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【结 构 式】

【药物名称】

【化学名称】Methyl [2,3,6-trideoxy-3-(2-guanidinoacetamido)-4-O-methyl-alpha-L-galactopyranosyloxy]-(1--4)-[2,3,6-trideoxy-3-(2-guanidinoacetamido)-alpha-L-galactopyranosyloxy]-(1--4)-[2,3,6-trideoxy-3-(2-guanidinoacetamido)-alpha-L-galactopyranosyloxy]-(1--4)-[2,3,6-trideoxy-3-(2-guanidinoacetamido)-alpha-L-galactopyranosyloxy]-(1--4)-[2,3,6-trideoxy-3-(2-guanidinoacetamido)-alpha-L-galactopyranoside

【CA登记号】

【 分 子 式 】C47H86N20O16

【 分 子 量 】1187.33387

【开发单位】Princeton University (Originator)

【药理作用】ONCOLYTIC DRUGS, DNA-Intercalating Drugs

合成路线1合成路线2合成路线3

合成路线1

Deoxy rhamnopyranoside derivative (I) was acetylated to (II) and subsequently reacted with thiophenol in the presence of boron trifluoride etherate to afford the phenylthio glycoside (III). Acetate hydrolysis of (III) with methanolic K2CO3 gave alcohol (IV). Inversion of the configuration of position 4 to provide the required epimeric alcohol (VII) was achieved via conversion of (IV) to triflate (V), followed by displacement with potassium benzoate and basic hydrolysis of the benzoate ester (VI). The sulfoxide monomer (IX) was obtained from (VII) by protection with trimethylsilyl triflate yielding (VIII), and then oxidation with m-chloroperbenzoic acid to (IX). Coupling of monomers (VII) and (IX) using the sulfoxide glycosylation method in the presence of triflic anhydride produced a mixture of disaccharide (X), its desilylated analogue (XI), and trisaccharide (XII), which were separated by flash chromatography. Oxidation of disaccharide sulfide (X) with m-chloroperbenzoic acid provided sulfoxide (XIII). On the other hand, trisaccharide (XII) was desilylated with HF.Pyr to afford the corresponding alcohol (XIV).

参考文献 中间体
【1】 Xuereb, H.; et al.; Design of an Oligosaccharide Scaffold that binds in the minor groove of DNA. J Am Chem Soc 2000, 122, 9, 1883-90.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12951 Benzenethiol; Phenylmercaptan; Phenylhydrosulfide 108-98-5 C6H6S 详情 详情
(I) 40216 (2S,3R,4S)-4-azido-6-hydroxy-2-methyltetrahydro-2H-pyran-3-yl acetate C8H13N3O4 详情 详情
(II) 40217 (2S,3R,4S)-6-(acetoxy)-4-azido-2-methyltetrahydro-2H-pyran-3-yl acetate C10H15N3O5 详情 详情
(III) 40218 (2S,3R,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl acetate C14H17N3O3S 详情 详情
(IV) 40219 (2S,3R,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-ol C12H15N3O2S 详情 详情
(V) 40220 (2S,3R,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl trifluoromethanesulfonate C13H14F3N3O4S2 详情 详情
(VI) 40221 (2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl benzoate C19H19N3O3S 详情 详情
(VII) 40222 (2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-ol C12H15N3O2S 详情 详情
(VIII) 40223 (2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl trimethylsilyl ether; [[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy](trimethyl)silane C15H23N3O2SSi 详情 详情
(IX) 40224 [[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfinyl)tetrahydro-2H-pyran-3-yl]oxy](trimethyl)silane; (2S,4S,5S,6S)-4-azido-6-methyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl phenyl sulfoxide C15H23N3O3SSi 详情 详情
(X) 40225 [((2S,3S,4S,6R)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy](trimethyl)silane; (2S,3S,4S,6R)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl trimethylsilyl ether C21H32N6O4SSi 详情 详情
(XI) 40226 (2S,3S,4S,6S)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-ol C18H24N6O4S 详情 详情
(XII) 40227 ([(2S,3S,4S,6R)-4-azido-6-[((2S,3S,4S,6S)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy]-2-methyltetrahydro-2H-pyran-3-yl]oxy)(trimethyl)silane; (2S,3S,4S,6R)-4-azido-6-[((2S,3S,4S,6S)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy]-2-methyltetrahydro-2H-pyran-3-yl trimethylsilyl ether C27H41N9O6SSi 详情 详情
(XIII) 40228 (2S,4S,5S,6S)-4-azido-5-([(2R,4S,5S,6S)-4-azido-6-methyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-6-methyltetrahydro-2H-pyran-2-yl phenyl sulfoxide; [((2S,3S,4S,6R)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfinyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy](trimethyl)silane C21H32N6O5SSi 详情 详情
(XIV) 40229 (2S,3S,4S,6S)-4-azido-6-[((2S,3S,4S,6S)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy]-2-methyltetrahydro-2H-pyran-3-ol C24H33N9O6S 详情 详情

