Regioselective synthesis of the 1-bromo-4-phenyl-tetrahydro-7-amino-benzocyclohepten-6-one, a subnanomolar aminopeptidase-N/CD13 inhibitor

A regioselective synthesis of the title 1-bromo-4-phenyl-tetrahydro-7-amino-benzocyclohepten-6-one 2 has been pursued and develop in order to allow a large scale synthesis of this highly potent and selective APN inhibitor (Ki 60 pM). The pivotal step in this approach was the desymmetrization of the ketones 6a,b through regioselective generation of the silyl enol ethers 5a,b. After obtention of the corresponding enones 13a,b and the ene-amides 4a,b–4′a,b, it was possible to separate the regioisomers at this step. Conversion to the desired phenylbromo-amide 17 was achieved from the both isolated major and minor regioisomers through chemical manipulations including Suzuki coupling and Sandmeyer reaction. The title compound 2·HCl was finally synthesized after a series of deprotections/protection.