Development of a Large-Scale Route to Glecaprevir: Synthesis of the Macrocycle via Intramolecular Etherification

Abstract

Glecaprevir was identified as a potent hepatitis C virus (HCV) protease inhibitor, and a large-scale synthesis was required to support the late-stage clinical trials and subsequent commercial launch. The large-scale synthetic route to glecaprevir required the development of completely new synthetic approaches to the two key structural features: the 18-membered macrocycle 3 and the difluoromethyl-substituted cyclopropyl amino acid 4. In this first manuscript, we describe the route development for the macrocycle 3; the second manuscript will describe the development of a new synthetic route to the difluoromethyl-substituted cyclopropyl amino acid 4 and the final assembly of glecaprevir. The large-scale synthetic route to the macrocycle employed a unique intramolecular etherification reaction as the key step in the macrocycle synthesis, avoiding the scalability limitations of the ringclosing metathesis (RCM) reaction of the enabling route. The large-scale synthetic route to the macrocycle was successfully used to produce the amount of glecaprevir required to support the late-stage clinical development.

Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates

“…[5][6][7][8][9][10] The two substituents are placed in a dened spacial arrangement to each other and the synthesis of such compounds is straightforward, as there is no additional chirality associated with the cyclopropane ring. In recent years more elaborate chiral cyclopropanes have been incorporated into therapeutic scaffolds, such as the trisubstituted cyclopropanes in beclabuvir (1), 11 paritaprevir (2) 12,13 and glecaprevir (3) [14][15][16] (Fig. 1).…”

Development of the Enabling Route for a Novel HCV NS3/4A Inhibitor, Furaprevir

“…As shown in Scheme 3, the synthesis of 7•HCl began with the Boc-amine 8. The Boc-amine 8 was deprotected with SOCl 2 /MeOH/tetrahydrofuran (THF), a similar method reported by Cink and co-workers, 13 as SOCl 2 is easier to store and transport compared to HCl/EA or HCl/dioxane. This step is quite early in our synthesis, and the formed genotoxic chloromethane can be removed as many processes such as trituration and distillation were utilized in the following steps.…”

Recent Applications of Pd-Catalyzed Suzuki-Miyaura and Buchwald-Hartwig Couplings in Pharmaceutical Process Chemistry.

“…Kallemeyn and coworkers 19 from AbbVie set out to design a large-scale synthetic method for a macrocycle intermediate towards the synthesis of Glecaprevir, 20 a potent hepatitis C virus (HCV) NS3/4A protease inhibitor. Two ring-closing options for the desired macrocycle were considered.…”