Asymmetric Synthesis of the TRPV1 Modulator AMG8562 via Lipase-Catalyzed Kinetic Resolution
Eric C Wang1, Pyeonghwa Jeong1, Chris Han1
1Department of Chemistry, Duke University, Durham, North Carolina 27708, United States.
None:
The transient receptor potential vanilloid-1 (TRPV1) channel is a key mediator of pain perception and responds to various stimuli such as heat, low pH, and inflammation. Among TRPV1 antagonists, (R,E)-N-(2-hydroxy-2,3-dihydro-1H-inden-4-yl)-3-(2-(piperidin-1-yl)-4-(trifluoromethyl)-phenyl)-acrylamide (AMG8562) shows promise as a nonopioid analgesic, attenuating pain behaviors in rodent models without eliciting hyperthermic side effects commonly associated with other TRPV1 antagonists. Despite its potential, there has been limited research regarding the synthesis of AMG8562. Here, we present an asymmetric synthesis of AMG8562 featuring a lipase-catalyzed kinetic resolution of racemic 4-nitroindan-2-ol. This approach enables scalable access to enantiomerically pure material and provides a platform for the synthesis of structurally diverse AMG8562 analogues with potential for improved pharmacological properties.
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