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Synfacts 2020; 16(11): 1258
DOI: 10.1055/s-0040-1706322
Synthesis of Natural Products and Potential Drugs

Synthesis of Glecaprevir. Part 1

Rezensent(en):
Philip Kocienski
Cink RD. * et al. AbbVie Inc., North Chicago, USA
Development of a Large-Scale Route to Glecaprevir: Synthesis of the Macrocycle via Intramolecular Etherification.

Org. Process Res. Dev. 2020;
24: 1373-1392
DOI: 10.1021/acs.oprd.0c00244.
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Key words

glecaprevir - SNAr reaction - intramolecular nucleophilic substitution - macrocyclization - cycloetherification

Significance

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.


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Comment

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).


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Publikationsverlauf

Artikel online veröffentlicht:
20. Oktober 2020

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