CN109336828B - Quinazoline derivative and preparation method and application thereof - Google Patents

Abstract

The invention discloses a 4-(4'-substituted phenyl) amino-6,7-dimethoxyquinazoline derivative; the synthesis method of the quinazoline derivative is to compound the compound of formula II 4-(4 '-Hydroxyphenyl) amino-6,7-dimethoxyquinazoline, the compound of formula III and the alkaline reagent are dissolved in the solvent, and the reaction is stirred at room temperature for 15h~24h; after the reaction is completed, the crude product is obtained by cooling and suction filtration. After refining, yellow solid powder is obtained; the quinazoline derivative of the present invention has good inhibitory activity on human cervical cancer cells, human liver cancer cells, human lung cancer cells, human breast cancer cells and human colon cancer cells, and can be used as a cancer cell The preparation method of the therapeutic lead compound is simple, feasible and easy to operate.

Description

A kind of quinazoline derivative and its preparation method and application

technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to a series of 4-(4'-substituted phenyl)amino-6,7-dimethoxyquinazoline derivatives and their preparation and antitumor medicinal uses.

Background technique

Quinazolines are a class of potent epidermal growth factor receptor (EGFR) inhibitors (TKIs), which have received extensive attention in recent years. 4-Substituted phenylquinazolines are an earlier class of epidermal growth factor receptor tyrosine kinase inhibitors, and there are many studies. Among them, 4-substituted arylamino-6,7-dimethoxyquinazoline derivatives The drugs have been proved to have good inhibitory activity, and the listed drugs have shown their superiority as traditional therapeutic drugs in the treatment of chronic myeloid leukemia, non-small cell lung cancer, renal cell carcinoma and other diseases, and some of them have become the treatment of tumors. First-line drugs, such as gefitinib, erlotinib, lapatinib, etc., and a large number of other EGFR small-molecule targeted inhibitors containing quinazoline core structure are being developed or have entered the clinic (Journal of Medicinal Chemistry, 2005 , 48, 7445; Journal of Medicinal Chemistry, 2008, 51, 3065; European Journal of Medicinal Chemistry, 2012, 47, 65; Bioorganic & Medicinal Chemistry Letters, 2014, 24, 884; European Journal of Medicinal Chemistry, 2015, 90, 124.).

However, with the listing 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 has prompted the emergence of new anti-tumor drugs to replace original drug.

SUMMARY OF THE INVENTION

One of the objectives of the present invention is to provide a novel antitumor drug.

An embodiment of the present invention provides a quinazoline derivative, the quinazoline derivative is 4-(4'-substituted phenyl)amino-6,7-dimethoxyquinazoline derivative, which is The general chemical structure is shown in formula I:

Wherein, R is selected from ethoxy, phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 2,3-difluorophenyl; amino, One of methylamino, dimethylamino, diethylamino, hydroxymethylamino, tetrahydropyrrole, morpholine, piperazine, N-methylpiperazine and N-ethylpiperazine.

Specifically, the present invention also provides the specific structure of each substituent of the quinazoline derivative, so the quinazoline derivative includes:

ethyl 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)acetate;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-acetophenone;

1-(4-Chlorophenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone;

1-(4-Methylphenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone;

1-(4-Methoxyphenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone;

1-(4-Hydroxyphenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone;

1-(2,3-Difluorophenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)acetamide;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-N-methylacetamide;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-N,N-dimethylacetamide;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-N,N-diethylacetamide;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-N-hydroxymethylacetamide;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-pyrrolyl ethanone;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-morpholinoethanone;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-piperazinyl ethanone;

2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-(4-methylpiperazinyl)ethanone;

2-(4-((6,7-Dimethoxyquinazolin-4-yl)amino)phenoxy)-1-(4-ethylpiperazinyl)ethanone.

One of the objects of the present invention is to provide a kind of method for preparing quinazoline derivatives, comprising the following steps:

Dissolve the compound of formula II, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, the compound of formula III and an alkaline reagent in a solvent, and stir the reaction at room temperature for 15h-24h; the reaction is completed After cooling and suction filtration to obtain the crude product, after the crude product is refined, a yellow solid powder is obtained; the synthesis route is as follows:

Wherein, R is selected from ethoxy, phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 2,3-difluorophenyl; 8 amino , one of methylamino, dimethylamino, diethylamino, hydroxymethylamino, tetrahydropyrrole, morpholine, piperazine, N-methylpiperazine and N-ethylpiperazine.

