4-hydroxy-3-nitrobenzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】18372

【品名】4-hydroxy-3-nitrobenzaldehyde

【CA登记号】3011-34-5

【分子式】C₇H₅NO₄

【分子量】167.12104

【元素组成】C 50.31% H 3.02% N 8.38% O 38.29%

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)

Reaction of 4-hydroxy-3-nitrobenzaldehyde (I) with hydroxylamine and sodium formate in refluxing formic acid gives 4-hydroxy-3-nitrobenzonitrile (II), which is treated with thioacetamide in hot DMF to yield the corresponding thiobenzamide (III). The cyclization of (III) with 2-chloroacetoacetic acid ethyl ester (IV) in refluxing ethanol affords 2-(4-hydroxy-3-nitrophenyl)-5-methylthiazole-4-carboxylic acid ethyl ester (V), which is alkylated at the phenolic group by means of isobutyl bromide (VI) and K2CO3 in hot DMF, providing the isobutyl ether (VII). The reduction of the NO2 group of (VII) with H2 over Pd/C in ethanol/ethyl acetate gives the expected amino derivative (VIII), which is converted into 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (IX) by diazotation with NaNO2/HCl and treatment with CuCN and KCN. Finally, this compound is hydrolyzed with NaOH in hot THF.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castaner, J.; Rabasseda, X.; Revel, L.; TMX-67. Drugs Fut 2001, 26, 1, 32.
【2】 Kondo, S.; Fukushima, H.; Hasegawa, M.; Tsuchimoto, M.; Nagata, I.; Osada, Y.; Komoriya, K.; Yamaguchi, H. (Teijin Ltd.); 2-Arylthiazole deriv. and pharmaceutical compsn. containing the same. EP 0513379; JP 1993500083; US 5614520; WO 9209279 .

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)	18372	4-hydroxy-3-nitrobenzaldehyde	3011-34-5	C₇H₅NO₄	详情	详情
(II)	43792	4-hydroxy-3-nitrobenzonitrile	3272-08-0	C₇H₄N₂O₃	详情	详情
(III)	43793	4-hydroxy-3-nitrobenzenecarbothioamide		C₇H₆N₂O₃S	详情	详情
(IV)	21337	ethyl 2-chloro-3-oxobutanoate	609-15-4	C₆H₉ClO₃	详情	详情
(V)	43794	ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate		C₁₃H₁₂N₂O₅S	详情	详情
(VI)	24599	1-bromo-2-methylpropane	78-77-3	C₄H₉Br	详情	详情
(VII)	43795	ethyl 2-(4-isobutoxy-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate		C₁₇H₂₀N₂O₅S	详情	详情
(VIII)	43796	ethyl 2-(3-amino-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate		C₁₇H₂₂N₂O₃S	详情	详情
(IX)	43797	ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate		C₁₈H₂₀N₂O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

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

Extended Information