合成路线:The synthesis of (R)- and (S)-isomers of OPC-12759 has been described:These optical isomers can be obtained in three different ways:1) The reaction of 4-(bromomethyl)quinolin-2(1H)-one (I) with hot phosphorus oxychloride gives a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III),which,without separation,is condensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) by means of butyllithium in hexane,yielding (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr).The hydrolysis of (Vr) with HCl affords 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr),which is treated with HCl and propylene oxide to give 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr).Finally,this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3 in acetone,affording (R)-OPC-12759.
合成路线:2) The same reaction sequence of (I) and (IVr) yields intermediates (Vs),(VIs) and (VIIs),and finally (S)-OPC-12759.
合成路线:3) The methylation of 3-(2-oxo-1,2-dihydroquinolin-4-yl)-(R,S)-alanine (IX) with SOCl2 and methanol yields the corresponding methyl ester (X),which is submitted to optical resolution with D-(-)-mandelic acid,affording adducts (XII) and (XIII).The hydrolytic treatment of (XII) and (XIII) with HCl and propylene oxide finally yields isomers (VIIr) and (VIIs),already obtained.Racemic OPC-12759 can also be resolved into its optical isomers by treatment with brucine and fractionated crystallization.
参考文献标题:Synthesis and antiulcer activity of optical isomers of 2-(4-chlorobenzoy lamino)-3-[2(1H)-quinolinon-4-yl]propionic acid (rebamipide)
文献作者:Otsubo,K.; Morita,S.; Uchida,M.; Yamasaki,K.; Kanbe,T.; Shimizu,T.
参考来源:Chem Pharm Bull 1991,39(11),2906
合成路线:The condensation of 4-(bromomethyl)quinolin-2(1H)-one (I) with diethyl acetamidomalonate (II) by means of sodium ethoxide in refluxing ethanol gives ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4yl)propionate (III),which is submitted to a decarboxylative hydrolysis with refluxing 20% HCl yielding 3-(2-oxo-1,2-dihydroquinolin-4yl)alanine (IV).Finaily this compound is acylated with 4-chlorobenzoyl chloride by means of K2CO3 in acetone water.
参考文献标题:Studies on 2(1H)-quinolinone derivatives as gastri
文献作者:Uchida,M.; Tabusa,F.; Komatsu,M.; Morita,S.; Kanbe,T.; Nakagawa,K.
参考来源:Chem Pharm Bull 1985,33(9),3775
产品链接: CAS No. 111911-87-6›› 产品链接: CAS No.90098-04-7››