Coumarin derivatives containing quinazoline units, and methods of making and using the same

Abstract

The application discloses a novel coumarin derivative containing a quinazoline unit (as shown in structural formula I), and a preparation method thereof. The preparation method comprises the following steps: subjecting a coumarin molecule A treated by a sodium hydroxide solution to etherification reaction with a 4-chloroquinazoline molecule B in acetonitrile by heating, and then subjecting an intermediate product C obtained by the reaction to reaction with benzyl chloride or bromoethane in acetonitrile by heating, so as to obtain the novel coumarin derivative I containing the quinazoline unit. The novel coumarin derivative containing the quinazoline unit is a novel compound, has obvious inhibiting effect on human pancreatic cancer cells (PANC-1), human gastric cancer cells (SGC7901) and human breast cancer cells (MDA-MB-231), and can be developed as a novel anti-tumor drug candidate molecule.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a novel coumarin derivative containing a quinazoline unit and a preparation method and application thereof. BACKGROUND

[0002] At present, the drug treatment for cancer mainly includes chemical drug treatment, targeted treatment and immunotherapy. The targeted treatment drug interferes with the growth and diffusion of cancer cells by inhibiting EGFR, VEGF and the like signal pathway, and the immunotherapy drug realizes the inhibition of cancer cells by enhancing the body's immune system. The above treatment strategies have the disadvantages of poor drug efficacy, large drug side effects, high drug cost and easy recurrence. Therefore, it is very necessary to develop a novel antitumor drug with better drug efficacy and smaller side effects. SUMMARY

[0003] The first object of the present application is to provide a novel coumarin derivative containing a quinazoline unit with antitumor activity. The second object of the present application is to provide a preparation method of the novel coumarin derivative containing a quinazoline unit. The third object of the present application is to provide the application of the novel coumarin derivative containing a quinazoline unit in the aspect of anti-tumor cells.

[0004] Technical scheme: The novel coumarin derivative containing a quinazoline unit provided by the present application has a structural formula as shown in formula I:

[0005]

[0006] wherein, R 1 is selected from hydrogen, 8-methyl, 6-methyl or 6,7-dimethoxy; R 2 is selected from benzyl, 3-methoxybenzyl, 3-methylbenzyl, 3-chlorobenzyl, 2-methylbenzyl, 4-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl, 2-chlorobenzyl or ethyl.

[0007] The preparation method of the novel coumarin derivative containing a quinazoline unit provided by the present application is that the coumarin molecule A treated with sodium hydroxide solution is heated in acetonitrile to occur etherification reaction with the 4-chloroquinazoline molecule B, and the obtained intermediate product C is heated in acetonitrile to react with different benzyl chloride or bromoethane to obtain the novel coumarin derivative containing a quinazoline unit I, and the synthesis route is as follows:

[0008]

[0009] The key intermediate compound B is prepared by the method reported by the research group in the early stage (Molecular Diversity, 2018, 22:791-802).

[0010] The application discloses a novel coumarin derivative containing a quinazoline unit and an application of the novel coumarin derivative in resisting tumor cells.

[0011] Beneficial effects: compared with the prior art, the application has the following remarkable advantages: (1) the novel coumarin derivative containing a quinazoline unit is a novel compound; (2) the preparation method of the novel coumarin derivative containing a quinazoline unit is novel, efficient, simple to operate and easy to obtain raw materials; (3) the novel coumarin derivative containing a quinazoline unit has strong inhibitory activity on tumor cells, can effectively inhibit the proliferation of tumor cells and has potential application prospects. BRIEF DESCRIPTION OF DRAWINGS

[0012] Figure 1 A nuclear magnetic resonance hydrogen spectrum of the novel coumarin derivative containing a quinazoline unit prepared in the embodiment 1;

[0013] Figure 2 A nuclear magnetic resonance carbon spectrum of the novel coumarin derivative containing a quinazoline unit prepared in the embodiment 1;

[0014] Figure 3 A high resolution mass spectrum of the novel coumarin derivative containing a quinazoline unit prepared in the embodiment 1. DETAILED DESCRIPTION

[0015] The technical solutions in the specific embodiments of the application will be described below.

