. https://doi.org/10.1007/s41981-019-00047-8

    Article  CAS  Google Scholar 

  11. Bloemendal VRLJ, Janssen MACH, van Hest JCM, Rutjes FPJT (2020) Continuous one-flow multi-step synthesis of active pharmaceutical ingredients. React Chem Eng. https://doi.org/10.1039/D0RE00087F

  12. Baumann M, Moody TS, Smyth M, Wharry S (2020) A perspective on continuous flow chemistry in the pharmaceutical industry. Org Process Res Dev. https://doi.org/10.1021/acs.oprd.9b00524

  13. Mougeot R, Jubault P, Legros J, Poisson T (2021) Continuous flow synthesis of propofol. Molecules 26(23):7183. https://doi.org/10.3390/molecules26237183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ivanova M, Legros J, Poisson T, Jubault P (2021) Continuous flow synthesis of celecoxib from 2-Bromo-3,3,3-Trifluoropropene. J Flow Chem. https://doi.org/10.1007/s41981-021-00205-x

  15. Heim C, Pliatsika D, Mousavizadeh F, Bär K, Hernandez Alvarez B, Giannis A, Hartmann MD (2019) De-novo design of cereblon (CRBN) effectors guided by natural hydrolysis products of thalidomide derivatives. J Med Chem:6615–6629

  16. Burslem GM, Ottis P, Jaime-Figueroa S, Morgan A, Cromm PM, Toure M, Crews CM (2018) Efficient synthesis of immunomodulatory drug analogues enables exploration of structure–degradation relationships. ChemMedChem 13:1508–1512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fox DJ, Reckless J, Warren SG, Grainger DJ (2002) Design, synthesis, and preliminary pharmacological evaluation of N-Acyl-3-Aminoglutarimides as broad-Spectrum chemokine inhibitors in vitro and anti-inflammatory agents in vivo. J Med Chem 45:360–370

    Article  CAS  PubMed  Google Scholar 

  18. Fujimoto H, Noguchi T, Kobayashi H, Miyachi H, Hashimoto Y (2006) Effects of immunomodulatory derivatives of thalidomide (IMiDs) and their analogs on cell-differentiation, cyclooxygenase activity and angiogenesis. Chem Pharm Bull (Tokyo) 54:855–860

    Article  CAS  PubMed  Google Scholar 

  19. Niwayama S, Turk BE, Liu JO (1996) Potent inhibition of tumor necrosis factor-α production by Tetrafluorothalidomide and Tetrafluorophthalimides. J Med Chem 39:3044–3045

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work is part of the API program supported by the European Union through the operational program FEDER/FSE 2014–2020 (no. 20E04976) and FNADT-DRACCARE program 2020–2023 ((N)15179). This work has been partially supported by University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Development Fund (ERDF), Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM), and by Région Normandie. T.P. thanks the Institut Universitaire de France (IUF) for support.

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Authors and Affiliations

  1. Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA, 76000, Rouen, France

    Maria Ivanova, Julien Legros, Thomas Poisson & Philippe Jubault

  2. Institut Universitaire de France, Paris, France

    Thomas Poisson

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  1. Maria Ivanova
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  2. Julien Legros
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  3. Thomas Poisson
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  4. Philippe Jubault
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Correspondence to Julien Legros, Thomas Poisson or Philippe Jubault.

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Ivanova, M., Legros, J., Poisson, T. et al. A multi-step continuous flow synthesis of pomalidomide. J Flow Chem 12, 383–387 (2022). https://doi.org/10.1007/s41981-022-00223-3

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