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【结 构 式】

【药物名称】Neratinib;HKI-272;WAY-179272

【化学名称】N-[4-[3-Chloro-4-(pyridin-2-ylmethoxy)phenylamino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)-2(E)-butenamide

【CA登记号】698387-09-6

【 分 子 式 】C30H29ClN6O3

【 分 子 量 】557.043

【开发单位】Pfizer, Inc. (US)

【药理作用】Pan-erbB Inhibitor;Oncolytic

合成路线1

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 .

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

The precursor 3-chloro-4-(2-pyridylmethoxy)aniline (I) is prepared by coupling of 2-chloro-1-fluoro-4-nitrobenzene (XIV) with 2-pyridylmethanol (XV) by means of KOH in acetonitrile to give the 2-chloro-4-nitrophenyl ether (XVI) , which is then reduced to the corresponding aniline (I) by means of H2 over Pt/C or Pd/C in THF, or Zn and NH4Cl in EtOH .

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.
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.
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
(XIV) 58441 2-chloro-1-fluoro-4-nitrobenzene; 3-Chloro-4-fluoronitrobenzene; 4-Fluoro-3-chloronitrobenzene 350-30-1 C6H3ClFNO2 详情 详情
(XV) 30208 2-pyridinylmethanol;pyridin-2-ylmethanol;2-pyridylmethanol 586-98-1 C6H7NO 详情 详情
(XVI) 69201 2-((2-chloro-4-nitrophenoxy)methyl)pyridine;2-chloro-4-nitrophenyl ether   C12H9ClN2O3 详情 详情

合成路线3

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 .

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

合成路线4

N-Protection of 2-amino-5-nitrophenol (XVII) with Ac2O in the presence of AcOH gives N-(2-hydroxy-4-nitrophenyl)acetamide (XXI), which upon O-alkylation with ethyl bromide (XX) in the presence of K2CO3 in DMF at 60 °C affords N-(2-ethoxy-4-nitrophenyl) acetamide (XXII). Reduction of the nitro derivative (XXII) with H2 over Pd/C in THF furnishes the corresponding aniline (XXIII), which by condensation with ethyl 2-cyano-3-ethoxy-2-propenoate (XXIV) at reflux produces enamine (XXV). Thermal cyclization of enamino ester (XXV) in Dowtherm at 250 °C then yields 4-hydroxyquinoline derivative (XXVI) , which upon chlorination with POCl3 in 1,2-diethoxyethane at 80-85 °C affords N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (VII) . Alternatively, condensation of ethyl cyanoacetate (II) with morpholine (XXVII) at 100-110 °C gives 4-(cyanoacetyl)morpholine (XXVIII), which after coupling with 4-acetamido-3-ethoxyaniline (XXIII) in the presence of triethyl orthoformate in i-PrOH at 50-60 °C produces the arylamino propenamide (XXIX). Finally, cyclization of (XXIX) in the presence of POCl3 in acetonitrile at 60-65 °C then leads to the target intermediate (VII) .

1 Wissner, A., Rabindran, S.K., Tsou, H.-R. (Wyeth). Substituted quinolines as protein tyrosine kinase enzyme inhibitors. EP 1670473, WO 2005034955.
2 Rabindran, S.K., Tsou, H.-R., Wissner, A. (Wyeth). Protein tyrosine kinase enzyme inhibitors. US 2005059678, US 7399865, WO 2005028443.
3 Bernier, C., Shaw, C.-C. (Wyeth). Method of preparing 4-halogenated quinoline intermediates. WO 2009139797.
4 Wang, Y., Warren, C. Papamichelakis, M. (Wyeth). Quinoline intermediates of receptor tyrosine kinase inhibitors and the synthesis thereof. WO 2005070890.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 11877 Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate 105-56-6 C5H7NO2 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
(XVII) 33067 2-amino-5-nitrophenol 121-88-0 C6H6N2O3 详情 详情
(XX) 30344 1-bromoethane;ethyl bromide 74-96-4 C2H5Br 详情 详情
(XXI) 69203 N-(2-hydroxy-4-nitrophenyl)acetamide   C8H8N2O4 详情 详情
(XXII) 69204 N-(2-ethoxy-4-nitrophenyl)acetamide   C10H12N2O4 详情 详情
(XXIII) 69205 N-(4-amino-2-ethoxyphenyl)acetamide   C10H14N2O2 详情 详情
(XXIV) 43563 ethyl (E)-2-cyano-3-ethoxy-2-propenoate;(E)-ethyl 2-cyano-3-ethoxyacrylate 94-05-3 C8H11NO3 详情 详情
(XXV) 69206 (E)-ethyl 3-((4-acetamido-3-ethoxyphenyl)amino)-2-cyanoacrylate   C16H19N3O4 详情 详情
(XXVI) 69207 N-(3-cyano-7-ethoxy-4-hydroxyquinolin-6-yl)acetamide   C14H13N3O3 详情 详情
(XXVII) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(XXVIII) 69208 4-(cyanoacetyl)morpholine;Cyanoacetic acid morpholide;N-(Cyanoacetyl)morpholine;3-Morpholin-4-yl-3-oxopropionitrile;3-(4-Morpholinyl)-3-oxopropanenitrile;(Morpholinocarbonyl)acetonitrile;(Morpholin-4-ylcarbonyl)acetonitrile 15029-32-0 C7H10N2O2 详情 详情
(XXIX) 69209 (E)-N-(4-((2-cyano-3-morpholino-3-oxoprop-1-en-1-yl)amino)-2-ethoxyphenyl)acetamide   C18H22N4O4 详情 详情
Extended Information