【摘要】 目的 优化TLR7小分子激动剂5-[2-甲氧基-4-（哌嗪-1-基甲基）苄基]-N⁴-戊基-5H-吡咯并[3,2-d]嘧啶-2,4-二胺的合成工艺，解决现有路线成本高、反应条件苛刻、收率低及大规模纯化难度大等问题。方法 首次设计了以4-氯-5H-吡咯并[3,2-d]嘧啶-2-胺为起始原料的全新合成路线；通过优化反应缚酸剂、反应溶剂、反应温度、后处理方法等策略提升合成效率。结果与结论经工艺优化，目标化合物的收率由17.3%提升至42.2%（以4-氯-5H-吡咯并[3,2-d]嘧啶-2-胺）,新路线总收率为7.6%（以异噁唑计）。目标化合物结构经¹H-NMR、¹³C-NMR和ESI-MS谱确证，优化后的合成工艺为TLR7激动剂的工业化生产提供了可行的解决方案。更多还原

【Abstract】 The synthetic process of the TLR7 agonist 5-[2-methoxy-4-（piperazine-1-ylmethyl）benzyl]-N⁴-pentyl-5H-pyrrolo[3,2-d]pyrimidine-2,4-diamine（A-01） has been optimized to address several issues in previous methods, including the high cost of starting materials, harsh reaction conditions, low yields, and challenges in scale-up.The new process significantly improved the yield, increasing from 17.3% to 42.2%（based on starting material 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine）.The total yield for the new route was 7.6%（based on isoxazole）.The structure was confirmed by ¹H-NMR,¹³C-NMR,and ESI-MS,with the final product exhibiting a purity of 99.94%.Additionally, a novel synthetic route for starting material 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine was developed, reducing its cost from 1 000 CNY/g to approximately 60 CNY/g.Combined with key optimizations such as low-cost acid-binding agent screening, solvent system improvement, and simplified post-treatment, the process provides an economically feasible solution for large-scale production.The optimized process offers a viable approach for the industrial production of TLR7 agonists, which have shown promising potential in cancer immunotherapy and other therapeutic areas.更多还原