Addition of 4-tolylmagnesium bromide (II) to 2,3-pyridinedicarboxylic acid anhydride (I) afforded ketoacid (III). Subsequent condensation of (III) with diethyl bromomalonate (VII) in the presence of Et3N, followed by DBU-promoted cyclization produced the pyridine lactone (VI). In an alternative procedure, acid (III) was converted to acid chloride (IV) using SOCl2, and then condensed with diethyl hydroxymalonate (V) in the presence of NaH to give (VI). The tertiary alcohol group of (VI) was then dehydrated with HCl in AcOH to give (VIII). Acid chloride (IX), prepared by treatment of (VIII) with SOCl2, was coupled with 3,5-bis(trifluoromethyl)benzylamine (X) to furnish amide (XI). The tetrahydropyranyl-protected aminoalcohol (XIII) was obtained by reduction of nitrile (XII) with LiAlH4. Reaction of (XIII) with lactone (XI), followed by treatment with DBU, produced the 1,7-naphthyridine system (XIV). Acid-catalyzed deprotection of the tetrahydropyranyl group yielded alcohol (XV).
Intermediate (XV) was converted to mesylate (XVI) with methanesulfonyl chloride and Et3N. Finally, cyclization of (XVI) in the presence of NaH in refluxing THF produced the target diazocinonaphthyridine.