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A comprehensive review of the disclosed approaches for the synthesis of Parvaquone, an anti-protozoan drug

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Abstract

In this work, we have systematically reviewed the till date disclosed routes pertaining to the synthesis of Parvaquone. Prior art search gave us around nineteen synthetic routes, involving invention and innovation towards the starting material selection and process path to synthesize Parvaquone. Interestingly, 2-hydroxy naphthalene-1,4-dione has been the predominant raw material used for the synthesis of Parvaquone. Every process was executed to attain higher atom economy, process economy, and better purity of the product. In most of the works, a significant focus was given on choosing cheap and easy-to-obtain raw materials/reagents. In the past six years, we have noticed the disclosure of mainly single and two-step processes with simple and mild reaction conditions for the preparation of Parvaquone. Only a few researchers had given an importance for the recovery and reuse of high-cost raw materials/reagents/solvents along with effluent management. If these aspects were collectively considered during the process development of drug, then the disclosed synthetic routes would become well accomplished for large-scale manufacturing.

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SYNOPSIS In this review work, we have gathered nineteen till date synthetic approaches of Parvaquone from the prior art disclosures. For the beneficial commercialization of Paravaquone, single or two-step processes would be favorable. This will provide much-needed control over the process of large-scale drug manufacturing.

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References

  1. Vitor F F, Alcione S D C, Patricia G F, Carolina G S L and Fernando D C D S 2021 Quinone-based drugs: An important class of molecules in medicinal chemistry Med. Chem. 17 1073

    Article  Google Scholar 

  2. Baneth G 2018 Antiprotozoal treatment of canine babesiosis Vet. Parasitol. 254 58

    Article  CAS  PubMed  Google Scholar 

  3. Hudson A T, Randall A W, Fry M, Ginger C D, Hill B, Latter V S, et al. 1985 Novel anti-malarial hydroxynaphthoquinones with potent broad spectrum anti-protozoal activity Parasitology 90 45

    Article  CAS  PubMed  Google Scholar 

  4. McHardy N, Haigh A J and Dolan T T 1976 Chemotherapy of theileria parva infection Nature 261 698

    Article  CAS  PubMed  Google Scholar 

  5. Nyormoi O, Bwayo J J and Hirumi H 1981 Theileria parva: Isolation of macroschizonts from in vitro propagated lymphoblastoid cells of cattle Exp. Parasitol. 52 303

    Article  CAS  PubMed  Google Scholar 

  6. Boehm P, Cooper K, Hudson A T, Elphick J P and McHardy N 1981 In vitro activity of 2-alkyl-3-hydroxy-1,4-naphthoquinones against Theileria parva J. Med. Chem. 24 295

    Article  CAS  PubMed  Google Scholar 

  7. Vos D J A and Roos J A 1983 Chemotherapy of Theileria parva lawrencei infections in cattle with halofuginone Onderstepoort J. Vet. Res. 50 33

    PubMed  Google Scholar 

  8. Mchardy N, Hudson A T, Morgan D W T, Rae D G and Dolan T T 1983 Activity of 10 naphthoquinones, including Parvaquone (993C) and Menoctone, in cattle artificially infected with Theileria parva Res. Vet. Sci. 35 347

    Article  CAS  PubMed  Google Scholar 

  9. Dolan T T 1986 Chemotherapy of East Coast Fever. Treatment of infections induced by isolates of Theileria parva with halofuginone Acta Trop. 43 165

    CAS  PubMed  Google Scholar 

  10. Dolan T T, Linyonyi A, McHardy N, Bond A L and Clampitt R B 1988 Chemotherapy of East Coast Fever: Parvaquone treatment of Theileria parva at intervals after infection Res. Vet. Sci. 44 15

    Article  CAS  PubMed  Google Scholar 

  11. Mchardy N 1978 In vitro studies on the action of Menoctone and other compounds on Theileria parva and Theileria annilata Ann. Trop. Med. Parasitol. 72 501

    Article  CAS  PubMed  Google Scholar 

  12. Unsuren H, Kurtdede A and Goksu K 1988 Effectiveness of Parvaquone in cattle infected with Theileria annulata Trop. Anim. Health Prod. 20 256

    Article  CAS  PubMed  Google Scholar 

  13. Hashemi-Fesharki R 1991 Chemotherapeutic value of Parvaquone and Buparvaquone against Theileria annulata infection of cattle Res. Vet. Sci. 50 204

