Scale-Up Synthesis of 1‑Methyladamantane and Its Functionalization as a Key Point for Promising Antiviral Agents

Methyladamantane and its derivatives are rare chemotypes for industrial and even wide research use. The proposed scalable and inexpensive approach to such compounds opens the door to further extensive study of biologically active derivatives based on this uncommon core. Optimized synthesis of the key precursor, the chiral (1S,3R,5R,7S)-3-methyl-5-phenyladamantane-1-carboxylic acid, showcases some significant innovations. The main one is very effective and cost-efficient stacked injections in preparative chiral chromatography and showed potential for enantioresolution of chiral cage compounds. Scaling the preparation of (1S,3R,5R,7S)-trans-N-(4-aminocyclohexyl)-3-methyl-5-phenyladamantane-1-carboxamide, which was recently shown to have notable activity against the Ebola virus, to multigram levels is an excellent example of our elaboration significance. It may push forward further biological investigation of this promising antiviral agent.

甲基金刚烷（Methyladamantane）及其衍生物属于工业乃至广泛科研领域中较为罕见的化学型。本文所提出的可规模化、低成本合成策略，为基于这一罕见核心骨架的生物活性衍生物的后续深入研究铺平了道路。关键前驱体——手性(1S,3R,5R,7S)-3-甲基-5-苯基金刚烷-1-羧酸的优化合成，展现出多项重要技术创新。其中核心亮点为制备型手性色谱中兼具高效性与成本优势的堆叠进样技术，该技术在手性笼状化合物的对映体拆分领域展现出可观应用潜力。将近期被证实具有显著抗埃博拉病毒活性的(1S,3R,5R,7S)-反式-N-(4-氨基环己基)-3-甲基-5-苯基金刚烷-1-甲酰胺的制备规模放大至多克级，充分印证了本研究工作的重要价值。这一成果或将推动这一极具前景的抗病毒候选药物的后续生物学研究。