[0016] Embodiment 1

[0017] The novel coumarin derivative containing a quinazoline unit, R 1 =H, R 2 =benzyl, the chemical name is benzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the English name is benzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, and the structural formula is as follows:

[0018]

[0019] Step 1: synthesis of an intermediate compound B

[0020] (1) synthesis of quinazolin-4(3H)-one

[0021]

[0022] Into a three-necked round bottom flask containing methyl anthranilate (10 g), formamide (15 mL) and formic acid (3 mL) were added, and the reaction was carried out at a temperature not lower than 135°C while monitoring the reaction by TLC. When no obvious change was observed, the reaction was stopped. The product in the reaction flask was directly poured into a beaker containing 300 mL of water while hot. After stirring, the product was allowed to settle. The precipitate was filtered off, dissolved in dichloromethane, and filtered again. The precipitate obtained was quinazolin-4(3H)-one (3.8 g).

[0023] (2) Synthesis of 4-chloroquinazoline

[0024]

[0025] Into a flask containing quinazolin-4(3H)-one (3 g), 12 drops of N,N-dimethylformamide, dichloroethane (18 mL) and sulfurous dichloride (25 mL) were added, and the reaction was carried out at 90°C while monitoring the reaction by TLC. When no obvious change was observed, the reaction was stopped. The residue was dissolved in petroleum ether, filtered, and the filtrate was distilled under reduced pressure to obtain 4-chloroquinazoline (2.8 g).

[0026] Second step: Synthesis of benzyl-(Z)-3-(2-(quinazolin-4-oxo)phenyl)acrylate

[0027]

[0028] Into a 100 mL flask containing coumarin (3 g), 4 mL of an aqueous solution of sodium hydroxide (1.86 g) and anhydrous ethanol (35 mL) were added, and the reaction was carried out at room temperature while monitoring the reaction by TLC. When the reaction was completed, the reaction was stopped. The residue was distilled under reduced pressure to obtain intermediate compound A (4.2 g). Then, intermediate compound A was added to refluxing acetonitrile (35 mL) along with intermediate B (2.8 g), and the reaction was carried out while monitoring the reaction by TLC. When the reaction was completed, the reaction was stopped. The residue was distilled under reduced pressure, extracted with dichloromethane and water, and the aqueous phase was reserved. The pH of the system was adjusted to 3 using hydrochloric acid (1 M), and the precipitate obtained was intermediate C (1.8 g). Intermediate C (500 mg), potassium carbonate (710 mg) and benzyl chloride (325 mg) were added to 20 mL of acetonitrile, and the reaction was carried out at 90°C while monitoring the reaction by TLC. When the reaction was completed, the reaction was stopped. The residue was distilled under reduced pressure, and the target product W1 was obtained by column chromatography using silica gel (eluent: petroleum ether: ethyl acetate = 12: 1).

[0029] The target compound W1 was a white solid with a yield of 82%; m.p. 96°C; 1H NMR (400 MHz, CDC13) δ 8.75 (s, 1H), 8.31 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.95 (t, J = 7.7 Hz, 1H), 7.66 (t, J = 8.9 Hz, 2H), 7.49 (t, J = 8.4 Hz, 1H), 7.37-7.33 (m, 3H), 7.31 (d, J = 11.0 Hz, 4H), 6.97 (d, J = 12.3 Hz, 1H), 5.96 (d, J = 12.3 Hz, 1H), 5.16 (s, 2H); 13 C NMR (101 MHz, CDC13) δ 166.52, 165.36, 154.21, 151.54, 149.81, 138.30, 135.60, 134.33, 130.60, 130.14, 128.88, 128.58-128.15, 127.83, 125.86, 123.59, 122.27, 116.16; HRMS (ESI) m / z [M+H] + calcd for C 24 H 18 N2O3: 383.1390, found: 383.1393.

