Lomustine is a DNA alkylating agent that has long been recognized as the standard of care for glioblastoma. The continuous flow telescoped synthesis of lomustine was previously developed; however, the method used dichloromethane as a solvent, thus motivating us to develop an efficient process using two biorenewable green solvents, 2-methyltetrahydrofuran and acetic acid. We tailored our continuous flow reactor to produce 99.9% pure lomustine in 85% yield by introducing a new solvent stream that would dissolve previous sources of intermediate precipitation and incorporating a continuous countercurrent extraction to improve the overall efficiency. The kinetic parameters for the reactions were also determined. This work shows that the productivity of continuous flow reactions is highly dependent on the reactor setup and solvent blends that maximize the solubility of the limiting species.

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洛莫司汀绿色合成的工艺开发和动力学分析

洛莫司汀是一种 DNA 烷化剂，长期以来被认为是胶质母细胞瘤的标准治疗方法。先前开发了洛莫司汀的连续流动伸缩合成；然而，该方法使用二氯甲烷作为溶剂，因此促使我们开发一种使用两种生物可再生绿色溶剂（2-甲基四氢呋喃和乙酸）的高效工艺。我们定制了连续流反应器，通过引入新的溶剂流来溶解先前的中间沉淀源，并结合连续逆流萃取以提高整体效率，以 85% 的产率生产 99.9% 纯度的洛莫司汀。还确定了反应的动力学参数。这项工作表明，连续流动反应的生产率高度依赖于反应器设置和溶剂混合物，以最大限度地提高限制物质的溶解度。