Iridium-catalyzed C−H methylation and d3-methylation of benzoic acids with application to late-stage functionalizations

iScience

Martin A. Hayes¹  Erik Weis²  Magnus J. Johansson³  Belén Martín-Matute⁴ 

[1] Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;Department of Organic Chemistry, Stockholm University, Stockholm 106 91, Sweden;Hit Discovery, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;

关键词: Chemistry;    Organic chemistry;    Green chemistry;    Applied chemistry;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Late-stage functionalization (LSF) has over the past years emerged as a powerful approach in the drug discovery process. At its best, it allows for rapid access to new analogues from a single drug-like molecule, bypassing the need for de novo synthesis. To be successful, methods able to tolerate the diverse functional groups present in drug-like molecules that perform under mild conditions are required. C−H methylation is of particular interest due to the magic methyl effect in medicinal chemistry. Herein we report an iridium-catalyzed carboxylate-directed ortho C−H methylation and d3-methylation of benzoic acids. The method uses commercially available reagents and precatalyst and requires no inert atmosphere or exclusion of moisture. Substrates bearing electron-rich and electron-poor groups were successfully methylated, including compounds with competing directing/coordinating groups. The method was also applied to the LSF of several marketed drugs, forming analogues with increased metabolic stability compared with the parent drug.

【 授权许可】

Unknown