Synthesis of 2′-C-methyl-β-D-ribofuranosylimidazo [4,5-d]-pyridazine derivatives (2-aza-3-deazapurine nucleoside analogues)

Article abstract of DOI:10.1081/NCN-200060225

In order to evaluate their antiviral properties, two imidazo[4,5-d] pyridazine 2′-C-methyl-β-D-ribofuranonucleoside derivatives have been synthesized. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200060225

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SYNTHESIS OF 2′-C-METHYL-β-D-
RIBOFURANOSYLIMIDAZO[4,5-D]PYRIDAZINE
DERIVATIVES (2-AZA-3-DEAZAPURINE NUCLEOSIDE
ANALOGUES)
F. Leroy a , D. Dukhan a , M. Durka a , D. Chaves a , N. Bragnier a , R. Storer b & G. Gosselin a
a Laboratoire Coopératif Idenix—CNRS , Université Montpellier II , Montpellier Cedex 5,
France
b Laboratoire de Chimie Médicinale Idenix , Parc Euromedecine, rue Louis Pasteur ,
Montpellier, France
Published online: 15 Nov 2011.
To cite this article: F. Leroy , D. Dukhan , M. Durka , D. Chaves , N. Bragnier , R. Storer & G. Gosselin (2005) SYNTHESIS OF
2′-C-METHYL-β-D-RIBOFURANOSYLIMIDAZO[4,5-D]PYRIDAZINE DERIVATIVES (2-AZA-3-DEAZAPURINE NUCLEOSIDE ANALOGUES),
Nucleosides, Nucleotides and Nucleic Acids, 24:5-7, 667-669, DOI: 10.1081/NCN-200060225
To link to this article: http://dx.doi.org/10.1081/NCN-200060225
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):667–669, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060225
SYNTHESIS OF 2’-C-METHYL-b-D-RIBOFURANOSYLIMIDAZO
[4,5-d]-PYRIDAZINE DERIVATIVES (2-AZA-3-DEAZAPURINE
NUCLEOSIDE ANALOGUES)
5
F. Leroy, D. Dukhan, M. Durka, D. Chaves, and N. Bragnier
Laboratoire
Coopeꢀratif Idenix -CNRS, UniversiteꢀMontpellier II, Montpellier Cedex 5, France
5
R. Storer
Laboratoire de Chimie Meꢀdicinale Idenix, Parc Euromedecine, rue Louis
Pasteur, Montpellier, France
5
G. Gosselin
Laboratoire Coopeꢀratif Idenix--CNRS, Universiteꢀ Montpellier II, Mont-
pellier Cedex 5, France
5
In order to evaluate their antiviral properties, two imidazo[4,5-d]pyridazine 2’-C-methyl-b-D-
ribofuranonucleoside derivatives have been synthesized.
Keywords 2’-C-Methyl Branched Nucleosides, 2-Aza-3-Deazapurines Derivatives
INTRODUCTION
In the search for improved therapeutic agents against chronic hepatitis C virus
(HCV) infection, a purine ribonucleoside analog, 2’-C-methyladenosine 1
(Scheme 1), was discovered several years ago as a potent and selective inhibitor
in cell culture of a number of related RNA viruses, including bovine viral diarrhea
(BVDV), yellow fever (YFV) and West Nile (WNV) viruses.[1,2] Subsequently,
the synthesis and biological evaluation of other C-branched-sugar nucleoside
analogues bearing natural or modified nucleic acid bases have been investigated
extensively.[3–7]
We report here the chemical syntheses of two hitherto unknown imidazo[4,5-
d]pyridazine 2’-C-methyl-b-D-ribofuranonucleoside derivatives, 2 and 3 (Scheme 1).
Until now, the few literature reports regarding imidazo[4,5-d]pyridazine nucleoside
analogues have dealt only with the ribose series.[8–11]
Address correspondence to G. Gosselin, Laboratoire Coopeꢀratif Idenix—CNRS, UniversiteꢀMontpellier II,
Place Eug`ene Bataillon, Case Courrier 008, 34095 Montpellier Cedex 5, France; Fax: +33-4-6754-9610; E-mail:
gosselin@univ-montp2.fr
667
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668
F. Leroy et al.
SCHEME 1 2’-C-methyladenosine (1) and title compounds (2, 3).
SCHEME 2 Synthesis of 4-amino-1-(2-C-methyl-b-D-ribofuranosyl)imidazo[4,5-d]pyridazine.
CHEMISTRY
4-Amino-1-(2-C-methyl-b-D-ribofuranosyl)imidazo[4,5-d]pyridazine 2 was syn-
thesized by direct glycosylation of imidazo[4,5-d]pyridazin-4-one 5[12] with 1,2,3,5-
tetra-O-benzoyl-2-C-methyl-b-D-ribofuranose 4[13] using 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) as
coupling agents. The chlorination of 6 followed by ammonolysis led to the
desired 2’-C-methyl-2-aza-3-deazaadenosine 2 (Scheme 2).
For the synthesis of 2’-C-methyl-3-amino-2-aza-3-deazaadenosine 3, the 4,5-
dicyanoimidazole 8[14] was proved to be a useful starting material. Reaction of
8 with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-b-D-ribofuranose 4[13] in the presence of
SCHEME 3 Synthesis of 4,7-diamino-1-(2-C-methyl-b-D-ribofuranosyl)imidazo[4,5-d] pyridazine.

F. Leroy et al.
669
DBU and TMSOTf gave the protected compound 9. The ring closure of 9 was
carried out with hydrazine hydrate in acetic acid to give the desired 2’-C-methyl-3-
amino-2-aza-3-deazaadenosine 3 (15% yield) (Scheme 3).
CONCLUSION
An original synthetic method using DBU/TMSOTf as coupling agent and
imidazo[4,5-d] pyridazin-4-one has been described for the synthesis of 2’-C-methyl-2-
aza-3-deazaadenosine 2. A simple synthesis of 2’-C-methyl-3-amino-2-aza-3-deazaa-
denosine 3 has been accomplished starting from 4,5-dicyanoimidazole. The
biological evaluation of these two imidazo[4,5-d]pyridazine 2-C-methyl-b-D-ribofur-
anonucleosides is currently in progress.
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