Suut-Tuule Elina, Schults Eve, Jarg Tatsiana, Adamson Jasper, Kananovich Dzmitry, Aav Riina
Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn, 12618, Estonia.
National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, Tallinn, 12618, Estonia.
ChemSusChem. 2025 May 5;18(9):e202402354. doi: 10.1002/cssc.202402354. Epub 2025 Jan 16.
Biotin[6]uril, a chiral, water-soluble and anion binding macrocycle, is formed via dynamic covalent chemistry. In this study, we present a scalable and high-yielding synthesis of biotin[6]uril via a mechanochemical solid-state approach. The optimized protocol involves mechanical grinding of solid d-biotin with paraformaldehyde in the presence of 0.3 equivalents of 48 % aqueous HBr, which functions as a catalyst, template, and liquid grinding additive. This mechanochemical process is carried out in a shaker or planetary mill, followed by aging at an elevated temperature to produce biotin[6]uril with an HPLC yield of up to 96 %. The condensation and macrocyclization reaction was successfully scaled up 82-fold, producing nearly 20 g of biotin[6]uril with a high 92 % isolated yield and 91 % purity. Compared to conventional solution-based method, this mechanochemical approach offers several advantages, including significantly higher yields, shorter reaction times, enhanced scalability, simpler operational requirements, and substantially lower process mass intensity.
生物素[6]脲，一种手性、水溶性且能结合阴离子的大环化合物，是通过动态共价化学形成的。在本研究中，我们展示了一种通过机械化学固态方法可扩展且高产率合成生物素[6]脲的方法。优化后的方案包括在0.3当量48%的氢溴酸水溶液（其作为催化剂、模板和液体研磨添加剂）存在下，将固体d-生物素与多聚甲醛进行机械研磨。该机械化学过程在振荡器或行星式球磨机中进行，随后在高温下老化，以产生HPLC产率高达96%的生物素[6]脲。缩合和大环化反应成功放大了82倍，得到了近20克生物素[6]脲，分离产率高达92%，纯度为91%。与传统的基于溶液的方法相比，这种机械化学方法具有几个优点，包括显著更高的产率、更短的反应时间、更强的可扩展性、更简单的操作要求以及大幅降低的过程质量强度。
