Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The impact of microwave synthesis on drug discovery

Nature Reviews Drug Discovery volume 5, pages 51–63 (2006)Cite this article

Key Points

  • Lead compound optimization and medicinal chemistry are known to be the bottlenecks in the drug discovery process, and so a need arises for technologies that allow more rapid synthesis of chemical substances. One such high-speed technology is microwave-assisted organic synthesis (MAOS).

  • Microwave heating, compared with conventional heating (which means heating with an external source such as an oil-bath) is much more efficient because the reaction mixture is heated internally by direct coupling of microwave energy with polar molecules (solvents, reagents and catalysts, for example). This allows faster heating to higher temperatures using sealed-vessel technology.

  • This enabling technology has gained significant influence in the lead optimization and lead generation processes in the pharmaceutical industry because microwave heating dramatically reduces reaction times from days or hours to minutes or seconds.

  • Many reaction parameters, such as time, temperature, solvents, concentration or catalysts, can now be evaluated in a fraction of the time, compared with conventional heating, in the optimization step.

  • Compound libraries can be rapidly synthesized either in a parallel or sequential automated format for lead discovery or structure–activity studies.

  • MAOS can also be combined with solid- or fluorous-phase synthesis or solid-supported solution-phase synthesis, respectively, to achieve simpler product isolation and purification.

  • Several examples for high-throughput microwave synthesis using parallel or sequential library production as well as lead optimization and generation studies are covered in this review.

Abstract

In the past few years, using microwave energy to heat and drive chemical reactions has become increasingly popular in the medicinal chemistry community. First described 20 years ago, this non-classical heating method has matured from a laboratory curiosity to an established technique that is heavily used in academia and industry. One of the many advantages of using rapid 'microwave flash heating' for chemical synthesis is the dramatic reduction in reaction times — from days and hours to minutes and seconds. As will be discussed here, there are good reasons why many pharmaceutical companies are incorporating microwave chemistry into their drug discovery efforts.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Differences between conventional and microwave heating, and examples of microwave reactor technology.
Figure 2: Dihydropyrimidine library synthesis and reaction optimization using automated sequential microwave synthesis.
Figure 3: Time savings associated with microwave-assisted library synthesis.
Figure 4: Lead generation and optimization of allosteric AKT kinase inhibitors derived from a 2,3-diphenyl-quinoxaline core.
Figure 5: Lead optimization of the malarial proteases plasmepsin I and II inhibitors.
Figure 6: Use of microwave heating in medicinal chemistry.
Figure 7: Integrating microwave heating with other technologies.

Similar content being viewed by others

References

  1. Kappe, C. O. & Stadler, A. Microwaves in Organic and Medicinal Chemistry (Wiley-VCH, Weinheim, 2005). This book provides the most comprehensive coverage of microwave-assisted organic synthesis, as well as a complete list of all other reviews.

    Google Scholar 

  2. Tierney, J. P. & Lidström, P. (eds) Microwave Assisted Organic Synthesis (Blackwell, Oxford, 2005).

    Google Scholar 

  3. Loupy, A. (ed.) Microwaves in Organic Synthesis (Wiley-VCH, Weinheim, 2002).

    Google Scholar 

  4. Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light (CEM Publishing, Matthews, 2002).

    Google Scholar 

  5. Kappe, C. O. Controlled microwave heating in modern organic synthesis. Angew. Chem. Int. Ed. 43, 6250–6284 (2004).

    CAS  Google Scholar 

  6. Hayes, B. L. Recent advances in microwave-assisted synthesis. Aldrichim. Acta 37, 66–77 (2004).

    CAS  Google Scholar 

  7. Leadbeater, N. E. Fast, easy, clean chemistry by using water as a solvent and microwave heating: the Suzuki coupling as an illustration. Chem. Commun. 2881–2902 (2005).

  8. Baghurst, D. R. & Mingos, D. M. P. Application of microwave dielectric heating effects to synthetic problems in chemistry. Chem. Soc. Rev. 20, 1–47 (1991).

    Google Scholar 

  9. Gabriel, C., Gabriel, S., Grant, E. H., Halstead, B. S. & Mingos, D. M. P. Dielectric parameters relevant to microwave dielectric heating. Chem. Soc. Rev. 27, 213–223 (1998). References 8 and 9 provide detailed reviews explaining the quite complex phenomena associated with microwave dielectric heating to synthetic chemists.

