Methods of Synthesis of Remdesivir, Favipiravir, Hydroxychloroquine, and Chloroquine: Four Small Molecules Repurposed for Clinical Trials during the Covid-19 Pandemic

Abstract

The novel coronavirus (COVID-19) disease has rapidly evolved into a sweeping pandemic despite public health measures. Screening and development of new vaccines and antivirals are expensive and time consuming. However, the repositioning of available drugs is an essential and universal strategy in the development of new drugs and therefore should receive priority attention as well as international government and agency support. Significant drugs such as chloroquine, hydroxychloroquine, favipiravir and remdesivir, are currently undergoing clinical studies to test their efficacy and safety. Some promising results have been achieved thus far in the treatment of COVID-19. In this article we summarize and discuss the most common synthetic strategies to apply in the preparation of these drug molecules. It is hoped that this compendium will provide an accessible useful guide and reference source for scientists, researchers and academia in their battle against COVD-19.

1 Introduction

2 Synthesis of Chloroquine (CQ) and Hydroxychloroquine (HCQ)

2.1 Synthesis of 4,7-Dichloroquinoline 1

2.2 Synthesis of 2-Amino-5-(diethylamino)pentane (Novoldiamine) 2

2.3 Synthesis of 5-(N-Ethyl-N-2-hydroxyethylamino)-2-pentylamine 4

2.4 Developed Methods for Synthesis of Chloroquine and Hydroxychloroquine

2.5 Synthesis of (R)-Chloroquine, (S)-Chloroquine, (R)-Hydroxychloroquine and (S)-Hydroxychloroquine

3 Synthesis of Favipiravir (Avigan)

4 Synthesis of Remdesivir

5 Conclusion

Key words

COVID-19 - chloroquine - favipiravir - remdesivir - hydroxychloroquine - synthesis - antiviral

