(3S,3aR,6R,6aR)-3,5,6-trihydroxytetrahydrofuro[3,2-b]furan-2(3H)-one -Drug Synthesis Database

【结构式】

【分子编号】18369

【品名】(3S,3aR,6R,6aR)-3,5,6-trihydroxytetrahydrofuro[3,2-b]furan-2(3H)-one

【CA登记号】32449-92-6

【分子式】C₆H₈O₆

【分子量】176.12592

【元素组成】C 40.92% H 4.58% O 54.5%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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

合成目标

【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

该中间体在本合成路线中的序号：(I)

Treatment of glucuronic acid gamma-lactone (I) with sodium methoxide in methanol affords methyl glucuronate (II), which is further acylated by acetic anhydride to form the tetraacetate ester (III). Bromination of (III) with TiBr4, followed by coupling of the resultant bromide (IV) with p hydroxybenzaldehyde (V) in the presence of Ag2O yields the peracetylated glucuronide (VI). Aldehyde (VI) reduction employing NaBH4 in the presence of silica gel leads to the benzyl alcohol (VII). The acetate ester groups of (VII) are then removed with sodium methoxide in methanol to furnish (VIII).

参考文献中间体

合成目标

【1】 Leu, Y.-L.; Roffler, S.R.; Chern, J.-W.; Design and synthesis of water-soluble glucuronide derivatives of camptothecin for cancer prodrug monotherapy and antibody-directed enzyme prodrug therapy (ADEPT). J Med Chem 1999, 42, 18, 3623.
【2】 Chern, J.-W.; Roffler, S.; Leu, Y.-L. (Academia Sinica); Proactive antitumor cpds.. EP 0990661; US 6043367 .

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)	62238	methyl (2S,3S,4S,5R)-3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate		C₇H₁₂O₇	详情	详情
(III)	17324	methyl (2S,3R,4S,5R)-3,4,5,6-tetrakis(acetoxy)tetrahydro-2H-pyran-2-carboxylate	7355-18-2	C₁₅H₂₀O₁₁	详情	详情
(IV)	17580	methyl (2S,3S,4S,5R,6R)-3,4,5-tris(acetoxy)-6-bromotetrahydro-2H-pyran-2-carboxylate		C₁₃H₁₇BrO₉	详情	详情
(V)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(VI)	62239	methyl (2S,3R,4S,5R)-3,4,5-tris(acetyloxy)-6-(4-formylphenoxy)tetrahydro-2H-pyran-2-carboxylate		C₂₀H₂₂O₁₁	详情	详情
(VII)	62240	methyl (2S,3R,4S,5R)-3,4,5-tris(acetyloxy)-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₂₀H₂₄O₁₁	详情	详情
(VIII)	62241	methyl (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]tetrahydro-2H-pyran-2-carboxylate		C₁₄H₁₈O₈	详情	详情

Extended Information