2-(2-ethoxy-4-nitrophenyl)isoindoline-1,3-dione -Drug Synthesis Database

【结构式】

【分子编号】69192

【品名】2-(2-ethoxy-4-nitrophenyl)isoindoline-1,3-dione

【CA登记号】　

【分子式】C₁₆H₁₂N₂O₅

【分子量】312.282

【元素组成】C 61.54% H 3.87% N 8.97% O 6.40%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

3-Chloro-4-(2-pyridylmethoxy)aniline (I) is condensed with ethyl cyanoacetate (II) at 100-115 °C to give the N-aryl 2-cyanoacetamide (III). Reduction of 3-ethoxy-4-phthalimido-1-nitrobenzene (IV) with H2 over Pd/C in THF at 50 °C followed by coupling of the resulting aniline with the cyano amide (III) by means of triethyl orthoformate in refluxing propanol affords the 3-amino-2-cyanopropenamide derivative (V). After intramolecular cyclization of propenamide (V) by means of POCl3 in acetonitrile at 60-70 °C, the obtained 6-phthalimidoquinoline derivative is hydrolyzed by means of NH4OH in EtOH at 62-68 °C to give the 6-aminoquinoline (VI) (1). Alternatively, the aminoquinoline (VI) can be obtained by condensation of the aniline derivative (I) with 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile (VII) in the presence of methanesulfonic acid at 70-75 °C, affording the diarylamine (VIII), which is then deacetylated to the aminoquinoline (VI) by hydrolysis with HCl . Finally, compound (VI) is acylated with 4-(dimethylamino)-2-butenoyl chloride (IX) , obtained by chlorination of the corresponding free acid (X) or its hydrochloride salt with either (COCl)2 by means of DMF in THF or DMF/i-PrOAc , POCl3 in DMAc, or SOCl2 in DMAc , in the presence of NMP .
In a related strategy, 4-chloro-7-ethoxy-6-nitroquinoline-3-carbonitrile (XI) is reduced to the corresponding amine (XII) by means of Fe and acetic acid in refluxing methanol. Subsequent acylation of (XII) with 4-(dimethylamino)-2-butenoyl chloride (IX) in the presence of NMP in acetonitrile or DMF yields carboxamide (XIII), which is finally coupled with 3-chloro-4-(2-pyridylmethoxy)aniline (I) by means of pyridinium chloride in refluxing isopropanol or 2-methoxyethanol .

参考文献中间体

合成目标

【1】 Chew, W., Papamichelakis, M. (Wyeth). Methods of preparing 3-cyanoquinolines and intermediates made thereby. WO 2006127205.
【2】 Wissner, A., Rabindran, S.K., Tsou, H.-R. (Wyeth). Substituted quinolines as protein tyrosine kinase enzyme inhibitors. EP 1670473, WO 2005034955.
【3】 Rabindran, S.K., Tsou, H.-R., Wissner, A. (Wyeth). Protein tyrosine kinase enzyme inhibitors. US 2005059678, US 7399865, WO 2005028443.
【4】 Chew, W., Cheal, G.K., Lunetta, J.F. (Wyeth). Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof. EP 1883631, JP 2008545688, US 2006270668, WO 2006127207.
【5】 Chew, W., Rabindran, S.K., Discafani-Marro, C., McGinnis, J.P. III, Wissner, A., Wang, Y. (Wyeth). Methods of synthesizing 6-alkylaminoquinoline derivatives. WO 2006127203.
【6】 Lu, Q., Ku, M.S., Chew, W., Cheal, G.K., Hadfield, A.F., Mirmehrabi, M. (Wyeth). Maleate salts of (E)-N-[4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide and crystalline forms thereof. EP 2212311, WO 2009052264.
【7】 Gontcharov, A., Eng, K.K., Sutherland, K., Sebastian, A., Yu, Q., Place, D.W. (Wyeth). Improved process for preparation of coupled products from 4-amino-3-cyanoquinolines using stabilized intermediates. WO 2010048477.
【8】 Tsou, R.H., Overbeck-Klumpers, E.G., Hallett, W.A. et al. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem 2005, 48(4): 1107-31.

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)	69190	3-Chloro-4-(2-pyridylmethoxy)aniline		C₁₂H₁₁ClN₂O	详情	详情
(II)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(III)	69191	N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-2-cyanoacetamide		C₁₅H₁₂ClN₃O₂	详情	详情
(IV)	69192	2-(2-ethoxy-4-nitrophenyl)isoindoline-1,3-dione		C₁₆H₁₂N₂O₅	详情	详情
(V)	69193	(Z)-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-2-cyano-3-((4-(1,3-dioxoisoindolin-2-yl)-3-ethoxyphenyl)amino)acrylamide		C₃₂H₂₄ClN₅O₅	详情	详情
(VI)	69194	6-amino-4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-7-ethoxyquinoline-3-carbonitrile		C₂₄H₂₀ClN₅O₂	详情	详情
(VII)	69196	6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile;4-Chloro-3-cyano-7-ethoxy-6-(acetylamino)quinoline	848133-76-6	C₁₄H₁₂ClN₃O₂	详情	详情
(VIII)	69195	N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)acetamide		C₂₆H₂₂ClN₅O₃	详情	详情
(IX)	69197	4-(dimethylamino)-2-butenoyl chloride;(E)-4-(dimethylamino)but-2-enoyl chloride		C₆H₁₀ClNO	详情	详情
(X)	69198	(E)-4-(dimethylamino)but-2-enoic acid	149586-32-3	C₆H₁₁NO₂	详情	详情
(XI)	61517	4-chloro-7-ethoxy-6-nitro-3-quinolinecarbonitrile		C₁₂H₈ClN₃O₃	详情	详情
(XII)	69199	6-amino-4-chloro-7-ethoxyquinoline-3-carbonitrile		C₁₂H₁₀ClN₃O	详情	详情
(XIII)	69200	(E)-4-chloro-6-((5-(dimethylamino)penta-1,3-dien-2-yl)amino)-7-ethoxyquinoline-3-carbonitrile		C₁₉H₂₁ClN₄O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

The intermediate N-(2-ethoxy-4-nitrophenyl)phthalimide (IV) is prepared by N-protection of 2-amino-5-nitrophenol (XVII) with phthalic anhydride (XVIII) in the presence of AcOH at 115-120 °C to give the corresponding phthalimide (XIX), which is then alkylated at the phenolic hydroxyl with ethyl bromide (XX) in the presence of K2CO3 in DMF .

参考文献中间体

合成目标

【1】 Chew, W., Papamichelakis, M. (Wyeth). Methods of preparing 3-cyanoquinolines and intermediates made thereby. WO 2006127205.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	69192	2-(2-ethoxy-4-nitrophenyl)isoindoline-1,3-dione		C₁₆H₁₂N₂O₅	详情	详情
(XVII)	33067	2-amino-5-nitrophenol	121-88-0	C₆H₆N₂O₃	详情	详情
(XVIII)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(XIX)	69202	2-(2-hydroxy-4-nitrophenyl)isoindoline-1,3-dione		C₁₄H₈N₂O₅	详情	详情
(XX)	30344	1-bromoethane；ethyl bromide	74-96-4	C₂H₅Br	详情	详情

Extended Information