Publication History

Received: 15 May 2020

Accepted after revision: 11 August 2020

Article published online:
11 September 2020

• References

• 1 Lai C.-C, Shih T.-P, Ko W.-C, Tang H.-J, Hsueh P.-R. Int. J. Antimicrob. Agents 2020; 105924
• 2 WHO announces COVID-19 outbreak a pandemic (accessed: 7th Sept., 2020): http://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/news/news/2020/3/who-announces-covid-19-outbreak-a-pandemic
• 3a COVID-19 Vaccine Development Pipeline; Vaccine Centre, London School of Hygiene and Tropical Medicine (accessed: 7th Sept., 2020): https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/
• 3b COVID-19 Vaccine Tracker. Lay summary, (accessed: 7th Sept., 2020): https://covid-19tracker.milkeninstitute.org/
• 4 Maxmen A. Nature 2020; 578: 347
• 5a Mercorelli B, Palù G, Loregian A. Trends Microbiol. 2018; 26: 865
• 5b Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, Doig A, Guilliams T, Latimer J, McNamee C. Nat. Rev. Drug Discovery 2019; 18: 41
• 6 Rosa SG. V, Santos WC. Revista Panamericana de Salud Pública 2020; 44
• 7 Colson P, Rolain J.-M, Raoult D. Int. J. Antimicrob. Agents 2020; 55: 105923
• 8a Coatney GR. Am. J. Trop. Med. Hyg. 1963; 12: 121
• 8b Peters W. Br. Med. J. 1971; 2: 95
• 9 Rainsford K, Parke AL, Clifford-Rashotte M, Kean W. Inflammopharmacology 2015; 23: 231
• 10 Colson P, Rolain J.-M, Lagier J.-C, Brouqui P, Raoult D. Int. J. Antimicrob. Agents 2020; 55: 105932
• 11 Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, Seidah NG, Nichol ST. Virol. J. 2005; 2: 69
• 12 Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Cell Res. 2020; 30: 269
• 13a Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ. Montgomery S. A, Hogg A, Babusis D, Clarke MO. Nat. Commun. 2020; 11: 222
• 13b Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I. Sci. Transl. Med. 2017; 9
• 14 Gao J, Tian Z, Yang X. BioScience Trends 2020; 14: 72
• 15 Gautret P, Lagier J.-C, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola B, Rolain J.-M, Brouqui P, Raoult D. Int. J. Antimicrob. Agents 2020; 105949
• 16 https://clinicaltrials.gov/ct2/results?cond = &term = hydroxychloroquine&cntry = &state = &city = &dist = (accessed: 7th Sept., 2020)
• 17a Kenyon RL, Wiesner JA, Kwartler CE. Ind. Eng. Chem. 1949; 41: 654
• 17b De D, Krogstad FM, Byers LD, Krogstad DJ. J. Med. Chem. 1998; 41: 4918
• 17c Su T, Zhu J, Sun R, Zhang H, Huang Q, Zhang X, Du R, Qiu L, Cao R. Eur. J. Med. Chem. 2019; 178: 154
• 17d Li S, Hu L, Li J, Zhu J, Zeng F, Huang Q, Qiu L, Du R, Cao R. Eur. J. Med. Chem. 2019; 162: 666
• 18 Price CC, Roberts RM. Org. Synth. 1948; 28: 38
• 19 Madrid PB, Sherrill J, Liou AP, Weisman JL, DeRisi JL, Guy RK. Bioorg. Med. Chem. Lett. 2005; 15: 1015
• 20 Gaber AE.-A. M, McNab H. Synthesis 2001; 2059
• 21 Surrey AR, Hammer HF. J. Am. Chem. Soc. 1946; 68: 113
• 22a Elderfield RC, Gensler WJ, Brody F, Head JD, Dickerman SC, Wiederhold LIII, Kremer CB, Hageman HA, Kreysa FJ, Griffing JM, Kupchan SM. J. Am. Chem. Soc. 1946; 68: 1579
• 22b Vardanyan RS, Hruby VJ. Synthesis of Essential Drugs . Elsevier; Amsterdam: 2006: 559
• 22c Lavrado J, Cabal GG, Prudêncio M, Mota MM, Gut J, Rosenthal PJ, Diaz C, Guedes RC, dos Santos DJ, Bichenkova E. J. Med. Chem. 2011; 54: 734
• 23 Nishizawa Y. Bull. Chem. Soc. Jpn. 1959; 32: 1282
• 24 Fleck TJ, Chen JJ, Lu CV, Hanson KJ. Org. Process Res. Dev. 2006; 10: 334
• 25 Becker R, Menger V, Reif W, Henne A. PCT US 5608113A, 1997
• 26 Wang Y.-H, Ye J.-L, Wang A.-E, Huang P.-Q. Org. Biomol. Chem. 2012; 10: 6504
• 27 Markofsky SB, Ahlkvist AM. PCT US 4910343A, 1990
• 28a Ballini R, Petrini M. Synthesis 1986; 1024
• 28b Quinet C, Sampoux L, Marko IE. Eur. J. Org. Chem. 2009; 1806
• 29 Surrey AR. PCT US 2546658A, 1951
