F-910754, -Drug Synthesis Database

【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 合成路线2

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).

参考文献中间体

【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.

参考文献中间体

【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