[0030] Example 2

[0031] The novel coumarin derivative containing quinazoline unit, R 1 = H, R 2 = 3-methoxybenzyl, the chemical name is 3-methoxybenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, and the English name is 3-methoxybenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, and the structural formula is as follows:

[0032]

[0033] Synthesis of 3-methoxybenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate

[0034]

[0035] The intermediate C in Example 1 (500 mg), potassium carbonate (710 mg) and 3-methoxybenzyl chloride (402 mg) were added into acetonitrile (20 mL), and the reaction was heated to reflux at 90°C. After TLC monitoring, the reaction was stopped when no obvious change was observed. Distillation under reduced pressure, and column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10:1) to obtain white solid W2.

[0036] The target compound W2 was a white solid with a yield of 76%; m.p. 65 °C; 1 H NMR (400 MHz, CDC13) δ 8.74 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.65 (t, J = 7.4 Hz, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H), 7.24 (s, 1H), 6.96 (d, J = 12.3 Hz, 1H), 6.88 - 6.82 (m, 3H), 5.95 (d, J = 12.3 Hz, 1H), 5.12 (s, 2H), 3.80 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 166.48, 165.34, 159.68, 154.26, 151.72, 149.85, 138.34, 137.10, 134.27, 130.62, 130.17, 129.58, 128.84, 127.85, 125.83, 123.58, 122.22, 120.58, 113.79, 66.18, 55.28; HRMS (ESI) m / z [M + H] + calcd for C 25 H 20 N2O4: 413.1496, found: 413.1495.

[0037] Example 3

[0038] The novel coumarin derivative containing quinazoline unit, R 1 = H, R 2 = 3-methylbenzyl, the chemical name is 3-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy) phenyl) acrylate, and the English name is 3-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy) phenyl) acrylate, and the structural formula is as follows:

[0039]

[0040] Synthesis of 3-methylbenzyl-(Z)-3-(2-(quinazoline-4-yloxy) phenyl) acrylate

[0041]

[0042] The intermediate C (500 mg), potassium carbonate (710 mg) and 3-methylbenzyl chloride (361 mg) in example 1 were added into acetonitrile (20 mL), heated to reflux at 90 °C, the reaction was stopped after TLC monitoring no obvious change. Distillation under reduced pressure, silica gel column chromatography (eluent was petroleum ether: ethyl acetate = 12: 1) to obtain white solid W3.

[0043] The target compound W3 was white solid, yield 81%; m.p. 72 °C; 1 H NMR (400 MHz, CDC13) δ 8.75 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.98-7.91 (m, 1H), 7.66 (t, J = 8.0 Hz, 2H), 7.49 (t, J = 7.1 Hz, 1H), 7.31 (dd, J = 14.9, 7.4 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.08 (s, 2H), 6.96 (d, J = 12.3 Hz, 1H), 5.96 (d, J = 12.3 Hz, 1H), 5.13 (s, 2H), 2.36 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 166.52, 165.43, 154.36, 151.68, 149.85, 138.19, 135.48, 134.26, 130.62, 130.12, 129.24-128.82, 128.42, 127.96, 127.75, 125.84, 125.43, 123.59, 122.30, 116.15, 66.25; HRMS (ESI) m / z [M+H] + calcd for C25H 20 N2O3: 397.1547, found: 397.1549.

[0044] Example 4

[0045] The novel coumarin derivative containing quinazoline unit described in the present application, R 1 = H, R2= 3-chlorobenzyl, the chemical name is 3-chlorophenyl-(Z)-3-(2-(quinazolin-4-yloxy) phenyl) acrylate, the English name is 3-chlorobenzyl(Z)-3-(2-(quinazolin-4-yloxy) phenyl) acrylate, the structure is as follows:

[0046]

[0047] Synthesis of 3-chlorobenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate

[0048]

[0049] The intermediate C (500 mg), potassium carbonate (710 mg) and 3-chlorobenzyl chloride (450 mg) in acetonitrile (20 mL) were heated to reflux at 90 °C, the reaction was stopped after TLC monitoring showed no obvious change. Distillation under reduced pressure, silica gel column chromatography (eluent petroleum ether: ethyl acetate = 14: 1) to obtain white solid target product W4.