    Article  CAS  PubMed  Google Scholar 

  14. Fieser L F 1948 Naphthoquinone Antimalarials. III. Diene synthesis of 1,4-naphthoquinones J. Am. Chem. Soc. 70 3165

    Article  CAS  PubMed  Google Scholar 

  15. Fieser L F 1946 Introduction of organic radicals into quinones U.S. Patent 2398418

  16. Fieser L F and Marlin T E 1951 Naphthoquinone compounds U.S. Patent 2553648

  17. Huyser E S and Amini B 1968 Free-radical alkylations of 2-hydroxy-1,4-naphthoquinone J. Org. Chem. 33 576

    Article  CAS  Google Scholar 

  18. Boehm P, Cooper K, Hudson A, Elphick J and McHardy N 1981 Additions and Corrections-In vitro activity of 2-alkyl-3-hydroxy-1,4-naphthoquinones against Theileria parva J. Med. Chem. 24 1540

    Article  Google Scholar 

  19. Hudson A T, Pether M J, Randall A W, Fry M, Latter V S and Mchardy N 1986 In vitro activity of 2-cycloalkyl-3-hydroxy-l,4-naphthoquinones against Theileria, Eimeria and Plasmodia species Eur. J. Med. Chem. Chim. Ther. 21 271

    CAS  Google Scholar 

  20. Hudson A T, Pether M J, Randall A W, Fry M, Latter V S and Mchardy N 1986 ChemInform abstract: In vitro activity of 2-cycloalkyl-3-hydroxy-1,4-naphthoquinones against Theileria, Eimeria and Plasmodia Species Chem. Inf. 17 52

    Google Scholar 

  21. Jacobsen N and Torssell K 1972 Alkylation of quinones with radicals: generation of radicals in redox reactions Just. Liebigs Ann. Chem. 763 135

    Article  CAS  Google Scholar 

  22. Jacobsen N and Torssell K 1973 Synthesis of naturally occuring quinones Acta Chem. Scand. 27 3211

    Article  CAS  Google Scholar 

  23. Goldman J, Jacobsen N and Torssell K 1974 Syntheses in the camphor series. Alkylation of quinones with cycloalkyl radicals. Attempted syntheses of Lagopodin A and Desoxyhelicobasidin Acta Chem. Scand. 28 492

    Article  CAS  Google Scholar 

  24. Khambay B S and Batty D 1996 Pesticidal compounds W.O. Patent 9621354.

  25. Harrity J P A, Kerr W J, Middlemiss D and Scott J S 1997 Total synthesis of Parvaquone and the serendipitous discovery of a novel chromium-mediated method for β-lactone formation J. Organomet. Chem. 532 219

    Article  CAS  Google Scholar 

  26. Harrity J P A, Kerr W J and Middlemiss D 1993 Promotion of the chromium carbene dötz annulation reaction under dry state adsorption conditions Tetrahedron Lett. 34 2995

    Article  CAS  Google Scholar 

  27. Harrity J P A, Kerr W J and Middlemiss D 1993 Promotion of the chromium carbene dötz annulation reaction under sonochemical and dry state adsorption conditions Tetrahedron 49 5565

    Article  CAS  Google Scholar 

  28. Desai N B, McKelvie N and Ramirez F 1962 A new synthesis of 1,1-dibromo-ölefins via phosphine-dibromomethylenes. The reaction of triphenylphosphine with carbon tetrabromide J. Am. Chem. Soc. 84 1745

    Article  Google Scholar 

  29. Corey E J and Fuchs P L 1972 A synthetic method for formyl→ethynyl conversion (RCHO→RC=CH or RC=CR′) Tetrahedron Lett. 13 3769

    Article  Google Scholar 

  30. Hegedus L S 1990 Chromium carbene complexes in the synthesis of molecules of biological interest Pure Appl. Chem. 62 691

    Article  CAS  Google Scholar 

  31. Liebeskind L S 1989 Cyclobutenediones as precursors to quinones and cyclopentenones Tetrahedron 45 3053

    Article  CAS  Google Scholar 

  32. Foland L D, Karlsson J O, Perri S T, Schwabe R, Xu S L, Patil S and Moore H W 1989 Rearrangement of 4-alkynylcyclobutenones. A new synthesis of 1,4-benzoquinones J. Am. Chem. Soc. 111 975

    Article  CAS  Google Scholar 

  33. Paquette L A and Doussot 1996 New transformations involving squarate esters. Multi-channel rearrangement options available to 2-(dimethoxy-methyl)-1-cycloalken-1-yl adducts Res. Chem. Intermed. 22 767

