Preparation of Pyrido[2,3-b]pyrazine Ring System via Regioselective Condensation Reaction

Author(s): Laszlo Kekesi, Andras Dancso, Eszter Illyes, Sandor Boros, Janos Pato, Zoltan Greff, Gabor Nemeth, Rita Garamvolgyi, Ferenc Baska, Laszlo Orfi, Gyorgy Keri.

Journal Name: Letters in Organic Chemistry

Volume 11 , Issue 9 , 2014

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Graphical Abstract:


The pyrido[2,3-b]pyrazine core structure can be found in several molecules that express biological activity. We have previously published a series of these compounds that showed erlotinib-resistant tumor inhibitor potential. The common way of their synthesis is the condensation of pyridinediamines and α-oxocarbonyl compounds. If the starting dioxo compound is unsymmetrical, two regioisomers can be formed, which can display significantly different biological activity. To study the regioselectivity of this reaction we chose a model reaction and examined the impact of the reaction temperature, the acidic or basic catalysis, the amount of starting materials or the usage of dehydrating agent on the outcome of the reaction. In summary, increased regioselectivity could be observed at low temperature in acidic solvents (e.g. acetic or trifluoroacetic acid). As a result, we were able to optimize the reaction conditions to increase the amount of the biologically more active isomer. The isomers were separated, characterized by their NMR spectra and HPLC retention values, and identified by single-crystal X-ray diffraction crystallography.

Keywords: Acidic catalysis, inhibitor, pyrido[2, 3-b]pyrazine, regioselectivity, thermal effect, X-ray crystal structure.

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Article Details

Year: 2014
Page: [651 - 656]
Pages: 6
DOI: 10.2174/1570178611666140606205028
Price: $58

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