Development of a Large-Scale Route to Glecaprevir: Synthesis of the Side Chain and Final Assembly

Abstract

The preceding article described the development of the large-scale synthetic route to macrocycle 3 of glecaprevir (1), a potent HCV protease inhibitor. This article describes the development of the synthesis of the difluoromethyl-substituted cyclopropyl amino acid 4, its conversion to the fully elaborated side chain, amino sulfonamide 2, and the subsequent final coupling to form glecaprevir. The synthesis of amino acid 4 consists of four key transformations: (a) formation of the difluoromethylsubstituted cyclopropane ring of (±)-diester 15 via Knoevenagel condensation and Corey−Chaykovsky cyclopropanation, (b) diastereoselective hydrolysis of (±)-diester 15 to yield (±)-monoacid 14a−b, (c) conversion of (±)-monoacid 14a−b to (±)-amino ester 10 via a Curtius rearrangement, and (d) resolution of (±)-amino ester 10 followed by saponification to give the desired (1R,2R)-amino acid 4. The large-scale synthetic route to amino acid 4 was successfully used to produce the fully elaborated side chain 2 and ultimately 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).…”

3,3-Difluoroallyl ammonium salts: highly versatile, stable and selective gem-difluoroallylation reagents

“…In contrast to –CH 2 F or –CF 3 substituents, –CF 2 –R containing bioactive compounds are significantly less explored and comparably few marketed therapeutic agents exist yet (for some examples see Fig. 1c ) 16 – 23 . So far, the most common route for their synthesis makes use of the fluorination of a pre-existing functional group using for example DAST or Deoxfluor 24 – 26 .…”

“…Especially, using gem -difluoroallyl moieties (a –CF 2 – group neighboring to an alkene unit) offers attractive possibilities because of the wide variety of subsequent functionalizations and its occurrence in existing pharmaceuticals (see also Fig. 1c ) 16 – 20 . Unfortunately, so far only a few methodologies for the direct intermolecular preparation of gem -difluoroallylic products are known 34 – 46 .…”

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

“…Based on the scale limitations of the enabling route, it was clear that new syntheses for macrocycle 3 and amino acid 4 would be required for large-scale production . The focus of this article is the development of a new route to macrocycle 3 ; the new route to amino acid 4 and the final assembly of glecaprevir are the subject of the following article …”

“…3 The focus of this article is the development of a new route to macrocycle 3; the new route to amino acid 4 and the final assembly of glecaprevir are the subject of the following article. 4 The synthetically challenging structural features to be addressed in the development of a new synthesis for macrocycle 3 are highlighted in red in Scheme 1. A new synthesis of macrocycle 3 posed two related synthetic challenges: a new approach to close the macrocycle and the construction of the red highlighted six-carbon section of the macrocycle.…”