Synthesis of the Enantiomers of the Dual Function 2‐Nitroimidazole Radiation Sensitizer RB 6145.

Abstract

Short, efficient pathways are described for the synthesis of racemic 2-nitroimidazole radiation sensitizer RB-6145 (2a) and each of its corresponding (R)-and (S)-enantiomers (2b and 2c, respectively). The synthesis of each enantiomer commences with the appropriate chiral epichlorohydrin and utilizes a novel application of 3-trimethylsilyl-2-oxazolidinone (3b) as a mild, safe surrogate for highly toxic aziridine. The synthesis of the (R)-enantiomer (2b) has been successfully scaled up to provide multi-kilo quantities of material for early stage preclinical evaluation.

[68Ga]‐HP‐DO3A‐nitroimidazole: a promising agent for PET detection of tumor hypoxia

“…As outlined in Scheme , HP‐DO3A‐NI was prepared in two steps in high yield. The key intermediate ( S )‐oxiranylmethyl‐nitro‐imidazole ( 1 ), prepared using established procedures , was conjugated to the macrocyclic unit via a nucleophilic attack by the only secondary nitrogen in DO3A‐ tris ‐t‐butyl ester to afford intermediate 2 in 60% yield. Finally, the t‐butyl protecting groups were removed by using trifluoroacetic acid (TFA) at room temperature overnight to produce the final ligand in quantitative yield.…”

“…The intermediate ( S )‐oxiranylmethyl‐nitro‐imidazole ( 1 ) and DO3A tris‐ t ‐butyl ester were prepared according to established procedures .…”

“…The intermediate (S)-oxiranylmethyl-nitro-imidazole (1) and DO3A tris-t-butyl ester were prepared according to established procedures (14,21). To a stirred solution of compound 2 (3.4 g, 5 mmol) in CH 2 Cl 2 (100 mL) at 0°C was added trifluoroacetic acid (20 mL).…”

2-Nitroimidazole-Tricarbocyanine Conjugate as a Near-Infrared Fluorescent Probe for in Vivo Imaging of Tumor Hypoxia

“…The process of synthesis was as follows. First, 4-aminomethylpiperidine ( 1 ) was converted to Schiff base N -benzylidene-1-(piperidin-4-yl)methanamine ( 2 ), then coupled to 2-nitro-1-(2-oxiranylmethyl)-1 H -imidazole ( 3 ) , to yield 1-[4-(aminomethyl)piperidin-1-yl]-3-(2-nitro-1 H -imidazol-1-yl)propan-2-ol hydrochloride ( 4 ) in 61% yield (3 steps), which was a derivative of Pimo with a functional amino group to be covalently modified. Tricarbocyanine dye 6 , which possesses bis alkyl linker moieties with carboxyl groups, was prepared from 1-(ε-carboxypentyl)-2,3,3-trimethyl-3 H -indoleninium-5-sulfonate ( 5 ) as previously reported .…”

Automated synthesis and PET evaluation of both enantiomers of [18F]FMISO

“…The reference enantiopure FMISO (both enantiomers) were prepared according to the reported procedure [15]. (R)-and (S)-2-nitro-1-(oxiran-2-ylmethyl)-1H-imidazoles, the ((R) and (S)-MISO-epoxides) were synthesized similarly to the previously described protocol [16]: a stirred suspension of 2-nitroimidazole (1.00 g, 8.84 mmol, 1.0 eq) and cesium carbonate (145 mg, 0.44 mmol, 0.05 eq.) in dry ethanol (20 mL) was treated with the (R)-or the (S)-epichlorohydrin (760 μL, 9.60 mmol, 1.1 eq.…”