    CAS  Google Scholar 

  10. Gronnow, M. J., White, R. J., Clark, J. H. & Macquarrie, D. J. Energy efficiency in chemical reactions: a comparative study of different reaction techniques. Org. Process Res. Dev. 9, 516–518 (2005).

    CAS  Google Scholar 

  11. Perreux, L. & Loupy, A. A tentative rationalization of microwave effects in organic synthesis according to the reaction medium, and mechanistic considerations. Tetrahedron 57, 9199–9223 (2001).

    CAS  Google Scholar 

  12. De La Hoz, A., Diaz-Ortiz, A. & Moreno, A. Microwaves in organic synthesis. Thermal and non-thermal microwave effects. Chem. Soc. Rev. 34, 164–178 (2005). A review summarizing and evaluating the latest theories on the existence of non-thermal and specific microwave effects.

    CAS  PubMed  Google Scholar 

  13. Gedye, R. et al. The use of microwave ovens for rapid organic synthesis. Tetrahedron Lett. 27, 279–282 (1986). This seminal publication describes for the first time the use of domestic microwave ovens for synthetic organic transformations.

    CAS  Google Scholar 

  14. Giguere, R. J., Bray, T. L., Duncan, S. M. & Majetich, G. Application of commercial microwave ovens to organic synthesis. Tetrahedron Lett. 27, 4945–4958 (1986).

    CAS  Google Scholar 

  15. Glasnov, T. N., Stadlbauer, W. & Kappe, C. O. Microwave-assisted multistep synthesis of functionalized 4-arylquinolin-2(1H)-ones using palladium-catalyzed cross-coupling chemistry. J. Org. Chem. 70, 3864–3870 (2005).

    CAS  PubMed  Google Scholar 

  16. Porcheddu, A., Ruda, G. F., Sega, A. & Taddei, M. A new, rapid, general procedure for the synthesis of organic molecules supported on methoxy-polyethylene glycol (MeOPEG) under microwave irradiation conditions. Eur. J. Org. Chem. 907–912 (2003).

  17. Alexandre, F. -R., Berecibar, A., Wrigglesworth, R. & Besson, T. Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two Niementowski condensations. Tetrahedron 59, 1413–1419 (2003).

    CAS  Google Scholar 

  18. Pemberton, N., Åberg, V., Almstedt, H., Westermark, A. & Almqvist, F. Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones. J. Org. Chem. 69, 7830–7835 (2004).

    CAS  PubMed  Google Scholar 

  19. Stadler, A. & Kappe, C. O. Automated library generation using sequential microwave-assisted chemistry. Application toward the Biginelli multicomponent condensation. J. Comb. Chem. 3, 624–630 (2001). This publication introduces and describes in full detail the concept of automated library generation using a robotized single-mode microwave synthesizer.

    CAS  PubMed  Google Scholar 

  20. Larhed, M. & Hallberg, A. Microwave-assisted high-speed chemistry: a new technique in drug discovery. Drug Discov. Today 6, 406–416 (2001). An excellent review aimed at the medicinal chemist, summarizing many of the concepts and ideas that have subsequently evolved in this area.

    CAS  PubMed  Google Scholar 

  21. Kappe, C. O. & Stadler, A. Building dihydropyrimidine libraries via microwave-assisted Biginelli multicomponent reactions. Method. Enzym. 369, 197–223 (2003).

    CAS  Google Scholar 

  22. Kappe, C. O. Recent advances in the Biginelli dihydropyrimidine synthesis. New tricks from an old dog. Acc. Chem. Res. 33, 879–888 (2000).

    CAS  PubMed  Google Scholar 

  23. Kappe, C. O. Biologically active dihydropyrimidones of the Biginelli-type. A literature survey. Eur. J. Med. Chem. 35, 1043–1052 (2000).

    CAS  PubMed  Google Scholar 

  24. Tye, H. Application of statistical 'design of experiments' methods in drug discovery. Drug Discov. Today 9, 485–491 (2004). Describes how microwave synthesis and experimental design can be efficiently interfaced with drug discovery and reaction optimization.

    CAS  PubMed  Google Scholar 

  25. Evans, M. D. et al. The accelerated development of an optimized synthesis of 1,2, 4-oxadiazoles: application of microwave irradiation and statistical design of experiments. Tetrahedron Lett. 44, 9337–9341 (2003).

