合成路线:1) The condensation of benzyloxycarbonyl-L-alanine (I) with 2-(4-piperidyloxy)acetic acid ethyl ester (II) by means of pivaloyl chloride and triethylamine in ethyl acetate gives the protected alanyl-piperidine (III),which is deprotected by hydrogenation over Pd/C in ethanol to yield compound (IV).The condensation of (IV) with 4-cyanobenzoyl chloride (V) by means of triethylamine in toluene affords the corresponding benzoyl derivative (VI),which is finally treated with hydroxylamine in the same solvent.
合成路线:Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) with DMSO and oxalyl chloride afforded the corresponding aldehyde (II).Subsequent pinacol dimerization by treatment with VCl3 and Zn gave diol (III) with a 98% diastereomeric purity.After protection of the hydroxyl groups of (III) as the [2-(trimethylsilyl) ethoxy]methyl (SEM) ethers upon treatment with SEMCl and diisopropyl ethylamine,(IV) was obtained,then the N-benzyloxycarbonyl groups were removed by hydrogenolysis in the presence of Pd/C.The resulting diamine (V) was cyclized with carbonyl diimidazole and pyridine to furnish the cyclic urea (VI).Alkylation with benzyl bromide (VII) and NaH provided the bisbenzylated compound,which was finally deprotected by treatment with HCl in MeOH-dioxan.
参考文献标题:Process for the preparation of mixed anhydrides
文献作者:Trussardi,R.; Karpf,M.(F.Hoffmann-La Roche AG)
参考来源:EP 0847994
合成路线:The acylation of 4-hydroxypiperidine (I) with benzyl chloroformate (II) by means of triethylamine in dichloromethane gives 4-hydroxypiperidine-1-carboxylic acid benzyl ester (III),which is condensed with tert-butyl bromoacetate (IV) by means of tetrabutylammonium hydrogensulfate and NaOH in toluene/water,affording 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (V).The deprotection of (V) by hydrogenation with H2 over Pd/C in ethanol gives the piperidine (VI),which is condensed with N-(benzyloxycarbonyl)-4-O-tert-butyl-L-tyrosine (VII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methylmorpholine (NMM) in dichloromethane,yielding the expected condensation product (VIII).The deprotection of the amino group of (VIII) by hydrogenation as before affords (IX),which is N-acylated with 4-amidinobenzoyl chloride (X),prepared by reaction of 4-amidinobenzoic acid (XI) with SOCl2,giving the bis-tert-butylated product (XII).Finally,this compound is deprotected by means of trifluoroacetic acid in dichloromethane.
合成路线:2) The reaction of 4-hydroxypiperidine (VII) with benzyl chloroformate (VIII) by means of triethylamine in dichloromethane gives the expected benzyloxycarbonyl derivative (IX),which is condensed with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium bisulfate and NaOH,yielding 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (XI).The deprotection of (XI) as ususal affords 2-(4-piperidinyloxy)acetic acid tert-butyl ester (XII),which is condensed with N-(benzyloxycarbonyl)-L-alanine (XIII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl-morpholine (NMM) in dichloromethane to yield the acylated piperidine (XIV).The deprotection of (XIV) as usual affords compound (XV),which is acylated at the free amino group with 4-cyanobenzoyl chloride (V) and tetrabutylammonium bisulfate to give 2-[1-[N-(4-cyanobenzoyl)-L-alanyl]piperidin-4-yloxy]acetic acid tert-butyl ester (XVI).The reaction of the cyano group of (XVI) with hydroxylamine affords compound (XVII) with a hydroxyamidino substituent.Finally,the tert-butyl ester group of (XVII) is converted in ethyl ester by hydrolysis with hot fomic acid to the corresponding acetic acid (XVIII) and subsequent esterification with ethanol/H2SO4.
参考文献标题:Low molecular weight,non-peptide fibrinogen receptor antagonists
文献作者:Alig,L.; Edenhofer,A.; Hadv醨y,P.; H黵zeler,M.; Knopp,D.; M黮ler,M.; Steiner,B.; Trzeciak,A.; Weller,T.
