Macrocyclization can help improve pharmacological activity, metabolic stability, cell permeability and oral absorption to create better drug candidates. For example, enhancing the oral absorption of the compounds can allow a change in administration route. We tried to improve the oral bioavailability of ceftriaxone, a third-generation cephalosporin having a unique side chain with a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-astriazin-3-yl group at the C-3 position of the cephem nucleus. We prepared novel macrocycles of ceftriaxone by valuable synthetic methods and confirmed their oral bioavailabilities.