Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor

Abstract

Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.

Cu-Catalyzed Couplings of Heteroaryl Primary Amines and (Hetero)aryl Bromides with 6-Hydroxypicolinamide Ligands

“…As an alternative to ligands possessing two amide donors, competitive reactivity was achieved when one of the two amides was replaced with a nitrogen heterocycle such as a pyridine ( L37 ), indole, pyrrole, or benzimidazole. AbbVie disclosed the use of a picolinamide ligand (Figure ) for the synthesis of dasabuvir, an HCV polymerase inhibitor with a related C–N coupling. Following this precedent, picolinamide ligands such as L37 were found to have sufficient reactivity but possessed relatively poor selectivity for the desired product 3 versus diarylated product 6 (Table , entry 8) .…”

Palladium-Catalyzed Amidation and Amination of (Hetero)aryl Chlorides under Homogeneous Conditions Enabled by a Soluble DBU/NaTFA Dual-Base System

“…Not only does this dictate that elevated reaction temperatures (typically ≥80 °C) and high catalyst loadings are often required to achieve reasonable reaction rates, but the heterogeneous nature of the reaction mixture also leads to a number of other factors impacting the reaction kinetics that are difficult to predict, including effects of the lot, form, particle size, and particle shape of the base , as well as effects of water content (both added and adventitious). , Furthermore, pronounced changes in reaction rate are often observed when moving from small-scale reactions conducted with magnetic stirring, where a grinding effect of the stir bar can lead to an increase in base surface area, to overhead stirring where such grinding effects are absent . While milling of the base can compensate for the lack of beneficial grinding with overhead stirring, , mixing effects may be observed when reactions are performed in vessels with different size or configuration or when different agitation speeds are employed . The combined impact of these complex factors renders the development and scale-up of transformations employing heterogeneous bases a highly challenging and time-consuming process. ,,, …”

Pd-Catalyzed Cross-Coupling of Hindered, Electron-Deficient Anilines with Bulky (Hetero)aryl Halides Using Biaryl Phosphorinane Ligands

“…We are interested in evaluating biaryl phosphorinanes as ligands for metal-catalyzed reactions . In order to rapidly prepare newer ligands, an improved synthetic procedure was needed.…”

“…Recently, we reported that biaryl phosphorinanes are highly effective ligands for Pd-catalyzed C–N and C–O cross-coupling reactions. , One of these ligands, VincePhos, was used in the multikilogram scale synthesis of dasabuvir, an HCV polymerase inhibitor . Herein, we report that the newly prepared biaryl phosphorinanes AlisonPhos and AliPhos are highly effective ligands for the Pd-catalyzed coupling of ortho - and ortho , ortho′ -substituted electron-deficient anilines (Hammett parameter (σ) > 0.15) with hindered (hetero)­aryl halides (Figure B).…”