Preferably, in the preparation method, the alkaline reagent is anhydrous potassium carbonate or anhydrous sodium carbonate; the solvent is DMF.

Preferably, the preparation method comprises the following steps:

5 mmol of the compound of formula II, 6 mmol of the compound of formula III and 10 mmol of anhydrous potassium carbonate were added to 50 ml of DMF solvent, and the reaction was stirred for 18 h at room temperature. Column chromatography is used for separation, and finally a yellow solid powder is obtained; the synthetic route is as follows:

Preferably, the synthetic method of the compound of formula III in the preparation method is:

Chloroacetyl chloride was dissolved in dichloromethane, compound RH was added to it, the reaction was stirred at room temperature, and after the reaction was completed, water was added to wash, and then the organic layer was separated, and the organic layer was dried and concentrated under reduced pressure to obtain the compound of formula III; its synthetic route is as follows. :

wherein R is selected from one of amino, methylamino, dimethylamino, diethylamino, hydroxymethylamino, tetrahydropyrrole, morpholine, piperazine, N-methylpiperazine and N-ethylpiperazine.

Preferably, the synthetic method of the compound of formula III in the preparation method is:

5 mmol of chloroacetyl chloride was dissolved in 20 mL of dichloromethane, 11 mmol of RH compound was added to it, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, water was added for washing. After washing, the organic layer was separated, and the organic layer was dried with anhydrous magnesium sulfate. The dried organic layer Concentrate under reduced pressure to obtain the compound of formula III.

One of the objects of the present invention is to provide the pharmaceutical use of the quinazoline derivatives, that is, the quinazoline derivatives and their solvates, hydrates, tautomers and pharmaceutically acceptable salts are used in the preparation of antitumor drugs Applications.

Preferably, tumors include cervical cancer, liver cancer, lung cancer, breast cancer and colon cancer.

Preferably, the dosage forms of antitumor drugs include tablets, pills, capsules, injections, suspensions and emulsions.

To sum up, the present invention has the following advantages:

The present invention is based on 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P131), and utilizes the biological electron isosteric principle and the splicing principle to form a hydroxyl group at the 4' position. Ether, introduced containing amide bond, basic group (such as amine, pyrrole, piperazine and morpholine, etc.) and aromatic ring, etc., designed and synthesized a series of new 4-(4'-substituted phenyl)amino-6,7 -Dimethoxyquinazoline derivatives can adjust the pK value and lipid-water partition coefficient of drugs, improve the bioavailability and efficacy of drugs, and obtain anticancer active molecules with high efficiency, low toxicity and strong selectivity .

The 4-(4'-substituted phenyl)amino-6,7-dimethoxyquinazoline derivatives of the present invention are effective against human cervical cancer cells (Hela), human liver cancer cells (HepG2), and human lung cancer cells (A549). , Human breast cancer cells (MCF-7) and human colon cancer cells (HCT116) have better inhibitory activity. Therefore, the 4-(4'-substituted phenyl)amino-6,7-dimethoxyquinazoline derivatives of the present invention can be used to prepare leading compounds for antitumor drugs.

Detailed ways

The present invention is further illustrated in detail by the following examples, but the scope of the present invention is not limited in any way by these examples.

Example 1:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)ethyl acetate (1)

Combine 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), ethyl chloroacetate (0.74 g, 6 mmol) with anhydrous K ₂ CO ₃ (1.38 g g, 10 mmol) was added to 50 mL of DMF, and the reaction was stirred at room temperature for 18 h. After the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane: methanol = 5: 1) to obtain Target molecule, pale yellow solid powder, yield 87%, mp=237-240°C. ESI-MS (m/z): 384.17 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 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).

