Synthesis of the Hepatitis B Nucleoside Analogue Lagociclovir Valactate

Abstract

2′,3′-Dideoxy-3′-fluoro-5-O-[(S)-(+)-2-(l-valyloxy)-propionyl] guanosine (lagociclovir valactate) is a prodrug of 3′-fluoro-2′,3′-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). A five-step synthesis of lagocyclovir valactate starting from 2-amino-6-chloropurine is described. The synthesis was performed at kilogram scale, and the target nucleoside prodrug was isolated as the hemisulphate salt with an overall yield of 23%. The major challenges were N-glycosylation of a 2-deoxyfluorosugar, which required separation of α- and β-anomers, and deprotection of the penultimate intermediate by hydrogenation.

Recent Advance of the Hepatitis B Virus Inhibitors: A Medicinal Chemistry Overview

“…Lagociclovir valactate (43,, invented by Medvir AB company, is a prodrug of the nucleoside analogue 3'-fluoro-2', 3'-dideoxyguanosine (FLG) and has high oral bioavailability in humans and potent activity against HBV [117][118][119]. Because of favorable plasma levels and good oral bioavailability of MIV-210 in Phase I studies, Phase II clinical trial has been started in South Korea.…”

Diversification of 4′-Methylated Nucleosides by Nucleoside Phosphorylases

“…As such, modified nucleosides mimicking their natural counterparts have a long history in medicinal and biological chemistry. − Today, modified nucleosides are indispensable pharmaceuticals for the treatment of various types of cancer and viral infections and further represent important tools in chemical biology for a spectrum of imaging applications. , Despite the great demand for these molecules, the synthesis of nucleosides is still regarded as challenging and inefficient . While nucleosides with ribosyl or 2′-deoxyribosyl moieties can be accessed from naturally occurring nucleosides or carbohydrates, − the preparation of sugar-modified nucleosides typically suffers from lengthy reaction sequences and low total yields. − Furthermore, a heavy reliance on protecting groups entails low overall efficiencies, and several sugar modifications at the 2′ or 4′ positions are known to limit diastereoselectivity in glycosylation approaches, , severely complicating the synthetic access to many target compounds. More importantly, established routes typically exhibit a lack of divergence as they tend to be specific to one nucleoside.…”

“…7 While nucleosides with ribosyl or 2′-deoxyribosyl moieties can be accessed from naturally occurring nucleosides or carbohydrates, 7−10 the preparation of sugar-modified nucleosides typically suffers from lengthy reaction sequences and low total yields. 11−18 Furthermore, a heavy reliance on protecting groups entails low overall efficiencies, 7 and several sugar modifications at the 2′ or 4′ positions are known to limit diastereoselectivity in glycosylation approaches, 19,20 severely complicating the synthetic access to many target compounds. More importantly, established routes typically exhibit a lack of divergence as they tend to be specific to one nucleoside.…”

Diversification of 4ʹ-Methylated Nucleosides by Nucleoside Phosphorylases

“…[7] While nucleosides with ribosyl or 2ʹ-desoxyribosyl moieties can be accessed from naturally occurring nucleosides or carbohydrates, [7][8][9][10] the preparation of sugar-modified nucleosides typically suffers from lengthy reaction sequences and low total yields. [11][12][13][14][15][16][17][18] Furthermore, a heavy reliance on protecting groups entails low overall efficiencies [7] and several sugar modifications at the 2ʹ or 4ʹ positions are known to limit diastereoselectivity in glycosylation approaches, [19,20] severely complicating the synthetic access to many target compounds. More importantly, established routes typically exhibit a lack of divergence as they tend to be specific to one nucleoside.…”