参考来源:J Med Chem 1992,35(23),4393
合成路线:2) The reaction of 4-hydroxypiperidine (VII) with benzyl chloroformate (VIII) by means of triethylamine in dichloromethane gives the expected benzyloxycarbonyl derivative (IX),which is condensed with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium bisulfate and NaOH,yielding 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (XI).The deprotection of (XI) as ususal affords 2-(4-piperidinyloxy)acetic acid tert-butyl ester (XII),which is condensed with N-(benzyloxycarbonyl)-L-alanine (XIII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl-morpholine (NMM) in dichloromethane to yield the acylated piperidine (XIV).The deprotection of (XIV) as usual affords compound (XV),which is acylated at the free amino group with 4-cyanobenzoyl chloride (V) and tetrabutylammonium bisulfate to give 2-[1-[N-(4-cyanobenzoyl)-L-alanyl]piperidin-4-yloxy]acetic acid tert-butyl ester (XVI).The reaction of the cyano group of (XVI) with hydroxylamine affords compound (XVII) with a hydroxyamidino substituent.Finally,the tert-butyl ester group of (XVII) is converted in ethyl ester by hydrolysis with hot fomic acid to the corresponding acetic acid (XVIII) and subsequent esterification with ethanol/H2SO4.
参考文献标题:Orally active fibrinogen receptor antagonists.2.Amidoximes as prodrugs of amidines
文献作者:Weller,T.; Alig,L.; Beresini,M.; Blackburn,B.K.; Bunting,S.; Hadvary,P.; Muller,M.H.; Knopp,D.; Levet-Trafit,B.; Lipari,M.T.; Modi,N.B.; Muller,M.; Refino,C.J.; Schmitt,M.; Schonholzer,P.; Weiss,S.; Steiner,B.
参考来源:J Med Chem 1996,39(16),3139
合成路线:1) The condensation of benzyloxycarbonyl-L-alanine (I) with 2-(4-piperidyloxy)acetic acid ethyl ester (II) by means of pivaloyl chloride and triethylamine in ethyl acetate gives the protected alanyl-piperidine (III),which is deprotected by hydrogenation over Pd/C in ethanol to yield compound (IV).The condensation of (IV) with 4-cyanobenzoyl chloride (V) by means of triethylamine in toluene affords the corresponding benzoyl derivative (VI),which is finally treated with hydroxylamine in the same solvent.
合成路线:2) The reaction of 4-hydroxypiperidine (VII) with benzyl chloroformate (VIII) by means of triethylamine in dichloromethane gives the expected benzyloxycarbonyl derivative (IX),which is condensed with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium bisulfate and NaOH,yielding 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (XI).The deprotection of (XI) as ususal affords 2-(4-piperidinyloxy)acetic acid tert-butyl ester (XII),which is condensed with N-(benzyloxycarbonyl)-L-alanine (XIII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl-morpholine (NMM) in dichloromethane to yield the acylated piperidine (XIV).The deprotection of (XIV) as usual affords compound (XV),which is acylated at the free amino group with 4-cyanobenzoyl chloride (V) and tetrabutylammonium bisulfate to give 2-[1-[N-(4-cyanobenzoyl)-L-alanyl]piperidin-4-yloxy]acetic acid tert-butyl ester (XVI).The reaction of the cyano group of (XVI) with hydroxylamine affords compound (XVII) with a hydroxyamidino substituent.Finally,the tert-butyl ester group of (XVII) is converted in ethyl ester by hydrolysis with hot fomic acid to the corresponding acetic acid (XVIII) and subsequent esterification with ethanol/H2SO4.
参考文献标题:Sibrafiban
文献作者:Castar,J.; Graul,A.; Merlos,M.
参考来源:Drugs Fut 1998,23(12),1297
产品链接: CAS No. 172927-65-0››