    CAS  Google Scholar 

  26. Tye, H. & Whittaker, M. Use of a design of experiments approach for the optimization of a microwave assisted Ugi reaction. Org. Biomol. Chem. 2, 813–815 (2004).

    CAS  PubMed  Google Scholar 

  27. McLean, N. J., Tye, H. & Whittaker, M. Microwave assisted Petasis boronic-Mannich reactions. Tetrahedron Lett. 45, 993–995 (2004).

    CAS  Google Scholar 

  28. Sarko, C. R. in Microwave Assisted Organic Synthesis (eds Tierney, J. P. & Lidström, P.) 222–236 (Blackwell, Oxford, 2005).

    Google Scholar 

  29. Cotterill, I. C. et al. Microwave-assisted combinatorial chemistry. Synthesis of substituted pyridines. Tetrahedron Lett. 39, 1117–1120 (1998). This paper describes for the first time the utilization of microtitre plates for high-speed parallel synthesis under microwave conditions.

    CAS  Google Scholar 

  30. Nüchter, M. & Ondruschka, B. Tools for microwave-assisted parallel synthesis and combinatorial chemistry. Mol. Diversity 7, 253–264 (2003).

    Google Scholar 

  31. Coleman, C. M., MacElroy, J. M. D., Gallagher, J. F. & O'Shea, D. F. Microwave parallel library generation: comparison of a conventional- and microwave-generated substituted 4(5)-sulfanyl-1H-imidazole library. J. Comb. Chem. 4, 87–93 (2002).

    CAS  PubMed  Google Scholar 

  32. Glass, B. M. & Combs, A. P. in High-Throughput Synthesis. Principles and Practices (ed. Sucholeiki, I.) 123–128 (Marcel Dekker, New York, 2001).

    Google Scholar 

  33. Alcázar, J. Reproducibility across microwave instruments: preparation of a set of 24 compounds on a multiwell plate under temperature-controlled conditions. J. Comb. Chem. 7, 353–355 (2005).

    PubMed  Google Scholar 

  34. Tan, D. S. Diversity-oriented synthesis: exploring the intersections between chemistry and biology. Nature Chem. Biol. 1, 74–84 (2005).

    CAS  Google Scholar 

  35. Zhao, Z., Leister, W. H., Strauss, K. A., Wisnoski, D. D. & Lindsley, C. W. Broadening the scope of 1,2,4-triazine synthesis by the application of microwave technology. Tetrahedron Lett. 44, 1123–1127 (2003).

    CAS  Google Scholar 

  36. Wolkenberg, S. E. et al. Efficient synthesis of imidazoles from aldehydes and 1,2-diketones using microwave irradiation. Org. Lett. 6, 1453–1456 (2004).

    CAS  PubMed  Google Scholar 

  37. Zhao, Z. et al. General microwave-assisted protocols for the expedient synthesis of quinoxalines and heterocyclic pyrazines. Tetrahedron Lett. 45, 4873–4876 (2004).

    CAS  Google Scholar 

  38. Lindsley, C. W. et al. Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg. Med. Chem. Lett. 15, 761–764 (2005).

    CAS  Google Scholar 

  39. Lindsley, C. W., Wisnoski, D. D., Wang, Y., Leister, W. H. & Zhao, Z. A one pot microwave-mediated synthesis of the basic canthine skeleton: expedient access to unnatural β-carboline alkaloids. Tetrahedron Lett. 44, 4495–4498 (2003).

    CAS  Google Scholar 

  40. Zhao, Z. et al. Discovery of 2, 3, 5-trisubstituted pyridine derivatives as potent Akt1 and Akt2 dual inhibitors. Bioorg. Med. Chem. Lett. 15, 905–909 (2005).

    CAS  PubMed  Google Scholar 

  41. Nöteberg, D., Schaal, W., Hamelink, E., Vrang, L. & Larhed, M. High-speed optimization of inhibitors of the malarial proteases plasmepsin I and II. J. Comb. Chem. 5, 456–464 (2003).

    PubMed  Google Scholar 

  42. Gardner, M. J. et al. Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498–511 (2002).

    Article  CAS  Google Scholar 

  43. Banerjee, R. et al. Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine. Proc. Natl Acad. Sci. USA 99, 990–995 (2002).

