新产品编号:660203
Chemical Name: 3-[1-(4-Fluorobenzyl)-8-oxo-7,8-dihydro-1H-imidazo[4,5-g]quinazolin-6-yl]-4-propoxybenzamide
CAS No. 252232-48-7
项目整合开发状态: Biological Testing
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:Nitration of 3-chlorobenzoic acid (I) with KNO3 and H2SO4 produced 2,4-dinitro-5-chlorobenzoic acid (II) which,after conversion to acid chloride (III),was reacted with ammonia to give amide (IV).Displacement of the chlorine of (IV) with 4-fluorobenzylamine (V) furnished aminobenzamide (VI).The nitro groups were then reduced by hydrogenation over PtO2,and the resulting triamine (VII) was cyclized to benzimidazole (VIII) by means of formic acid.5-Bromo-2-propoxybenzoic acid (X) was prepared from 5-bromosalicylic acid (IX) by alkylation with n-propyl iodide.Coupling of carboxylic acid (X) with amine (VIII) using EDC and HOBt afforded amide (XI),which was cyclized to the imidazoquinazoline (XII) in the presence of potassium tert-butoxide.Substitution of the bromine atom of (XII) with cuprous cyanide in NMP yielded nitrile (XIII).This was finally converted to the desired amide by hydrolysis to the carboxylic acid,followed by coupling with ammonia in the presence of EDC.
📌 参考资料/链接：
参考文献标题:Quinazolinone inhibitors of cGMP phosphodiesterase
文献作者:Weller,H.N.III; Rotella,D.P.; Yevich,J.P.; Cushman,D.W.; Macor,J.E.(Bristol-Myers Squibb Co.)
参考来源:US 6087368; WO 9964004
📄 详细内容
合成路线:Nitration of 3-chlorobenzoic acid (I) with KNO3 and H2SO4 produced 2,4-dinitro-5-chlorobenzoic acid (II) which,after conversion to acid chloride (III),was reacted with ammonia to give amide (IV).Displacement of the chlorine of (IV) with 4-fluorobenzylamine (V) furnished aminobenzamide (VI).The nitro groups were then reduced by hydrogenation over PtO2,and the resulting triamine (VII) was cyclized to benzimidazole (VIII) by means of formic acid.5-Bromo-2-propoxybenzoic acid (X) was prepared from 5-bromosalicylic acid (IX) by alkylation with n-propyl iodide.Coupling of carboxylic acid (X) with amine (VIII) using EDC and HOBt afforded amide (XI),which was cyclized to the imidazoquinazoline (XII) in the presence of potassium tert-butoxide.Substitution of the bromine atom of (XII) with cuprous cyanide in NMP yielded nitrile (XIII).This was finally converted to the desired amide by hydrolysis to the carboxylic acid,followed by coupling with ammonia in the presence of EDC.
参考文献标题:N-3-Substituted imidazoquinazolinones: Potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction
文献作者:Rotella,D.P.; Sun,Z.; Zhu,Y.; Krupinski,J.; Pongrac,R.; Seliger,L.; Normandin,D.; Macor,J.E.
参考来源:J Med Chem 2000,43(7),1257