Example 2:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-acetophenone (2)

Combine 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), 2-chloroacetophenone (0.93 g, 6 mmol) with anhydrous K ₂ CO ₃ ( 1.38g, 10mmol) was added to 50mL of DMF, and the reaction was stirred at room temperature for 18h. After the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane:methanol=7:1) The target molecule was obtained as a yellow solid powder with a yield of 85% and mp>250°C. ESI-MS (m/z): 416.16 (M+H) ⁺ , ¹ H NMR (400 MHz, 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).

Example 3:

Synthesis of 1-(4-Chlorophenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone (3)

Combine 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), 2,4'-dichloroacetophenone (1.13 g, 6 mmol) with anhydrous K ₂ CO ₃ (1.38 g, 10 mmol) was added to 50 mL of DMF, and the reaction was stirred at room temperature for 18 h. After the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane: methanol =7:1) The target molecule was obtained as a yellow solid powder with a yield of 90%, mp>250°C. ESI-MS (m/z): 450.10 (M+H) ⁺ , ¹ H NMR (400 MHz, 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).

Example 4:

Synthesis of 1-(4-methylphenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone (4)

4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), 2-chloro-4'-methoxyacetophenone (1.01 g, 6 mmol) Add anhydrous K ₂ CO ₃ (1.38 g, 10 mmol) to 50 mL of DMF, and stir the reaction at room temperature for 18 h. After the reaction is completed, pour it into an appropriate amount of ice water, filter it with suction to obtain the crude product, dry it, and perform silica gel column chromatography (dichloromethane). Methane:methanol=5:1) to obtain the target molecule as a yellow solid powder, the yield is 88%, mp>250°C. ESI-MS (m/z): 430.17 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.71 (s, 1H), 8.15 (s, 1H), 7.79-7.49 (m, 5H ), 6.91-6.71(m, 4H), 4.33(s, 2H), 4.11(brs, 1H), 3.98(s, 3H), 3.96(s, 3H), 2.35(s, 3H).

Example 5:

Synthesis of 1-(4-Methoxyphenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone (5)

4-(4'-Hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), 2-chloro-4'-methoxyacetophenone (1.11 g, 6 mmol) Add anhydrous K ₂ CO ₃ (1.38 g, 10 mmol) to 50 mL of DMF, and stir the reaction at room temperature for 18 h. After the reaction is completed, pour it into an appropriate amount of ice water, filter it with suction to obtain the crude product, dry it, and perform silica gel column chromatography (dichloromethane). Methane:methanol=5:1) to obtain the target molecule as a yellow solid powder, the yield is 83%, mp>250°C. ESI-MS (m/z): 446.17 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.77 (s, 1H), 8.11 (s, 1H), 7.72-7.53 (m, 5H) ), 6.82-6.69(m, 4H), 4.37(s, 2H), 4.08(brs, 1H), 3.95(s, 3H), 3.90(s, 3H), 3.81(s, 3H). 4-Methoxyphenyl

Example 6:

Synthesis of 1-(4-hydroxyphenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone (6)

Combine 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), 2-chloro-4'-hydroxyacetophenone (1.03 g, 6 mmol) with no Water K ₂ CO ₃ (1.38 g, 10 mmol) was added to 50 mL of DMF, and the reaction was stirred at room temperature for 18 h. After the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane: Methanol=3:1) to obtain the target molecule, pale yellow solid powder, the yield is 73%, mp>250°C. ESI-MS (m/z): 432.15 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 10.37 (brs, 1H), 8.66 (s, 1H), 8.16 (s, 1H), 7.83-7.57(m,5H), 6.92-6.73(m,4H), 4.27(s,2H), 4.09(brs,1H), 3.92(s,3H), 3.88(s,3H).

Example 7:

Synthesis of 1-(2,3-Difluorophenyl)-2-(4-((6,7-dimethoxyquinazolin-4-yl)phenoxy)ethanone (7)

4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (1.49 g, 5 mmol), 2-chloro-2',3'-difluoroacetophenone (1.15 g, 6mmol) and anhydrous K ₂ CO ₃ (1.38g, 10mmol) were added to 50mL of DMF, and the reaction was stirred at room temperature for 18h. After the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography ( Dichloromethane:methanol=6:1) to obtain the target molecule as a yellow solid powder with a yield of 79%, mp>250°C. ESI-MS (m/z): 453.13 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.70 (s, 1H), 8.09 (s, 1H), 7.93-7.77 (m, 4H) ), 6.89-6.70(m, 4H), 4.23(s, 2H), 4.12(brs, 1H), 3.99(s, 3H), 3.96(s, 3H).

