AR-0598
Chemical Name: trans-3-[4-(5-Amidino-1-benzofuran-2-ylcarboxamido)cyclohexyl]propionic acid ethyl ester
项目整合开发状态: Preclinical
项目研究机构: Mitsubishi Pharma (Originator)
合成路线:Selective O-alkylation of trans-4-aminocyclohexanol (I) was effected by protection of the amino group as the triazinone (III) upon treatment with N,N-dimethylurea and formaldehyde.Subsequent alkylation of (III) with tert-butyl bromoacetate under phase-transfer conditions afforded ether (IV).The protecting group of (IV) was then removed by treatment with ammonium chloride.
合成路线:Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (VI) gave imidate (VII) and subsequent treatment with ethanolic ammonia afforded amidine (VIII).After basic hydrolysis of the ester group of (VIII),protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IX).Coupling of (IX) with aminoester (V) in the presence of EDC and HOBt yielded amide (X).Sequential cleavage of benzyloxycarbonyl and tert-butyl groups orf (X) provided amidino acid (XI),which was finally esterified with EtOH and methanesulfonic acid.
合成路线:Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (I) gave imidate (II) and subsequent treatment with ethanolic ammonia afforded amidine (III).After basic hydrolysis of the ester group of (III),protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IV).Coupling of (IV) with ethyl trans-3-(4-aminocyclohexyl)propionate (V) in the presence of EDC and HOBt yielded amide (VI).Finally,hydrogenolysis of the benzyloxycarbonyl protecting group of (VI) provided the title amidino ester.
📌 参考资料/链接：
参考文献标题:Novel fused-ring carboxylic acid cpds.or salt thereof,and medicinal use thereof
文献作者:Ono,S.; Yoshida,T.; Ashimori,A.; Kosaka,K.; Okada,T.; Maeda,K.; Eda,M.; Mori,F.; Inoue,Y.; Ebisu,H.; Imada,T.; Ikegawa,R.; Wang,F.; Nakamura,N.(Welfide Corporation)
参考来源:EP 0712844; JP 1996053398; JP 1996231548; US 5635527; US 5753670; WO 9533720
📄 详细内容
合成路线:Selective O-alkylation of trans-4-aminocyclohexanol (I) was effected by protection of the amino group as the triazinone (III) upon treatment with N,N-dimethylurea and formaldehyde.Subsequent alkylation of (III) with tert-butyl bromoacetate under phase-transfer conditions afforded ether (IV).The protecting group of (IV) was then removed by treatment with ammonium chloride.
合成路线:Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (VI) gave imidate (VII) and subsequent treatment with ethanolic ammonia afforded amidine (VIII).After basic hydrolysis of the ester group of (VIII),protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IX).Coupling of (IX) with aminoester (V) in the presence of EDC and HOBt yielded amide (X).Sequential cleavage of benzyloxycarbonyl and tert-butyl groups orf (X) provided amidino acid (XI),which was finally esterified with EtOH and methanesulfonic acid.
合成路线:Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (I) gave imidate (II) and subsequent treatment with ethanolic ammonia afforded amidine (III).After basic hydrolysis of the ester group of (III),protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IV).Coupling of (IV) with ethyl trans-3-(4-aminocyclohexyl)propionate (V) in the presence of EDC and HOBt yielded amide (VI).Finally,hydrogenolysis of the benzyloxycarbonyl protecting group of (VI) provided the title amidino ester.
参考文献标题:Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists.2.Condensed heterocyclic derivatives
文献作者:Ono,S.; Yoshida,T.; Maeda,K.; Kosaka,K.; Inoue,Y.; Imada,T.; Fukaya,C.; Nakamura,N.
参考来源:Chem Pharm Bull 1999,47(12),1694