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Quinazoline derivative and preparation method and application thereof
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A derivative, quinazoline technology, applied in the field of medicinal chemistry, can solve problems such as drug resistance and side effects
Active Publication Date: 2019-02-15
雅安职业技术学院
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[0003] However, with the marketing and long-term use of such targeted drugs, they still show many shortcomings, such as drug resistance, toxic and side effects, etc. Therefore, the continuous demand for anti-tumor drugs prompts the emergence of new anti-tumor drugs to replace original drug
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Embodiment 1
[0048] Synthesis of ethyl 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)acetate (1)
[0049]
[0050] 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49g, 5mmol), ethyl chloroacetate (0.74g, 6mmol) and anhydrous K 2 CO 3 (1.38g, 10mmol) was added in 50mL of DMF, stirred and reacted at room temperature for 18h, after the reaction was completed, poured into an appropriate amount of ice water, filtered with suction to obtain the crude product, dried, silica gelcolumn chromatography (dichloromethane:methanol=5:1 ) to obtain the target molecule as light yellow solidpowder with a yield of 87%, m.p.=237-240°C. ESI-MS(m / z):384.17(M+H) + , 1 H NMR (400MHz, DMSO-d6 ):8.75(s,1H),8.23(s,1H),7.79-7.53(m,3H),6.88-6.82(m,2H),4.32(s,2H),4.03(brs,1H),3.96( s,3H), 3.92(s,3H), 2.52(m,2H), 1.53(t,3H).
Embodiment 2
[0052] Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-acetophenone (2)
[0053]
[0054] 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49g, 5mmol), 2-chloroacetophenone (0.93g, 6mmol) and anhydrous K 2 CO 3 (1.38g, 10mmol) was added in 50mL of DMF, stirred and reacted at room temperature for 18h, after the reaction was completed, poured into an appropriate amount of ice water, filtered with suction to obtain the crude product, dried, silica gelcolumn chromatography (dichloromethane:methanol=7:1 ) to obtain the target molecule, a yellow solidpowder, with a yield of 85%, m.p.>250°C. ESI-MS(m / z):416.16(M+H) + , 1 H NMR (400MHz, DMSO-d 6 ):8.73(s,1H),8.19(s,1H),7.83-7.62(m,6H),6.82-6.73(m,4H),4.46(s,2H),4.13(brs,1H),3.95( s,3H), 3.91(s,3H).
Embodiment 3
[0056] Synthesis of 1-(4-chlorophenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone (3)
[0057]
[0058] 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49g, 5mmol), 2,4'-dichloroacetophenone (1.13g, 6mmol) and anhydrous K 2 CO 3 (1.38g, 10mmol) was added in 50mL of DMF, stirred and reacted at room temperature for 18h, after the reaction was completed, poured into an appropriate amount of ice water, filtered with suction to obtain the crude product, dried, silica gelcolumn chromatography (dichloromethane:methanol=7:1 ) to obtain the target molecule as a yellow solid powder with a yield of 90% and m.p.>250°C. ESI-MS(m / z):450.10(M+H) + , 1 H NMR (400MHz, DMSO-d 6 ):8.70(s,1H),8.17(s,1H),7.87-7.60(m,5H),6.80-6.75(m,4H),4.50(s,2H),4.07(brs,1H),3.96( s,3H), 3.93(s,3H).
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Abstract
The invention discloses a 4-(4'-substituted phenyl)amino-6,7-dimethoxyquinazoline derivative. A synthesis method of the quinazoline derivative comprises the following steps: dissolving a compound 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline shown as a formula II, a compound shown as a formula III and an alkaline reagent in a solvent, and reacting for 15-24h while stirring at normal temperature; after completion of a reaction, cooling and performing suction filtration to obtain a crude product, and refining the crude product to obtain yellow solidpowder. The quinazoline derivative has relatively good activity in inhibiting human cervical cancer cells, human livercancer cells, human lungcancer cells, human breastcancer cells and human colon cancer cells, and can be used as a lead compound for cancer treatment; a preparation method thereof is simple, feasible and easy to operate.
Description
technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a series of 4-(4'-substituted phenyl) amino-6,7-dimethoxyquinazoline derivatives and their preparation and anti-tumor medical application. Background technique [0002] Quinazoline compounds are a class of effective epidermal growth factorreceptor (EGFR) inhibitors (TKI), which have received extensive attention in recent years. 4-Substituted phenylquinazolines are an earlier class of epidermal growth factorreceptortyrosinekinase inhibitors, which have been studied more, among them, 4-substituted arylamino-6,7-dimethoxyquinazoline derivatives Drugs have been proven to have good inhibitory activity. The marketed drugs have shown their superiority as traditional therapeutic drugs in the treatment of chronic myelogenous leukemia, non-small celllung cancer, renal cell carcinoma and other diseases, and some of them have become therapeutic drugs for tumors. First-lin...
Claims
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