Englitazone sodium, CP-72467-2, CP-68722(racemate), CP-72467-02
恩格列酮2,4-硫唑里地二酮,5-[[3,4-二氢-2-(苯甲基)-2H-1-苯并吡喃-6-基]甲基]-,钠盐(1:1)Chemical Name: (-)-5-[2(R)-Benzyl-3,4-dihydro-2H-benzopyran-6-ylmethyl]thiazolidine-2,4-dione sodium salt
CAS No. 109229-58-5 (free acid, non-specified stereoch.), 109229-57-4 (undefined stereoch.)
项目整合开发状态: Phase I
项目研究机构: Pfizer (Originator)
合成路线:CP-72467-2 has been prepared by two synthetic routes which share a common intermediate.1) In the initial route,diazotization of D-phenylalanine followed by esterification afforded the methyl ester of (R)-phenyllactic acid (I).Mitsunobu coupling with methyl 4-hydroxybenzoate using diisopropyl azodicarboxylate,selective reduction with sodium borohydride,and conversion to the bromide by in situ generation of triphenylphosphine dibromide produced intermediate (II).Friedel-Crafts alkylation of (II) using alpha-hydroxyhippuric acid/methanesulfonic acid,azalactone formation with acetic anhydride/triethylamine,followed by in situ spiroalkylation produced the N-benzoyl amino acid (III).Oxidative decarboxylation of (III) with 15% sodium hypochlorite led to the chromanone (V),presumably through hydrolysis of the intermediate N-benzoyl imine (IV).Catalytic hydrogenation over 10% Pd on carbon of the chromanone (V),reduction of the ester with Red-Al,and subsequent oxidation of the alcohol with manganese dioxide afforded the key aldehyde intermediate (VI).Condensation of aldehyde (VI) with 2,4-thiazolidinedione/pyridine,catalytic hydrogenation of the resultant olefin,and salt formation with sodium methoxide produced CP-72467-2.2) An alternative synthesis of the key intermediate aldehyde (VI) utilizes an enzymatic resolution of the benzopyran ester (VII).Reduction of the 2(R)-ester with sodium borohydride followed by reaction with triflic anhydride generates the triflate (VIII).Copper-catalyzed reaction of the triflate (VIII) with phenyl magnesium bromide afforded the benzyl derivative (IX),which is readily formylated with phosphorous oxychloride/N-methyl formanilide to produce aldehyde (VI).
📌 参考资料/链接：
参考文献标题:Substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2,4-diones as hypoglycemic agents
文献作者:Clark,D.A.; Goldstein,S.W.; Volkmann,R.A.; Eggler,J.F.; Holland,G.F.; Hulin,B.; Stevenson,R.W.; Kreutter,D.K.; Gibbs,E.M.; Krupp,M.N.; et al.
参考来源:J Med Chem 1991,34(1),319
📄 详细内容
合成路线:CP-72467-2 has been prepared by two synthetic routes which share a common intermediate.1) In the initial route,diazotization of D-phenylalanine followed by esterification afforded the methyl ester of (R)-phenyllactic acid (I).Mitsunobu coupling with methyl 4-hydroxybenzoate using diisopropyl azodicarboxylate,selective reduction with sodium borohydride,and conversion to the bromide by in situ generation of triphenylphosphine dibromide produced intermediate (II).Friedel-Crafts alkylation of (II) using alpha-hydroxyhippuric acid/methanesulfonic acid,azalactone formation with acetic anhydride/triethylamine,followed by in situ spiroalkylation produced the N-benzoyl amino acid (III).Oxidative decarboxylation of (III) with 15% sodium hypochlorite led to the chromanone (V),presumably through hydrolysis of the intermediate N-benzoyl imine (IV).Catalytic hydrogenation over 10% Pd on carbon of the chromanone (V),reduction of the ester with Red-Al,and subsequent oxidation of the alcohol with manganese dioxide afforded the key aldehyde intermediate (VI).Condensation of aldehyde (VI) with 2,4-thiazolidinedione/pyridine,catalytic hydrogenation of the resultant olefin,and salt formation with sodium methoxide produced CP-72467-2.2) An alternative synthesis of the key intermediate aldehyde (VI) utilizes an enzymatic resolution of the benzopyran ester (VII).Reduction of the 2(R)-ester with sodium borohydride followed by reaction with triflic anhydride generates the triflate (VIII).Copper-catalyzed reaction of the triflate (VIII) with phenyl magnesium bromide afforded the benzyl derivative (IX),which is readily formylated with phosphorous oxychloride/N-methyl formanilide to produce aldehyde (VI).
参考文献标题:Englitazone Sodium
文献作者:Stevenson,R.W.; Urban,F.J.; Clark,D.A.
参考来源:Drugs Fut 1992,17(3),182
产品链接: CAS No. 109229-58-5›› 产品链接: CAS No.109229-57-4››