Example 8:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)acetamide (8)

Chloroacetamide (0.47 g, 5 mmol) was dissolved in DMF (30 mL), and to the above solution was added 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (0.89 g, 3 mmol) ) and anhydrous K ₂ CO ₃ (0.69 g, 5 mmol), stirred and reacted at room temperature for 12 h, after the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane: methanol = 2:1) The target molecule was obtained as a yellow solid powder with a yield of 88%, mp=243-245°C. ESI-MS (m/z): 355.15 (M+H) ⁺ , ¹ HNMR (400 MHz, DMSO-d ₆ ): 8.67 (s, 1H), 8.01 (s, 1H), 7.83-7.67 (m, 3H) , 6.81-6.66(m, 2H), 5.33(brs, 2H), 4.21(s, 2H), 4.13(brs, 1H), 3.93(s, 3H), 3.90(s, 3H).

Example 9:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-N-methylacetamide (9)

2-Chloro-N-methylacetamide (0.54 g, 5 mmol) was dissolved in DMF (30 mL), and to the above solution was added 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinoline The oxazoline (0.89g, 3mmol) and anhydrous K ₂ CO ₃ (0.69g, 5mmol) were stirred and reacted at room temperature for 15h, after the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane:methanol=3:1) to obtain the target molecule as a yellow solid powder, the yield is 90%, mp=239-242°C. ESI-MS (m/z): 369.16 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.71 (s, 1H), 8.12 (s, 1H), 7.96-7.83 (m, 3H ),6.84-6.67(m,2H),5.21(brs,1H),4.31(s,2H),4.11(brs,1H),3.95(s,3H),3.92(s,3H),3.53(s, 3H).

Example 10:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-N,N-dimethylacetamide (10)

2-Chloro-N,N-dimethylacetamide (0.61 g, 5 mmol) was dissolved in DMF (30 mL), to the above solution was added 4-(4'-hydroxyphenyl)amino-6,7-dimethyl Oxyquinazoline (0.89 g, 3 mmol) and anhydrous K ₂ CO ₃ (0.69 g, 5 mmol) were reacted with stirring at room temperature for 16 h. After the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, silica gel Column chromatography (dichloromethane:methanol=4:1) gave the target molecule as a yellow solid powder with a yield of 87% and mp>250°C. ESI-MS (m/z): 383.17 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.63 (s, 1H), 8.00 (s, 1H), 7.91-7.71 (m, 3H ),6.78-6.65(m,2H),4.33(s,2H),4.09(brs,1H),3.96(s,3H),3.93(s,3H),3.51(s,3H),3.48(s, 3H).

Example 11:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-N,N-diethylacetamide (11)

2-Chloro-N,N-diethylacetamide (0.75 g, 5 mmol) was dissolved in DMF (30 mL), to the above solution was added 4-(4'-hydroxyphenyl)amino-6,7-dimethylene Oxyquinazoline (0.89g, 3mmol) and anhydrous K ₂ CO ₃ (0.69g, 5mmol) were stirred and reacted at room temperature for 15h, after the reaction was completed, poured into an appropriate amount of ice water, filtered to obtain the crude product, dried, silica gel Column chromatography (dichloromethane:methanol=4:1) gave the target molecule as a yellow solid powder with a yield of 81%, mp>250°C. ESI-MS (m/z): 411.18 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.69 (s, 1H), 8.07 (s, 1H), 7.97-7.73 (m, 3H) ),6.75-6.69(m,2H),4.29(s,2H),4.15(brs,1H),3.98(s,3H),3.95(s,3H),3.43(m,4H),1.27(t, 6H).

