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Chemical Modification of 2,6,9-Trisubstituted Purine CDK Inhibitors: tert-Butylation at N7/N9 and Access to
Michal Valenta1, Jakub Stýskala1
1Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46 Olomouc, Czech Republic.
Abstract:
This study focuses on the chemical modification of known 2,6,9-trisubstituted purine cyclin-dependent kinase (CDK) inhibitors as model compounds, with particular emphasis on the incorporation of the less-explored tert-butyl group (representing tert-alkyl substituents) at the N7 and N9 positions of the purine core to prepare 2,6,7- and 2,6,9-trisubstituted analogs. Primarily chemical aspects of these modifications are studied, focusing on the effect of the tert-butyl group on chlorine reactivity at C2/C6 position and purine ring stability during substitution reactions, especially in the case of 2,6,7-trisubstituted compounds. The effect of the tert-butyl group is also evaluated in comparison with other substituents at the purine ring. Furthermore, a novel and unambiguous synthetic route to key intermediates -7 and 9-(tert-butyl)-2,6-dichloropurines-has been developed by a new method to enable targeted substitution at the chlorine-bearing positions.
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