[0050] The target compound W4 was a white solid, with a yield of 72%; m.p. 83 °C; 1 H NMR (400 MHz, CDC13) δ 8.73 (s, 1H), 8.28 (d, J = 9.0 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.93 (t, J = 7.7 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.59 (d, J = 6.9 Hz, 1H), 7.48 (t, J = 7.1 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.27 (s, 1H), 7.26 (d, J = 4.0 Hz, 1H), 7.21 (s, 1H), 7.13 (d, J = 7.1 Hz, 1H), 6.99 (d, J = 12.2 Hz, 1H), 5.95 (d, J = 12.2 Hz, 1H), 5.10 (s, 2H); 13 C NMR (101 MHz, CDC13) δ 166.44, 165.25, 154.23, 151.70, 149.77, 138.71, 137.54, 134.33, 130.46, 130.25, 129.76, 128.92, 128.31, 127.97, 127.77, 126.27, 125.87, 123.52, 122.32, 122.08, 116.15, 65.33; HRMS (ESI) m / z [M + H] + calcd for C24H17ClN2O3: 417.1001, found: 417.1032.

[0051] Example 5

[0052] The novel coumarin derivatives containing quinazoline units described in the present application, R 1 = H, R 2= 2-methylbenzyl, chemical name 2-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, English name 2-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the structure is as follows:

[0053]

[0054] Synthesis of 2-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate

[0055]

[0056] The intermediate C in Example 1 (500 mg), potassium carbonate (710 mg) and 2-methylbenzyl chloride (361 mg) were added into acetonitrile (20 mL), and the reaction was heated to reflux at 90°C. After TLC monitoring showed no obvious change in the reaction, the reaction was stopped. Distillation under reduced pressure, and silica gel column chromatography separation (eluent petroleum ether: ethyl acetate = 12:1) to obtain the white solid target product W5.

[0057] The target compound W5 is a white solid, with a yield of 75%; m.p. 61°C; 1 H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.98-7.91 (m, 1H), 7.66 (dd, J = 15.5, 7.4 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.15 (m, 4H), 6.97 (d, J = 12.3 Hz, 1H), 5.96 (d, J = 12.3 Hz, 1H), 5.18 (s, 2H), 2.27 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 166.48, 165.46, 154.27, 151.65, 149.84, 138.26, 137.09, 134.27, 133.59, 130.57, 130.22, 129.35, 128.89, 128.53, 127.96, 127.75, 125.91, 123.60, 122.26, 116.18, 64.66, 18.97; HRMS (ESI) m / z [M+H] + calcd for C 25 H 20 N2O3: 397.1547, found: 397.1549.

[0058] Example 6

[0059] The novel coumarin derivatives containing quinazoline unit described in the present application, R 1 = H, R 2 = 4-methoxybenzyl, the chemical name is 4-methoxybenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, the English name is 4-methoxybenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, and the structural formula is as follows:

[0060]

[0061] Synthesis of 4-methoxybenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate

[0062]

[0063] The intermediate C in Example 1 (500 mg), potassium carbonate (710 mg) and 4-methoxybenzyl chloride (402 mg) were added into acetonitrile (20 mL), and the reaction was heated to reflux at 90°C. After TLC monitoring showed no obvious change in the reaction, the reaction was stopped. Distillation under reduced pressure, and silica gel column chromatography separation (eluent petroleum ether: ethyl acetate = 10:1) to obtain the white solid target product W6.

[0064] The target compound W6 is a white solid, with a yield of 78%; m.p. 70°C; 1 H NMR (400 MHz, CDCI3) δ 8.73 (s, 1 H), 8.28 (d, J = 8.2 Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.95-7.89 (m, 1 H), 7.63 (dd, J = 14.6, 7.7 Hz, 2 H), 7.46 (t, J = 7.1 Hz, 1 H), 7.29 (dd, J = 17.3, 5.3 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H), 6.92 (d, J = 12.3 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 2 H), 5.91 (d, J = 12.3 Hz, 1 H), 5.07 (s, 2 H), 3.81 (s, 3 H); 13CNMR (101 MHz, CDC13) δ 165.44, 159.62, 154.27, 151.71, 149.83, 138.06, 134.26, 130.62, 130.19, 128.88, 128.04-127.64, 125.82, 123.59, 122.31, 116.18, 113.89, 66.04, 55.33; HRMS (ESI) m / z [M+H] + calcd for C 25 H 20 N2O3: 413.1496, found: 413.1495.

