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【结 构 式】 
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【分子编号】66435 【品名】2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile 【CA登记号】675126-27-9 |
【 分 子 式 】C15H21N3O3 【 分 子 量 】291.35016 【元素组成】C 61.84% H 7.27% N 14.42% O 16.47% |
合成路线1
该中间体在本合成路线中的序号：(V)
| 【1】 Welham MJ．2005．Process for the manufacture。gefitinib. W0 2005023783（本专利为AstraZeneca plc所有） |
| 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) | 18455 | 3-hydroxy-4-methoxybenzaldehyde; Isovanillin | 621-59-0 | C8H8O3 | 详情 | 详情 |
| (II) | 54574 | 3-hydroxy-4-methoxybenzonitrile | 52805-46-6 | C8H7NO2 | 详情 | 详情 |
| (III) | 66433 | 4-methoxy-3-(3-morpholinopropoxy)benzonitrile | C15H20N2O3 | 详情 | 详情 | |
| (IV) | 66434 | 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile | 675126-26-8 | C15H19N3O5 | 详情 | 详情 |
| (V) | 66435 | 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile | 675126-27-9 | C15H21N3O3 | 详情 | 详情 |
| (VI) | 66436 | (E)-N,N'-bis(3-chloro-4-fluorophenyl)formimidamide | C13H8Cl2F2N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)
| 【1】 Wang JQ, Gao MZ, Miller KD, et al.2006. Synthesis of (11 C) iressa as a new potential PET cancer imaging agent for epidermal growth factor receptor tyrosine kinase. Bioorg Med Chem Lett, 16 (15): 4102~4106 |
| 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) | 54574 | 3-hydroxy-4-methoxybenzonitrile | 52805-46-6 | C8H7NO2 | 详情 | 详情 |
| (II) | 18691 | 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine | 7357-67-7 | C7H14ClNO | 详情 | 详情 |
| (III) | 66433 | 4-methoxy-3-(3-morpholinopropoxy)benzonitrile | C15H20N2O3 | 详情 | 详情 | |
| (IV) | 66434 | 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile | 675126-26-8 | C15H19N3O5 | 详情 | 详情 |
| (V) | 66435 | 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile | 675126-27-9 | C15H21N3O3 | 详情 | 详情 |
| (VI) | 66441 | 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzamide | C15H23N3O4 | 详情 | 详情 | |
| (VII) | 66445 | 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(1H)-one | C16H21N3O4 | 详情 | 详情 | |
| (VIII) | 66443 | 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine | C16H20ClN3O3 | 详情 | 详情 | |
| (IX) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (X) | 66448 | 4-((3-chloro-4-fluorophenyl)amino)-6-(3-morpholinopropoxy)quinazolin-7-ol | 847949-49-9 | C21H22ClFN4O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXII)Reaction of 2-nitrovanillin (III) with NH4OH and I2 in H2O/THF yields nitrile (XVIII), which is then condensed with 4-(3-chloropropyl)morpholine hydrochloride (XII) —prepared by alkylation of morpholine (XIX) with 1-bromo-3-chloropropane (XX) in toluene at 84 °C— by means of Cs2CO3 in DMF at 75 °C to give the morpholinopropyl ether (XXI). Reduction of the nitro group in compound (XXI) with Fe and AcOH affords amine (XXII), which by cyclization with ethylenediamine (VII) and sulfur at 100 °C produces the imidazoline derivative (XXIII). Finally, aminoimidazoline (XXIII) is then subjected to ring closure with cyanogen bromide (IX) in the presence of Et3N in CH2Cl2 .
| 【1】 Hentemann, M., Wood, J., Scott, W. et al. (Bayer Pharmaceuticals Corp.). Substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis. EP 2096919, JP 2010511718, US 2011083984, US 8466283, US 201326113, WO 2008070150. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 68129 | 2-nitrovanillin；4-Hydroxy-3-methoxy-2-nitrobenzaldehyde | C8H7NO5 | 详情 | 详情 | |
| (VII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| (IX) | 28017 | cyanic bromide；cyanogen bromide | 506-68-3 | CBrN | 详情 | 详情 |
| (XII) | 18691 | 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine | 7357-67-7 | C7H14ClNO | 详情 | 详情 |
| (XIII) | 68137 | 7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine | C18H25N5O3 | 详情 | 详情 | |
| (XVIII) | 68140 | 4-hydroxy-3-methoxy-2-nitrobenzonitrile | C8H6N2O4 | 详情 | 详情 | |
| (XIX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XX) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (XXI) | 66434 | 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile | 675126-26-8 | C15H19N3O5 | 详情 | 详情 |
| (XXII) | 66435 | 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile | 675126-27-9 | C15H21N3O3 | 详情 | 详情 |
| (XXIII) | 68141 | 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholinopropoxy)aniline | C17H26N4O3 | 详情 | 详情 |