Reaction of 3-(cyanomethyl)pyridine-N-oxide (I) with cyanotrimethylsilane and dimethylcarbamoyl chloride provided dinitrile (II). Subsequent cyclization of (II) in the presence of HBr gave rise to 6-amino-8-bromo-1,7-naphthyridine (III). Attachment of a 3-nitrophenyl group to (III) to afford (V) was carried out by Suzuki coupling of (III) with 3-nitrophenylboronic acid (IV) in the presence of bis(dibenzylideneacetone)palladium and triphenylphosphine. The required triflate (VI) was then obtained by nitrosation of aminonaphthyridine (V) in trifluromethanesulfonic acid/DMF. Finally, a second Suzuki coupling of (VI) with 4-carboxyphenylboronic acid (VII) provided the title 6,8-diarylnaphthyridine.
The precursor benzofurazan boronic acid (V) was prepared as follows. Bromination of o-nitroaniline (I) by means of N-bromosuccinimide in AcOH afforded 4-bromo-2-nitroaniline (II). Treatment of (II) with NaOCl gave rise to the 5 bromobenzofurazan N-oxide (III), which was reduced to (IV) employing triphenylphosphine in boiling xylene. Then, lithiation of (IV), followed by reaction with triethyl borate furnished the target boronic acid (V).
3-(Cyanomethyl)pyridine-N-oxide (VI) was converted to the pyridine dinitrile (VII) by treatment with cyanotrimethylsilane and dimethylcarbamoyl chloride. Cyclization of dinitrile (VII) in the presence of HBr gave rise to 6-amino-8-bromo-1,7-naphthyridine (VIII). Attachment of the benzofurazanyl moiety to (VIII) was performed by Suzuki coupling with boronic acid (V) in the presence of bis(dibenzylideneacetone)palladium and tri(o-tolyl)phosphine. The resultant 6 amino-8-aryl naphthyridine (IX) was subjected to diazotization in the presence of trifluoromethanesulfonic acid to furnish triflate (X). Further Suzuki coupling of triflate (X) with 4-carboxyphenylboronic acid (XI) led to the title compound.
In an alternative synthetic procedure, dinitrile (VII) was cyclized in the presence of sodium methoxide to produce 6-amino-8-methoxy-1,7-naphthyridine (XII). This was converted to triflate (XIII) by diazotization in the presence of trifluoromethanesulfonic acid. Suzuki coupling of triflate (XIII) with 4 carboxyphenylboronic acid (XI) yielded adduct (XIV). The 8-methoxy group of (XIV) was then displaced with PBr3 to produce bromide (XV), which was subjected to further Suzuki coupling with the benzofurazan boronic acid (V) to provide the title compound.