Department of Discovery Chemistry, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
Department of Process Research and Development, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.
J Org Chem. 2020 Apr 3;85(7):4807-4812. doi: 10.1021/acs.joc.0c00020. Epub 2020 Mar 20.
The therapeutic application of nitric oxide, an endogenous cellular signaling molecule, has been limited due to the difficulty of developing stable pro-drugs with slow kinetics of NO release. Diazeniumdiolates are valuable NO donors; however, synthetic challenges have hampered their use. O-alkylation or arylation of diazeniumdiolates form stable pro-drugs which have found application in hypertension, cancer, and as antimicrobial agents. The synthesis of sodium diazeniumdiolates has proven to be challenging due to hazardous reaction conditions (high NO concentrations, and flammable solvents), which can lead to detonation and suffered from limited scope. We have previously disclosed that synthesis of calcium diazeniumdiolate salts are a safer and more scalable alternative. Herein, we report the expanded scope of calcium diazeniumdiolates from benzylic amines, amides, and sterically bulky amines hitherto inaccessible and a comparison of their reactivity in comparison to sodium diazeniumdiolate.
由于难以开发具有缓慢 NO 释放动力学的稳定前药，作为内源性细胞信号分子的一氧化氮的治疗应用受到限制。叠氮醇盐是有价值的一氧化氮供体；然而，合成方面的挑战阻碍了它们的使用。叠氮醇盐的 O-烷基化或芳基化形成稳定的前药，已在高血压、癌症和抗菌剂中得到应用。由于危险的反应条件（高浓度的 NO 和易燃溶剂），合成叠氮醇盐已被证明具有挑战性，这可能导致爆炸，并受到有限范围的限制。我们之前已经披露，合成钙叠氮醇盐盐是一种更安全和更可扩展的替代方法。在此，我们报告了钙叠氮醇盐从前药不可及的苄基胺、酰胺和空间位阻大的胺扩展的范围，并比较了它们与钠叠氮醇盐的反应性。