• 30 Kumar A, Vyas KD, Singh D, Nandavadekar S, Bhise S, Jadhav A. PCT Int. Appl WO 2005/062723 A2, 2005
• 31 Yu E, Mangunuru HP, Telang NS, Kong CJ, Verghese J, Gilliland SE. III, Ahmad S, Dominey RN, Gupton BF. Beilstein J. Org. Chem. 2018; 14: 583
• 32 Surrey AR, Cutler RA. J. Am. Chem. Soc. 1951; 73: 2623
• 33 Michałowicz J, Duda W. Pol. J. Environ. Stud. 2007; 16: 347
• 34 Vashi K. IN 2007MU02210, 2009
• 35a Min YS, Cho H.-S, Mo KW. WO 2010/027150 A2, 2010
• 35b Tang M, Gong D, Yang Z, Liu Y, Yang J, Cai Z, Zha Z, Wang Y. CN 104230803, 2017
• 35c Pi J, Ding Y, Yue R, Wei J, Pan W, Xie G. CN 103724261, 2014
• 36a Fu S, Björkman A, Wåhlin B, Ofori-Adjei D, Ericsson O, Sjöqvist F. Br. J. Clin. Pharmacol. 1986; 22: 93
• 36b Sinha M, Dola VR, Soni A, Agarwal P, Srivastava K, Haq W, Puri SK, Katti SB. Bioorg. Med. Chem. 2014; 22: 5950
• 37 Haberkorn A, Kraft H, Blaschke G. Tropenmed. Parasitol. 1979; 30: 308
• 38a Ofori-Adjei D, Ericsson O, Lindstrom B, Sjoqvist F. Br. J. Clin. Pharmacol. 1986; 22: 356
• 38b Ofori-Adjei D, Ericsson O, Lindström B, Hermansson J, Adjepon-Yamoah K, Sjöqvist F. Ther. Drug Monit. 1986; 8: 457
• 38c McLachlan A, Cutler D, Tett S. Eur. J. Clin. Pharmacol. 1993; 44: 481
• 39 Glenn JS, Pham EA. PCT Int. Appl WO 2017/004454 A1, 2018
• 40 Blaney PM, Byard SJ, Carr G, Ellames GJ, Herbert JM, Peace JE, Smith DI, Michne WF, Sanner MS. Tetrahedron: Asymmetry 1994; 5: 1815
• 41a McLachlan AJ, Tett SE, Cutler DJ. J. Chromatogr. B, Anal. Technol. Biomed. Life Sci. 1991; 570: 119
• 41b Iredale J, Wainer IW. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 1992; 573: 253
• 41c Craiga JC, Ansari AM. Chirality 1993; 5: 188
• 42 Blauer G, Akkawi M, Fleischhacker W, Hiessböck R. Chirality 1998; 10: 556
• 43 Craig JC, Bhargava HN, Everhart ET, LaBelle B, Ohnsorge U, Webster RV. J. Org. Chem. 1988; 53: 1167
• 44 McNulty J, McLeod D, Das P, Zepeda-Velázquez C. Phosphorus, Sulfur Silicon Relat. Elem. 2015; 190: 619
• 45 Dunetz JR, Magano J, Weisenburger GA. Org. Process Res. Dev. 2016; 20: 140
• 46a Xie JH, Zhu SF, Zhou QL. Chem. Rev. 2011; 111: 1713
• 46b Mathew S, Yun H. ACS Catal. 2012; 2: 993
• 47 Reznichenko AL, Nawara-Hultzsch AJ, Hultzsch KC. Top. Curr. Chem. 2014; 343: 191
• 48 Terada M, Momiyama N. In Chiral Amine Synthesis . Nugent TC. Wiley-VCH Verlag GmbH & Co. KGaA, Chap. 3,; Weinheim: 2010: 75
• 49a Furuta Y, Egawa H. WO 2000/010569, 2000
• 49b Furuta Y, Egawa H, Nomura N. US 2002/0013316 A1, 2002
• 49c Egawa H, Furuta Y. PCT. Appl EP 1112743 A1, 2001
• 50a Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Antiviral Res. 2013; 100: 446
• 50b Furuta Y, Takahashi K, Shiraki K, Sakamoto K, Smee DF, Barnard DL, Gowen BB, Julander JG, Morrey JD. Antiviral Res. 2009; 82: 95
• 50c Furuta Y, Takahashi K, Kuno-Maekawa M, Sangawa H, Uehara S, Kozaki K, Nomura N, Egawa H, Shiraki K. Antimicrob. Agents Chemother. 2005; 49: 981
• 50d Gowen BB, Wong M.-H, Jung K.-H, Sanders AB, Mendenhall M, Bailey KW, Furuta Y, Sidwell RW. Antimicrob. Agents Chemother. 2007; 51: 3168
• 50e Oestereich L, Lüdtke A, Wurr S, Rieger T, Muñoz-Fontela C, Günther S. Antiviral Res. 2014; 105: 17
• 51 https://www.theguardian.com/world/2020/mar/18/japanese-flu-drug-clearly-effective-in-treating-coronavirus-says-china
• 52 Pilkington V, Pepperrell T, Hill A. J. Virus Erad. 2020; 6: 45
• 53 Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, Liao X, Gu Y, Cai Q, Yang Y, Shen C, Li X, Peng L, Huang D, Zhang J, Zhang S, Wang F, Liu J, Chen L, Chen S, Wang Z, Zhang Z, Cao R, Zhong W, Liu Y, Liu L. Engineering 2020; in press; DOI: 10.1016/j.eng.2020.03.007.
• 54 Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J, Chen S, Zhang Y, Chen B, Lu M, Luo Y, Ju L, Zhang J, Wang X. medRxiv 2020; DOI: 10.1101/2020.03.17.20037432.
