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Journal of Flow Chemistry

, Volume 9, Issue 1, pp 13–17 | Cite as

Diastereoselective synthesis of cis-N-Boc-4-aminocyclohexanol with reductive ring opening method using continuous flow

  • Balázs Szabó
  • Bálint Tamás
  • Ferenc FaiglEmail author
  • János Éles
  • István Greiner
Communications
  • 11 Downloads

Abstract

The N-protected cis-4-aminocyclohexanol derivatives have proven to be valuable intermediates in the syntheses of active pharmaceutical ingredients (APIs). A novel continuous flow process for hydrogenation of N-protected 2-oxa-3-azabicyclo[2.2.2]oct-5-ene cycloadducts to the corresponding cis-4-aminocyclohexanols has been reported using H-Cube Pro. A > 99% selectivity towards the desired product was obtained using Raney nickel catalyst cartridge. Under carefully selected hydrogenation parameters the reduction could stop at the also valuable 2-oxa-3-azabicyclo[2.2.2] octane intermediate, with a selectivity of >99%. The N-protected 2-oxa-3-azabicyclo[2.2.2]oct-5-ene producing nitroso hetero-Diels–Alder cycloaddition was also accomplished in a flow system using an Omnifit column packed with MnO2. The two flow reactions were successfully merged in a system, thus the product was obtained in a multistep flow synthesis without any isolation or purification steps. Compared with the previously reported batch processes, the present multistep procedure facilitates an efficient cis selective preparation of numerous synthetically valuable 4-aminocyclohexanol derivatives.

Keywords

Flow chemistry Reductive ring opening Diastereomer selective Nitroso-Diels-Alder cycloaddition 

Notes

Acknowledgements

B.Sz. thanks Gedeon Richter Talentum and the Pro Progressio Foundations for financial support. This work was performed in the frame of FIEK_16-1-2016-0007 project, implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the FIEK_16 funding scheme.

Supplementary material

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41981_2018_28_MOESM2_ESM.sk2 (6 kb)
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References

  1. 1.
    Mak XY, Laurino P, Seeberger PH (2009). Beilstein J Org Chem 5:19CrossRefGoogle Scholar
  2. 2.
    Atodiresei J, Vila C, Rueping M (2015). ACS Catal 5:1972–1985CrossRefGoogle Scholar
  3. 3.
    Zhao D, Ding K (2013). ACS Catal 3:928–944CrossRefGoogle Scholar
  4. 4.
    Dirikolu L, Chakkath T, Fan T, Mente NR (2009). J Anal Toxicol 33:595–603CrossRefGoogle Scholar
  5. 5.
    Ackermann J, Aebi J, Blum D, Chucholowski A, Dehmlow H, Maerki HP, Morand O, Trussardi R, Von der Mark E, Wallbaum S, Weller T (2002) Novel aminocyclohexane derivatives. WO 200214267, Febr 21, 2002; (2002). Chem Abstr 136:199955Google Scholar
  6. 6.
    Li YL, Yao W (2007) Modulators of 11-β-hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same. WO 2007101270, Sept 07, 2007; (2007). Chem Abstr 147:343966Google Scholar
  7. 7.
    Himmelsbach F, Jung B (2008) Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for productions of same. WO 2008055854, May 15, 2008; (2008). Chem Abstr 148:538297Google Scholar
  8. 8.
    Ackermann J, Aebi J, Dehmlow H, Maerki HP, Morand O (2003) Heteroaryl-substituted aminocyclohexane derivatives. WO 2003053933, Jul 03, 2003; (2003). Chem Abstr 139:8504Google Scholar
  9. 9.
    Bruhn JA, Pasteris RJ (2008) Fungicidal mixtures. WO 2008091594, Jul 31, 2008; (2008). Chem Abstr 149:193346Google Scholar
  10. 10.
    Asedegbega NE (2008). Carbon 46:1046–1052CrossRefGoogle Scholar
  11. 11.
    Li H (2017). ACS Catal 7:4446–4450CrossRefGoogle Scholar
  12. 12.
    Latli B (2010). J Label Compd Radiopharm 53:15–23Google Scholar
  13. 13.
    Hutchins RO (1983). J Org Chem 48:3412–3422CrossRefGoogle Scholar
  14. 14.
    Harrison J (1994). Tetrahedron Lett 35:5201–5204CrossRefGoogle Scholar
  15. 15.
    Hudlicky T (1991). Tetrahedron Lett 32:6077–6080CrossRefGoogle Scholar
  16. 16.
    Keck GE, Fleming S, Nickel D, Weider P (1979). Synth Commun 9:281–286CrossRefGoogle Scholar
  17. 17.
    Naylor A (1993). Tetrahedron 49:451–468CrossRefGoogle Scholar
  18. 18.
    Kresze G (1987). Eur J Org Chem 12:1129–1130Google Scholar
  19. 19.
    Cowart M (1999). J Org Chem 64:2240–2249CrossRefGoogle Scholar
  20. 20.
    Miller CA (2004). Org Lett 6:699–702CrossRefGoogle Scholar
  21. 21.
    Barfoot C (2010). Tetrahedron Lett 51:2846–2848CrossRefGoogle Scholar
  22. 22.
    Ranganathan S (1997). Tetrahedron 53:3347–3362CrossRefGoogle Scholar
  23. 23.
    Griffen JA (2013). Tetrahedron 69:5989–5997CrossRefGoogle Scholar
  24. 24.
    Wang Y (2013). C R Chimie 16:761–764CrossRefGoogle Scholar
  25. 25.
    Cohen AD, Zeng BB, King SB, Toscano JP (2003). J Am Chem Soc 125:1444–1445CrossRefGoogle Scholar
  26. 26.
    Monbaliu JCMR, Cukalovic A (2010). Tetrahedron Lett 51:5830–5833CrossRefGoogle Scholar
  27. 27.
    Nakashima E (2015). Chem Commun 51:12309–12312CrossRefGoogle Scholar
  28. 28.
    Argyle MD, Bartholomew CH (2015). Catalysts 5:145–269CrossRefGoogle Scholar
  29. 29.
    Ding P, Miller MJ, Chen Y, Helquist P, Oliver AJ, Wiest O (2004). Org Lett 6:1805–1808CrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó 2019

Authors and Affiliations

  1. 1.Department of Organic Chemistry and TechnologyBudapest University of Technology and EconomicsBudapestHungary
  2. 2.Chemical Works of Gedeon Richter PlcBudapestHungary

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