Elarofiban, RWJ-53308-药物合成数据库

【药物名称】Elarofiban, RWJ-53308

化学结构式(Chemical Structure):

参考文献No.	34816
标题:	Carboxamide derivs. of pyrrolidine, piperidine and hexahydroazepine for the treatment of thrombosis disorders
作者:	Costanzo, M.J.; Hoekstra, W.J.; Maryanoff, B.E. (Ortho-McNeil Pharmaceutical, Inc.)
来源:	EP 0923555; JP 2000510111; US 6069254; WO 9741102

合成路线图解说明: 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).

合成路线图解说明: 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No.	560979
标题:	Potent orally active GPIIb/IIIa antagonists containing a nipecotic acid subunit. Structure - Activity studies leading to the discovery of RWJ-53308
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.
来源:	J Med Chem 1999,42(25),5254

合成路线图解说明: 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).

合成路线图解说明: 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.