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【结 构 式】 
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【分子编号】12633 【品名】Quinone; Benzo-1,4-quinone; 2,5-Cyclohexadiene-1,4-dione 【CA登记号】106-51-4 |
【 分 子 式 】C6H4O2 【 分 子 量 】108.09656 【元素组成】C 66.67% H 3.73% O 29.6% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The Diels-Alder cyclization of butadiene (VII) with 1,4-benzoquinone (VIII) in THF gives the naphthalenetrione (IX), which is acylated with acetic anhydride and TEA to yield the tetralone derivative (X). The Grignard reaction of (X) with vinylmagnesium bromide (XI) and CeCl3, followed by acylation with acetic anhydride, affords the tetraline derivative (XII), which is treated with NaBH4 and oxidized with cerium ammonium nitrate to provide the tetrahydronaphthoquinone (XIII). The cyclization of (XIII) with 4-acetoxy-3,4-dihydro-1H-2-benzopyran-1,3-dione (XIV) by means of NaH in THF gives the intermediate (XV), which rearranges to the tetracyclic dione (XVI). The palladium-catalyzed (PdCl2(MeCN)2) rearrangement of (XVI) in toluene yields the allyl acetate derivative (XVII), which is oxidized with peracetic acid and RuCl3 in water/acetonitrile/dichloromethane to afford the protected intermediate (XVIII). Finally, this compound is deprotected and simultaneously epimerized by a treatment with HCl in refluxing isopropanol/water to provide the desired target intermediate (II).
| 【1】 Hottop, T.; et al.; Synthesis of 4-demethoxyadriamycinone utilizing ruthenium-catalyzed oxidation of allyl acetates. Tetrahedron Lett 2001, 42, 19, 3343. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 50740 | (7S,9S)-9-glycoloyl-6,7,9,11-tetrahydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C20H16O8 | 详情 | 详情 | |
| (VII) | 50730 | [[(E)-3-(tert-butoxy)-1-methylene-2-propenyl]oxy](trimethyl)silane; (E)-3-(tert-butoxy)-1-methylene-2-propenyl trimethylsilyl ether | C11H22O2Si | 详情 | 详情 | |
| (VIII) | 12633 | Quinone; Benzo-1,4-quinone; 2,5-Cyclohexadiene-1,4-dione | 106-51-4 | C6H4O2 | 详情 | 详情 |
| (IX) | 50731 | 8-(tert-butoxy)-4a,7,8,8a-tetrahydro-1,4,6(5H)-naphthalenetrione | C14H18O4 | 详情 | 详情 | |
| (X) | 50732 | 4-(acetoxy)-5-(tert-butoxy)-7-oxo-5,6,7,8-tetrahydro-1-naphthalenyl acetate | C18H22O6 | 详情 | 详情 | |
| (XI) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (XII) | 50733 | (2S,4S)-5,8-bis(acetoxy)-4-(tert-butoxy)-2-vinyl-1,2,3,4-tetrahydro-2-naphthalenyl acetate | C22H28O7 | 详情 | 详情 | |
| (XIII) | 50734 | (2S,4S)-4-(tert-butoxy)-5,8-dioxo-2-vinyl-1,2,3,4,5,8-hexahydro-2-naphthalenyl acetate | C18H22O5 | 详情 | 详情 | |
| (XIV) | 50735 | 1,3-dioxo-3,4-dihydro-1H-isochromen-4-yl acetate | C11H8O5 | 详情 | 详情 | |
| (XV) | 50736 | (2S,4S)-6-(acetoxy)-4-(tert-butoxy)-11-hydroxy-5,12-dioxo-2-vinyl-1,2,3,4,5,12-hexahydro-2-naphthacenyl acetate | C28H28O8 | 详情 | 详情 | |
| (XVI) | 50737 | (2S,4S)-2-(acetoxy)-4-(tert-butoxy)-12-hydroxy-6,11-dioxo-2-vinyl-1,2,3,4,6,11-hexahydro-5-naphthacenyl acetate | C28H28O8 | 详情 | 详情 | |
| (XVII) | 50738 | 2-[5-(acetoxy)-4-(tert-butoxy)-12-hydroxy-6,11-dioxo-3,4,6,11-tetrahydro-2(1H)-naphthacenylidene]ethyl acetate | C28H28O8 | 详情 | 详情 | |
