Skip to main content
SpringerLink
Log in

Highly selective deuteration of pharmaceutically relevant nitrogen-containing heterocycles: a flow chemistry approach

  • Full-length Paper
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

A simple and efficient flow-based technique is reported for the catalytic deuteration of several model nitrogen-containing heterocyclic compounds which are important building blocks of pharmacologically active materials. A continuous flow reactor was used in combination with on-demand pressure-controlled electrolytic D2 production. The D2 source was D2O, the consumption of which was very low. The experimental set-up allows the fine-tuning of pressure, temperature, and flow rate so as to determine the optimal conditions for the deuteration reactions. The described procedure lacks most of the drawbacks of the conventional batch deuteration techniques, and additionally is highly selective and reproducible.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Blake MI, Crespi HL, Katz J (1975) Studies with deuterated drugs. J Pharm Sci 64: 367–391. doi:10.1002/jps.2600640306

    Article  PubMed  CAS  Google Scholar 

  2. Baldwin JE, Raghavan AS, Hess BA, Smentek L (2006) Thermal [1,5] hydrogen sigmatropic shifts in cis,cis-1,3-cyclononadienes probed by gas-phase kinetic studies and density functional theory calculations. J Am Chem Soc 128: 14854–14862. doi:10.1021/ja065656s

    Article  PubMed  CAS  Google Scholar 

  3. Kharasch ED, Bedynek PS, Park S, Whittington D, Walker A, Hoffer C (2008) Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. Clin Pharmacol Ther 84: 497–505. doi:10.1038/clpt.2008.104

    Article  PubMed  CAS  Google Scholar 

  4. Perrin CL, Lau JS (2006) Hydrogen-bond symmetry in zwitterionic phthalate anions: symmetry breaking by solvation. J Am Chem Soc 128: 11820–11824. doi:10.1021/ja063797o

    Article  PubMed  CAS  Google Scholar 

  5. Salzmann M, Pervushin K, Wider G, Senn H, Wüthrich K (1998) TROSY in triple-resonance experiments: new perspectives for sequential NMR assignment of large proteins. Proc Natl Acad Sci USA 95: 13585–13590

    Article  PubMed  CAS  Google Scholar 

  6. Zhou H, Ranish JA, Watts JD, Aebersold R (2002) Quantitative proteome analysis by solid-phase isotope tagging and mass spectrometry. Nat Biotechnol 20: 512–515. doi:10.1038/nbt0502-512

    Article  PubMed  CAS  Google Scholar 

  7. Skaddan MB, Yung CM, Bergman RG (2004) Stoichiometric and catalytic deuterium and tritium labeling of “unactivated” organic substrates with cationic Ir(III) complexes. Org Lett 6: 11–13. doi:10.1021/ol0359923

    Article  PubMed  CAS  Google Scholar 

  8. Kurita T, Aoki F, Mizumoto T, Maejima T, Esaki H, Maegawa T, Monguchi Y, Sajiki H (2008) Facile and convenient method of deuterium gas generation using a Pd/C-catalyzed H-2-D-2 exchange reaction and its application to synthesis of deuterium-labelled compounds. Chem Eur J 14: 3371–3379. doi:10.1002/chem.200701245

    Article  CAS  Google Scholar 

  9. Maegawa T, Fujiwara Y, Inagaki Y, Esaki H, Monguchi Y, Sajiki H (2008) Mild and efficient H/D exchange of alkanes based on C–H activation catalyzed by rhodium on charcoal. Angew Chem Int Ed 47: 5394–5397. doi:10.1002/anie.200800941

    Article  CAS  Google Scholar 

  10. Darvas F, Dorman G, Lengyel L, Kovacs I, Jones R, Urge L (2009) High pressure, high temperature reactions in continuous flow merging discovery and process chemistry. Chim Oggi 27: 40–43

    CAS  Google Scholar 

  11. Belfiore LA (2003) Transport phenomena for chemical reactor design. Wiley, New Jersey

    Book  Google Scholar 

  12. Jones RV, Godorhazy L,Varga N, Szalay D, Urge L, Darvas F (2006) Continuous-flow high pressure hydrogenation reactor for optimization and high-throughput synthesis. J Comb Chem 8:110–116. doi:10.1021/cc050107o; http://www.thalesnano.com

    Google Scholar 

  13. Mandity IM, Martinek TA, Darvas F, Fülöp F (2009) A simple, efficient, and selective deuteration via a flow chemistry approach. Tetrahedron Lett 50: 4372–4374. doi:10.1016/j.tetlet.2009.05.050

    Article  CAS  Google Scholar 

  14. Brase S, Gil C, Knepper K (2002) The recent impact of solid-phase synthesis on medicinally relevant benzoannelated nitrogen heterocycles. Bioorg Med Chem 10: 2415–2437. doi:10.1016/S0968-0896(02)00025-1

    Article  PubMed  Google Scholar 

  15. Noble S, Faulds D (1996) Saquinavir—a review of its pharmacology and clinical potential in the management of HIV infection. Drugs 52: 93–112

    Article  PubMed  CAS  Google Scholar 

  16. Palmer KJ, Holliday SM, Brogden RN (1993) Mefloquine—a review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 45: 430–475

