新产品编号:146053
Chemical Name: (2R,4R)-4-Amino-1-(1-napthylmethyl)pyrrolidine-2,4-dicarboxylic acid
CAS No. 178415-88-8
项目整合开发状态: Biological Testing
项目研究机构: Lilly (Originator)
合成路线:The esterification of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (I) with ethanol and sulfuric acid gives the expected ethyl ester (II),which is N-protected with benzyl bromide and DIEA in dichloromethane to the N-benzyl derivative (III).The oxidation of (III) with oxalyl chloride in DMSO affords the pyrrolidinone (IV),which is cyclized with ammonium carbamate and KCN in hot ethanol/water to afford the spiro imidazolidinedione (V).Opening of the imidazolidinedione ring of (V) with refluxing 3N NaOH,followed by esterification with ethanol/SOCl2 provides (2R,4R)-4-amino-1-benzylpyrrolidine-2,4-dicarboxylic acid diethyl ester (VI),which is protected at the amino group with tert-butoxycarbonyl anhydride giving the carbamate (VII) (1).Hydrogenolysis of the N-benzyl group of (VII) in the presence of Pd/C yields (VIII) with a free imino group,which is alkylated with 1-(chloromethyl)naphthalene (IX) by means of DIEA and Bu4NI affording the naphthylmethyl derivative (X).Removal of the Boc protecting group of (X) with HCl in ethyl ether gives (2R,4R)-4-amino-1-(1-naphthylmethyl)pyrrolidine-2,4-dicarboxylic acid diethyl ester (XI),which is finally hydrolyzed with NaOH to the target diacid (2).
📌 参考资料/链接：
参考文献标题:Synthesis of the four isomers of 4-aminopyrrolidine-2,4-dicarboxylate: Identification of a potent,highly selective,and systemically-active agonist for metabotropic glutamate receptors negatively coupled to adenylate cyclase
文献作者:Monn,J.A.; Valli,M.J.; Johnson,B.G.; Salhoff,C.R.; Wright,R.A.; Howe,T.J.; Bond,A.; Lodge,D.; Spangle,L.A.; Paschal,J.W.; Campbell,J.B.; Griffey,K.; Tizzano,J.P.; Schoepp,D.D.
参考来源:J Med Chem 1996,39(15),2990
📄 详细内容
合成路线:The esterification of (2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (I) with ethanol and sulfuric acid gives the expected ethyl ester (II),which is N-protected with benzyl bromide and DIEA in dichloromethane to the N-benzyl derivative (III).The oxidation of (III) with oxalyl chloride in DMSO affords the pyrrolidinone (IV),which is cyclized with ammonium carbamate and KCN in hot ethanol/water to afford the spiro imidazolidinedione (V).Opening of the imidazolidinedione ring of (V) with refluxing 3N NaOH,followed by esterification with ethanol/SOCl2 provides (2R,4R)-4-amino-1-benzylpyrrolidine-2,4-dicarboxylic acid diethyl ester (VI),which is protected at the amino group with tert-butoxycarbonyl anhydride giving the carbamate (VII) (1).Hydrogenolysis of the N-benzyl group of (VII) in the presence of Pd/C yields (VIII) with a free imino group,which is alkylated with 1-(chloromethyl)naphthalene (IX) by means of DIEA and Bu4NI affording the naphthylmethyl derivative (X).Removal of the Boc protecting group of (X) with HCl in ethyl ether gives (2R,4R)-4-amino-1-(1-naphthylmethyl)pyrrolidine-2,4-dicarboxylic acid diethyl ester (XI),which is finally hydrolyzed with NaOH to the target diacid (2).
参考文献标题:Synthesis and metabotropic glutamate receptor antagonist activity of N'-substituted analogs of 2R,4R-4-aminopyrrolidine-2,4-dicarboxylic acid
文献作者:Valli,M.J.; Schoepp,D.D.; Wright,R.A.; Johnson,B.G.; Kingston,A.E.; Tomlinson,R.; Monn,J.A.
参考来源:Bioorg Med Chem Lett 1998,8(15),1985