  34. Ohno M, Yamamoto Y and Eguchi S 1998 Highly selective synthesis of polyfunctionalized carbo-and heterocycles based on ring expansion of squaric acid derivatives Synlett 11 1167

    Article  Google Scholar 

  35. Cesar R S A, Cristina G R C and Eduardo P C 2003 A short total synthesis of Parvaquone Arkivoc. 11 172

    Google Scholar 

  36. Rogelio S A, Eduardo P C and Cecilio A T 2004 A short synthesis of two analogues of Parvaquone Arkivoc. 1 64

    Google Scholar 

  37. Cesar R S A, Eduardo P C, Jesus G S, Juana L G, Felipe J G and Alejandro A H 2009 2-Hydroxynaphthoquinones. Synthesis, electrochemical study, and biological essays of activity Arkivoc. 2 239

    Google Scholar 

  38. Saralaya S S, Somashekar S H, Shashiprabha, Kanakamajalu S, Ranganathan K R, Anathalakshmi V, Jeyaraman G, Rao K S and Nagarajan K 2010 Preparation of naphthoquinone compounds using 2,3-dihalonapthoquinone W.O. Patent 2009122432 A3

  39. Saralaya S S, Somashekar S H, Shashiprabha, Kanakamajalu S, Ranganathan K R, Anathalakshmi V, Jeyaraman G, Rao K S and Nagarajan K 2012 Preparation of naphthoquinone compounds using 2,3-dihalonaphthoquinone U.S. Patent 8283499 B2

  40. Saralaya S S, Shashiprabha, Kanakamajalu S, Nagarajan K and Ranganathan K R 2022 A systematic study towards the synthesis, isolation, and recrystallization of Atovaquone, an antimalarial drug: A sustainable synthetic pathway Mapana J. Sci. 21 19

  41. Newman M S 1977 Synthesis of o-acetylbenzoic acid. An experiment for an honors, organic laboratory course J. Chem. Edu. 54 191

    Article  CAS  Google Scholar 

  42. Britton H, Catterick D, Dwyer A N, Gordon A H, Leach S G, McCormick C, et al. 2012 Discovery and development of an efficient process to atovaquone Org. Process Res. Dev. 16 1607

    Article  CAS  Google Scholar 

  43. Barcia J C, Cruces J, Estévez J C, Estévez R J and Castedo L 2002 Palladium-catalyzed synthesis of o-acetylbenzoic acids: a new, efficient general route to 2-hydroxy-3-phenyl-1,4-naphthoquinones and indolo[2,3-b]naphthalene-6,11-diones Tetrahedron Lett. 43 5141

  44. Perkin R P 1936 Method of alkylating phenols U.S. Patent 2125310

  45. Patil P C and Akamanchi K G 2014 Simple and effective route for synthesis of Parvaquone, an antiprotozoal drug RSC Adv. 4 58214

  46. Echavarren A M, Frutos Ó D, Tamayo N, Noheda P and Calle P 1997 Palladium-catalyzed coupling of naphthoquinone triflates with stannanes. Unprecedented nucleophilic aromatic substitution on a hydroxynaphthoquinone triflate J. Org. Chem. 62 4524

    Article  CAS  PubMed  Google Scholar 

  47. Gan X, Jiang W, Wang W and Hu L 2009 An approach to 3,6-disubstituted 2,5-dioxybenzoquinones via two sequential Suzuki couplings. three-step synthesis of leucomelone Org. Lett. 11 589

    Article  CAS  PubMed  Google Scholar 

  48. Rao M L N and Giri S 2012 Pd-catalyzed threefold arylations of mono, di and tetra-bromoquinones using triarylbismuth reagents RSC Adv. 2 12739

  49. Fujiwara Y, Domingo V, Seiple I B, Gianatassio R, Bel M D and Baran P S 2011 Practical C-H functionalization of quinones with boronic acids J. Am. Chem. Soc. 133 3292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Walker S E, Jordan H J A, Johnson D G, Macgregor S A and Lee A L 2014 Palladium-catalyzed direct C-H functionalization of benzoquinone Angew. Chem. Int. Ed. Engl. 53 13876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wang J, Wang S, Wang G, Zhang J and Yu X Q 2012 Iron-mediated direct arylation with arylboronic acids through an aryl radical transfer pathway Chem. Commun. 48 11769

