合成路线1

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.