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【结 构 式】 
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【药物名称】Bosutinib, SKI-606 【化学名称】4-(2,4-Dichloro-5-methoxyphenylamino)-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile 【CA登记号】380843-75-4 【 分 子 式 】C26H29Cl2N5O3 【 分 子 量 】530.45873 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, Leukemia Therapy, NEUROLOGIC DRUGS, Oncolytic Drugs, Stroke, Treatment of, Abl Kinase Inhibitors, Apoptosis Inducers, Inhibitors of Signal Transduction Pathways, Src Kinase Inhibitors |
合成路线1
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 |