Vol. 21 No. 3 (2022): Mapana Journal of Sciences
Research Articles

A Novel and Sustainable Method for the Synthesis of 2-chloro-3-[trans-4-(4-chlorophenyl) cyclohexyl]-1,4-naphthoquinone, accomplished by systematic process development studies - Trans-Cl synthesis

PDF
  • Sanjay Sukumar Saralaya,
  • Shashiprabha,
  • Shridhara Kanakamajalu,
  • Kuppuswamy Nagarajan,
  • Koottungalmadhom Ramaswamy Ranganathan
Sanjay Sukumar Saralaya
SDM Institute of Technology, Ujire.
Bio
Shashiprabha
SDM College (Autonomous), Ujire.
Bio
Shridhara Kanakamajalu
ArkGen Pharma Private Limited, Bangalore.
Bio
Kuppuswamy Nagarajan
Retired Consultant for Alkem Labs and KOP Research Centre, Bangalore.
Bio
Koottungalmadhom Ramaswamy Ranganathan
Retired Head of R & D, Alkem Labs and KOP Research Centre, Bangalore.
Bio

Published 2022-12-06

Keywords

  • 2-Chloro-3-[trans-4-(4-chlorophenyl) cyclohexyl]-1,
  • 4-naphthoquinone,
  • 2,3-Dichloro-1,
  • Synthesis,
  • Characterization,
  • Process Development
    • ...More
    Less

Copyright (c) 2022

Creative Commons License

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.

Abstract

Present work reports a novel and commercially viable method for the synthesis of 2-chloro-3-[trans-4-(4-chlorophenyl) cyclohexyl]-1,4-naphthoquinone 1, a renowned intermediate of Atovaquone (an antimalarial drug). Majority of the prior arts disclose the synthesis of this intermediate from the expensive starting material 2-chloro-1,4-naphthoquinone 2, in relatively low yield. In this regard, it was considered worthwhile to synthesize 1 by a novel route using cheaper starting material 2,3-dichloro-1,4-naphtoquinone 5, in high yield and purity. In the present study, emphasis was given for selecting the reagents and solvents, optimizing the reaction conditions, recovery and reuse of solvents and silver salt. This optimized novel process is cost effective and would generate less effluent.  

