Z-15370A
Chemical Name: 1-(3,5-Dichloropyridin-4-ylmethyl)-6-methoxy-4-(1H-1,2,4-triazol-1-yl)phthalazine
CAS No. 256443-12-6
项目整合开发状态: Preclinical
项目研究机构: Zambon (Originator)
合成路线:Friedel-Crafts hydroxymethylation of 3-methoxybenzoic acid (I) using aqueous formaldehyde and HCl gave rise to 6-methoxyisobenzofuran-1-one (II).After radical bromination of (II) with N-bromosuccinimide in the presence of benzoyl peroxide,the resulting 3-bromo derivative (III) was condensed with triphenyl phosphine to afford the phosphonium salt (IV).Wittig condensation of 3,5-dichloropyridine-4-carbaldehyde (V) with the phosphonium bromide (IV) provided the 3-(pyridylmethylene)isobenzofuranone (VI).Reaction of the enol lactone function of (VI) with hydrazine produced the phthalazinone derivative (VII),which was further converted to the 4-chlorophthalazine (VIII) upon treatment with POCl3.The 4-chloro group of (VIII) was finally displaced with the sodium salt of 1,2,4-triazole (IX) to give the title compound.
📌 参考资料/链接：
参考文献标题:Phthalazine derivs.phosphodiesterase 4 inhibitors
文献作者:Norcini,G.; Morazzoni,G.; Leali,G.M.; Napoletano,M.; Grancini,G.; Pellacini,F.(Zambon Group SpA)
参考来源:EP 1097142; US 6329370; WO 0005218
📄 详细内容
合成路线:Friedel-Crafts hydroxymethylation of 3-methoxybenzoic acid (I) using aqueous formaldehyde and HCl gave rise to 6-methoxyisobenzofuran-1-one (II).After radical bromination of (II) with N-bromosuccinimide in the presence of benzoyl peroxide,the resulting 3-bromo derivative (III) was condensed with triphenyl phosphine to afford the phosphonium salt (IV).Wittig condensation of 3,5-dichloropyridine-4-carbaldehyde (V) with the phosphonium bromide (IV) provided the 3-(pyridylmethylene)isobenzofuranone (VI).Reaction of the enol lactone function of (VI) with hydrazine produced the phthalazinone derivative (VII),which was further converted to the 4-chlorophthalazine (VIII) upon treatment with POCl3.The 4-chloro group of (VIII) was finally displaced with the sodium salt of 1,2,4-triazole (IX) to give the title compound.
参考文献标题:Phathalazine PDE4 inhibitors.Part 2: The synthesis and biological evaluation of 6-methoxy-1,4-disubstituted derivatives
文献作者:Napoletano,M.; Norcini,G.; Pellacini,F.; Marchini,F.; Morazzoni,G.; Ferlenga,P.; Pradella,L.
参考来源:Bioorg Med Chem Lett 2001,11(1),33