Preparation of Nucleosides Derived from 2-Nitroimidazole and d-Arabinose, d-Ribose, and d-Galactose by the Vorbrüggen Method and Their Conversion to Potential Precursors for Tracers To Image Hypoxia

Abstract

2-Nitroimidazole was silylated using hexaethyldisilazane and then reacted with 1-O-acetyl derivatives of d-arabinose, d-ribose, and d-galactose in acetonitrile at mild temperatures (−20 °C to rt), catalyzed by triethylsilyl triflate (Vorbrüggen conditions). The α-anomer was formed in the former case and the β-anomers in the latter two cases (highly) selectively. When d-arabinose and d-ribose were silylated with tert-butyldiphenylsilyl chloride in pyridine at the hydroxyl groups at C-5 and acetylated at the other ones in a one-pot reaction, mixtures of anomeric 1-O-acetyl derivatives were obtained. These were coupled by the Vorbrüggen method and then deblocked at C-5 and tosylated to give precursors for tracers to image hypoxia in four steps without using Hg(CN)2 necessary for other methods. The Vorbrüggen conditions enable a shorter route to azomycin nucleoside analogues than the previous coupling procedures.

Functionalized Nitroimidazole Scaffold Construction and Their Pharmaceutical Applications: A 1950–2021 Comprehensive Overview

“…These were then coupled by using the Vorbruggen method followed by cascades to furnish the precursors for tracers to image hypoxia. [ 77 ] The representative example of nitroimidazole-ribose-based conjugate and arabinose-based hypoxia images is shown in Scheme 15 .…”

Preparation of Nonradioactive Standards and a Precursor for a Hypoxia 18F PET Tracer Derived from 1-(β-d-Galactopyranosyl)-2-nitroimidazole

“…Pentaacetyl-β-D-galactopyranose and N-triethyl-silylated 2-nitroimidazole (TES-NI) were coupled, catalyzed by TESOTf, to give nucleoside 6 in high yield (92%). 11 Zemplen saponification furnished 7 (88%), which was first tosylated (50%) and finally acetylated (93%) to deliver the desired precursor 9 for radiotracer [ 18 F]5. The three compounds 7-9 are stable crystalline products, which were fully characterized.…”

“…1-(2′,3′,4′-Tri-O-acetyl-6′-deoxy-6′-fluoro-β-D-galactopyranosyl)-2-nitroimidazole (β-11) and 1-(2′,3′,4′-Tri-O-acetyl-6′-deoxy-6′fluoro-α-D-galactopyranosyl)-2-nitroimidazole (α-11) A mixture of 2-nitroimidazole (189 mg, 1.67 mmol) and hexaethyldisilazane (820 mg, 3.34 mmol, 2 equiv) in anhyd pyridine (2.8 mL) was refluxed until it was homogeneous (30 min). 11 On cooling N-silylated 2-nitroimidazole crystallized, and pyridine and excess hexaethyldisilazane were removed by bulb to bulb distillation (70-75 °C/0.4 mbar) to leave N-triethylsilyl-2-nitroimidazole as a pale brownish crystalline residue.…”

“…Anhyd MeCN (6 mL) was added to triethylsilylated 2-nitroimidazole (prepared from 103 mg, 0.91 mmol of 2-nitroimidazole) 11 under argon, followed by a solution of 4-deoxy-4-fluoroglucopyranose tetraacetates α-and β-14 (0.428 g, 0.904 mmol by 1 H NMR, contained 74 mol% of product and 0.26 mol% of methyl glucopyranoside) in anhyd MeCN (5.4 mL). The mixture was ultrasonicated for 5 min.…”