Study On Synthesis Of The Akt Allosteric Inhibitorscontaining Thiazole Core Structure

Synthesis of thiazole core based AKT allosteric inhibitors was introduced (in this study). As informational molecules in PI3K signal transduction pathway downstream, AKT played crucial role in cell regulation, including inhibiting apoptosis, promoting cell cycle progression and adjustingcell proliferation, and has shown potency in promoting cancer cell invasion and migration, making it a new target for antitumor drugs.On the basis of literature review and retrosynthetic analysis, an11-step reaction leading to the key intermediate6tertbutyl (1R,3R)-1-(4-(2-bromine-5-phenylthiazol-4-yl)phenyl)-3-hydroxy-3-methylcyclobutylamineformatewas proposed with the overall yield of7.9%. A compound library was easily established by virtue of those key intermediates.The synthesis of target compounds started withp-bromobenzeneacetic acid,and was prepared afterpropylene oxide rearrangement, esterification, Swern oxidation, nucleophilic addition, hydrolysis, Curtius rearrangement, nucleophilic addition, NBS bromination, ring closure, diazotization, andbromination.A series of pharmaceutically active compounds were obtained from intermediates6,7and8via Suzuki couping, thiourea ring closure, condensation andsubstitution.Tertbutyl trans-3-hydroxy-3-methyl-1-(4-(2-phenylethyl)phenyl)cyclobutylamine-formate was prepared in several ways with tertbutyl trans-l-(4-bromophenyl)-3-hydroxy-3-methylcyclobutylammoniaformate as raw material, of which, the most feasible method is realized by catalytic cyanation, benzyl Grignard reagents and nucleophilic addition, with good maneuverability, high selectivity and excellent yield.Structures of the final product and some intermediates were confirmed byLC-MSand1H NMR.