    CAS  PubMed  Google Scholar 

  44. Berry, C. Plasmepsins as antimalarial targets. Curr. Opin. Drug Discovery Dev. 3, 624–629 (2000).

    CAS  Google Scholar 

  45. Boss, C. et al. Inhibitors of the Plasmodium falciparum parasite aspartic protease plasmepsin II as potential malarial agents. Curr. Med. Chem. 10, 883–907 (2003).

    CAS  PubMed  Google Scholar 

  46. Nöteberg, D. et al. Design and synthesis of plasmepsin I and plasmepsin II inhibitors with activity in Plasmodium falciparum-infected cultured human erythrocytes. J. Med. Chem. 46, 734–746 (2003).

    PubMed  Google Scholar 

  47. Ersmark, K., Larhed, M. & Wannberg, J. Microwave-enhanced medicinal chemistry: a high-speed opportunity for convenient preparation of protease inhibitors. Curr. Opin. Drug. Discov. Develop. 7, 417–427 (2004). A stimulating account on the use of microwave synthesis in medicinal chemistry from an academic perspective, written by a pioneer in this area. See also reference 20.

    CAS  Google Scholar 

  48. Ersmark, E. et al. Potent inhibitors of the Plasmodium falciparum enzyme plasmepsin I and II devoid of cathepsin D inhibitory activity. J. Med. Chem. 47, 110–122 (2004).

    CAS  PubMed  Google Scholar 

  49. Wannberg, J. et al. High-speed synthesis of potent C2-symmetric HIV-1 protease inhibitors by in-situ aminocarbonylations. J. Comb. Chem. 7, 611–617 (2005).

    CAS  PubMed  Google Scholar 

  50. Ax, A. et al. Cyclic sulfamide HIV-1 protease inhibitors, with sidechains spanning from P2/P2' to P1/P1'. Bioorg. Med. Chem. 13, 755–764 (2005).

    CAS  PubMed  Google Scholar 

  51. Wan, Y. et al. Design, synthesis and biological evaluation of the first selective nonpeptide AT2 receptor antagonist. J. Med. Chem. 47, 5995–6008 (2004).

    CAS  PubMed  Google Scholar 

  52. Organ, M. S., Mayer, S., Lepifre, F., N'Zemba, B. & Khatri, J. Combining the use of solid-supported transition metal catalysis with microwave irradiation in solution-phase parallel library synthesis. Mol. Diversity 7, 211–227 (2003).

    CAS  Google Scholar 

  53. Coats, S. J. et al. Parallel methods for the preparation and SAR exploration of N-ethyl-4-[(8-alkyl-8-azabicyclo[3.2.1]-oct-3-ylidene)-aryl-methyl]-benzamides, powerful μ and δ opioid agonists. Bioorg. Med. Chem. Lett. 14, 5493–5498 (2004).

    CAS  PubMed  Google Scholar 

  54. Vasudevan, A., Villamil, C. I. & Djuric, S. W. Synthesis of diazepinones via intramolecular transamidation. Org. Lett. 6, 3361–3364 (2004).

    CAS  PubMed  Google Scholar 

  55. Kempson, J. et al. Fused pyrimidine based inhibitors of phosphodiesterase 7 (PDE7): synthesis and initial structure–activity relationships. Bioorg. Med. Chem. Lett. 15, 1829–1833 (2005).

    CAS  PubMed  Google Scholar 

  56. Lehmann, F., Currier, E. A., Olsson, R., Hacksell, U. & Luthman, K. Isochromanone-based urotensin-II receptor agonists. Bioorg. Med. Chem. 13, 3057–3068 (2005).

    CAS  PubMed  Google Scholar 

  57. Santagada, V. et al. Efficient microwave combinatorial parallel and nonparallel synthesis of N-alkylated glycine methyl esters as peptide building blocks. J. Comb. Chem. 7, 618–621 (2005).

    CAS  PubMed  Google Scholar 

  58. Dai, W. -M., Wang, X. & Ma, C. Microwave-assisted one-pot regioselective synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1, 4-benzoxazines. Tetrahedron 61, 6879–6885 (2005).

    CAS  Google Scholar 

  59. Wang, Y., Miller, R. L., Sauer, D. R. & Djuric, S. W. Rapid and efficient synthesis of 1,2,4-oxadiazoles utilizing polymer-supported reagents under microwave heating. Org. Lett. 7, 925–928 (2005).

