The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor

Abstract

The process development and kilogram-scale synthesis of beclabuvir (BMS-791325, 1) is described. The convergent synthesis features the use of asymmetric catalysis to generate a chiral cyclopropane fragment and coupling with an indole fragment via an alkylation. Subsequent palladium-catalyzed intramolecular direct arylation efficiently builds the central seven-membered ring. The target was prepared in 12 linear steps with five isolations in an overall yield of 8%.

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

“…Exploratory studies were also conducted to determine whether the cyclopropanation reactions were amenable to scaleup. 11,[41][42][43][44] The replacement of molecular sieves with HFIP enabled the reaction to be performed on multi-gram scale, providing 39 in 95% yield and 98% ee (Scheme 3). Performing the reaction on large scale also enabled the use of considerably lower catalyst loading (0.16 mol% vs. 1.0 mol%).…”

“…[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).…”

Role of Additives to Overcome Limitations of Intermolecular Rhodium-Catalyzed Asymmetric Cyclopropanation

“…Exploratory studies were also conducted to determine whether the cyclopropanation reactions were amenable to scale-up. [3,18] The replacement of molecular sieves with HFIP enabled the reaction to be performed on multi-gram scale, since the large quantity of sieves required to promote the reaction was considered prohibitive, providing 39 in 95% yield and 98% ee (Scheme 4). Performing the reaction on large scale also enabled the use of considerably lower catalyst loading (0.16 mol % vs. 1.0 mol %).…”

“…[2] The two substituents are placed in a defined 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), [3] paritaprevir (2) [4] and glecaprevir (3) [5] (Figure 1). In these cases, three substituents are placed in a defined orientation.…”

Metal-Dependent Umpolung Reactivity of Carbenes Derived from Cyclopropenes

“…Beyond the typical carbene reactions, many unique conversions have been reported in recent decades, for example, carbene migratory insertions (Xia et al., 2017) and gold-carbene-mediated annulations (Obradors and Echavarren, 2014). These studies can enable powerful synthetic pathways in diversity-oriented synthesis, total synthesis, and pharmaceutical process development, making this field dynamic for development purposes (Bertrand, 2002, Chiu, 2005, Bien et al., 2018).…”