An improved synthesis of α-AZA, α-AZP and α-AZG, the precursors to clinical markers of tissue hypoxia

Article abstract of DOI:10.1016/S0040-4039(01)00099-5

α-[¹²³I]-IAZA and α-[¹²³I]-IAZP are experimental diagnostic radiopharmaceuticals which have been used clinically to diagnose hypoxia in a number of pathologies, including cancer, peripheral vascular disease, rheumatoid arthritis and brain trauma. These nitroimidazole nucleosides are synthesized from the non-iodinated nucleosides AZA, AZP and AZG, respectively. Earlier methods report low chemical yields for the synthesis of these precursors. The modified procedures now reported provide nearly quantitative yields of these compounds, thereby substantially reducing the cost and effort of synthesis.

Full text of DOI:10.1016/S0040-4039(01)00099-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2077–2078
An improved synthesis of a-AZA, a-AZP and a-AZG, the
precursors to clinical markers of tissue hypoxia
Piyush Kumar, Leonard I. Wiebe,* Elena Atrazheva and Manju Tandon
Faculty of Pharmacy & Pharmaceutical Sciences, 3118 Dent-Pharm Building, University of Alberta, Edmonton,
Alberta, Canada T6G 2N8
Received 31 October 2000; accepted 2 January 2001
Abstract—a-[123I]-IAZA and a-[123I]-IAZP are experimental diagnostic radiopharmaceuticals which have been used clinically to
diagnose hypoxia in a number of pathologies, including cancer, peripheral vascular disease, rheumatoid arthritis and brain
trauma. These nitroimidazole nucleosides are synthesized from the non-iodinated nucleosides AZA, AZP and AZG, respectively.
Earlier methods report low chemical yields for the synthesis of these precursors. The modified procedures now reported provide
nearly quantitative yields of these compounds, thereby substantially reducing the cost and effort of synthesis. © 2001 Elsevier
Science Ltd. All rights reserved.
1 - (a -
D
- 5 - Iodoarabinofuranosyl) - 2 - nitroimidazole1
-4-iodoxylopyranosyl)-2-nitroimida-
have now been synthesized using hydrogen bromide
(HBr) gas that is easily removed from the reaction
mixture before coupling to azomycin (2-nitroimida-
zole). Furthermore, azomycin was converted to its N-1-
trimethylsilyl derivative before coupling with the
respective bromosugars. These reaction modifications
provide neutral reaction conditions, leading to quanti-
tative coupling. The formation of the nucleoside prod-
ucts was confirmed by comparison of their physical and
spectroscopic data with those reported in the litera-
ture.1,2,8 Table 1 shows the reaction times for bromina-
tion and coupling, the reaction temperature and
chemical yields for the synthesis of protected AZA,
AZP and AZG.
(IAZA) and 1-(a-
L
zole2 (IAZP) are being developed as diagnostic radio-
pharmaceuticals to detect and monitor regional
hypoxia in disease. [123I]-a-IAZA has been shown to be
useful in diagnosing a wide range of hypoxic tissue in
cancer,3,4 diabetes,5 rheumatoid arthritis,6 and blunt
trauma of the brain.7 These iodinated nitroimidazole
nucleosides were initially synthesized by generating cor-
responding, protected 1-a-bromosugars using 30% HBr
in glacial acetic acid, followed sequentially by coupling
to 2-nitroimidazole, deprotection and subsequent selec-
tive iodination.1,2,8 The coupling steps afforded benzoy-
lated AZA, acetylated AZP and acetylated AZG,
respectively, in only moderate chemical yields. Low
yields of the coupled products have been attributed to
residual acid, which cleaves the glycoside bond of the
coupled product and, subsequently, leads to significant
decomposition. These brominated sugar precursors
1-(a-D-2,3,5-Tri-O-benzoylarabinofuranosyl)-2-nitroim-
idazole (tribenzoyl AZA). 1-O-Methyl-2,3,5-tri-O-ben-
zoylarabinofuranose, 1 (10 g, 17.5 mmol) was dissolved
in anhydrous CH2Cl2 and the solution was cooled to
Table 1. Reaction conditions and the chemical yields of 1, 2 and 3
Compound
Bromination time (h)
Coupling time (h)
Temperature (°C)
Yield (%)
AZA
AZP
AZG
3
2.5
2.5
16
16
8
50
50
30
100
100
99
Abbreviations: 1-(a-
zole, AZP.
D-galactosyl)-2-nitroimidazole, AZG; 1-(a-D-arabinofuranosyl)-2-nitroimidazole, AZA; 1-(a-
D-xylopyranosyl)-2-nitroimida-
Keywords: improved synthesis; hypoxia markers; AZA; AZP; AZG; azomycin nucleosides.
* Corresponding author. E-mail: leonard.wiebe@ualberta.ca
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00099-5

2078
P. Kumar et al. / Tetrahedron Letters 42 (2001) 2077–2078
Scheme 1. Where i=HMDS/reflux; ii=Hg(CN)2, 50°C and R=-COC6H5.
galactose in 100 and 99% yields, respectively (Scheme
0–5°C. Hydrogen bromide gas was slowly bubbled
through this solution while the temperature of the
reaction was maintained cold. Once 1 was completely
exhausted (checked by TLC examination), excess HBr
was removed by bubbling argon through this solution.
The solvent was removed on a rotavapor in vacuo and
the contents were dried on hi-vac pump. Hexamethyl-
disilazane (75 mL) was added to another flask contain-
ing 2-nitroimidazole (2.44 g, 21.4 mmol). A catalytic
amount of ammonium sulfate was then added, and the
mixture was heated at reflux for 4 h. At this time,
2-nitroimidazole (azomycin) had completely dissolved
and formation of 1-N-trimethylsilyl-2-nitroimidazole
was complete. Excess HMDS was removed under com-
plete exclusion of moisture, and the product was dried
under high vacuum to remove the traces of HMDS.
The bromosugar, described above, was dissolved in
anhydrous acetonitrile (1 L) and added to the flask
containing 1-N-trimethylsilyl-2-nitroimidazole. This
was followed by the addition of mercuric cyanide (2.2
equivalents), after which the reaction flask was filled
with argon. The reaction mixture was heated at 50°C
for 16 h. TLC examination at this time showed com-
plete conversion of the bromosugar to the azomycin
nucleoside. The solvent was evaporated on a rotary
evaporator, the residue was dissolved in CH2Cl2, and
then washed sequentially with 30% w/v aqueous potas-
sium iodide and then cold water. The dichloromethane
phase was dried over anhydrous sodium sulfate,
filtered, evaporated and purified on a silica gel column
to yield 1† in quantitative yield.
1).
This modification yields azomycin nucleosides in nearly
quantitative yields, and can be applied to the synthesis
of other related compounds.
Acknowledgements
The authors gratefully acknowledge Alberta Cancer
Board, Edmonton, Canada for financial support (grant
RP-14) of this work.
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reported2); mp 3, 99°C (100°C reported).
.