PDF

References

  1. Anderson, J. M., & Kochi, J. K. (1970). Silver (I)-catalyzed oxidative decarboxylation of acids by peroxydisulfate. Role of silver (II). Journal of the American Chemical Society, 92(6), 1651–1659. https://doi.org/10.1021/ja00709a039
  2. Jacobsen, N., & Torssell, K. (1972). Radikalische Alkylierung von Chinonen: Erzeugung von Radikalen in Redoxreaktionen. Justus Liebigs Annalen der Chemie, 763(1), 135–147. https://doi.org/10.1002/jlac.19727630115
  3. Jacobsen, N., Torssell, K., Lien, T., Pilotti, Å., Svensson, S., & Swahn, C.-G. (1973). Synthesis of naturally occurring Quinones. Alkylation with the silver ion-peroxydisulphate-carboxylic acid system. Acta Chemica Scandinavica (Copenhagen, Denmark: 1989), 27, 3211–3216. https://doi.org/10.3891/acta.chem.scand.27-3211
  4. Jacobsen, N. (1977). Free-radical alkylation of quinones: 2-phenoxymethyl-1,4-benzoquinone. Organic Syntheses; an Annual Publication of Satisfactory Methods for the Preparation of Organic Chemicals, 56, 68. https://doi.org/10.15227/orgsyn.056.0068
  5. Hudson, A. T., Pether, M. J., Randall, A. W., Fry, M., Latter, V. S., & Mchardy, N. (1986). ChemInform Abstract: In vitro Activity of 2-Cycloalkyl-3-hydroxy-1,4-naphthoquinones Against Theileria, Eimeria and Plasmodia Species. Chemischer Informationsdienst, 17(52). https://doi.org/10.1002/chin.198652144
  6. Latter, V. S., & Gutteridge, W. E. US Patent 4981874 (1991).
  7. A. T. Hudson, A. T., & Yeates, C. L. EP Patent 445141 (1996).
  8. Gutteridge, W. E., David, B. A. H., Latter, V. S., & Mary, P. US Patent 6291488 (2001).
  9. Williams, D. R., & Clark, M. P. (1998). Synthesis of atovaquone. Tetrahedron Letters, 39(42), 7629–7632. https://doi.org/10.1016/s0040-4039(98)01691-8
  10. Y. Wang, J. Liao, Q. Li and Q. Liu, CN Patent 101265171A (2008).
  11. Kumar, A., Dike, S.Y., Mathur, P., Nellithanath, B. T., Sharma, B., Kore, S. S., & Buchde, V. WO Patent 2009007991A3 (2009).
  12. Commandeur, C., Chalumeau, C., Dessolin, J., & Laguerre, M. (2007). Study of radical decarboxylation toward functionalization of naphthoquinones. European Journal of Organic Chemistry, 2007(18), 3045–3052. https://doi.org/10.1002/ejoc.200700135
  13. Ilangovan, A., Saravanakumar, S., & Malayappasamy, S. (2013). Γ-carbonyl Quinones: Radical strategy for the synthesis of evelynin and its analogues by C–H activation of Quinones using cyclopropanols. Organic Letters, 15(19), 4968–4971. https://doi.org/10.1021/ol402229m
  14. Gutiérrez-Bonet, Á., Remeur, C., Matsui, J. K., & Molander, G. A. (2017). Late-stage C–H alkylation of heterocycles and 1,4-Quinones via oxidative homolysis of 1,4-dihydropyridines. Journal of the American Chemical Society, 139(35), 12251–12258. https://doi.org/10.1021/jacs.7b05899
  15. Sutherland, D. R., Veguillas, M., Oates, C. L., & Lee, A.-L. (2018). Metal-, photocatalyst-, and light-free, late-stage C–H alkylation of heteroarenes and 1,4-Quinones using carboxylic acids. Organic Letters, 20(21), 6863–6867. https://doi.org/10.1021/acs.orglett.8b02988
  16. Fujiwara, Y., Domingo, V., Seiple, I. B., Gianatassio, R., Del Bel, M., & Baran, P. S. (2011). Practical C−H functionalization of Quinones with boronic acids. Journal of the American Chemical Society, 133(10), 3292–3295. https://doi.org/10.1021/ja111152z
  17. Kianmehr, E., Khalkhali, M. R., Rezaeefard, M., Khan, K. M., & Ng, S. W. (2015). Pd-catalyzed dehydrogenative cross-coupling of 1,4-Quinones with N,N′-dialkyluracils. Australian Journal of Chemistry, 68(1), 165. https://doi.org/10.1071/ch14412
  18. Wang, Y., Zhu, S., & Zou, L.-H. (2019). Recent advances in direct functionalization of Quinones: Recent advances in direct functionalization of Quinones. European Journal of Organic Chemistry, 2019(12), 2179–2201. https://doi.org/10.1002/ejoc.201900028
  19. Cotos, L., Donzel, M., Elhabiri, M., & Davioud-Charvet, E. (2020). A mild and versatile Friedel–crafts methodology for the diversity‐oriented synthesis of redox‐active 3‐benzoylmenadiones with tunable redox potentials. Chemistry (Weinheim an Der Bergstrasse, Germany), 26(15), 3314–3325. https://doi.org/10.1002/chem.201904220
  20. Naturale, G., Lamblin, M., Commandeur, C., Felpin, F.-X., & Dessolin, J. (2012). Direct C-H alkylation of naphthoquinones with amino acids through a revisited kochi-Anderson radical decarboxylation: Trends in reactivity and applications. European Journal of Organic Chemistry, 2012(29), 5774–5788. https://doi.org/10.1002/ejoc.201200722
  21. Li, X., Yan, X., Wang, Z., He, X., Dai, Y., Yan, X., Zhao, D., & Xu, X. (2020). Complementary oxidative generation of iminyl radicals from α-imino-oxy acids: Silver-catalyzed C–H cyanoalkylation of heterocycles and Quinones. The Journal of Organic Chemistry, 85(4), 2504–2511. https://doi.org/10.1021/acs.joc.9b03204
  22. Westwood, M. T., Lamb, C. J. C., Sutherland, D. R., & Lee, A.-L. (2019). Metal-, photocatalyst-, and light-free direct C–H acylation and carbamoylation of heterocycles. Organic Letters, 21(17), 7119–7123. https://doi.org/10.1021/acs.orglett.9b02679
  23. Galloway, J. D., Mai, D. N., & Baxter, R. D. (2017). Silver-catalyzed minisci reactions using selectfluor as a mild oxidant. Organic Letters, 19(21), 5772–5775. https://doi.org/10.1021/acs.orglett.7b02706
  24. Galloway, J. D., & Baxter, R. D. (2019). Progress towards metal-free radical alkylations of quinones under mild conditions. Tetrahedron, 75(46), 130665. https://doi.org/10.1016/j.tet.2019.130665
  25. Liu, S., Huang, Y., Qing, F.-L., & Xu, X.-H. (2018). Transition-metal-free decarboxylation of 3,3,3-trifluoro-2,2-dimethylpropanoic acid for the preparation of C(CF3)me2-containing heteroarenes. Organic Letters, 20(17), 5497–5501. https://doi.org/10.1021/acs.orglett.8b02451
  26. Donzel, M., Karabiyikli, D., Cotos, L., Elhabiri, M., & Davioud-Charvet, E. (2021). Direct C−H radical alkylation of 1,4‐Quinones. European Journal of Organic Chemistry, 2021(25), 3622–3633. https://doi.org/10.1002/ejoc.202100452
  27. Sanjay, S. S., Shashikumar, H. S., Shashiprabha, Shridhara, K., Koottungalmadhom, R. R., Veeraswamy, A., Govindaraju, J., Kothapalli, S. R., & Kuppuswamy, N. US Patent 8283499 (2012).
  28. Takacs, L. (2007). The mechanochemical reduction of AgCl with metals: Revisiting an experiment of M. Faraday. Journal of Thermal Analysis and Calorimetry, 90(1), 81–84. https://doi.org/10.1007/s10973-007-8479-8
  29. Rerenc, S., & Gordon, L. History of Analytical Chemistry. (1992).
  30. Murphy, J. A., Ackerman, A. H., & Heeren, J. K. (1991). Recovery of silver from and some uses for waste silver chloride. Journal of Chemical Education, 68(7), 602. https://doi.org/10.1021/ed068p602
  31. Arias, C., Mata, F., & Perez-Benito, J. F. (1990). Kinetics and mechanism of oxidation of iodide ion by the molybdenum (VI) – hydrogen peroxide system. Canadian Journal of Chemistry, 68(9), 1499–1503. https://doi.org/10.1139/v90-230
  32. Bromocyclopropane. (1963). Organic Syntheses; an Annual Publication of Satisfactory Methods for the Preparation of Organic Chemicals, 43, 9. https://doi.org/10.15227/orgsyn.043.0009
  33. Marcotullio, M. C., Epifano, F., & Curini, M. (2005). Recent advances in the use of oxone in organic synthesis. ChemInform, 36(26). https://doi.org/10.1002/chin.200526212