SCH-62373
Chemical Name: 1-Benzyl-N-[2-[2-(3,4-dichlorophenyl)-4-(3,5-dimethylbenzoyl)piperazin-1-yl]-2-oxoethyl]piperidin-4-amine
CAS No. 185108-18-3
项目整合开发状态: Biological Testing
项目研究机构: Schering-Plough (Originator)
合成路线:Reaction of 2-chloropyrazine (I) with 3,4-dichlorophenylmagnesium bromide (II) in the presence of [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride produced the 2-arylpyrazine (III),which was reduced to the corresponding piperazine (IV) by means of DIBAL in THF.In a different procedure,bromination of methyl 3,4-dichlorophenylacetate (V) using N-bromosuccinimide,followed by reaction of the resulting bromo ester (VI) with ethylenediamine (VII) afforded the piperazinone (VIII),which was further reduced to (IV) by using LiAlH4 in Et2O.
合成路线:Regioselective coupling of the 2-arylpiperazine (IV) with 3,5-dimethylbenzoic acid (IX) at the less hindered N atom by means of EDC and HOBt afforded the 4-benzoyl piperazine (X).This was subsequently acylated with bromoacetyl bromide (XI) to yield the bromo amide (XII).Bromide displacement in (XII) with 4-amino-1-benzylpiperidine (XIII) then gave the title compound.
📌 参考资料/链接：
参考文献标题:Piperazino derivs.as neurokinin antagonists
文献作者:Shue,H.-J.; Shih,N.-Y.; Blythin,D.J.; Chen,X.; Tom,W.C.; Piwinski,J.J.; McCormick,K.D.(Schering Corp.)
参考来源:EP 0823906; US 5719156; WO 9634864
📄 详细内容
合成路线:Reaction of 2-chloropyrazine (I) with 3,4-dichlorophenylmagnesium bromide (II) in the presence of [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride produced the 2-arylpyrazine (III),which was reduced to the corresponding piperazine (IV) by means of DIBAL in THF.In a different procedure,bromination of methyl 3,4-dichlorophenylacetate (V) using N-bromosuccinimide,followed by reaction of the resulting bromo ester (VI) with ethylenediamine (VII) afforded the piperazinone (VIII),which was further reduced to (IV) by using LiAlH4 in Et2O.
合成路线:Regioselective coupling of the 2-arylpiperazine (IV) with 3,5-dimethylbenzoic acid (IX) at the less hindered N atom by means of EDC and HOBt afforded the 4-benzoyl piperazine (X).This was subsequently acylated with bromoacetyl bromide (XI) to yield the bromo amide (XII).Bromide displacement in (XII) with 4-amino-1-benzylpiperidine (XIII) then gave the title compound.
参考文献标题:Piperazino derivs.as neurokinin antagonists
文献作者:Piwinski,J.J.; McCormick,K.D.; Shue,H.-J.; Chen,X.; Shih,N.-Y.; Blythin,D.J.(Schering Corp.)
参考来源:EP 0850236; JP 2000344766; US 5795894; US 5892039; WO 9708166
合成路线:Reaction of 2-chloropyrazine (I) with 3,4-dichlorophenylmagnesium bromide (II) in the presence of [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride produced the 2-arylpyrazine (III),which was reduced to the corresponding piperazine (IV) by means of DIBAL in THF.In a different procedure,bromination of methyl 3,4-dichlorophenylacetate (V) using N-bromosuccinimide,followed by reaction of the resulting bromo ester (VI) with ethylenediamine (VII) afforded the piperazinone (VIII),which was further reduced to (IV) by using LiAlH4 in Et2O.
合成路线:In a related method,the 2-arylpiperazine (IV) was first protected as the 4-tert-butyl carbamate (XIV) upon treatment with di-tert-butyl dicarbonate in MeOH at -78 C.Subsequent acylation of (XIV) with bromoacetyl bromide (XI) produced the bromo amide (XV),which was then condensed with the aminopiperidine (XIII),yielding the glycinamide derivative (XVI).Acidic cleavage of the Boc group of (XVI) afforded the 1-acyl piperazine (XVII).This was finally coupled with 3,5-dimethylbenzoic acid using EDC and HOBt.
参考文献标题:Discovery of Sch 62373 and analogs,of novel series of 2-phenylpiperazines exhibiting potent dual NK1/NK2 antagonist activity
文献作者:Anthes,J.C.; McPhail,A.T.; Blythin,D.J.; Shue,H.-J.; Chen,X.; Piwinski,J.J.; shih,N.-Y.
参考来源:221st ACS Natl Meet (April 1 2001,San Diego) 2001,Abst MEDI 244