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
Key words
glecaprevir - S
NAr 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.
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).
