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Synthesis of Glecaprevir. Part 1
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Macrocycle via Intramolecular Etherification.
Org. Process Res. Dev. 2020;
Key wordsglecaprevir - SNAr reaction - intramolecular nucleophilic substitution - macrocyclization - cycloetherification
The combination of glecaprevir and pibrentasvir was approved in 2017 for the treatment of chronic hepatitis C virus infections. A new large-scale synthesis of glecaprevir is described in two parts. Part 1 shown here concerns the construction of the 18-membered macrocycle A featuring as the key step an intramolecular cycloetherification of allylic bromide J. For part 2, see Org. Process Res. Dev. 2020 24, 1393; Synfacts 2020, 16, 1259.
The identification of solvates with low solubility allowed the crystallization of macrocycle A in high purity directly from the reaction mixture. The overall yield to macrocycle A was 20% for the lowest yielding sequence through carbamate H, a significant improvement on the 15% yield of the enabling route based on ring-closing metathesis (Org. Process Res. Dev. 2020, 24, 183).
20 October 2020 (online)
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