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【结 构 式】 
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【分子编号】12618 【品名】3-(Hydroxymethyl)-2-[(E)-3-hydroxy-1-propenyl]-5-methoxy-1-methyl-1H-indole-4,7-dione 【CA登记号】 |
【 分 子 式 】C14H15NO5 【 分 子 量 】277.27684 【元素组成】C 60.64% H 5.45% N 5.05% O 28.85% |
合成路线1
该中间体在本合成路线中的序号：(XXII)1) The nitrosation of 3-chlorophenol (I) with NaNO2 and H2SO4 in water gives 3-chloro-4-nitrophenol (III), which is methylated with SO4(Me)2 and NaH in THF to yield 3-chloro-4-nitroanisole (IV). The condensation of (IV) with ethyl cyanoacetate (V) by means of NaH in DMF affords ethyl 2-(5-methoxy-2-nitrophenyl)cyanoacetate (VI), which is submitted to ethanolysis with ethanol/HCl affording the malonic ester derivative (VII). The hydrogenation of (VII) with H2 over PtO2 in toluene/ethanol gives the corresponding amino derivative (VIII), which is condensed with methyl 3-formylacrylate (IX) in ethanol yielding the intermediate imine (X). This imine (X), without isolation, is cyclized with zinc acetate in methanol affording 3-[3,3-bis(ethoxycarbonyl)-5-methoxy-2,3-dihydro-1H-indol-2-yl]acrylic acid methyl ester (XI), which is acetylated with acetic anhydride to the N-acetyl derivative (XII). The decarboxylative hydrolysis of (XII) with KOH in ethanol gives 3-(1-acetyl-3-carboxy-5-methoxy-2,3-dihydro-1H-indol-2-yl)acrylic acid (XIII), which is converted into its dimethyl ester (XIV) with SO4(Me)2 and K2CO3. The dehydrogenation of (XIV) with dichlorodicyanobenzoquinone (DDQ) in refluxing toluene yields 3-[1-acetyl-5-methoxy-3-(methoxycarbonyl)-1H-indol-2-yl]acrylic acid methyl ester (XV), which is deacetylated to (XVI) by column chromatography over basic alumina in dichloromethane/acetone. The nitration of (XVI) with fuming nitric acid in acetic acid affords the 4-nitro derivative (XVII), which is methylated with NaH and methyl iodide to the N-methyl derivative (XVIII). The reduction of (XVIII) with Sn and 3N HCl in ethanol/water yields the corresponding 4-amino derivative (XIX), 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 methyl ester (XX). The reduction of (XX) with Na2S2O4 in CHCl3/ethanol/water gives the corresponding hydroquinone (XXI), 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】 Oostveen, E.A.; Speckamp, W.N.; Mitomycin analogues I. Indoloquinones as (potential) bisalkylating agents. Tetrahedron 1987, 43, 255-62. |
| 【3】 Speckamp, W.N.; Oostveen, E.A. (University of Amsterdam); Indoloquinone cpds. JP 1989502906; US 5079257; WO 8706227 . |
| 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) | 12597 | 3-Chlorophenol; m-Chlorophenol | 108-43-0 | C6H5ClO | 详情 | 详情 |
| (II) | 12598 | 3-Chloro-4-nitrosophenol | C6H4ClNO2 | 详情 | 详情 | |
| (III) | 12599 | 3-Chloro-4-nitrophenol | 491-11-2 | C6H4ClNO3 | 详情 | 详情 |
| (IV) | 12600 | 3-Chloro-4-nitrophenyl methyl ether; 2-Chloro-4-methoxy-1-nitrobenzene; 3-Chloro-4-nitroanisole | 28987-59-9 | C7H6ClNO3 | 详情 | 详情 |
| (V) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (VI) | 12602 | ethyl 2-cyano-2-(5-methoxy-2-nitrophenyl)acetate | C12H12N2O5 | 详情 | 详情 | |
| (VII) | 12603 | diethyl 2-(5-methoxy-2-nitrophenyl)malonate | C14H17NO7 | 详情 | 详情 | |
| (VIII) | 12604 | diethyl 2-(2-amino-5-methoxyphenyl)malonate | C14H19NO5 | 详情 | 详情 | |
| (IX) | 12605 | methyl (E)-4-oxo-2-butenoate | 7327-99-3 | C5H6O3 | 详情 | 详情 |
| (X) | 12606 | diethyl 2-(5-methoxy-2-[[(E,2E)-4-methoxy-4-oxo-2-butenylidene]amino]phenyl)malonate | C19H23NO7 | 详情 | 详情 | |
| (XI) | 12607 | diethyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1,2-dihydro-3H-indole-3,3-dicarboxylate | C19H23NO7 | 详情 | 详情 | |
| (XII) | 12608 | diethyl 1-acetyl-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1,2-dihydro-3H-indole-3,3-dicarboxylate | C21H25NO8 | 详情 | 详情 | |
| (XIII) | 12609 | 1-Acetyl-2-[(E)-2-carboxyethenyl]-5-methoxy-3-indolinecarboxylic acid | C15H15NO6 | 详情 | 详情 | |
| (XIV) | 12610 | methyl 1-acetyl-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-3-indolinecarboxylate | C17H19NO6 | 详情 | 详情 | |
| (XV) | 12611 | methyl 1-acetyl-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1H-indole-3-carboxylate | C17H17NO6 | 详情 | 详情 | |
| (XVI) | 12612 | methyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1H-indole-3-carboxylate | C15H15NO5 | 详情 | 详情 | |