| (XVIII) | 50739 | (2S,4R)-2-[2-(acetoxy)acetyl]-4-(tert-butoxy)-2,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-5-naphthacenyl acetate | C28H28O10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVII)3) The cyclization of benzoquinone (XXXVII) with 3-amino-4-methoxycrotonic acid methyl ester (XXXVIII) gives 5-hydroxy-2-(methoxymethyl)-1H-indole-3-carboxylic acid methyl ester (XXXIX), which is methylated to 5-methoxy-2-(methoxymethyl)-1-methylindole-3-carboxylic acid methyl ester (XL). The oxidation of (XL) with DDQ yields the corresponding aldehyde (XLI), which is submitted to a Horner-Emmonds condensation with 2-(dimethoxyphosphoryl)acetic acid ethyl ester (XLII) in a basic medium to afford the corresponding acrylic ester (XLIII). The nitration of (XLIII) gives 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4-nitroindol-2-yl]acrylic acid ethyl ester (XLIV), the monoethyl ester analogue of compound (XVIII).The reduction of (XLIV) with Sn and 3N HCl in ethanol/water yields the corresponding 4-amino derivative (XLV), which is oxidized with Fremy's salt (nitrodisulfonic acid potassium salt) to afford 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4,7-dioxo-4,7-dihydro-1H-indo l -2-yl]acrylic acid ethyl ester (XLVI). The reduction of (XLVI) with Na2S2O4 in CHCl3/ethanol/water gives the corresponding hydroquinone (XLVII), which is first reduced with DIBAL (diisobutylaluminum hydride) in toluene/dichloromethane and then oxidized again with FeCl3 to afford 3-(hydroxymethyl)-2-(3-hydroxy-1-propenyl)-5-methoxy-1-methyl-4,7-dihydro-1H-indole-4,7-dione (XXII). Finally, this compound is treated with aziridine (XXIII) in hot methanol.
| 【1】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143. |
| 【2】 Kinugawa, M.; Arai, H.; Nishikawa, H.; Masuda, Y.; Ogasa, T.; Tomioka, S.; Kasai, M.; Synthetic studies of the indoloquinone antitumor agent EO9. 13th Int Symp Med Chem (Sept 19-23, Paris) 1994, Abst P250. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXII) | 12618 | 3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione | C14H15NO5 | 详情 | 详情 | |
| (XXIII) | 10151 | Ethyleneimine; Aziridine; Azirane | 151-56-4 | C2H5N | 详情 | 详情 |
| (XXXVII) | 12633 | Quinone; Benzo-1,4-quinone; 2,5-Cyclohexadiene-1,4-dione | 106-51-4 | C6H4O2 | 详情 | 详情 |
| (XXXVIII) | 12634 | methyl (E)-3-amino-4-methoxy-2-butenoate | C6H11NO3 | 详情 | 详情 | |
| (XXXIX) | 12635 | methyl 5-hydroxy-2-(methoxymethyl)-1H-indole-3-carboxylate | C12H13NO4 | 详情 | 详情 | |
| (XL) | 12636 | methyl 5-methoxy-2-(methoxymethyl)-1-methyl-1H-indole-3-carboxylate | C14H17NO4 | 详情 | 详情 | |
| (XLI) | 12637 | methyl 2-formyl-5-methoxy-1-methyl-1H-indole-3-carboxylate | C13H13NO4 | 详情 | 详情 | |
| (XLII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (XLIII) | 12639 | methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-1H-indole-3-carboxylate | C17H19NO5 | 详情 | 详情 | |
| (XLIV) | 12640 | methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-4-nitro-1H-indole-3-carboxylate | C17H18N2O7 | 详情 | 详情 | |
| (XLV) | 63466 | 2-propenyl 6-(1-hydroxyethyl)-3-({5-[2-(5-isothiazolyl)ethenyl]-1-[(2-propenyloxy)carbonyl]-3-pyrrolidinyl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C26H31N3O6S2 | 详情 | 详情 | |
| (XLVI) | 63467 | methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-3-carboxylate | C17H17NO7 | 详情 | 详情 | |
| (XLVII) | 63468 | methyl 2-[(E)-3-ethoxy-3-oxo-1-propenyl]-4,7-dihydroxy-5-methoxy-1-methyl-1H-indole-3-carboxylate | C17H19NO7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Diazotization of 4-nitroaniline (I) with NaNO2 in cold concentrated HCl produces diazonium salt (II), which is subsequently coupled to 1,4-benzoquinone (III) in the presence of NaHCO3 to furnish the target 2-aryl benzoquinone.
| 【1】 Reynolds, K.; et al.; The identification of nanomolar 1,4-benzoquinone inhibitors of shikimate kinase. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-745. |