    Article  PubMed  CAS  Google Scholar 

  17. Houlihan WJ, Munder PG, Handley DA, Cheon SH, Parrino VA (1995) Antitumor activity of 5-aryl-2,3-dihydroimidazo[2,1-A]isoquinolines. J Med Chem 38: 234–240. doi:10.1021/jm00002a004

    Article  PubMed  CAS  Google Scholar 

  18. Brogden RN, Heel RC, Speight TM, Avery GS (1979) Nomifensine—review of its pharmacological properties and therapeutic efficacy in depressive-illness. Drugs 18: 1–24

    Article  PubMed  CAS  Google Scholar 

  19. Jarvis B, Markham A (2000) Montelukast—a review of its therapeutic potential in persistent asthma. Drugs 59: 891–928

    Article  PubMed  CAS  Google Scholar 

  20. Davis R, Markham A, Balfour JA (1996) Ciprofloxacin—an updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs 51: 1019–1074

    Article  PubMed  CAS  Google Scholar 

  21. Hazeldine ST, Polin L, Kushner J, Paluch J, White K, Edelstein M, Palomino E, Corbett TH, Horwitz JP (2001) Design, synthesis, and biological evaluation of analogues of the antitumor agent, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}-propionic acid (XK469). J Med Chem 44: 1758–1776. doi:10.1021/jm0005149

    Article  PubMed  CAS  Google Scholar 

  22. Cerecetto H, Di Maio R, Gonzalez M, Risso M, Saenz P, Seoane G, Denicola A, Peluffo G, Quijano C, Olea-Azar C (1999) 1,2,5-oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs: structure–activity relationships. J Med Chem 42: 1941–1950. doi:10.1016/S0223-5234(01)01265-X

    Article  PubMed  CAS  Google Scholar 

  23. Kim KS, Qian L, Bird JE, Dickinson KE, Moreland S, Schaeffer TR, Waldron TL, Delaney CL, Weller HN, Miller AV (1993) Quinoxaline N-oxide containing potent angiotensin-II receptor antagonists—synthesis, biological properties, and structure–activity-relationships. J Med Chem 36: 2335–2342. doi:10.1021/jm00068a010

    Article  PubMed  CAS  Google Scholar 

  24. Sarges R, Howard HR, Browne RG, Lebel LA, Seymour PA, Koe BK (1990) 4-amino[1,2,4]triazolo[4,3-A]quinoxalines—A novel class of potent adenosine receptor antagonists and potential rapid-onset antidepressants. J Med Chem 33: 2240–2252. doi:10.1021/jm00170a031

    Article  PubMed  CAS  Google Scholar 

  25. Bentley KW (2006) Beta-Phenylethylamines and the isoquinoline alkaloids. Nat Prod Rep 23: 444–463. doi:10.1039/b509523a

    Article  PubMed  CAS  Google Scholar 

  26. Kushner DJ, Baker A, Dunstall TG (1999) Pharmacological uses and perspectives of heavy water and deuterated compounds. Can J Physiol Pharmacol 77: 79–88. doi:10.1139/cjpp-77-2-79

    Article  PubMed  CAS  Google Scholar 

  27. Derdau V (2004) Deuterated ammonium formate as deuterium source in a mild catalytic deuterium transfer reaction of pyridines, pyrazines and isoquinolines. Tetrahedron Lett 45: 8889–8893. doi:10.1016/j.tetlet.2004.09.165

    Article  CAS  Google Scholar 

  28. Esaki H, Ito N, Sakai S, Maegawa T, Monguchi Y, Sajiki H (2006) General method of obtaining deuterium-labelled heterocyclic compounds using neutral D2O with heterogeneous Pd/C. Tetrahedron 62: 10954–10961. doi:10.1016/j.tet.2006.08.088

    Article  CAS  Google Scholar 

  29. Sullivan JA, Flanagan KA, Hain H (2008) Selective H–D exchange catalysed by aqueous phase and immobilised Pd nanoparticles. Catal Today 139: 154–160. doi:10.1016/j.cattod.2008.03.031

    Article  CAS  Google Scholar 

  30. Oba M, Terauchi T, Hashimoto J, Tanaka T, Nishiyama K (1997) Stereoselective synthesis of (2S,3S,4R,5S)-proline-3,4,5-d(3). Tetrahedron Lett 38: 5515–5518. doi:10.1016/S0040-4039(97)01189-1

    Article  CAS  Google Scholar 

  31. Oba M, Ohkuma K, Hitokawa H, Shirai A, Nishiyama K (2006) Convenient synthesis of deuterated glutamic acid, proline and leucine via catalytic deuteration of unsaturated pyroglutamate derivatives. J Label Compd Radiopharm 49: 229–235. doi:10.1002/jlcr.1038

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös utca 6, 6720, Szeged, Hungary

    Sándor B. Ötvös, István M. Mándity & Ferenc Fülöp

Authors
  1. Sándor B. Ötvös
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. István M. Mándity
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ferenc Fülöp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ferenc Fülöp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ötvös, S.B., Mándity, I.M. & Fülöp, F. Highly selective deuteration of pharmaceutically relevant nitrogen-containing heterocycles: a flow chemistry approach. Mol Divers 15, 605–611 (2011). https://doi.org/10.1007/s11030-010-9276-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-010-9276-z

Keywords

Search

Navigation