• 55 https://www.trialsitenews.com/category/favipiravir/ (accessed: 7th Sept., 2020)
• 56a Furuta Y, Egawa H. PCT Int. Appl WO 2000010569A1, 2000
• 56b Egawa H, Furuta Y, Sugita J, Uehara S, Hamamoto S, Yonezawa K. WO 2001/060834, 2001
• 56c Hara T, Norimatsu N, Kurushima H, Kano T. PCT. Appl US 8,835,636B2, 2014
• 56d Shi F, Li Z, Kong L, Xie Y, Zhang T, Xu W. Drug Discov. Ther. 2014; 8: 117
• 56e Zheng JZ. T, Feng B, Gong X, Kong L, Chen M, Li Y, Niu H, Zhou H, Ding S. PCT CN102603658A, 2012
• 57a Caldwell JJ, Veillard N, Collins I. Tetrahedron 2012; 68: 9713
• 57b Buckland PR. J. Heterocycl. Chem. 1980; 17: 397
• 58 Wolfe JP, Åhman J, Sadighi JP, Singer RA, Buchwald SL. Tetrahedron Lett. 1997; 38: 6367
• 59a Bolta M, De Angelis F, Nicoletti R. J. Heterocycl. Chem. 1979; 16: 193
• 59b Pierra C, Counor C, Storer R, Gosselin G. Collect. Czech. Chem. Commun. 2011; 76: 1327
• 60 Hara H, Norimatsu N, Kurushima H, Kano T. US 2011/0275817A1, 2011
• 61 Takamatsu T, Yonezawa K. WO 2009/041473, 2009
• 62 Liu F.-L, Li C.-Q, Xiang H.-Y, Feng S. Chem. Pap. 2017; 71: 2153
• 63a Li M. CN 107226794, 2017
• 63b Nakamura K, Murakami T, Naitou H, Hanaki N, Watanabe K. US 2013/0245264A1, 2013
• 64 Tinschert A, Tschech A, Heinzmann K, Kiener A. Appl. Microbiol. Biotechnol. 2000; 53: 185
• 65 Guo Q, Xu M, Guo S, Zhu F, Xie Y, Shen J. Chem. Pap. 2019; 73: 1043
• 66 Pu X, Li Q, Lu Z, Yang X. Eur. J. Org. Chem. 2016; 5937
• 67 Chun BK, Clarke MO. H, Doerffler E, Hui HC, Jordan R, Mackman RL, Parrish JP, Ray AS, Siegel D. US 2016/0122374Al, 2017
• 68a Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen S.-S, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S. Nature 2016; 531: 381
• 68b Lo MK, Jordan R, Arvey A, Sudhamsu J, Shrivastava-Ranjan P, Hotard AL, Flint M, McMullan LK, Siegel D, Clarke MO. Sci. Rep. 2017; 43395
• 69 Lo MK, Feldmann F, Gary JM, Jordan R, Bannister R, Cronin J, Patel NR, Klena JD, Nichol ST, Cihlar T. Sci. Transl. Med. 2019; 11: eaau9242
• 70 Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Götte M. J. Biol. Chem. 2020; 295: 4773
• 71 Coronavirus COVID-19 (SARS-CoV-2); Johns Hopkins ABX Guide. Retrieved. Remdesivir: Likely the most promising drug. 2020 12 April.
• 72 ‘Solidarity’ clinical trial for COVID-19 treatment. World Health Organization. 27 April 2020. Retrieved 1 May 2020; Kupferschmidt K C. J., WHO launches global megatrial of the four most promising coronavirus treatments. Science (22 March 2020).
• 73 Launch of a European clinical trial against COVID-19. INSERM. 22 March 2020. Retrieved 1 May 2020.
• 74 https://www.fda.gov/media/137564/download (accessed: 7th Sept., 2020) Remdesivir EUA Letter of Authorization. 2020.
• 75 NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19. National Institute of Allergy and Infectious Diseases 29 April 2020.
• 76 https://clinicaltrials.gov/ct2/results?cond = &term = remdesivir&cntry = &state = &city = &dist = (accessed: 7th Sept., 2020).
• 77 Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, Neville S, Carra E, Lew W, Ross B, Wang Q, Wolfe L, Jordan R, Soloveva V, Knox J, Perry J, Perron M, Stray KM, Barauskas O, Feng JY, Xu Y, Lee G, Rheingold AL, Ray AS, Bannister R, Strickley R, Swaminathan S, Lee WA, Bavari S, Cihlar T, Lo MK, Warren TK, Mackman RL. J. Med. Chem. 2017; 60: 1648
• 78 Daniel O’Day, An Update on COVID-19 from our Chairman & CEO. Stories@Gilead, April 04, 2020, (accessed: 7th Sept., 2020), https://www.gilead.com/stories/articles/an-update-on-covid-19-from-our-chairman-and-ceo
• 79 Barker R, Fletcher HG. J. Org. Chem. 1961; 26: 4605
• 80 Zhu C, Wei Y, Ji L. Synth. Commun. 2010; 40: 2057
• 81 Patil SA, Otter BA, Klein RS. J. Heterocycl. Chem. 1994; 31: 781
• 82 Krasovskiy A, Knochel P. Angew. Chem. Int. Ed. 2004; 43: 3333