title: Solid-Phase Synthesis of 3,4,5-Substituted 1,5-Benzodiazepin-2-ones.
abstract: The preparation of 3,4,5-substituted 8-carboxamido-1,5-benzodiazepin-2-ones using a solid-phase synthetic method is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the aryl fluoride with either an alpha- or beta-substituted beta-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group is accomplished in the presence of SnCl(2).H(2)O. Hydrolysis of the ester is carried out in the presence of a heterogeneous mixture of 1 N NaOH/THF (1:1). The resulting aniline acid is cyclized to form the benzodiazepinone skeleton with DIC and HOBt. Selective alkylation at the N-5 position of the benzodiazepinone is accomplished with alkyl halides in the presence of K(2)CO(3) in acetone. The desired products are cleaved from solid supports and obtained in 46-98% isolated yields.
authors.affiliation: The R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477.
authors.forename: Jung
authors.initials: J
authors.lastname: Lee
authors.forename: Diane
authors.initials: D
authors.lastname: Gauthier
authors.forename: Ralph A.
authors.initials: RA
authors.lastname: Rivero