    CAS  PubMed  Google Scholar 

  60. Holmberg, P., Tedenborg, L., Rosqvist, S. & Johansson, A. M. Novel 3-aminochromans as potential pharmacological tools for the serotonin 5-HT7 receptor. Bioorg. Med. Chem. Lett. 15, 747–750 (2005).

    CAS  PubMed  Google Scholar 

  61. Seijas, J. A., Vàzquez-Tato, M. P. & Carballido-Reboredo, R. Solvent-free synthesis of functionalized flavones under microwave irradiation. J. Org. Chem. 70, 2855–2858 (2005).

    CAS  PubMed  Google Scholar 

  62. Liu, J. -F. et al. Novel one-pot total syntheses of deoxyvasicinone, mackinazolinone, isaindigotone, and their derivatives promoted by microwave irradiation. Org. Lett. 7, 3363–3366 (2005).

    CAS  PubMed  Google Scholar 

  63. Appukkuttan, P., Dehaen, W. & Van der Eycken, E. Microwave-enhanced synthesis of N-shifted buflavine analogues via a Suzuki-ring-closing metathesis protocol. Org. Lett. 7, 2723–2726 (2005).

    CAS  PubMed  Google Scholar 

  64. Vvedensky, V. Y. et al. Microwave-mediated reactions of 3-aminomethylpyridines with acetylenedicarboxylates. A novel synthetic route to dihydronaphthyridines and naphthyridine-1-ones. Tetrahedron Lett. 46, 3953–3956 (2005).

    CAS  Google Scholar 

  65. Cheung, W. S., Patch, R. J. & Player, M. R. A tandem Heck-carbocyclization/Suzuki-coupling approach to the stereoselective syntheses of asymmetric 3,3-(diarylmethylene)indolinones. J. Org. Chem. 70, 3741–3744 (2005).

    CAS  PubMed  Google Scholar 

  66. Alterman, M. et al. Design and fast synthesis of C-terminal duplicated potent C2-symmetric P1/P1′-modified HIV-1 protease inhibitors. J. Med. Chem. 42, 3835–3844 (1999). This is probably the first publication on the use of controlled microwave heating in a lead optimization project.

    CAS  PubMed  Google Scholar 

  67. Zaragoza Dörwald, F. Organic Synthesis on Solid Phase (Wiley-VCH, Weinheim, 2002).

    Google Scholar 

  68. Gladysz, J. A., Curran, D. P. & Horváth, I. (eds). Handbook of Fluorous Chemistry (Wiley-VCH, Weinheim, 2005).

    Google Scholar 

  69. Ley, S. V. & Baxendale, I. R. New tools and concepts for modern organic synthesis. Nature Rev. Drug Discov. 1, 573–586 (2002).

    CAS  Google Scholar 

  70. Frutos Hoener, A. P., Henkel, B. & Gauvin, J. -C. Novel one-pot microwave assisted Gewald synthesis of 2-acyl amino thiophenes on solid support. Synlett 63–66 (2003).

  71. Vallin, K. S. A., Zhang, Q., Larhed, M., Curran, D. P. & Hallberg, A. A new regioselective Heck vinylation with enamides. Synthesis and investigation of fluorous-tagged bidentate ligands for fast separation. J. Org. Chem. 68, 6639–6645 (2003).

    CAS  PubMed  Google Scholar 

  72. Sauer, D. R., Kalvin, D. & Phelan, K. M. Microwave-assisted synthesis utilizing supported reagents: A rapid and efficient acylation procedure. Org. Lett. 5, 4721–4724 (2003).

    CAS  PubMed  Google Scholar 

  73. Erdelyi, M. & Gogoll, A. Rapid microwave-assisted solid phase peptide synthesis. Synthesis 1592–1596 (2002).

  74. Matsushita, T., Hinou, H., Kurogochi, M., Shimizu, H. & Nishimura, S. -I. Rapid microwave-assisted solid-phase glycopeptide synthesis. Org. Lett. 7, 877–880 (2005).

    CAS  PubMed  Google Scholar 

  75. Murray, J. K. & Gellman, S. H. Application of microwave irradiation to the synthesis of 14-helical β-peptides. Org. Lett. 7, 1517–1520 (2005).

    CAS  PubMed  Google Scholar 

  76. Murray, J. K. et al. Efficient synthesis of a β-peptide combinatorial library with microwave irradiation, J. Am. Chem. Soc. 127, 13271–13280 (2005). An excellent article describing in full detail the concept of microwave-assisted solid-phase peptide synthesis under controlled conditions.