| (XVII) | 12613 | methyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-4-nitro-1H-indole-3-carboxylate | C15H14N2O7 | 详情 | 详情 | |
| (XVIII) | 12614 | methyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-methyl-4-nitro-1H-indole-3-carboxylate | C16H16N2O7 | 详情 | 详情 | |
| (XIX) | 12615 | methyl 4-amino-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-methyl-1H-indole-3-carboxylate | C16H18N2O5 | 详情 | 详情 | |
| (XX) | 12616 | methyl 5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-3-carboxylate | C16H15NO7 | 详情 | 详情 | |
| (XXI) | 12617 | methyl 4,7-dihydroxy-5-methoxy-2-[(E)-3-methoxy-3-oxo-1-propenyl]-1-methyl-1H-indole-3-carboxylate | C16H17NO7 | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XXII)2) The esterification of 2-hydroxy-3-methoxybenzaldehyde (XXIV) with methanesulfonyl chloride and triethylamine gives the corresponding mesylate (XXV), which is nitrated with fuming HNO3 to 2-(methanesulfonyloxy)-3-methoxy-6-nitrobenzaldehyde (XXVI). The condensation of (XXVI) or 2-(benzenesulfonyloxy)-3-methoxy-6-nitrobenzaldehyde (XXVIII) with 2-(diethoxyphosphoryl)acetic acid methyl ester by means of NaH in THF yields 3-(2-hydroxy-3-methoxy-6-nitrophenyl)acrylic acid methyl ester (XXVII), which is benzylated with benzyl bromide and K2CO3 to the benzyl derivative (XXIX). The cyclization of (XXIX) with refluxing triethyl phosphite affords 4-benzyloxy-5-methoxy-1H-indole-2-carboxylic acid methyl ester (XXX), which is reduced to the corresponding carbaldehyde (XXXI) according to Tetrahedron Lett 1994, 50: 7657. The methylation of (XXXI) with NaH and methyl iodide in DMF yields the N-methyl derivative (XXXII), which is condensed with 2-(diethoxyphosphoryl)acetic acid methyl ester by means of NaH in THF to afford 3-(4-benzyloxy-5-methoxy-1-methylindol-2-yl)acrylic acid methyl ester (XXXIII). The formylation of (XXXIII) with POCl3 and DMF gives the 4-formyl derivative (XXXIV), which is debenzylated with trimethylsilyl iodide in acetonitrile to the 4-hydroxy compound (XXXV). The oxidation of (XXXV) with Fremy's salt as before yields 3-(3-formyl-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indole-2-yl) acrylic acid methyl ester (XXXVI), which is treated successively with Na2S2O4, DIBAL, and finally with FeCl3, as before, to afford the dihydroxy quinone (XXII), already obtained.
| 【1】 Cotterill, A.S.; Moody, C.J.; Roffey, J.R.; An improved synthesis of the indolequinone anticancer agent EO9. Tetrahedron 1995, 51, 26, 7223-30. |
| 【2】 Bailey, S.M.; Lohmeyer, M.; Dimbleby, R.; Castaner, J.; EO9. Drugs Fut 1996, 21, 2, 143. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 | |
| (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 |
| (XXIV) | 12620 | o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde | 148-53-8 | C8H8O3 | 详情 | 详情 |
| (XXV) | 12621 | 2-formyl-6-methoxyphenyl methanesulfonate | C9H10O5S | 详情 | 详情 | |
| (XXVI) | 12622 | 2-formyl-6-methoxy-3-nitrophenyl methanesulfonate | C9H9NO7S | 详情 | 详情 | |
| (XXVII) | 12623 | methyl (E)-3-(2-hydroxy-3-methoxy-6-nitrophenyl)-2-propenoate | C11H11NO6 | 详情 | 详情 | |
| (XXVIII) | 12624 | 2-formyl-6-methoxy-3-nitrophenyl benzenesulfonate | C14H11NO7S | 详情 | 详情 | |
| (XXIX) | 12625 | methyl (E)-3-[2-(benzyloxy)-3-methoxy-6-nitrophenyl]-2-propenoate | C18H17NO6 | 详情 | 详情 | |
| (XXX) | 12626 | methyl 4-(benzyloxy)-5-methoxy-1H-indole-2-carboxylate | C18H17NO4 | 详情 | 详情 | |
| (XXXI) | 12627 | 4-(Benzyloxy)-5-methoxy-1H-indole-2-carbaldehyde | C17H15NO3 | 详情 | 详情 | |
| (XXXII) | 12628 | 4-(Benzyloxy)-5-methoxy-1-methyl-1H-indole-2-carbaldehyde | C18H17NO3 | 详情 | 详情 | |
| (XXXIII) | 12629 | ethyl (E)-3-[4-(benzyloxy)-5-methoxy-1-methyl-1H-indol-2-yl]-2-propenoate | C22H23NO4 | 详情 | 详情 | |
| (XXXIV) | 12630 | ethyl (E)-3-[4-(benzyloxy)-3-formyl-5-methoxy-1-methyl-1H-indol-2-yl]-2-propenoate | C23H23NO5 | 详情 | 详情 | |
| (XXXV) | 12631 | ethyl (E)-3-(3-formyl-4-hydroxy-5-methoxy-1-methyl-1H-indol-2-yl)-2-propenoate | C16H17NO5 | 详情 | 详情 | |
| (XXXVI) | 12632 | ethyl (E)-3-(3-formyl-5-methoxy-1-methyl-4,7-dioxo-4,7-dihydro-1H-indol-2-yl)-2-propenoate | C16H15NO6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXII)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 |