PD-123319
Chemical Name: 1-[4-(Dimethylamino)-3-methylbenzyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6(S)-carboxylic acid
CAS No. 114785-14-7 (racemate), 114785-90-9 (R-isomer)
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:Alkylation of di-Boc-histidine methyl ester (III) with triflate (II) (prepared from 3-methyl-4-nitrobenzyl alcohol (I)) produced the intermediate imidazolium salt (IV) which,upon aqueous quenching with pH 7 phosphate buffer,led to the 3-substituted imidazole (V).Subsequent acid hydrolysis of the remaining N-Boc group of (V) furnished the 3-benzyl histidine (VI).Pictet-Spengler cyclization of (VI) with formaldehyde in the presence of HCl gave the corresponding imidazopyridine derivative,and further reesterification with trimethyl orthoformate led to the methyl ester (VII).Coupling of (VII) with diphenylacetic acid afforded amide (VIII).The nitro group of (VIII) was then reduced to aniline (IX) by catalytic hydrogenation in the presence of Raney Ni.Reductive alkylation of amine (IX) with formaldehyde and sodium cyanoborohydride yielded the dimethylamino derivative (X).The methyl ester group of (X) was finally hydrolyzed to the target carboxylic acid under basic conditions.
📌 参考资料/链接：
参考文献标题:4,5,6,7-Tetrahydro-1H-imidazo[4,5-c]pyridine derivs.and analogs having antihypertensive activity
文献作者:Blankley,C.J.; Hodges,J.C.; Kiely,J.S.; Klutchko,S.R.(Pfizer Inc.)
参考来源:EP 0245637; JP 1987240683; JP 1996208652; US 4812462; US 4816463
📄 详细内容
合成路线:Alkylation of di-Boc-histidine methyl ester (III) with triflate (II) (prepared from 3-methyl-4-nitrobenzyl alcohol (I)) produced the intermediate imidazolium salt (IV) which,upon aqueous quenching with pH 7 phosphate buffer,led to the 3-substituted imidazole (V).Subsequent acid hydrolysis of the remaining N-Boc group of (V) furnished the 3-benzyl histidine (VI).Pictet-Spengler cyclization of (VI) with formaldehyde in the presence of HCl gave the corresponding imidazopyridine derivative,and further reesterification with trimethyl orthoformate led to the methyl ester (VII).Coupling of (VII) with diphenylacetic acid afforded amide (VIII).The nitro group of (VIII) was then reduced to aniline (IX) by catalytic hydrogenation in the presence of Raney Ni.Reductive alkylation of amine (IX) with formaldehyde and sodium cyanoborohydride yielded the dimethylamino derivative (X).The methyl ester group of (X) was finally hydrolyzed to the target carboxylic acid under basic conditions.
参考文献标题:Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype
文献作者:Blankley,C.J.; Hodges,J.C..; Klutchko,S.R.; Himmelsbach,R.J.; Chucholowski,A.W.; Connolly,C.J.C.; Neergaard,S.J.; Van Nieuwenhze,M.S.; Sebastian,A.; Quin,J.III; et al.
参考来源:J Med Chem 1991,34(11),3248