合成路线2

Application of the sulfoxide glycosylation method to a mixture of disaccharide (XIII) and trisaccharide (XIV) generated the pentasaccharide core (XV). After cleavage of the trimethylsilyl ether of (XV) with HF.Pyr, methylation with iodomethane and NaH produced methyl ether (XVI). Installation of a further methoxy group in the alpha-position of the sulfide was achieved by oxidation with mercuric trifluoroacetate in the presence of MeOH, yielding (XVII). Desulfurization and simultaneous reduction of all azido groups of (XVII) by hydrogenation over PtO-2 furnished (XVIII).

参考文献 中间体
【1】 Xuereb, H.; et al.; Design of an Oligosaccharide Scaffold that binds in the minor groove of DNA. J Am Chem Soc 2000, 122, 9, 1883-90.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIII) 40228 (2S,4S,5S,6S)-4-azido-5-([(2R,4S,5S,6S)-4-azido-6-methyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-6-methyltetrahydro-2H-pyran-2-yl phenyl sulfoxide; [((2S,3S,4S,6R)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfinyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy](trimethyl)silane C21H32N6O5SSi 详情 详情
(XIV) 40229 (2S,3S,4S,6S)-4-azido-6-[((2S,3S,4S,6S)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy]-2-methyltetrahydro-2H-pyran-3-ol C24H33N9O6S 详情 详情
(XV) 40230 　 C39H59N15O10SSi 详情 详情
(XVI) 40231 　 C37H53N15O10S 详情 详情
(XVII) 40232 　 C38H55N15O11S 详情 详情
(XVIII) 40233 　 C32H61N5O11 详情 详情

合成路线3

The pentaamino compound (XVIII) was coupled with N-(benzyloxycarbonyl)glycine (XIX) employing EDC and HOBt to afford penta amide (XX). The carbobenzoy protecting groups of (XX) were then removed by hydrogenation over PtO2 to give (XXI). Finally, installation of the guanidino groups in (XXI) was carried out by condensation with N,N'-di(carbobenzoxy)-S-methylisothiourea (XXII), followed by hydrogenolysis of the carbobenzoxy groups.

参考文献 中间体
【1】 Xuereb, H.; et al.; Design of an Oligosaccharide Scaffold that binds in the minor groove of DNA. J Am Chem Soc 2000, 122, 9, 1883-90.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVIII) 40234 　 C82H106N10O26 详情 详情
(XIX) 17764 N-Carbobenzyloxyglycine; 2-[[(benzyloxy)carbonyl]amino]acetic acid 1138-80-3 C10H11NO4 详情 详情
(XX) 40235 　 C42H76N10O16 详情 详情
(XXI) 40236 ethyl (2E,4E)-2,4-hexadienoate 2396-84-1 C8H12O2 详情 详情
(XXII) 32861 benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate C18H18N2O4S 详情 详情
Extended Information