Discovery and Synthesis of Remdesivir, a COVID-19's Potential Antiviral Agent

COVID-19, a novel coronavirus affecting the respiratory system, is genetically close to bat-derived coronaviruses...

Discovery and Synthesis of Remdesivir, a COVID-19's Potential Antiviral Agent

COVID-19, a novel coronavirus affecting the respiratory system, is genetically close to bat-derived coronaviruses. It is categorized as beta genus coronavirus, which is the same as the strains including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Antiviral drugs commonly used in clinical practice, including neuraminidase inhibitors (oseltamivir, paramivir, zanamivir, etc.), ganciclovir, acyclovir and ribavirin, are invalid and not recommended for the COVID-19.1 At present, remdesivir is theoretically the most potent treatment.

Remdesivir is not only a new nucleoside analogue, but also a broad-spectrum antiviral drug. It was originally designed to fight filoviruses such as Ebola virus. With the deepening of the research, it was found that the antiviral effect of remdesivir is not limited to filoviruses, it has inhibitory effect on coronavirus and other viruses. On January 31, 2020, after an article on the first case of COVID-19 infection in the United States treated by remdesivir was published in the NEJM (New England Journal of Medicine)2, the therapeutic effect of remdesivir quickly attracted attention, and clinical research on the treatment of COVID-19 using remdesivir was carried out rapidly. So how is remdesivir synthesized?

The Synthesis Scheme 1

 First Generation Synthesis of 4baScheme 1. First Generation Synthesis of 4ba

aReagents and conditions: (a) n-BuLi, (TMS)Cl, THF, – 78 °C, 25%; (b) 1,2-bis(chlorodimethylsilyl)ethane, NaH, n-BuLi, THF, – 78 °C, 60%; (c) (TMS)CN, BF3·Et2O, CH2Cl2, – 78 °C, 58% (89:11β-17/α); (d) BCl3, CH2Cl2, – 78 °C, 74%; (e) 19, NMI, OP(OMe)3, 21%; (f) OP(OPh)Cl2, Et3N, CH2Cl2, 0 °C, 23%.

In the synthesis scheme 1, the amino group (- NH2) of compound 15 is first protected by TMS. The generated product reacts with compound 14 and protected by de-TMS to form compound 16. Cyanation of compound 16 is introduced into cyano (- CN) to obtain compound 17, which is debenzylated to obtain compound 4. Racemic compound 4a is obtained through the reaction between compound 4 and compound 19. Finally, compound 4c and the desired final product Remdesivir (4b) were separated by chiral HPLC. While this route initially provided quantities of 4b, the variability in yields, suboptimal selectivity, frequent use of cryogenic temperatures, and chiral chromatography hindered this route from being suited to larger scales.3

The Synthesis Scheme 2

Second Generation Synthesis of 4baScheme 2. Second Generation Synthesis of 4ba

aReagents and conditions: (a) TMSCl, PhMgCl, i-PrMgCl·LiCl, THF, – 20 °C, 40%; (b) TMSCN, TfOH, TMSOTf, CH2Cl2, – 78 °C, 85%; (c) BCl3, CH2Cl2, – 20 °C, 86%; (d) 2,2-dimethoxypropane, H2SO4, acetone, rt, 90%; (e) 22b, MgCl2, (i-Pr)2NEt, MeCN, 50 °C, 70%; (f) 37% HCl, THF, rt, 69%; (g) OP(OPh)Cl2, Et3N, CH2Cl2, – 78 °C, then 4-nitrophenol, Et3N, 0 °C, 80%; (h) i-Pr2O, 39%.

Because the first-generation synthesis route requires chiral resolution to obtain target compound, when designing the second-generation route, pharmaceutical chemists used the method of chiral synthesis to achieve large-scale preparation of chiral target compounds. In this route, the iodide 20 is used to replace the bromide 15 of the first-generation route, and the reaction conditions are changed to increase the yield of this step from 25% of the first-generation to 40%. Through the optimization of reaction conditions, the yields of cyanation and debenzylation were increased from 58% of the first generation route to 85% and from 74% to 86%, respectively. After the successful acquisition of compound 4, the subsequent process changed compared with the first generation synthesis route. Compound 21 was obtained in high yield (90%) by protecting the ortho-dihydroxy (- OH) of compound 4.3

In this route, the most critical step is the synthesis of the single configuration compound 22b. Compound 18a reacted with phenyl dichlorophosphate and p-nitrophenol to obtain racemic compound 22a (yield 80%). Through the screening and exploration of a variety of solvents and conditions, pharmaceutical chemists found that gently stirring racemic compound 22a in isopropyl ether for 22h and filtering in a vacuum can obtain a white solid, which is a single configuration compound 22b. The most important chirality was introduced.

Compound 21 then reacted with single configuration compound 22b, and deprotected to obtain a single configuration target compound Remdesivir (4b). Compared with the first generation synthesis route, a large number of remdesivir can be prepared using this route.

At present, researchers from China-Japan Friendship Hospital have designed a clinical randomized controlled trial program to evaluate the efficacy of remdesivir in patients infected with COVID-19. This study has been registered (mild to moderate 2019 nCoV: NCT04252664; severe 2019-nCoV: NCT04257656).1

Reference:

  1. Li Hui et al. (2020). Potential antiviral therapeutics for 2019 Novel Coronavirus. Chin J Tuberc Respir Dis. 43(00): E002-E002. DOI: 10.3760/cma.j.issn.1001-0939.2020.0002
  2. Michelle L. Holshue et al. (2020). First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. DOI:10.1056 / NEJMoa2001191
  3. Siegel D et al. (2017). Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo(2,1-f] [triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses. Journal of Medicinal Chemistry. 60(5):1648-1661. DOI: 10.1021/acs.jmedchem.6b01594
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