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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information