NVP-ABE-171

Chemical Name: 4-[8-(2,1,3-Benzoxadiazol-5-yl)-1,7-naphthyridin-6-yl]benzoic acid
项目整合开发状态: Preclinical
项目研究机构: Novartis (Originator)
合成路线: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.

合成路线: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).

合成路线: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.

合成路线: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.