Example 12:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-N-hydroxymethylacetamide (12)

Chloroacetamide-N-methanol (0.62 g, 5 mmol) was dissolved in DMF (30 mL), and to the above solution was added 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline ( 0.89g, 3mmol) and anhydrous K ₂ CO ₃ (0.69g, 5mmol) were stirred at room temperature for 22h. After the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane). Methane:methanol=2:1) to obtain the target molecule as a yellow solid powder, the yield is 53%, mp=221-224°C. ESI-MS (m/z): 385.15 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.72 (s, 1H), 8.10 (s, 1H), 7.93-7.70 (m, 3H ),6.83-6.71(m,2H),5.54(m,2H),4.31(s,2H),4.17(brs,1H),3.99(s,3H),3.96(s,3H),3.67(brs, 1H).

Example 13:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-pyrrolyl ethanone (13)

Chloroacetyl chloride (0.57 g, 5 mmol) was dissolved in 20 mL of dichloromethane, tetrahydropyrrole (0.78 g, 11 mmol) was added to it, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, an appropriate amount of water was added to wash, and the organic layer was washed with anhydrous magnesium sulfate. Dry and concentrate under reduced pressure to obtain N-(2-chloroacetyl)tetrahydropyrrole, which is used in the next step without purification.

The above N-(2-chloroacetyl)tetrahydropyrrole was directly dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline was added to the above solution (0.89g, 3mmol) and anhydrous K ₂ CO ₃ (0.69g, 5mmol), stirred and reacted at room temperature for 24h, after the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (two Methyl chloride: methanol = 3: 1) to obtain the target molecule as a yellow solid powder with a yield of 53%, mp>250°C. ESI-MS (m/z): 409.19 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.70 (s, 1H), 8.07 (s, 1H), 7.97-7.71 (m, 3H ),6.88-6.72(m,2H),4.32(s,2H),4.19(brs,1H),3.99(s,3H),3.96(s,3H),3.11(m,4H),1.77(m, 4H).

Example 14:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-morpholinoethanone (14)

Chloroacetyl chloride (0.57 g, 5 mmol) was dissolved in 20 mL of dichloromethane, morpholine (0.96 g, 11 mmol) was added to it, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, an appropriate amount of water was added to wash, and the organic layer was dried over anhydrous magnesium sulfate. , concentrated under reduced pressure to obtain N-chloroacetylmorpholine, which was directly used in the next step without purification.

The above N-chloroacetylmorpholine was directly dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (0.89 g, 3 mmol) was added to the above solution. ) and anhydrous K ₂ CO ₃ (0.69 g, 5 mmol), stirred and reacted at room temperature for 20 h, after the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane: methanol = 3:1) The target molecule was obtained as a yellow solid powder with a yield of 57% and mp>250°C. ESI-MS (m/z): 425.16 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.66 (s, 1H), 8.01 (s, 1H), 7.87-7.65 (m, 3H ),6.87-6.70(m,2H),4.37(s,2H),4.12(brs,1H),3.96(s,3H),3.92(s,3H),3.65(m,4H),3.55(m, 4H).

Example 15:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-piperazinyl ethanone (15)

Chloroacetyl chloride (0.57 g, 5 mmol) was dissolved in 20 mL of dichloromethane, piperazine (0.95 g, 11 mmol) was added to it, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, an appropriate amount of water was added for washing, and the organic layer was dried over anhydrous magnesium sulfate. , concentrated under reduced pressure to obtain N-chloroacetylpiperazine, which was directly used in the next step without purification.

The above N-chloroacetylpiperazine was directly dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (0.89 g, 3 mmol) was added to the above solution. ) and anhydrous K ₂ CO ₃ (0.69 g, 5 mmol), stirred and reacted at room temperature for 24 h, after the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and subjected to silica gel column chromatography (dichloromethane: methanol = 2:1) The target molecule was obtained as a yellow solid powder with a yield of 43% and mp>250°C. ESI-MS (m/z): 424.18 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.71 (s, 1H), 8.06 (s, 1H), 7.92-7.68 (m, 3H ),6.92-6.71(m,2H),4.34(s,2H),4.02(brs,1H),3.98(s,3H),3.95(s,3H),3.51(m,4H),2.94(m, 4H), 1.87 (brs, 1H).

