合成路线:The intermediate chiral aldehyde (XIV) has been obtained as follows: Acylation of sarcosine methyl ester (II) with 3,5-dichlorobenzoyl chloride (I) provides the N-benzoyl aminoester (III).The dilithium derivative of 3,4-dichlorophenylacetic acid (IV) is condensed with ester (III) to furnish,after acidic work-up,the N-benzoyl amino ketone (V).Subsequent alkylation of (V) with 1-bromo-3-methyl-2-butene (VI) affords (VII).Treatment of ketone (VII) with hydroxylamine yields a mixture of E- and Z- oximes,from which the Z-isomer (VIII) is isolated by column chromatography.Resolution of racemic (VIII) is then accomplished by two procedures.Coupling of (VIII) with N-Boc-D-phenylglycine (IX) produces a diastereomeric mixture of O-acyl oximes,from which isomer (X) can be separated by recrystallization.Hydrazinolysis of the N-acyl oxime (X) furnishes the target (R)-enantiomer (XI).Alternatively,oxime (VIII) is acylated by pivaloyl chloride,and subsequently separated into enantiomers by means of chiral chromatography.The desired isomer (XII) is then subjected to hydrazinolysis,yielding (XI)
合成路线:Alkylation of oxime (XI) with iodomethane in the presence of NaH provides the O-methyl oxime (XIII).Then,ozonolytic cleavage of the dimethylallyl group of (XIII),followed by reductive treatment with dimethylsulfide leads to aldehyde (XIV)
合成路线:3-(Carbomethoxy)propionyl chloride (XV) is condensed with the chiral oxazolidine (XVI) to provide (XVII).Titanium-catalyzed Michael addition of acrylonitrile to the N-acyl oxazolidine (XVII) affords nitrile (XVIII),which is reduced to the primary amine (XIX) by catalytic hydrogenation in the presence of PtO2.Reductive alkylation of amine (XIX) with N-Boc-4-piperidone (XX) gives rise to the aminopiperidine (XXI).This is then cyclized to the piperidinyl piperidone (XXII) upon heating in acetonitrile.After alkaline hydrolysis of the methyl ester group of (XXII),coupling of the resultant acid (XXIII) with methylamine gives rise to the corresponding amide (XXIV).The N-Boc protecting group of (XXIV) is then removed by treatment with trifluoroacetic acid to furnish piperidine (XXV)
合成路线:The title compound is obtained by reductive condensation between the chiral intermediate aldehyde (XIV) and piperidine (XXV) in the presence of NaBH(OAc)3 in trifluoroethanol
合成路线:Acylation of sarcosine methyl ester (I) with 3,5-dichlorobenzoyl chloride (II) produced the corresponding amide (III).Claisen condensation of (III) with the dianion of 3,4-dichlorophenylacetic acid (IV),generated in the presence of lithium hexamethyldisilazide,gave,after acid decarboxylation,ketone (V).The lithium enolate of ketone (V) was then alkylated with 1-bromo-3-methyl-2-butene (VI) to afford (VII).Treatment of ketone (VII) with hydroxylamine produced a geometric mixture of oximes from which the desired (E)-isomer (VIII) was isolated by column chromatography.Resolution of the racemic (VIII) was achieved by coupling with N-Boc-D-phenylglycine (IX) followed by fractional crystallization of the desired diastereoisomer (X).Hydrazinolysis of the oxime ester then furnished the chiral intermediate (XI).
合成路线:An alternative procedure for the resolution of (VIII) consisted in the O-acylation of oxime group with pivaloyl chloride (XII) to give (XIII),which was resolved into enantiomers by means of chiral HPLC.Hydrazinolysis of the desired (R)-enantiomer provided (XI).
合成路线:Oxime (XI) was O-methylated with methyl iodide and NaH to afford (XIV).Subsequent ozonolysis of the double bond of (XIV) generated aldehyde (XV).
参考文献标题:Substd.oximes as neurokinin antagonists
文献作者:Carruthers,N.I.; Reichard,G.A.; Shih,N.-Y.; Lavey,B.J.; Alaimo,C.A.; Ting,P.C.(Schering Corp.)
参考来源:US 6063926
合成路线:In a different strategy,the racemic intermediate aldehyde (IX) has been obtained as follows: Swern oxidation of the known racemic alcohol (I) yields aldehyde (II),which is further reductively aminated with methylamine to produce the secondary amine (III).Acylation of amine (III) with 3,5-dichlorobenzoyl chloride (IV) leads to amide (V).Subsequent desilylation of (V) with HF in acetonitrile provides alcohol (VI).The thioketal group of (VI) is then removed by treatment with HgClO4 and CaCO3,yielding ketone (VII).Treatment of (VII) with O-methyl hydroxylamine,followed by separation of the resultant E-/Z- mixture of isomers furnishes the desired O-methyl oxime (VIII).The primary alcohol function of (VIII) is then oxidized under Swern conditions to provide aldehyde (IX)
合成路线:Acylation of 4-amino-1-benzylpiperidine (X) with 5-chloropentanoyl chloride (XI) gives the chloro amide (XII),which is further cyclized to the 2-piperidone (XIII) in the presence of NaH.Replacement of the N-benzyl (XIII) for a N-Boc (XIV) protecting group is then accomplished by catalytic hydrogenolysis in the presence of Boc2O (1,2).Alkylation of piperidone (XIV) with allyl bromide (XV) yields the racemic 3-allyl-2-piperidone (XVI),which is subjected to oxidative cleavage with RuO2/NaIO4,producing carboxylic acid (XVII).After coupling of acid (XVII) with methylamine,the resultant N-methyl amide (XVIII) is deprotected by treatment with trifluoroacetic acid to give piperidine (XIX)
合成路线:Reductive condensation between racemic intermediate aldehyde (IX) and racemic piperidine (XIX) leads to a diastereoisomeric mixture of substituted piperidines,from which the target isomer is finally isolated through chiral chromatography
参考文献标题:Identification of a novel 1'-[5-((3,5-dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]- 2-oxo-(1,4'-bipiperidine) as a dual NK(1)/NK(2) antagonist
文献作者:Ting,P.C.; Lee,J.F.; Shih,N.-Y.; Piwinski,J.J.; Anthes,J.C.; Chapman,R.W.; Rizzo,C.A.; Hey,J.A.; Ng,K.; Nomeir,A.A.
参考来源:Bioog.Med.Chem.Lett.2002,12(16),2125
产品链接: CAS No. 226915-43-1››