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Optimization of the Ugi Reaction Using Parallel Synthesis and Automated Liquid Handling
Published on: November 11, 2008
Scalable Mechanochemical Synthesis of Biotin[6]uril
Elina Suut-Tuule1, Eve Schults1, Tatsiana Jarg1
1Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, Tallinn, 12618, Estonia.
Abstract:
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.
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