[0065] Example 7

[0066] The novel coumarin derivative containing quinazoline unit described in the present application, R 1 = H, R 2 = 4-methylbenzyl, the chemical name is 4-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, the English name is 4-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, and the structural formula is as follows:

[0067]

[0068] Synthesis of 4-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate

[0069]

[0070] The intermediate C in Example 1 (500 mg), potassium carbonate (710 mg) and 4-methylbenzyl chloride (361 mg) were added into acetonitrile (20 mL), and the reaction was heated to reflux at 90°C. After TLC monitoring showed no obvious change in the reaction, the reaction was stopped. Distillation under reduced pressure, and silica gel column chromatography separation (eluent petroleum ether: ethyl acetate = 10:1) to obtain the white solid target product W7.

[0071] The target compound W7 is a white solid, with a yield of 89%; m.p. 67°C; 1H NMR (400 MHz, CDC13) δ 8.75 (s, 1H), 8.30 (d, J = 8.9 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.97 - 7.91 (m, 1H), 7.66 (t, J = 7.0 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.31 (dd, J = 14.8, 8.0 Hz, 2H), 7.17 (d, J = 2.2 Hz, 4H), 6.95 (d, J = 12.3 Hz, 1H), 5.95 (d, J = 12.3 Hz, 1H), 5.12 (s, 2H), 2.37 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 166.60 - 166.40, 165.41, 154.30, 151.72, 149.84, 138.12, 134.26, 132.62, 130.64, 130.12, 129.19, 128.89, 128.55, 127.95, 127.74, 125.83, 123.60, 122.29, 116.18, 66.19, 21.21; HRMS (ESI) m / z [M + H] + calcd for C 25 H 20 N2O3: 397.1547, found: 397.1549.

[0072] Example 8

[0073] The novel coumarin derivatives containing quinazoline unit described in the present application, R 1 = H, R 2 = 4-chlorobenzyl, the chemical name is 4-chlorobenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, the English name is 4-chlorobenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, the structure formula is as follows:

[0074]

[0075] Synthesis of 4-chlorobenzyl-(Z)-3-(2-(quinazoline 4-yloxy)phenyl) acrylate

[0076]

[0077] The intermediate C in Example 1 (500 mg), potassium carbonate (710 mg) and 4-chlorobenzyl chloride (413 mg) were added into acetonitrile (20 mL), and the reaction was heated to reflux at 90 °C. After TLC monitoring, the reaction was stopped when no obvious change was observed. The reaction was distilled under reduced pressure, and the target product W8 was obtained as a white solid by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 14:1).

[0078] The target compound W8 was a white solid with a yield of 87%; m.p. 90 °C; 1 H NMR (400 MHz, CDC13) δ 8.74 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.97-7.91 (m, 1H), 7.68-7.59 (m, 2H), 7.49 (t, J = 8.3 Hz, 1H), 7.31 (dd, J = 10.6, 4.6 Hz, 4H), 7.19 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 12.2 Hz, 1H), 5.95 (d, J = 12.3 Hz, 1H), 5.11 (s, 2H); 13 C NMR (101 MHz, CDC13) δ 166.44, 165.30, 154.23, 151.73, 149.82, 138.60, 134.39-133.72, 130.53, 130.18, 129.71, 128.91, 128.66, 127.98, 127.75, 125.84, 123.46, 122.30, 122.08, 116.15, 65.74-65.55; HRMS (ESI) m / z [M+H] + calcd for C 24 H 17 ClN2O3: 417.1001, found: 417.1032.

