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Synthesis of a Key Intermediate towards the Preparation of Efavirenz Using n-Butyllithium

Abstract

A key reaction in one of the routes to efavirenz, an essential drug used in the treatment of acquired immunodeficiency syndrome (AIDS), is the ortho-lithiation reaction of N-Boc-4-chloroaniline. For the first time, we demonstrate that the reaction may be conducted using n-BuLi and show that the reaction may be performed in a flow reactor with a significantly higher yield (70%) compared to batch (28%) when using n-BuLi for the ortho-metalation reaction at a temperature of −45 °C. In addition, it was shown that tetramethylethylenediamine (TMEDA) did not need to be added to the flow reaction, which simplified the purification procedure.

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References

  1. Clayden, J. Organolithiums: Selectivity for Synthesis; Elsevier: Oxford, 2002.

    Google Scholar 

  2. Schlosser, M. Organometallics in Synthesis Third Manual; Wiley: Hoboken, 2013.

    Book  Google Scholar 

  3. Reich, H. J. J. Org. Chem. 2012, 77, 5471–5491.

    CAS  Article  Google Scholar 

  4. Reich, H. J. Chem. Rev 2013, 113, 7130–7178.

    CAS  Article  Google Scholar 

  5. Capriati, V.; Perna, F. M.; Salomone, A. Dalton Trans. 2014, 43, 14204–14210.

    CAS  Article  Google Scholar 

  6. Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992, 57, 6833–6837.

    CAS  Article  Google Scholar 

  7. Siddaiah, V.; Mahaboob Basha, G.; Srinuvasa, R.; Yessayya, V. Green Chem. Lett. Rev. 2012, 5, 337–342.

    CAS  Article  Google Scholar 

  8. Desponds, M.; Lehmann, O.; Moret, R.; Rauchschwalbe, E. Tetrahedron 1993, 49, 10175–10203.

    Article  Google Scholar 

  9. Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 311–314.

    Google Scholar 

  10. Kessar, S. V.; Singh, P. Chem. Rev 1997, 97, 721–738.

    CAS  Article  Google Scholar 

  11. Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, L. Adv Heterocycl. Chem. 1991, 52, 187–304.

    CAS  Article  Google Scholar 

  12. Undheim, K.; Benneche, T. Act. Chem. Scand. 1993, 47, 102–121.

    CAS  Article  Google Scholar 

  13. Nagaki, A.; Ichinari, D.; Yoshida, J.-I. J. Am. Chem. Soc. 2014, 136, 12245–12248.

    CAS  Article  Google Scholar 

  14. Yoshida, J.-I. Chem. Rev 2010, 10, 332–341.

    CAS  Google Scholar 

  15. Usutani, H.; Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2007, 129, 3046–3047.

    CAS  Article  Google Scholar 

  16. Murray, P. R. D.; Browne, D. L.; Pastre, J. C.; Butters, C.; Guthrie, D.; Ley, S. V. Org. Process Res. Dev 2013, 17, 1192–1208.

    CAS  Article  Google Scholar 

  17. Correia, C. A.; Gilmore, K.; McQuade, D. T.; Seeberger, P. H. Angew. Chem. Int. Ed. 2015, 54, 4945–4948.

    CAS  Article  Google Scholar 

  18. Kensen, K. J. AIChE Journal 2017, 63, 858–869.

    Article  Google Scholar 

  19. Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem., Int. Ed. 2015, 54, 6688–6729.

    CAS  Article  Google Scholar 

  20. Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 4798–4801.

    CAS  Article  Google Scholar 

  21. Radesca, L. A.; Lo, Y. S.; Moore, J. R.; Pierce, M. E. Synth. Comm. 1997, 27, 4383–4384.

    Article  Google Scholar 

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Correspondence to Paul Watts.

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Chada, S., Mandala, D. & Watts, P. Synthesis of a Key Intermediate towards the Preparation of Efavirenz Using n-Butyllithium. J Flow Chem 7, 37–40 (2017). https://doi.org/10.1556/1846.2017.00008

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  • DOI: https://doi.org/10.1556/1846.2017.00008

Keyword

  • Efavirenz
  • n-butyllithium
  • continuous flow
  • trifluoroacetylation