Example 16:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-(4-methylpiperazinyl)ethanone (16)

Chloroacetyl chloride (0.57 g, 5 mmol) was dissolved in 20 mL of dichloromethane, N-methylpiperazine (1.10 g, 11 mmol) was added to it, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, an appropriate amount of water was added to wash, and the organic layer was washed with It was dried over magnesium sulfate and concentrated under reduced pressure to obtain 2-chloro-1-(4-methylpiperazinyl)ethanone, which was used in the next step without purification.

The above 2-chloro-1-(4-methylpiperazinyl)ethanone was directly dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl)amino-6,7-dimethyl was added to the above solution Oxyquinazoline (0.89g, 3mmol) and anhydrous K ₂ CO ₃ (0.69g, 5mmol) were reacted with stirring at room temperature for 24h, after the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, silica gel Column chromatography (dichloromethane:methanol=2:1) gave the target molecule as a yellow solid powder, the yield was 46%, mp>250°C. ESI-MS (m/z): 438.19 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.74 (s, 1H), 8.11 (s, 1H), 7.88-7.58 (m, 3H ),6.95-6.68(m,2H),4.38(s,2H),4.08(brs,1H),3.94(s,3H),3.90(s,3H),3.45(m,4H),2.47(m, 7H).

Example 17:

Synthesis of 2-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenoxy)-1-(4-ethylpiperazinyl)ethanone (17)

Chloroacetyl chloride (0.57 g, 5 mmol) was dissolved in 20 mL of dichloromethane, N-ethylpiperazine (1.25 g, 11 mmol) was added to it, and the reaction was stirred at room temperature for 24 h. After the reaction was completed, an appropriate amount of water was added for washing. It was dried over magnesium sulfate and concentrated under reduced pressure to obtain 2-chloro-1-(4-ethylpiperazinyl)ethanone, which was used in the next step without purification.

The above 2-chloro-1-(4-ethylpiperazinyl)ethanone was directly dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl)amino-6,7-dimethyl was added to the above solution Oxyquinazoline (0.89g, 3mmol) and anhydrous K ₂ CO ₃ (0.69g, 5mmol) were reacted with stirring at room temperature for 24h, after the reaction was completed, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, silica gel Column chromatography (dichloromethane:methanol=2:1) gave the target molecule as a yellow solid powder with a yield of 51%, mp>250°C. ESI-MS (m/z): 452.21 (M+H) ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ): 8.65 (s, 1H), 8.03 (s, 1H), 7.95-7.66 (m, 3H) ),6.89-6.57(m,2H),4.27(s,2H),4.03(brs,1H),3.97(s,3H),3.94(s,3H),3.48(m,4H),2.42(m, 4H), 2.37 (m, 2H), 1.17 (t, 3H).

The yields of Examples 12 to 17 are 43% to 57%, which are significantly lower than those of Examples 1 to 11. This is mainly because the functional groups of Examples 12 to 17 are hydroxymethylamino, Tetrahydropyrrole, morpholine, piperazine, N-methylpiperazine and N-ethylpiperazine. Compared with the groups in Examples 1 to 11, these groups increase the difficulty of synthesizing the compounds of Formula II and Formula III, increase the by-products, and thus reduce the yield. In order to reduce the negative impact of the above-mentioned groups on the synthesis reaction, a catalyst can be added to improve the yield. In the present application, sodium lignosulfonate and cerium nitrate are used as combined catalysts to improve the yields of Examples 12 to 17.

Experimental example: Dissolve the compound of formula II, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, the compound of formula III and an alkaline reagent in a solvent, add sodium lignosulfonate to The mass fraction of the final concentration is 5%, and the mass fraction of cerium nitrate to the final concentration is 3%, and the reaction is stirred at room temperature for 15h to 24h; after the reaction is completed, the crude product is obtained by cooling and suction filtration, and the yellow solid powder is obtained after the crude product is refined.

