【结 构 式】 |
【分子编号】12599 【品名】3-Chloro-4-nitrophenol 【CA登记号】491-11-2 |
【 分 子 式 】C6H4ClNO3 【 分 子 量 】173.5554 【元素组成】C 41.52% H 2.32% Cl 20.43% N 8.07% O 27.66% |
合成路线1
该中间体在本合成路线中的序号:(III)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:(II)Lenvatinib is prepared by condensation of 4-chloro-7-methoxyquinoline-6-carbonitrile (I) with 3-chloro-4-nitrophenol (II) in hot 2,6-lutidine to afford the 4-aryloxy quinoline (III), which by reduction of its nitro group by means of iron and ammonium chloride yields aniline (IV). Aniline (IV) is then condensed with cyclopropyl isocyanate (V), producing urea (VI), which is finally submitted to partial hydrolysis of the nitrile group under basic conditions .
【1】 Funahashi, Y., Arimoto, I., Matsukura, M. et al. (Eisai R&D Management Co., Ltd.). Nitrogenous aromatic ring compounds. CA 2426461, EP 1415987, EP1506962, EP 1777218, JP 2005272474, JP 2009215313, US 2004953908, US 2006160832, US 2006247259, US 7253286, US 7612092, US 2010197911, US 2011118470, US 7973160, US 8372981, WO 2002032872. |
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) | 67702 | 4-chloro-7-methoxyquinoline-6-carbonitrile | C11H7ClN2O | 详情 | 详情 | |
(II) | 12599 | 3-Chloro-4-nitrophenol | 491-11-2 | C6H4ClNO3 | 详情 | 详情 |
(III) | 67703 | 4-(3-chloro-4-nitrophenoxy)-7-methoxyquinoline-6-carbonitrile | C17H10ClN3O4 | 详情 | 详情 | |
(IV) | 67704 | 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carbonitrile | C17H12ClNO2 | 详情 | 详情 | |
(V) | 67705 | cyclopropyl isocyanate | 4747-72-2 | C4H5NO | 详情 | 详情 |
(VI) | 67706 | 1-(2-chloro-4-((6-cyano-7-methoxyquinolin-4-yl)oxy)phenyl)-3-cyclopropylurea | C21H17ClN4O3 | 详情 | 详情 |