Synthesis of 1-chloro-3-aminopyrazolylisoquinoline

In doing research on the latest patents on WIPO (28.06.2007), I found a patent from Hoffmann-La Roche describing the synthesis of different isoquinoline aminopyrazoles, this type of molecules are protein kinase inhibitors (Aurora A)(I don't find it on Kinasepro's blog, but maybe I am wrong, otherwise nobody's perfect...).

I present here, only the synthesis of the main nucleus.

Interestingly, this synthesis starts with 1-indanone, which upon the treatment of butylnitrite, furnishes the 2-oxime derivative in 2 hours and in 65% yield (19.5g scale). Then the 2-cyanomethylbenzoic acid is obtained with a Beckmann rearrangement of the oxime previously prepared using the para-toluenesulfonylchloride (Yield = 74%). The reaction of the 2-cyanomethylbenzoic acid and 3-amino-5-pyrazole by a microwave-assisted cyclization in acetic acid in sealed vessel provides the isoquinolone in 75% yield (2g scale). Finally, the chlorination is performed using POCl3 to deliver the 1-chloro-3-aminopyrazolylisoquinoline in 61% yield.

Of course the synthesis continues with either O or S nucleophilic substitution on the chlorine atom or by Suzuki cross-coupling, furthermore different substituents can be introduced on either the pyrazole ring or the phenyl ring of the isoquinoline.

WO/2007/071348

Synthesis of alkylpyridine

I am just reading the Tetrahedron report number 800 on "Titanium carbenoid reagents for converting carbonyl groups into alkenes" by Hartley and that reminds me a paper of Nicolaou, I read some years ago, concerning the reaction of Titanocene methylidene with isoquinoline N-oxide.




In his paper, KCN noticed that the different "pyridine" N-oxides can be deoxygenated by Tebbe reagent and in the same time the introduction of a methyl group in also possible (in alpha of the N), and regioselectively in the case of isoquinoline. The same reactivity has been observed with Petasis reagent, but with longer time reaction and higher temperature.

Angew. Chem. Int. Ed. 2000, 39, 2529.