Suzuki-Miyaura coupling on nanomole scale

药物研究中复杂中间体的稀缺性促使人们追求亚毫克级的反应优化方案。我们在此报告了一种自动化的基于流程的合成平台的开发，该平台由市售组件设计而成，将快速纳摩尔级反应筛选和微摩尔级合成集成到一个模块化单元中。通过在高温下探索 Suzuki-Miyaura 偶联中的各种反应变量来验证该系统，以每 24 小时 >1500 次反应的速率生成 5760 个反应的液相色谱-质谱数据点。通过多次注入同一片段，该系统直接产生了微摩尔量级的所需材料。最佳条件也在 50 至 200 毫克规模的传统流动和批量模式下复制，以提供良好至优异的产量。

The scarcity of complex intermediates in drug research has driven the pursuit of sub-milligram-scale reaction optimization protocols. Herein, we report the development of an automated flow-based synthetic platform constructed from commercially available components, which integrates rapid nanomolar-scale reaction screening and micromolar-scale synthesis into a single modular unit. The system was validated by exploring diverse reaction variables in Suzuki-Miyaura cross-coupling at elevated temperatures, generating liquid chromatography-mass spectrometry (LC-MS) data points for 5760 reactions at a rate of >1500 reactions per 24 hours. By performing multiple injections of the same fragment, the system directly yields the desired materials in micromolar quantities. The optimal reaction conditions were also replicated in conventional flow and batch modes at scales of 50 to 200 mg, affording good to excellent yields.

搜集汇总

背景与挑战

背景概述

该数据集聚焦于Suzuki-Miyaura偶联反应在纳摩尔尺度上的自动化筛选与合成平台开发，旨在解决药物研究中复杂中间体稀缺的问题。数据集包含5760个反应的液相色谱-质谱数据点，验证了平台的高通量能力（>1500次反应/24小时），并展示了从纳摩尔筛选到微摩尔合成及传统毫克级放大的全流程优化，为药物发现中的反应优化提供了高效工具。