    CAS  PubMed  Google Scholar 

  77. Scharn, D., Wenschuh, H., Reineke, U., Schneider-Mergener, J. & Germeroth, L. Spatially addressed synthesis of amino- and amino-oxy-substituted 1,3,5-triazine arrays on polymeric membranes. J. Comb. Chem. 2, 361–369 (2000).

    CAS  PubMed  Google Scholar 

  78. Scharn, D., Germeroth, L., Schneider-Mergener, J. & Wenschuh, H. Sequential nucleophilic substitution on halogenated triazines, pyrimidines, and purines: a novel approach to cyclic peptidomimetics. J. Org. Chem. 66, 507–513 (2001).

    CAS  PubMed  Google Scholar 

  79. Bowman, M. D., Jeske, R. C. & Blackwell, H. E. Microwave-accelerated SPOT-synthesis on cellulose supports. Org. Lett. 6, 2019–2022 (2004).

    CAS  PubMed  Google Scholar 

  80. Watts, P. Continuous flow microreactors for drug discovery. Curr. Opin. Drug Discov. Develop. 7, 807–812 (2004)

    CAS  Google Scholar 

  81. Watts, P. & Haswell, S. W. Microfluidic combinatorial chemistry. Curr. Opin. Chem. Biol. 7, 380–387 (2003).

    CAS  PubMed  Google Scholar 

  82. He, P., Haswell, S. J. & Fletcher, P. D. I. Microwave heating of heterogeneously catalyzed Suzuki reactions in a micro reactor. Lab Chip 4, 38–41 (2004).

    CAS  PubMed  Google Scholar 

  83. He, P., Haswell, S. J. & Fletcher, P. D. I. Microwave-assisted Suzuki reactions in a continuous flow capillary reactor. Appl. Catal. A. 274, 111–114 (2004).

    CAS  Google Scholar 

  84. He, P., Haswell, S. J. & Fletcher, P. D. I. Efficiency, monitoring and control of microwave heating within a continuous flow capillary reactor. Sensors Actuators B 105, 516–520 (2005).

    CAS  Google Scholar 

  85. Comer, E. & Organ, M. G. A microreactor for microwave-assisted capillary (continuous flow) organic synthesis. J. Am. Chem. Soc. 127, 8160–8167 (2005).

    CAS  PubMed  Google Scholar 

  86. Comer, E. & Organ, M. G. A. Microcapillary system for simultaneous, parallel microwave assisted synthesis. Chem. Eur. J. 11, in press (2005).

  87. Pivonka, D. E. & Empfield, J. R. Real-time in situ Raman analysis of microwave-assisted organic reactions. Appl. Spect. 58, 41–46 (2004).

    CAS  Google Scholar 

  88. Stadler, A. et al. Scalability of microwave-assisted organic synthesis. From single-mode to multimode parallel batch reactors. Org. Process Res. Dev. 7, 707–716 (2003).

    CAS  Google Scholar 

  89. Deetlefs, M. & Seddon, K. R. Improved preparation of ionic liquids using microwave irradiation. Green Chem. 5, 181–186 (2003).

    CAS  Google Scholar 

  90. Lehmann, F., Pilotti, Å. & Luthman, K. Efficient large scale microwave assisted Mannich reactions using substituted acetophenones. Mol. Diversity 7, 145–152 (2003).

    CAS  Google Scholar 

  91. Shackelford, S. A. et al. Electrophilic tetraalkylammonium nitrate nitration. II. Improved anhydrous aromatic and heteroaromatic mononitration with tetramethylammonium nitrate and triflic anhydride, including selected microwave examples. J. Org. Chem. 68, 267–275 (2003). References 88 and 91 summarize some of the concepts and problems of scaling-up microwave-assisted reactions.

    CAS  PubMed  Google Scholar 

  92. Roberts, B. A. & Strauss C. R. in Microwave Assisted Organic Synthesis (eds Tierney, J. P. & Lidström, P.) 237–271 (Blackwell, Oxford, 2005).

    Google Scholar 

  93. Shieh, W. -C., Dell, S. & Repiĉ, O. Large scale microwave-accelerated esterification of carboxylic acids with dimethyl carbonate. Tetrahedron Lett. 43, 5607–5609 (2002).

