State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 2A Nanwei Road, Xicheng District, Beijing 100050, China.
College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China.
Molecules. 2023 Jun 21;28(13):4888. doi: 10.3390/molecules28134888.
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.
匹那地尔，一种处于 I 期临床试验阶段的抗癫痫候选药物，是市售药物瑞替加滨的结构类似物，具有更好的化学稳定性、更强的疗效和更大的安全边际。已报道的匹那地尔最短合成路线包含 6 步，涉及高度有毒的氯甲酸甲酯和危险的氢气的操作。为了提高药物生产的可行性，我们使用非传统的甲氧基羰基化和高效的 Buchwald-Hartwig 交叉偶联开发了一种简洁的三步法。新的合成路线以公斤级规模生成了匹那地尔，无需柱层析纯化，并避免了危险试剂的危险操作。
