Elarofiban, RWJ-53308
Chemical Name: 3(S)-[1-[3-(4-Piperidinyl)propionyl]piperidin-3(R)-ylcarboxamido]-3-(3-pyridyl)propionic acid
CAS No. 198958-88-2
项目整合开发状态: Phase II
项目研究机构: R.W. Johnson (Originator)
合成路线:Knoevenagel condensation of pyridine-3-carboxaldehyde (I) with malonic acid in the presence of ammonium acetate afforded the racemic amino acid (III),which was acylated with phenylacetyl chloride (IV) to give amide (V).Optical resolution of (V) by means of penicillin amidase produced the hydrolysis of the undesired (R)-enantiomer.After isolation of the unreacted (S)-enantiomer (VI),its hydrolysis with aqueous HCl furnished the chiral amino acid (VII),which was converted to methyl ester (VIII) with 2,2-dimethoxypropane in MeOH.Coupling of (VIII) with N-Boc-(R)-nipecotic acid (IX) using 2-benzotriazolyl-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) provided amide (X).Deprotection of the Boc group of (X) was then achieved with HCl in dioxan resulting amine (XI).
合成路线:Compound (XI) was coupled with N-Boc-3-(4-piperidinyl)propionic acid (XII) to produce diamide (XIII).Finally,hydrolysis of the methyl ester of (XIII) with LiOH,followed by acid removal of the Boc group yielded the title compound.
📌 参考资料/链接：
参考文献标题:Carboxamide derivs.of pyrrolidine,piperidine and hexahydroazepine for the treatment of thrombosis disorders
文献作者:Costanzo,M.J.; Hoekstra,W.J.; Maryanoff,B.E.(Ortho-McNeil Pharmaceutical,Inc.)
参考来源:EP 0923555; JP 2000510111; US 6069254; WO 9741102
📄 详细内容
合成路线:Knoevenagel condensation of pyridine-3-carboxaldehyde (I) with malonic acid in the presence of ammonium acetate afforded the racemic amino acid (III),which was acylated with phenylacetyl chloride (IV) to give amide (V).Optical resolution of (V) by means of penicillin amidase produced the hydrolysis of the undesired (R)-enantiomer.After isolation of the unreacted (S)-enantiomer (VI),its hydrolysis with aqueous HCl furnished the chiral amino acid (VII),which was converted to methyl ester (VIII) with 2,2-dimethoxypropane in MeOH.Coupling of (VIII) with N-Boc-(R)-nipecotic acid (IX) using 2-benzotriazolyl-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) provided amide (X).Deprotection of the Boc group of (X) was then achieved with HCl in dioxan resulting amine (XI).
合成路线:Compound (XI) was coupled with N-Boc-3-(4-piperidinyl)propionic acid (XII) to produce diamide (XIII).Finally,hydrolysis of the methyl ester of (XIII) with LiOH,followed by acid removal of the Boc group yielded the title compound.
参考文献标题:Potent orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit.Structure - Activity studies leading to the discovery of RWJ-53308
文献作者:Hoekstra,W.J.; Maryanoff,B.E.; Damiano,B.P.; Andrade-Gordon,P.; Cohen,J.H.; Costanzo,M.J.; Haertlein,B.J.; Hecker,L.R.; Hulshizer,B.L.; Kauffman,J.A.; Keane,P.; McComsey,D.F.; Mitchell,J.A.; Scott,L.; Shah,R.D.; Yabut,S.C.
参考来源:J Med Chem 1999,42(25),5254
产品链接: CAS No. 198958-88-2››