Synthesis of 1-.BETA.-D-(5-Deoxy-5-iodoarabinofuranosyl)-2-nitroimidazole (.BETA.-IAZA): A Novel Marker of Tissue Hypoxia.

Abstract

The present work describes the synthesis of the beta-isomer of 1-alpha-D-(5-deoxy-5-iodoarabinofuranosyl)-2-nitroimidazole (IAZA). Radioiodinated IAZA ((123)I-IAZA) has been extensively studied as a radiopharmaceutical for the diagnosis of regional and/or focal tissue hypoxia in a variety of clinical pathologies. The beta-anomer of IAZA, 1-beta-D-(5-deoxy-5-iodoarabinofuranosyl)-2-nitroimidazole (beta-IAZA, 1), was synthesized via an unconventional route starting from 1-beta-D-(ribofuranosyl)-2-nitroimidazole (AZR), with a change of configuration at the C-2'-position to afford 1-beta-D-(arabinofuranosyl)-2-nitroimidazole (beta-AZA, 7). Nucleophilic iodination of the 5'-O-toluenesulfonyl-2',3'-di-O-acetyl precursor of beta-AZA, 9, followed by deprotection, afforded 1 in satisfactory yield. beta-IAZA (1) was also synthesized from 7 using molecular iodine and triphenylphosphine.

2-Nitroimidazole-Furanoside Derivatives for Hypoxia Imaging—Investigation of Nucleoside Transporter Interaction, 18F-Labeling and Preclinical PET Imaging

“…An improved synthesis of the β -arabinose-derived nucleoside analog β -FAZA from the known starting material β - 1 (prepared as described by Kumar et al [25]) was developed (Scheme 1). Selective silylation of the primary hydroxyl group at C-5′ with TBDMSCl/imidazole in pyridine, followed by acetylation, furnished crystalline and fully protected nucleoside β - 2 (80%).…”

“…β -FAZA was recently prepared by a different approach [14]. Here, we were able to improve the overall process compared to [14] by a reduction of synthetic steps (for initial reaction steps from the commercially available 1- β -D-(ribofuranosyl)-2-nitroimidazole, see [14,25]), overall reaction times, and an increase in yield to 48% for the three steps shown in Scheme 1, compared to 21% for the last three steps in [14]. The improvement was obviously due to the utilization of the commercial fluorination agent, Deoxo-Fluor ® , in the penultimate step.…”

“…1-(5′- tert .-Butyldimethylsilyl-2′,3′-di- O -acetyl- β -D-arabinofuranosyl)-2-nitroimidazole ( β -2): A solution of TBDMSCl (0.068 g, 0.45 mmol, 1.1 equiv.) in dry pyridine (1.43 mL) was added to a mixture of 1-(2′- O -acetyl- β -D-arabinofuranosyl)-2-nitroimidazole ( β −1 ; [25]) (0.118 g, 0.41 mmol) and imidazole (0.056 g, 0.82 mmol, 2 equiv.) at –20 °C under argon atmosphere.…”

“…Three-step synthesis of the 5′-fluoro nucleoside analog β -FAZA, starting from 1-(2′- O -acetyl- β -D-arabinofuranosyl)-2-nitroimidazole ( β - 1 ; [25]). Reagents for and yields of the individual steps are given in the scheme.…”

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

“…21d,27 The hydroxyl groups at C-5′ and C-3′ were protected with the 3′,5′- O , O -(1,1,3,3-tetraisopropyldisiloxanylidene) group, and the configuration of the free hydroxyl at C-2′ was inverted by substituting the triflate with tetrabutylammonium acetate. (27) Then the disiloxanylidene group was removed, and the diol was monotosylated and acetylated to give β- 7 . We thought that we could shorten the lengthy synthesis by starting from a β- d -ribose derivative already containing the disiloxanylidene group (Scheme 8).…”