    CAS  Google Scholar 

  94. Shieh, W. -C., Dell, S. & Repiĉ, O. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and microwave-accelerated green chemistry in methylation of phenols, indoles, and benzimidazoles with dimethyl carbonate. Org. Lett. 3, 4279–4281 (2001).

    CAS  PubMed  Google Scholar 

  95. Wilson, N. S., Sarko, C. R. & Roth, G. Development and applications of a practical continuous flow microwave cell. Org. Process Res. Dev. 8, 535–538 (2004).

    CAS  Google Scholar 

  96. Arvela, R. K., Leadbeater, N. E. & Collins, M. J. Jr. Automated batch scale-up of microwave-promoted Suzuki and Heck coupling reactions in water using ultra-low metal catalyst concentrations, Tetrahedron 61, 9349–9355 (2005).

    CAS  Google Scholar 

  97. Loones, K. T. J., Maes, B. U. W., Rombouts, G., Hostyn, S. & Diels, G. Microwave-assisted organic synthesis: scale-up of palladium-catalyzed aminations using single-mode and multi-mode microwave equipment, Tetrahedron 61, 10338–10348 (2005).

    CAS  Google Scholar 

  98. Howarth, P. & Lockwood, M. Reactor Design 1: Come of Age. The Chemical Engineer 756, 29–31 (2004).

    CAS  Google Scholar 

Download references

Acknowledgements

The work of the Kappe research laboratories in the area of microwave chemistry has been supported by the Austrian Science Fund, the 'Jubiläumsfonds der Österreichischen Nationalbank', the European Union COST program, the Austrian Academic Exchange Service, the University of Graz and various industrial contributors. We wish to thank all members of the Microwave Synthesis (MAOS) Lab in Graz for their essential contributions to microwave chemistry.

Author information

Authors and Affiliations

  1. Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, Graz, A-8010, Austria

    C. Oliver Kappe & Doris Dallinger

Authors
  1. C. Oliver Kappe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Doris Dallinger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Oliver Kappe.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

MAOS Webpages

MAOS Reaction Database

MAOS Hot Articles

MicrowaveSynthesis.Net Webpages

Glossary

Combinatorial chemistry

The generation of large collections, or 'libraries', of compounds by synthesizing all possible combinations of a set of smaller chemical structures.

Compound libraries

Large collections of compounds (hundreds to millions), often synthesized through reactions performed simultaneously (in parallel) or by using combinatorial chemistry principles.

Chemical space

The space spanned by all possible (energetically stable) combinations of atoms and topologies in molecules.

Microwave irradiation

Electromagnetic irradiation in the frequency range of 0.3–300 GHz, corresponding to wavelengths of 1 cm–1 m. All microwave reactors for chemical synthesis operate at a frequency of 2.45 GHz (corresponding to a wavelength of 12.25 cm) to avoid interference with telecommunication and cellular phone frequencies.

Arrhenius law

The relationship between reaction rate and temperature. The rate of a chemical reaction increases when the temperature is raised according to: k = A exp(−Ea/RT).

Microtitre plates

Sample holders used for synthesis, storage, analysis and screening of compound libraries. The plates typically have 6, 24, 96, 384 or even 1,536 sample wells arranged in a 2:3 rectangular matrix.

Design of experiment

(DoE). The use of factorial experiments instead of the one-factor-at-a-time method for the optimization of reaction conditions. This allows studying the effect of each factor on the response variable, while requiring fewer observations than by conducting separate experiments for each factor independently.

Dielectric properties

The ability of a specific sub-stance to convert electro-magnetic energy into heat at a given frequency and temp-erature is determined by the 'loss tangent', tan δ. A reaction medium with a high (>0.5) tan δ value is required for efficient absorption and rapid heating.

Diversity-oriented synthesis

(DOS). Efficient synthesis of a collection (combinatorial library) of structurally diverse and complex small molecules that differ in stereochemistry, functional groups and molecular framework. Rather than being directed toward a single biological target, DOS libraries can be used to identify new ligands for a variety of targets.

Microreactor

Continuous-flow device that consists of a series of interconnecting channels (50–500 μm diameter) and facilitates the performance of chemical reactions on a micro-litre scale. Independent reactants are brought together through different feeder channels to the main channel, where they mix and react as they travel to a reservoir where the products are collected.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kappe, C., Dallinger, D. The impact of microwave synthesis on drug discovery. Nat Rev Drug Discov 5, 51–63 (2006). https://doi.org/10.1038/nrd1926

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1926

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing