lundi 4 juin 2007

Synthesis of Indazole nucleus

In reading about kinasepro blog, you can notice the important number of biologically active compounds possessing the indazole core (in blue), Axitinib was synthesized by Pfizer and WO/2007/056170 was developed by Baeyer US as potent IGF-1R kinase inhibitors and ABT-102 was developped in Abbot lab and is currently in clinical development for the treatment of chronic pain.

I was looking for a straigthforward synthesis of indazole nucleus, I found a paper from Abbot lab.
They have depicted the synthesis of indazole starting from benzaldehyde with fluorine as leaving group and hydrazine, we can hope in that case to have formation of the hydrazone and subsequent intramolecular cyclization, but the reaction is very low yielding, because the cyclization is very slow and there is a competitive Wolf-Kishner reduction.

With some experiments they have confirmed that the reaction did not proceed via intramolecular cyclization of the hydrazone, but through a transient aminal (obtained by a previous nucleophilic subsitution of hydrazine on fluorine) which give the indazole core after elimination of hydrazine.

In order to circumvent this problem, they condensed the methyloxime on o-fluorobenzaldehydes to avoid Wolf-Kishner elimination, and with hydrazine cleanly gave indazoles. Good Job....

New Practical Synthesis of Indazoles via Condensation of o-Fluorobenzaldehydes and Their O-Methyloximes with Hydrazine
Kirill Lukin, Margaret C. Hsu, Dilinie Fernando, and M. Robert Leanna
J. Org. Chem. 2006, 71, 8166-8172.

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