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【结 构 式】 
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【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 |