Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jun 21;28(13):4888.
doi: 10.3390/molecules28134888.

Three-Step Synthesis of the Antiepileptic Drug Candidate Pynegabine

Yi-Jing Sun  1   2 , Ya-Ling Gong  1 , Shi-Chao Lu  1 , Shi-Peng Zhang  1 , Shu Xu  1   2
Affiliations

Three-Step Synthesis of the Antiepileptic Drug Candidate Pynegabine

Yi-Jing Sun et al. Molecules. .

Abstract

Pynegabine, an antiepileptic drug candidate in phase I clinical trials, is a structural analog of the marketed drug retigabine with improved chemical stability, strong efficacy, and a better safety margin. The reported shortest synthetic route for pynegabine contains six steps and involves the manipulation of highly toxic methyl chloroformate and dangerous hydrogen gas. To improve the feasibility of drug production, we developed a concise, three-step process using unconventional methoxycarbonylation and highly efficient Buchwald-Hartwig cross coupling. The new synthetic route generated pynegabine at the decagram scale without column chromatographic purification and avoided the dangerous manipulation of hazardous reagents.

Keywords: Buchwald–Hartwig cross coupling; antiepileptic drug; pynegabine.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of retigabine and pynegabine.
Scheme 1
Scheme 1
Previously reported synthetic routes for pynegabine. Ts = p-toluenesulfonyl; Boc = tert-butoxycarbonyl; DMAP = 4-(dimethylamino)pyridine; DIPEA = diisopropylethylamine.
Scheme 2
Scheme 2
Proposed synthetic route for pynegabine.
Figure 2
Figure 2
Localized 1H-NMR spectra (400 MHz) of the compounds 15 (a) and pynegabine (b).
Scheme 3
Scheme 3
Successful and scalable three-step route for synthesizing pynegabine. DMF = N,N-dimethylformamide.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. World Health Organization Epilepsy, 9 February 2023. [(accessed on 27 May 2023)]; Available online: https://www.who.int/en/news-room/fact-sheets/detail/epilepsy.
    1. Elkommos S., Mula M. Current and future pharmacotherapy options for drug-resistant epilepsy. Expert Opin. Pharmacother. 2022;23:2023–2034. doi: 10.1080/14656566.2022.2128670. - DOI - PubMed
    1. Zhou Z., Li K., Chu Y., Li C., Zhang T., Liu P., Sun T., Jiang C. ROS-removing nano-medicine for navigating inflammatory microenvironment to enhance anti-epileptic therapy. Acta Pharm. Sin. B. 2023;13:1246–1261. doi: 10.1016/j.apsb.2022.09.019. - DOI - PMC - PubMed
    1. Stafstrom C.E., Grippon S., Kirkpatrick P. Ezogabine (retigabine) Nat. Rev. Drug Discov. 2011;10:729–730. doi: 10.1038/nrd3561. - DOI - PubMed
    1. Clark S., Antell A., Kaufman K. New antiepileptic medication linked to blue discoloration of the skin and eyes. Ther. Adv. Drug Saf. 2015;6:15–19. doi: 10.1177/2042098614560736. - DOI - PMC - PubMed

LinkOut - more resources