Synthesis of ABBV-168, a 2′-Bromouridine for the Treatment of Hepatitis C

Abstract

ABBV-168 is a dihalogenated nucleotide under investigation for the treatment of hepatitis C virus. Three synthetic routes aimed at achieving the stereoselective installation of the C2′ gem-Br,F substitution and subsequent Vorbruggen glycosylation were explored to prepare the penultimate nucleoside intermediate. Development culminated in a route to ABBV-168 featuring a de novo chromatography-free furanose synthesis, protecting group-directed Vorbruggen glycosylation, and highly selective phosphoramidation to furnish the API.

Diastereoselective Synthesis of 2′-Dihalopyrimidine Ribonucleoside Inhibitors of Hepatitis C Virus Replication

“…Indeed, Vorbrüggen-type condensation (S N 1 mechanism) resulted in poor diastereoselectivities with β/α anomer ratios between 1/2 10 and 1/1. 11 We, therefore, sought to overcome this selectivity issue by introducing the nucleobase via an S N 2-type reaction. The literature shows that addition of a silylated uracil (without a Lewis acid) on a pure α-1-chloro or -bromo sugar can lead selectively to the formation of β nucleoside anomers.…”

“…We then turned our attention to the glycosylation step, which is one of the major limitations in the existing synthetic routes. Indeed, Vorbrüggen-type condensation (S N 1 mechanism) resulted in poor diastereoselectivities with β/α anomer ratios between 1/2 and 1/1 . We, therefore, sought to overcome this selectivity issue by introducing the nucleobase via an S N 2-type reaction.…”

“…After the completion of our work, Voight et al. (Scheme ) published an approach for the large-scale synthesis of ABBV-168 ( 4 ) in which the introduction of the two halogens is achieved through the Reformatsky reaction . Despite the fact that the pure isomer 18 could be easily isolated via crystallization, the yield of this reaction was quite low (25%).…”

Polyhalogenated Carbohydrates: Synthesis and Applications of Sugar Halides from Fluorine to Iodine

“…[9] Another representative example of useful polyhalogenated carbohydrates is shown in Figure 1. Thus, ABBV-168 2 is a 2'-bromouridine developed by AbbVie for the treatment of hepatitis C. [10] The de novo synthetic route allowed the installation of the C2' gem-Br,F moiety without any chromatographic purification. This synthetic tour de force clearly shows the importance of developing new methods to heavily halogenated carbohydrates.…”

Follow the Silyl Cation: Insights into the Vorbrüggen Reaction

“…This property is on display in the Vorbrüggen reaction, a method for the synthesis of nucleosides from anomeric glycosyl esters and unprotected nucleobases . The key feature of this reaction is the use of TMSOTf to transform an unreactive and insoluble nucleobase into a highly nucleophilic silylated analogue which can react with a glycosyl electrophile in the presence of an added Lewis acid, commonly a tin­(II) or tin­(IV) salt, in traditional organic solvents (Figure , eq 1).…”