    Article  CAS  Google Scholar 

  52. Pandit R P and Lee Y R 2014 Direct oxidative arylation of C(sp3)-H bonds adjacent to oxygen of ethers and alcohols Adv. Synth. Catal. 356 3171

    Article  CAS  Google Scholar 

  53. Ratnikov M O and Doyle M P 2013 Mechanistic investigation of oxidative Mannich reaction with tert-butyl hydroperoxide. The role of transition metal salt J. Am. Chem. Soc. 135 1549

    Article  CAS  PubMed  Google Scholar 

  54. Baral E R, Kim S H and Lee Y R 2016 Copper-Catalyzed C(Sp2)-C(Sp3) Cross-Dehydrogenative Coupling of Quinones with Cyclic Alkanes: One-Step Access to Parvaquone and Its Analogs Asian J. Org. Chem. 5 1134

    Article  CAS  Google Scholar 

  55. Lee Y R 2018 Naphthoquinone derivatives, benzoquinone derivatives, and anthracenedione derivatives, their use and novel method for preparation K.R. Patent 20180134632 A

  56. Shockravi A, Kamali M, Sharifi N, Nategholeslam M and Moghanlo S P 2013 One-pot and solvent-free synthesis of 1,4-dihydropyridines and 3,4-dihydropyrimidine-2-ones using new synthetic recyclable catalyst via biginelli and Hantzsch reactions Synth. Commun. 43 1477

    Article  CAS  Google Scholar 

  57. Bonet G A, Remeur C, Matsui J K and Molander G A 2017 Late-stage C-H alkylation of heterocycles and 1,4-quinones via oxidative homolysis of 1,4-dihydropyridines J. Am. Chem. Soc. 139 12251

    Article  Google Scholar 

  58. Patil P C and Akamanchi K G 2017 A new combination of cyclohexylhydrazine and IBX for oxidative generation of cyclohexyl free radical and related synthesis of Parvaquone Tetrahedron Lett. 58 1883

    Article  CAS  Google Scholar 

  59. Weitz E and Scheffer A 1921 Über die einwirkung von alkalischem wasserstoffsuperoxyd auf ungesättigte verbindungen Ber. Dtsch. Chem. Ges. (A & B series). 54 2327

  60. Zhu R, Xing L, Wang X, Cheng C, Liu B and Hu Y 2007 Practical preparation of diosphenols by ring opening of α,β-epoxyketones catalyzed by silica gel supported acids Synlett 14 2267

  61. Nasiri H R, Madej M G, Panisch R, Lafontaine M, Bats J W, Lancaster C R D and Schwalbe H 2013 Design, synthesis, and biological testing of novel naphthoquinones as substrate-based inhibitors of the quinol/fumarate reductase from Wolinella succinogenes J. Med. Chem. 56 9530

    Article  CAS  PubMed  Google Scholar 

  62. Louvis A D R, Silva N A A, Semaan F S, Silva F D C D, Saramago G, Souza L C S V D, et al. 2016 Synthesis, characterization and biological activities of 3-aryl-1,4-naphthoquinones-green palladium-catalysed Suzuki cross coupling New J. Chem. 40 7643

    Article  CAS  Google Scholar 

  63. Ai B R, Chen X L, Dong Y, Tang L and Wang J Y 2017 Tetrabutylammonium iodide catalyzed epoxidation of naphthoquinone derivatives with tert-butyl hydroperoxide as an oxidant Synthesis 49 4017

    Article  CAS  Google Scholar 

  64. Ai B R, Chen X L, Dong Y, Tang L and Wang J Y 2018 Tetrabutylammonium iodide catalyzed hydroxylation of naphthoquinone derivatives with tert-butyl hydroperoxide as an oxidant Tetrahedron Lett. 59 3620

    Article  Google Scholar 

  65. Minisci F, Bernardi R, Bertini F, Galli R and Perchinummo M 1971 Nucleophilic character of alkyl radicals-VI Tetrahedron 27 3575

    Article  CAS  Google Scholar 

  66. Galloway J D, Mai D N and Baxter R D 2017 Silver-catalyzed minisci reactions using selectfluor as a mild oxidant Org. Lett. 19 5772

    Article  CAS  PubMed  Google Scholar 

  67. Wang J, Li G X, He G and Chen G 2018 Photoredox-mediated minisci alkylation of N-heteroarenes using carboxylic acids and hypervalent iodine Asian J. Org. Chem. 7 1307

