• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】50011

【品名】methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate

【CA登记号】

【 分 子 式 】C15H21ClN2O4

【 分 子 量 】328.79552

【元素组成】C 54.8% H 6.44% Cl 10.78% N 8.52% O 19.46%

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:(VII)

Alkylation of 4-hydroxy-5-methoxy benzoic acid methyl ester (I) with 3-chloropropyl p-toluene sulfonate (III) by means of K2CO3 and methyl-tricapryl ammonium chloride (Aliquat 128) in refluxing acetone affords compound (III), which is then nitrated by means of HNO3 in HOAc to furnish 2-nitro derivative (IV). Reduction of the nitro moiety of (IV) by means of Fe in H2O/MeOH in the presence of ammonium chloride yields 2-amino compound (V), which is subjected to reaction with refluxing dimethylformamide dimethylacetal (VI) to provide amidine (VII). Condensation of (VII) with acetonitrile by means of n-BuLi in hexane/THF/HOAc gives substituted quinoline-carbonitrile (IX), whose hydroxyl group is replaced by a chlorine by treatment of (IX) with refluxing POCl3 to afford compound (X). Coupling of (X) with 2,4-dichloro-5-methoxyaniline (XI) in 2-ethoxyethanol in the presence of pyridine hydrochloride yields compound (XII), which is finally converted into the desired compound by condensation with 1-methylpiperazine (XII) by means of NaI in refluxing ethylene glycol dimethyl ether.

1 Boschelli, D.H.; Ye, F.; Wang, Y.D.; Dutia, M.; Johnson, S.L.; Wu, B.; Miller, K.; Powell, D.W.; Yaczko, D.; Young, M.; Tischler, M.; Arndt, K.; Discafani, C.; Etienne, C.; Gibbons, J.; Grod, J.; Lucas, J.; Weber, J.M.; Boschelli, F.; Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 2001, 44, 23, 3965.
2 Boschelli, D.H.; Dutia, M.; Ye, F.; et al.; Inhibition of SRC kinase activity by 4-phenylamino-3-quinolinecarbonitriles Part 2: Optimization of the side chain at C-7. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 145.
3 Boschelli, D.H.; Wang, Y.D.; Ye, F.; et al.; Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles. J Med Chem 2001, 44, 5, 822.
4 Tsou, H.-R.; Wissner, A.; Johnson, B.D.; Reich, M.F.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); Substituted 3-cyano quinolines. US 6002008 .
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) 29176 methyl 4-hydroxy-3-methoxybenzoate 3943-74-6 C9H10O4 详情 详情
(II) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(III) 50008 methyl 4-(3-chloropropoxy)-3-methoxybenzoate C12H15ClO4 详情 详情
(IV) 50009 methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate C12H14ClNO6 详情 详情
(V) 50010 methyl 2-amino-4-(3-chloropropoxy)-5-methoxybenzoate C12H16ClNO4 详情 详情
(VI) 11984 N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine; Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal 4637-24-5 C5H13NO2 详情 详情
(VII) 50011 methyl 4-(3-chloropropoxy)-2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxybenzoate C15H21ClN2O4 详情 详情
(VIII) 37210 acetonitrile 75-05-8 C2H3N 详情 详情
(IX) 50012 7-(3-chloropropoxy)-4-hydroxy-6-methoxy-3-quinolinecarbonitrile C14H13ClN2O3 详情 详情
(X) 48519 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile C14H12Cl2N2O2 详情 详情
(XI) 50013 2,4-dichloro-5-methoxyphenylamine; 2,4-dichloro-5-methoxyaniline C7H7Cl2NO 详情 详情
(XII) 50014 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-3-quinolinecarbonitrile C21H18Cl3N3O3 详情 详情
(XIII) 10061 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine 109-01-3 C5H12N2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(X)

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.

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