Markovic Tim, Rocke Benjamin N, Blakemore David C, Mascitti Vincent, Willis Michael C
Department of Chemistry , University of Oxford , Chemical Research Laboratory , Mansfield Road , Oxford , OX1 3TA , UK . Email:
Medicine Design , Pfizer Inc. , Eastern Point Road , Groton , CT 06340 , USA.
Chem Sci. 2017 Jun 1;8(6):4437-4442. doi: 10.1039/c7sc00675f. Epub 2017 Apr 28.
Pyridine rings are ubiquitous in drug molecules; however, the pre-eminent reaction used to form carbon-carbon bonds in the pharmaceutical industry, the Suzuki-Miyaura cross-coupling reaction, often fails when applied to these structures. This phenomenon is most pronounced in 2-substituted pyridines, and results from the difficulty in preparing, the poor stability of, and low efficiency in reactions of pyridine-2-boronates. We demonstrate that by replacing these boronates with pyridine-2-sulfinates, a cross-coupling process of unrivalled scope and utility is realized. The corresponding 3- and 4-substituted pyridine variants are also efficient coupling partners. In addition, we apply these sulfinates in a library format to the preparation of medicinally relevant derivatives of the drugs varenicline (Chantix) and mepyramine (Anthisan).
吡啶环在药物分子中普遍存在；然而，制药行业用于形成碳 - 碳键的卓越反应——铃木 - 宫浦交叉偶联反应，应用于这些结构时常常失败。这种现象在2 - 取代吡啶中最为明显，这是由于吡啶 - 2 - 硼酸酯的制备困难、稳定性差以及反应效率低所致。我们证明，通过用吡啶 - 2 - 亚磺酸盐取代这些硼酸酯，可以实现一个具有无与伦比的范围和实用性的交叉偶联过程。相应的3 - 和4 - 取代吡啶变体也是有效的偶联伙伴。此外，我们将这些亚磺酸盐以文库形式应用于制备药物伐尼克兰（畅沛）和美吡拉敏（安替司丁）的医学相关衍生物。