[0079] Example 9

[0080] The novel coumarin derivative containing a quinazoline unit described in the present application, R 1 = H, R 2 = 2-chlorobenzyl, the chemical name is 2-chlorobenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, and the English name is 2-chlorobenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate, and the structural formula is as follows;

[0081]

[0082] Synthesis of 2-chlorobenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl) acrylate

[0083]

[0084] The intermediate C in Example 1 (500 mg), potassium carbonate (710 mg) and 2-chlorobenzyl chloride (413 mg) were added into acetonitrile (20 mL) and heated to reflux at 90 °C. The reaction was monitored by TLC and no obvious change was observed, so the reaction was stopped. The solvent was distilled under reduced pressure and the target product W9 was obtained as a white solid by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 14: 1).

[0085] The target compound W9 was a white solid with a yield of 91%; m.p. 69 °C; 1 H NMR (400 MHz, CDC13) δ 8.74 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (t, J = 7.7 Hz, 1H), 7.67 (t, J = 7.9 Hz, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.33-7.27 (m, 2H), 7.23 (t, J = 6.2 Hz, 3H), 7.00 (d, J = 12.3 Hz, 1H), 5.98 (d, J = 12.3 Hz, 1H), 5.26 (s, 2H); 13 C NMR (101 MHz, CDC13) δ 166.48, 165.19, 154.25, 151.70, 149.86, 138.71, 134.28, 133.42, 130.57, 130.19, 129.76, 129.44, 128.87, 127.87, 126.85, 125.85, 123.56, 122.27, 122.01, 116.17, 63.51; HRMS (ESI) m / z [M + H] + calcd for C 24 H 17 ClN2O3: 417.1001, found: 417.1032.

[0086] Example 10

[0087] The novel coumarin derivatives containing a quinazoline unit described in the present application, R 1 = H, R 2= ethyl, chemical name ethyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, English name ethyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the structure is as follows:

[0088]

[0089] Synthesis of ethyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate

[0090]

[0091] Synthesis of ethyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate

[0092] The target compound W10 is a light yellow oil, the yield is 70%; 1 H NMR (500 MHz, CDCl3) δ 8.75 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 7.7 Hz, 1H), 7.67 (d, J = 4.1 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 12.3 Hz, 1H), 5.90 (d, J = 12.3 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H); 13 CNMR (126 MHz, CDCl3) δ 166.44, 165.54, 154.22, 151.71, 149.96, 137.57, 134.18, 130.62, 129.99, 128.95, 127.94, 127.67, 125.66, 123.53, 122.58, 122.17, 116.19, 60.30, 14.03; HRMS (ESI) m / z [M+H] + calcd for C 19 H 16 N2O3: 321.1234, found: 321.1235.

[0093] Example 11

[0094] The novel coumarin derivatives containing quinazoline unit, R 1 = H, R 2 = 4-phenyl-1-butyl, chemical name 4-phenylbutyl-(Z)-3-(2-(quinazolin-4-yloxy) phenyl) acrylate, English name 4-phenylbutyl-(Z)-3-(2-(quinazolin-4-yloxy) phenyl) acrylate, the structure is as follows:

[0095]

[0096] Synthesis of 4-phenylbutyl-(Z)-3-(2-(quinazolin-4-yloxy) phenyl) acrylate

[0097]

[0098] The intermediate C in Example 1 (500 mg), potassium carbonate (710 mg) and 4-phenyl-1-butyl bromide (547 mg) were added into acetonitrile (20 mL), and the reaction was heated to reflux at 90°C. After TLC monitoring, the reaction was stopped when no obvious change was observed. Distillation under reduced pressure, and silica gel column chromatography separation (eluent petroleum ether: ethyl acetate = 12:1) to obtain the target product W11 as a light yellow oil.

[0099] The target compound W11 is a light yellow oil, with a yield of 88%; 1 H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.95 (t, J = 7.7 Hz, 1H), 7.67 (dd, J = 14.6, 7.5 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.36-7.28 (m, 4H), 7.21 (dd, J = 19.9, 7.2 Hz, 3H), 6.95 (d, J = 12.3 Hz, 1H), 5.92 (d, J = 12.3 Hz, 1H), 4.14 (s, 2H), 2.62 (s, 2H), 1.62 (s, 4H); 13 C NMR (101 MHz, CDCl3) δ 166.47, 165.78, 154.27, 151.71, 142.03, 137.77, 134.31, 130.57, 130.05, 129.05, 128.40, 127.96, 127.75, 125.83, 123.58, 122.63, 122.22, 116.20, 64.40, 35.51, 27.73; HRMS (ESI) m / z [M+H] +calcd for C 27 H 24 N2O3: 425.1860, found: 425.1860.

