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项目整合精选>>>Telmisartan, YM-086, BIBR-277-SE, BIBR-277, Kinzalmono, Pritor, Micardis
Telmisartan, YM-086, BIBR-277-SE, BIBR-277, Kinzalmono, Pritor, Micardis
替米沙坦Chemical Name: 4'-[4-Methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H-benzimidazol-1-ylmethyl]biphenyl-2-carboxylic acid
CAS No. 144701-48-4
项目整合开发状态: Launched-1999
项目研究机构: Boehringer Ingelheim (Originator), Nippon Boehringer Ingelheim (Originator), GlaxoSmithKline (Licensee), Yamanouchi (Licensee), Abbott (Comarketer), Bayer (Comarketer)
合成路线:The acylation of 4-amino-3-methylbenzoic acid methyl ester (I) with butyryl chloride (II) in hot chlorobenzene gives the corresponding amide (III),which is nitrated with HNO3/H2SO4 yielding 4-butyramido-3-methyl-5-nitrobenzoic acid methyl ester (IV).The hydrogenation of (IV) with H2 over Pd/C in methanol affords the expected amino compound (V),which is cyclized in refluxing acetic acid to 2-propyl-4-methylbenzimidazole-6-carboxylic acid methyl ester (VI).The hydrolysis of (VI) with NaOH in refluxing methanol/water affords the corresponding free acid (VII),which is cyclized with N-methyl-o-phenylenediamine (VIII) by means of polyphosphoric acid (PPA) at 150 C,giving 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazole (IX).The condensation of (IX) with 4'-(bromomethyl)biphenyl-4-carboxylic acid tert-butyl ester (X) by means of potassium tert-butoxide in DMSO yields the tert-butyl ester (XI),which is finally hydrolyzed with trifluoroacetic acid.
📌 参考资料/链接：
参考文献标题:Benzimidazoles,medicaments containing them and process for their preparation
文献作者:Hauel,N.; Narr,B.; Ries,U.; Van Meel,J.; Wienen,W.; Entzeroth,M.(Dr.Karl Thomae GmbH)
参考来源:DE 4103492; DE 4117121; EP 0502314; EP 0543263; JP 1992346978
📄 详细内容
合成路线:The acylation of 4-amino-3-methylbenzoic acid methyl ester (I) with butyryl chloride (II) in hot chlorobenzene gives the corresponding amide (III),which is nitrated with HNO3/H2SO4 yielding 4-butyramido-3-methyl-5-nitrobenzoic acid methyl ester (IV).The hydrogenation of (IV) with H2 over Pd/C in methanol affords the expected amino compound (V),which is cyclized in refluxing acetic acid to 2-propyl-4-methylbenzimidazole-6-carboxylic acid methyl ester (VI).The hydrolysis of (VI) with NaOH in refluxing methanol/water affords the corresponding free acid (VII),which is cyclized with N-methyl-o-phenylenediamine (VIII) by means of polyphosphoric acid (PPA) at 150 C,giving 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazole (IX).The condensation of (IX) with 4'-(bromomethyl)biphenyl-4-carboxylic acid tert-butyl ester (X) by means of potassium tert-butoxide in DMSO yields the tert-butyl ester (XI),which is finally hydrolyzed with trifluoroacetic acid.
参考文献标题:6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: Synthesis,biological activity,and structure-activity relationships
文献作者:Ries,U.J.; Mihm,G.; Narr,B.; Hasselbach,K.M.; Wittneben,H.; Entzeroth,M.; van Meel,J.C.A.; Wienen,W.; Hauel,N.H.
参考来源:J Med Chem 1993,36(25),4040-51
合成路线:The acylation of 4-amino-3-methylbenzoic acid methyl ester (I) with butyryl chloride (II) in hot chlorobenzene gives the corresponding amide (III),which is nitrated with HNO3/H2SO4 yielding 4-butyramido-3-methyl-5-nitrobenzoic acid methyl ester (IV).The hydrogenation of (IV) with H2 over Pd/C in methanol affords the expected amino compound (V),which is cyclized in refluxing acetic acid to 2-propyl-4-methylbenzimidazole-6-carboxylic acid methyl ester (VI).The hydrolysis of (VI) with NaOH in refluxing methanol/water affords the corresponding free acid (VII),which is cyclized with N-methyl-o-phenylenediamine (VIII) by means of polyphosphoric acid (PPA) at 150 C,giving 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazole (IX).The condensation of (IX) with 4'-(bromomethyl)biphenyl-4-carboxylic acid tert-butyl ester (X) by means of potassium tert-butoxide in DMSO yields the tert-butyl ester (XI),which is finally hydrolyzed with trifluoroacetic acid.
参考文献标题:Telmisartan
文献作者:Merlos,M.; Casas,A.; Castar,J.
参考来源:Drugs Fut 1997,22(10),1112
产品链接: CAS No. 144701-48-4››