Department of Process Research & Development, Merck Research Laboratories (MRL), Merck Sharp & Dohme Corp, Rahway, NJ, 07065, USA.
Chemistry. 2018 May 17;24(28):7133-7136. doi: 10.1002/chem.201801494. Epub 2018 Apr 26.
The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on H, C, and N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of S. The synthetic utility of S was demonstrated with the efficient synthesis of [ S]phosphorothioates [ S ]-PS-ODNs-TTT and [ C, N, S]-ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [ S]phosphorothioates using elemental S without isotope dilution was developed.
合成与母体化合物相比质量增加≥3 个单位的稳定同位素标记（SIL）复合药物分子对于药物发现和开发至关重要。典型的依赖于 H、C 和 N 同位素的方法可能极具挑战性甚至难以解决，并且可能会延迟药物开发过程。这项工作介绍了一种新的合成标记化合物的概念，该方法依赖于 S 的使用。S 的合成实用性通过高效合成 [S]硫代磷酸酯 [S]PS-ODNs-TTT 和 [C、N、S]-头孢他啶得到了证明。此外，还开发了一种在不进行同位素稀释的情况下使用元素 S 将亚膦酸酯直接氧化为 [S]硫代磷酸酯的方法。