Experimental Example 1 to Experimental Example 6 correspond to Example 12 to Example 17 one-to-one, that is, Experimental Example 1 corresponds to Experimental Example 12, that is, the preparation method of Experimental Example 1 is to add lignosulfonic acid on the basis of Example 12. Sodium and cerium nitrate, i.e., the method is as follows: chloroacetamide-N-methanol (0.62 g, 5 mmol) is dissolved in DMF (30 mL), and 4-(4'-hydroxyphenyl)amino-6,7 is added to the above solution -Dimethoxyquinazoline (0.89g, 3mmol) and anhydrous K ₂ CO ₃ (0.69g, 5mmol) and sodium lignosulfonate 5% and cerium nitrate 3%, the reaction was stirred at room temperature for 22h, the reaction was completed Then, poured into an appropriate amount of ice water, suction filtered to obtain the crude product, dried, and silica gel column chromatography (dichloromethane: methanol = 2: 1) to obtain the target molecule, yellow solid powder

Experimental example 2 added 5% sodium lignosulfonate and 3% cerium nitrate based on the method of Example 13; by analogy, Experimental Example 3 added sodium lignosulfonate based on the method of Example 14. 5% and 3% of cerium nitrate; Experimental example 4 added 5% sodium lignosulfonate and 3% of cerium nitrate on the basis of the method of Example 15; Experimental example 5 added lignin on the basis of the method of Example 16 5% sodium lignosulfonate and 3% cerium nitrate; Experimental Example 6 is based on the method of Example 17, adding 5% sodium lignosulfonate and 3% cerium nitrate.

The yields of Experimental Example 1 to Experimental Example 6 were checked respectively, wherein the yield of Experimental Example 1 was 72%, the yield of Experimental Example 2 was 68%, the yield of Experimental Example 3 was 75%; the yield of Experimental Example 4 was The yield of Experimental Example 5 was 58%; the yield of Experimental Example 6 was 77%. It can be seen that the yield is significantly improved after adding 5% sodium lignosulfonate and 3% cerium nitrate.

In order to verify whether the increase in yield is due to the effect of sodium lignosulfonate or cerium nitrate, the yield in the experiment using sodium lignosulfonate alone as the catalyst did not increase significantly, and the yield in the experiment when cerium nitrate alone was used as the catalyst The yield is not significantly improved, indicating that the two have little effect on the yield when used alone.

When adding sodium lignosulfonate and cerium nitrate to the method of Example 1 to Example 11 to conduct experiments, due to the change of R group, the R group of Example 1 to Example 11 is not in the lignosulfonic acid. Under the action of sodium and cerium nitrate, the yield is improved, and it can be seen that the influence of sodium lignosulfonate and cerium nitrate on the yield of the groups in Examples 1 to 11 is low. Thus, it can be seen that only when the two catalysts are used at the same time can the compound reaction of the groups in Examples 12 to 17 be promoted well, and the yield can be improved.

Example 18:

In vitro antitumor activity test of 4-(4'-substituted phenyl)amino-6,7-dimethoxyquinazoline derivatives

Proliferation inhibitory activity of the target compounds on human cervical cancer cells (Hela), human liver cancer cells (HepG2), human lung cancer cells (A549), human breast cancer cells (MCF-7) and human colon cancer cells (HCT116) by MTT assay test.

Adherent cells: Tumor cells in logarithmic growth phase were harvested and trypsinized. Experimental cells were cultured in RPMI1640 medium containing 10% fetal bovine serum (FBS) (Gibco, Thermo Scientific). HCT116 cells (4000 cells/well), Hela cells (4000 cells/well), A549 cells (4000 cells/well), MCF-7 cells (5000 cells/well) and HepG2 cells (5000 cells/well) were cultured at the edge, respectively Wells were filled in 96 microwell plates with sterile PBS, and cells were allowed to adhere for 12 hours at 37°C, 5% CO ₂ . The cells in the experimental group were given fresh culture medium containing different concentrations of drugs (0.1μM/L, 1μM/L, 10μM/L, 100μM/L, 1μM/L, 10μM/L) after adhering, and the control group was given no drug. treated with the same broth. Three parallel control wells were prepared for each test well. After 24h and 48h, MTT (0.5mg/mL) was added to each experimental cell and left at 37°C for 4h. After the liquid was carefully aspirated, 150 μL of dimethyl sulfoxide (DMSO) was added to dissolve the formazan crystals and placed on a uniform shaker to mix for 10 minutes (250 r/min). The 96-well plate was finally placed in an enzyme labeling instrument (Cytation3, BioTek) to detect the absorbance value (OD) at a wavelength of 490 nm.

