合成路线1

Palladium-catalyzed coupling of phenyloxadiazol derivative (VIII) with 4-boronobenzoic acid (IX) yielded biphenyl (X). Further treatment of (X) with SOCl2 afforded acid chloride (XI). This was finally condensed with amine (VII) to provide the title carboxamide.

合成路线2

Bromination of 2-amino-5-methylpyrazine (I) with Br2 in CHCl3 affords the bromopyrazine (II). Subsequent bromide displacement in (II) by means of sodium methoxide gives rise to the methoxypyrazine (III). The amino group of (III) is then protected by acylation with isobutyl chloroformate, to produce carbamate (IV). Diazotization of 3-amino-2-chloropyridine (V), followed by treatment with sulfur dioxide in the presence of CuCl furnishes sulfonyl chloride (VI). Carbamate (IV) is then acylated by means of NaH and sulfonyl chloride (VI) in DMF to furnish the N-sulfonyl carbamate (VII). Esterification of 4-carboxyphenylboronic acid (VIII) with H2SO4 in MeOH gives 4-(methoxycarbonyl)phenylboronic acid (IX). Mitsunobu coupling between boronic acid (IX) and chloropyridine (VII) furnishes adduct (X). Methyl ester (X) is converted into hydrazide (XI) by treatment with hydrazine hydrate in refluxing methanol. Then, cyclization of the acyl hydrazide (XI) with boiling triethyl orthoformate gives rise to the target oxadiazole derivative.

合成路线3

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4

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5

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.

合成路线6

合成路线7

In one strategy, condensation of 4-bromobenzohydrazide (I) with HC(OEt)3 in the presence of H2SO4 in refluxing methylated spirit gives 2-(4-bromophenyl)-1,3,4-oxadiazole (II), which upon treatment with (i-PrO)3B in the presence of MeLi and BuLi in THF at –65 °C affords the boronic acid derivative (III). Suzuki coupling between the boronic acid (III) and the chloropyridine derivative (IV) in the presence of Pd(OAc)2, 3,3′,3′′-phosphinidynetris(benzenesulfonic acid) trisodium salt (TPPTS) and NMM in H2O/i-PrOH at 83 °C affords N-protected zibotentan (V). Finally, intermediate (V) is deprotected with ethanolamine in H2O/i-PrOH at 42 °C or with NH3 in H2O/methylated spirit at 60 °C and acidified with AcOH in H2O .
In a second strategy, 4-carboxyphenylboronic acid (VI) is esterified with MeOH in the presence of H2SO4, yielding boronic acid (VII), which undergoes Suzuki coupling with the chloropyridine derivative (IV) in the presence of Pd(PPh3)4 and KF in refluxing toluene/H2O to provide adduct (VIII). Finally, methyl ester (VIII) is converted to hydrazide (IX) by treatment with hydrazine hydrate in refluxing methanol and cyclized by condensation with refluxing HC(OEt)3 .