【结 构 式】 |
【分子编号】12604 【品名】diethyl 2-(2-amino-5-methoxyphenyl)malonate 【CA登记号】 |
【 分 子 式 】C14H19NO5 【 分 子 量 】281.3086 【元素组成】C 59.78% H 6.81% N 4.98% O 28.44% |
合成路线1
该中间体在本合成路线中的序号:(VIII)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 |