NAPAP-PS
Chemical Name: 4-[2-[2(R)-[N-[1-(4-Amidinobenzyl)-2-oxo-2-(1-piperidinyl)ethyl]carbamoyl]-2-(2-naphthylsulfonamido)ethylsulfanyl]acetamido]-N-[11-(1-O-methyl-2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl)(4--1)(3-O-methyl-2-O-sulfo-alpha-L-idopyranosyluronic acid)(4--1)(2,3,6-tri-O-sulfo-alpha-D-glucopyranosyl)(4--1)(3-O-methyl-2-O-sulfo-beta-D-glucopyranosyluronic acid)(4--1)(2,3,6-tri-O-sulfo-alpha-D-glucopyranos-4-yloxy)]-3,6,9-trioxaundecyl]benzamide
CAS No. 244606-25-5 (free acid)
项目整合开发状态: Preclinical
项目研究机构: Organon (Originator), Universiteit Leiden (Originator)
合成路线:Condensation of S-(4-monomethoxytrityl)-L-cysteine (I) with 2-naphthalenesulfonyl chloride (II) under Schotten-Baumann conditions afforded sulfonamide (III).Cleavage of the trityl group of (III) by treatment with trifluoroacetic acid and triisopropylsilane gave thiol (IV),which was protected as the thiopyridyl derivative (V) using dithiodipyridine.Coupling of (V) with 4-amidinophenylalanyl piperidine (VI) by means of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide - HCl (EDC),1-hydroxybenzotriazole (HOBt) and N-ethylmorpholine (NEM) furnished dipeptide (VII).The thiopyridyl group of (VII) was then deprotected by treatment with tributyl phosphine to afford thiol (VIII).
合成路线:The known pentasaccharide (IX) was reacted with N-(benzyloxycarbonyl)succinimide (X) yielding carbamate (XI).Sulfation of the free hydroxyl groups of (XI) with triethylamine-sulfur trioxide complex gave the sulfated compound which,after acid cleavage of the formed N-SO3- groups,was converted to the corresponding sodium salt (XII).Hydrogenolysis of the N-benzyloxycarbonyl group then liberated amine (XIII).
合成路线:Amine (XIII) was coupled with the 4-(iodoacetamido)benzoic acid active ester (XIV) to produce amide (XV).
合成路线:Displacement of the iodide of (XV) by thiol (VIII) gave rise to the title sulfide derivative.
📌 参考资料/链接：
参考文献标题:Antithrombotic cpds.
文献作者:Van Boeckel,C.A.A.; Basten,J.E.M.; Dreef-Tromp,C.M.; Buijsman,R.C.(Akzo Nobel N.V.; Universiteit Leiden)
参考来源:WO 9965934
📄 详细内容
合成路线:Condensation of S-(4-monomethoxytrityl)-L-cysteine (I) with 2-naphthalenesulfonyl chloride (II) under Schotten-Baumann conditions afforded sulfonamide (III).Cleavage of the trityl group of (III) by treatment with trifluoroacetic acid and triisopropylsilane gave thiol (IV),which was protected as the thiopyridyl derivative (V) using dithiodipyridine.Coupling of (V) with 4-amidinophenylalanyl piperidine (VI) by means of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide - HCl (EDC),1-hydroxybenzotriazole (HOBt) and N-ethylmorpholine (NEM) furnished dipeptide (VII).The thiopyridyl group of (VII) was then deprotected by treatment with tributyl phosphine to afford thiol (VIII).
合成路线:The known pentasaccharide (IX) was reacted with N-(benzyloxycarbonyl)succinimide (X) yielding carbamate (XI).Sulfation of the free hydroxyl groups of (XI) with triethylamine-sulfur trioxide complex gave the sulfated compound which,after acid cleavage of the formed N-SO3- groups,was converted to the corresponding sodium salt (XII).Hydrogenolysis of the N-benzyloxycarbonyl group then liberated amine (XIII).
合成路线:Amine (XIII) was coupled with the 4-(iodoacetamido)benzoic acid active ester (XIV) to produce amide (XV).
合成路线:Displacement of the iodide of (XV) by thiol (VIII) gave rise to the title sulfide derivative.
参考文献标题:Design and synthesis of a novel synthetic NAPAP-pentasaccharide conjugate displaying a dual antithrombotic action
文献作者:Buijsman,R.C.; Basten,J.E.; van Dinther,T.G.; van der Marel,G.A.; van Boeckel,C.A.; van Boom,J.H.
参考来源:Bioorg Med Chem Lett 1999,9(14),2013