-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-6-methoxy-7-[3-(4-morpholinyl)propoxy]quinoline-3-carbonitrile

【CA登记号】263171-01-3

【分子式】C₂₈H₂₉ClN₆O₃S

【分子量】565.09873

【开发单位】Wyeth Pharmaceuticals (Originator)

【药理作用】ONCOLYTIC DRUGS, MEK1 Inhibitors

合成路线1 合成路线2

合成路线1

Condensation of 3-chloro-4-fluoronitrobenzene (I) with the sodium derivative of 2-mercapto-1-methylimidazole (II) affords the diaryl sulfide (III). Subsequent nitro group reduction in (III) using iron dust and ammonium chloride provides the intermediate aniline (IV).

参考文献中间体

【1】 Dutia, M.; Powell, D.W.; Berger, D.M.; et al.; Synthesis and evaluation of 4-anilino substituted 3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 105.

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)	58441	2-chloro-1-fluoro-4-nitrobenzene; 3-Chloro-4-fluoronitrobenzene; 4-Fluoro-3-chloronitrobenzene	350-30-1	C₆H₃ClFNO₂	详情	详情
(II)	18783	1-methyl-1H-imidazol-2-ylhydrosulfide; 1-methyl-1H-imidazole-2-thiol	60-56-0	C₄H₆N₂S	详情	详情
(III)	58442	2-chloro-4-nitrophenyl 1-methyl-1H-imidazol-2-yl sulfide; 2-[(2-chloro-4-nitrophenyl)sulfanyl]-1-methyl-1H-imidazole		C₁₀H₈ClN₃O₂S	详情	详情
(IV)	58443	3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]aniline; 3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenylamine		C₁₀H₁₀ClN₃S	详情	详情

合成路线2

Alkylation of vanillic acid methyl ester (V) with 3-chloropropyl tosylate (VI) in the presence of K2CO3 and Aliquat 336 gives the chloropropyl ether (VII). Subsequent electrophilic nitration of (VII) in hot HOAc affords the ortho-nitrobenzoate (VIII), which is further reduced to the amino benzoate analogue (IX) employing Fe/NH4Cl. Condensation of amino ester (IX) with dimethylformamide dimethylacetal provides adduct (X). This is then converted to the key quinoline derivative (XI) upon condensation with acetonitrile in the presence of butyllithium. Chlorination of (XI) with boiling POCl3 leads to the 4-chloroquinoline (XII). This is then coupled with the (imidazolylsulfanyl)aniline (IV) using pyridinium chloride in refluxing ethoxyethanol to furnish the anilino quinoline adduct (XIII). Finally, displacement of the chloride group of (XIII) with morpholine (XIV) in DMF provides the title compound.

参考文献中间体

【1】 Dutia, M.; Powell, D.W.; Berger, D.M.; et al.; Synthesis and evaluation of 4-anilino substituted 3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 105.
【2】 Frost, P.; Floyd, M.B. Jr.; Wissner, A.; Hamann, P.R.; Zhang, N.; Tsou, H.-R.; Berger, D.M.; Salvati, M.E. (Wyeth); Substd. 3-cyanoquinolines as protein tyrosine kinase inhibitors. EP 1117659; JP 2002525369; WO 0018761 .
【3】 Frost, P.; Floyd, M.B. Jr.; Wissner, A.; Hamann, P.R.; Zhang, N.; Tsou, H.-R.; Berger, D.M.; Salvati, M.E. (Wyeth); Substd. 3-cyanoquinolines. US 6288082 .

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)	58443	3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]aniline; 3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]phenylamine		C₁₀H₁₀ClN₃S	详情	详情
(V)	29176	methyl 4-hydroxy-3-methoxybenzoate	3943-74-6	C₉H₁₀O₄	详情	详情
(VI)	55581	3-Chloropropyl-p-toluenesulfonate		C₁₀H₁₃ClO₃S	详情	详情
(VII)	50008	methyl 4-(3-chloropropoxy)-3-methoxybenzoate		C₁₂H₁₅ClO₄	详情	详情
(VIII)	50009	methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate		C₁₂H₁₄ClNO₆	详情	详情
(IX)	50010	methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate		C₁₂H₁₆ClNO₄	详情	详情
(X)	50011	methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate		C₁₅H₂₁ClN₂O₄	详情	详情
(XI)	50012	7-(3-chloropropoxy)-4-hydroxy-6-methoxy-3-quinolinecarbonitrile		C₁₄H₁₃ClN₂O₃	详情	详情
(XII)	48519	4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile		C₁₄H₁₂Cl₂N₂O₂	详情	详情
(XIII)	58444	4-{3-chloro-4-[(1-methyl-1H-imidazol-2-yl)sulfanyl]anilino}-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile		C₂₄H₂₁Cl₂N₅O₂S	详情	详情
(XIV)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)