    Article  CAS  Google Scholar 

  68. Zhang X Y, Weng W Z, Liang H, Yang H and Zhang B 2018 Visible-light-initiated, photocatalyst-free decarboxylative coupling of carboxylic acids with N-heterocycles Org. Lett. 20 4686

    Article  CAS  PubMed  Google Scholar 

  69. Sanchez G R A, Aca T A, Tavakoli G and Glorius F 2017 Visible light-mediated direct decarboxylative C-H functionalization of heteroarenes ACS Catal. 7 4057

    Article  Google Scholar 

  70. Sutherland D R, Veguillas M, Oates C L and Lee A L 2018 Metal-, photocatalyst-, and light-free, late-stage C-H alkylation of heteroarenes and 1,4-quinones using carboxylic acids Org. Lett. 20 6863

    Article  CAS  PubMed  Google Scholar 

  71. Hamsath A, Galloway J and Baxter R 2018 Quinone C-H alkylations via oxidative radical processes Synthesis 50 2915

    Article  CAS  Google Scholar 

  72. Dong Y, Yang J, He S, Shi Z C, Wang Y, Zhang X M and Wang J Y 2019 Metal-free oxidative cross-dehydrogenative coupling of quinones with benzylic C(sp3)-H bonds RSC Adv. 9 27588

  73. Yang J, Dong Y, He S, Shi Z C, Wang Y and Wang J Y 2019 Bismuth-catalyzed methylation and alkylation of quinone derivatives with tert-butyl peroxybenzoate as an oxidant Tetrahedron. 75 130729

    Article  Google Scholar 

  74. Liu S, Shen T, Luo Z and Liu Z Q 2019 A free radical alkylation of quinones with olefins Chem. Commun. 55 4027

    Article  CAS  Google Scholar 

  75. Kulthe A D, Nadiveedhi M R, Mainkar P S and Akondi S M 2021 Visible light-promoted selectfluor-mediated quinone functionalization with unactivated Csp3-H components Arkivoc. 3 115

  76. Zhao H and Jin J 2019 Visible light-promoted aliphatic C-H arylation using selectfluor as a hydrogen atom transfer reagent Org. Lett. 21 6179

    Article  CAS  PubMed  Google Scholar 

  77. Niu L, Liu J, Liang X A, Wang S and Lei A 2019 Visible light-induced direct α C-H functionalization of alcohols Nat. Commun. 10 467

    Article  PubMed  PubMed Central  Google Scholar 

  78. Liang X A, Niu L, Wang S, Liu J and Lei A 2019 Visible-light-induced C(sp3)-H oxidative arylation with heteroarenes Org. Lett. 21 2441

    Article  CAS  PubMed  Google Scholar 

  79. Shuang S, Lei Q, Ting Y and Qifu Y 2014 Method for preparing lawsone from lawsonia inermis C.N. Patent 103848732.

  80. Hamama W S, Hassanien A E D E and Zoorob H H 2017 Advanced routes in synthesis and reactions of Lawsone molecules (2-hydroxynaphthalene-1,4-dione) J. Heterocycl. Chem. 54 2155

    Article  CAS  Google Scholar 

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Acknowledgements

We got the inspiration, motivation and guidance for this initiative from Dr. Kuppuswamy Nagarajan (retired Consultant), his contribution is gratefully acknowledged by our team. Furthermore, I would like to thank the management of SDME, Society, Ujire., for their continuous support to this review work.

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Authors and Affiliations

  1. Department of Chemistry, Sri Dharmasthala Manjunatheshwara Institute of Technology, SDMIT {affiliated to Visvesvaraya Technological University (VTU), Belagavi}, Ujire, Dakshina Kannada, Karnataka, 574 240, India

    Sanjay Sukumar Saralaya

  2. PG Department of Chemistry, Sri Dharmasthala Manjunatheshwara College (Autonomous), Ujire, Dakshina Kannada, Karnataka, 574 240, India

    Shashiprabha

  3. Technical Coordinator, Arkgen Pharma Private Limited, Peenya Industrial Area, Bangalore, Karnataka, 560 058, India

    Shridhara Kanakamajalu

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  1. Sanjay Sukumar Saralaya
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Correspondence to Sanjay Sukumar Saralaya.

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Saralaya, S.S., Shashiprabha & Kanakamajalu, S. A comprehensive review of the disclosed approaches for the synthesis of Parvaquone, an anti-protozoan drug. J Chem Sci 135, 26 (2023). https://doi.org/10.1007/s12039-023-02145-6

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