[0100] Example 12

[0101] The novel coumarin derivatives containing quinazoline unit described in the present application, R 1 = 8-methyl, R 2 = 3-methylbenzyl, the chemical name is 3-methylbenzyl-(Z)-3-(2-(8-methylquinazoline 4-oxo) phenyl) acrylate, the English name is 3-methylbenzyl-(Z)-3-(2-((8-methylquinazolin-4-yl) oxy) phenyl) acrylate, and the structural formula is as follows:

[0102]

[0103] First step: synthesis of intermediate compound B

[0104] (1) Synthesis of 8-methylquinazolin-4(3H)-one

[0105]

[0106] A three-necked round-bottom flask containing methyl 2-amino-3-methylbenzoate (10 g) was added formamide (15 mL) and formic acid (3 mL), and the reaction was carried out under the condition that the temperature was not lower than 135°C, and TLC was used to monitor the reaction. After no obvious change was found in the reaction, the reaction was stopped, and the product in the reaction bottle was directly poured into a beaker containing 300 mL of water while hot. After stirring, it was allowed to stand and precipitate, and then suction filtration was carried out. The filter cake was dissolved in dichloromethane, and then suction filtration was carried out again. The obtained filter cake was 8-methylquinazolin-4(3H)-one (3.6 g).

[0107] (2) Synthesis of 4-chloro-8-methylquinazoline

[0108]

[0109] A flask containing 8-methylquinazolin-4(3H)-one (3 g) was added with 12 drops of N,N-dimethylformamide, dichloroethane (18 mL) and thionyl chloride (25 mL), and the reaction was carried out at 90°C. After TLC was used to monitor the reaction and no obvious change was found in the reaction, the reaction was stopped. After distillation under reduced pressure, the residue was dissolved in petroleum ether, suction filtration was carried out, and then the filter cake was distilled under reduced pressure to obtain 4-chloro-8-methylquinazoline (2.4 g).

[0110] Second step: synthesis of 3-methylbenzyl-(Z)-3-(2-(8-methylquinazoline-4-oxo) phenyl) acrylate

[0111]

[0112] To a 100 mL flask containing coumarin (3 g) was added 4 mL of sodium hydroxide (1.86 g) aqueous solution and anhydrous ethanol (35 mL), stirred at room temperature, after TLC monitoring reaction was completed, the reaction was stopped. Distillation under reduced pressure, obtained intermediate compound A (4.2 g). Then, it was added to refluxing acetonitrile (35 mL) with intermediate B (2.8 g), after TLC monitoring reaction was completed, the reaction was stopped. Distillation under reduced pressure, extraction with dichloromethane and water, the water phase was retained, the system pH was adjusted to 3 with hydrochloric acid (1M), the precipitate separated was intermediate C (1.65 g). Intermediate C (500 mg), potassium carbonate (710 mg), 3-methyl benzyl chloride (345 mg) was added to 20 mL of acetonitrile, heated to reflux at 90°C, after TLC monitoring reaction was completed, the reaction was stopped. Distillation under reduced pressure, silica gel column chromatography separation (eluent was petroleum ether: ethyl acetate = 8: 1) to obtain white solid target product W12.

[0113] The target compound W12 was a white solid, the yield was 85%; m.p. 58°C; 1 H NMR (400 MHz, CDC13) δ 8.77 (s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 7.1 Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.53-7.49 (m, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.06 (s, 2H), 6.93 (d, J = 12.3 Hz, 1H), 5.92 (d, J = 12.3 Hz, 1H), 5.10 (s, 2H), 2.76 (s, 3H), 2.33 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 153.22, 138.20, 134.29, 130.60, 130.10, 129.17-128.81, 128.40, 127.23, 125.73, 125.41, 122.24, 17.68; HRMS (ESI) m / z [M+H] + calcd for C 26 H 22 N2O3: 411.1703, found: 411.1699.

