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. 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.

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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

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