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【结 构 式】

【药物名称】F-910754

【化学名称】N-[4-(beta-D-Glucopyranuronosyloxy)-3-nitrobenzyloxycarbonyl]daunomycin

【CA登记号】

【 分 子 式 】C41H42N2O21

【 分 子 量 】898.79269

【开发单位】Aventis Pharma (Originator), Dade Behring Marburg (Originator), Institut Curie (Originator)

【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, ONCOLYTIC DRUGS

合成路线1

Ring opening of D-glucuronolactone (I) with NaOMe, followed by peracetylation and bromination of the resulting methyl uronate (II), afforded bromopyranose (III). Coupling of (III) with benzaldehyde (IV) using silver oxide in acetonitrile provided aldehyde (V), which was reduced with NaBH4 in the presence of silica gel in CHCl3-i-PrOH at 0 C to give benzyl alcohol (VI). Subsequent reaction with 4-nitrophenyl chloroformate (VII) in the presence of Et3N formed nitrophenyl carbonate (VIII) which, without purification, was coupled with doxorubicin (IX) in the presence of Et3N in DMF to give (X).

1 Florent, J.-C.; Dong, X.; Gaudel, G.; Mitaku, S.; Monneret, C.; Gesson, J.P.; Jacquesy, J.C.; Mondon, M.; Renoux, B.; Andrianomenjanahary, S.; Michel, S.; Koch, M.; Tillequin, F.; Gerken, M.; Czech, J.; Straub, R.; Bosslet, K.; Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy. J Med Chem 1998, 41, 19, 3572.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 18369 (3S,3aR,6R,6aR)-3,5,6-trihydroxytetrahydrofuro[3,2-b]furan-2(3H)-one 32449-92-6 C6H8O6 详情 详情
(II) 18370 methyl (3S,4R,6S)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate C7H12O7 详情 详情
(III) 18371 methyl (3S,4R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate 21085-72-3 C13H17BrO9 详情 详情
(IV) 18372 4-hydroxy-3-nitrobenzaldehyde 3011-34-5 C7H5NO4 详情 详情
(V) 18373 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-(4-formyl-2-nitrophenoxy)tetrahydro-2H-pyran-2-carboxylate C20H21NO13 详情 详情
(VI) 18374 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-[4-(hydroxymethyl)-2-nitrophenoxy]tetrahydro-2H-pyran-2-carboxylate C20H23NO13 详情 详情
(VII) 16605 4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene 7693-46-1 C7H4ClNO4 详情 详情
(VIII) 18376 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-[2-nitro-4-[([[(4-nitrobenzyl)oxy]carbonyl]oxy)methyl]phenoxy]tetrahydro-2H-pyran-2-carboxylate C28H28N2O17 详情 详情
(IX) 18377 (8S,10S)-10-[[(2R,4S,5S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-glycoloyl-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione C27H29NO11 详情 详情
(X) 18378 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-[4-[([[((3S,4S,6R)-6-[[(1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy]-3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl)amino]carbonyl]oxy)methyl]-2-nitrophenoxy]tetrahydro-2H-pyran-2-carboxylate C48H50N2O25 详情 详情

合成路线2

Deacetylation of (X) on treatment with NaOMe in MeOH-DMF yielded methyl ester (XI), which was finally hydrolyzed with NaOH in H2O-THF at -10 C to furnish the target uronic acid.

1 Florent, J.-C.; Dong, X.; Gaudel, G.; Mitaku, S.; Monneret, C.; Gesson, J.P.; Jacquesy, J.C.; Mondon, M.; Renoux, B.; Andrianomenjanahary, S.; Michel, S.; Koch, M.; Tillequin, F.; Gerken, M.; Czech, J.; Straub, R.; Bosslet, K.; Prodrugs of anthracyclines for use in antibody-directed enzyme prodrug therapy. J Med Chem 1998, 41, 19, 3572.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 18378 methyl (3R,4R,6S)-3,4,5-tris(acetoxy)-6-[4-[([[((3S,4S,6R)-6-[[(1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy]-3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl)amino]carbonyl]oxy)methyl]-2-nitrophenoxy]tetrahydro-2H-pyran-2-carboxylate C48H50N2O25 详情 详情
(XI) 18379 methyl (3S,4R,6S)-6-[4-[([[((3S,4S,6R)-6-[[(1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy]-3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl)amino]carbonyl]oxy)methyl]-2-nitrophenoxy]-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate C42H44N2O22 详情 详情
Extended Information