Inhibition rate (%)=[1-(mean OD value of experimental group-mean value of OD of blank group)/(mean value of OD of control group-mean value of OD of blank group)]×100%.

According to the determined OD value, the corresponding half inhibitory concentration (IC ₅₀ ) of the target compound was calculated, as shown in Table 1 below:

Table 1: Experimental Results

The results of in vitro anti-tumor activity test by MTT method showed that WHI-P131 was the lead compound of the present invention. The 4-(4'-substituted phenyl)amino-6,7-dimethoxyquinazoline derivatives of the present invention are effective against human cervical cancer cells (Hela), human liver cancer cells (HepG2), and human lung cancer cells (A549). , Human breast cancer cells (MCF-7) and human colon cancer cells (HCT116) have better inhibitory activity. Therefore, the 4-(4'-substituted phenyl)amino-6,7-dimethoxyquinazoline derivatives of the present invention can be used in the preparation of leading compounds for antitumor drugs. The tumor activity was overwhelmingly higher than that of the lead compound.

The invention improves or adjusts the pK value and the lipid-water distribution coefficient of the medicine by introducing structural modification means such as amide, basic group or aromatic ring, improves the bioavailability of the medicine and improves the medicine effect, and obtains a high-efficiency, low-efficiency and low-cost medicine. Toxic and selective anticancer active molecules.

Claims (5)

1. A preparation method of a quinazoline derivative is disclosed, wherein the quinazoline derivative is a 4- (4' -substituted phenyl) amino-6, 7-dimethoxy quinazoline derivative, and the chemical structural general formula is shown as a formula I:

wherein R is selected from one of hydroxymethyl amino, tetrahydropyrrole, morpholine, piperazine, N-methylpiperazine and N-ethylpiperazine;

the preparation method comprises the following steps:

dissolving a compound of a formula II, namely 4- (4' -hydroxyphenyl) amino-6, 7-dimethoxyquinazoline, a compound of a formula III and an alkaline reagent in a solvent, adding sodium lignosulfonate until the mass fraction of the final concentration of the solution is 5%, adding cerium nitrate until the mass fraction of the final concentration of the solution is 3%, and stirring for reacting for 15-24 h at normal temperature; after the reaction is finished, cooling and filtering to obtain a crude product, and refining the crude product to obtain yellow solid powder; the synthetic route is as follows:

2. the method of claim 1, wherein: the alkaline reagent is anhydrous potassium carbonate or anhydrous sodium carbonate; the solvent is DMF.

3. The method of claim 1, comprising the steps of:

adding 5mmol of a compound shown in a formula II, 6mmol of a compound shown in a formula III and 10mmol of anhydrous potassium carbonate into 50ml of DMF solvent, adding sodium lignosulfonate until the mass fraction of the final concentration of the solution is 5%, adding cerium nitrate until the mass fraction of the final concentration of the solution is 3%, stirring at normal temperature for reacting for 18h, pouring ice water for cooling after the reaction is finished, then performing suction filtration to obtain a crude product, drying the crude product, separating by using silica gel column chromatography, and finally obtaining yellow solid powder; the synthetic route is as follows:

4. the method of claim 1, wherein the compound of formula iii is synthesized by:

dissolving chloroacetyl chloride in dichloromethane, adding a compound RH, stirring at normal temperature for reaction, adding water for washing after the reaction is finished, then separating an organic layer, and drying and concentrating the organic layer under reduced pressure to obtain a compound shown in the formula III; the synthetic route is as follows:

wherein R is selected from one of hydroxymethyl amino, tetrahydropyrrole, morpholine, piperazine, N-methylpiperazine and N-ethylpiperazine.

5. The method of claim 4, wherein: the synthesis method of the compound shown in the formula III comprises the following steps:

dissolving chloroacetyl chloride 5mmol in dichloromethane 20mL, adding 11mmol RH compound, stirring at normal temperature for reaction for 24h, after the reaction is finished, adding water for washing, separating an organic layer after washing, drying the organic layer with anhydrous magnesium sulfate, and concentrating the dried organic layer under reduced pressure to obtain the compound shown in the formula III.