[0114] Example 13

[0115] The novel coumarin derivative containing quinazoline unit, R 1 = 8-methyl, R 2 = 3-methoxybenzyl, chemical name 3-methoxybenzyl-(Z)-3-(2-(8-methylquinazolin-4- yloxy)phenyl)acrylate, English name 3-methoxybenzyl-(Z)-3-(2-((8-methylquinazolin-4- yl)oxy)phenyl)acrylate, structural formula as follows;

[0116]

[0117] Synthesis of 3-methoxybenzyl-(Z)-3-(2-(8-methylquinazolin-4-yloxy)phenyl)acrylate

[0118]

[0119] The intermediate C in Example 12 (500 mg), potassium carbonate (710 mg) and 3- methoxybenzyl chloride (410 mg) were added into acetonitrile (20 mL), heated to reflux at 90 ℃, the reaction was stopped after TLC monitoring showed no obvious change. Distillation under reduced pressure, silica gel column chromatography separation (eluent was petroleum ether: ethyl acetate = 10: 1) to obtain white solid target product W13.

[0120] The target compound W13 was white solid, yield 79%; m.p. 76 ℃; 1 H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.76 (d, J = 7.1 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 3.7 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), 6.97 (d, J = 12.3 Hz, 1H), 6.89-6.83 (m, 3H), 5.95 (d, J = 12.3 Hz, 1H), 5.13 (s, 2H), 3.80 (s, 3H), 2.78 (s, 3H); 13C NMR (101 MHz, CDC13) δ 166.75, 165.35, 159.69, 153.21, 150.80, 150.04, 138.37, 137.13, 136.35, 134.33, 130.62, 130.18, 129.57, 128.85, 127.27, 125.76, 122.31, 122.08, 121.16, 120.57, 116.04, 113.80, 66.11, 55.27, 17.70; HRMS (ESI) m / z [M+H] + calcd for C 26 H 22 N2O4: 427.1652, found: 427.1651.

[0121] Example 14

[0122] The novel coumarin derivatives containing quinazoline unit described in the present application, R 1 = 6-methyl, R 2 = 3-methylbenzyl, the chemical name is 3-methylbenzyl-(Z)-3-(2-(6-methylquinazoline 4-oxo) phenyl) acrylate, the English name is 3-methylbenzyl-(Z)-3-(2-((6-methylquinazolin-4-yl) oxy) phenyl) acrylate, the structural formula is as follows:

[0123]

[0124] First step: synthesis of intermediate compound B

[0125] (1) Synthesis of 6-methylquinazolin-4(3H)-one

[0126]

[0127] Into a three-necked round bottom flask containing methyl 2-amino-5-methylbenzoate (10 g), formamide (15 mL) and formic acid (3 mL) were added, and the reaction was carried out under the condition that the temperature was not lower than 135 °C, and TLC monitoring showed no obvious change in the reaction. The reaction was stopped, and the product in the reaction bottle was directly poured into a beaker containing 300 mL of water while hot. After stirring, it was allowed to stand and precipitate, and was suction filtered. The filter cake was dissolved in dichloromethane and suction filtered again. The obtained filter cake was 6-methylquinazolin-4(3H)-one (3.9 g).

[0128] (2) Synthesis of 4-chloro-6-methylquinazoline

[0129]

[0130] To a flask containing 6-methylquinazolin-4(3H)-one (3 g) was added 12 drops of N,N-dimethylformamide, dichloroethane (18 mL) and sulphuric acid monohydrate (25 mL) and the reaction was allowed to proceed at 90 °C. The reaction was monitored by TLC and was stopped when no further change was observed. The residue was dissolved in petroleum ether and filtered under reduced pressure. The filtrate was distilled under reduced pressure to obtain 4-chloro-6-methylquinazoline (2.8 g).

[0131] Second Step: Synthesis of 3-methylbenzyl-(Z)-3-(2-(6-methylquinazolin-4- yloxy)phenyl)acrylate

[0132]

[0133] To a 100 mL flask containing coumarin (3 g) was added 4 mL of aqueous sodium hydroxide (1.86 g) and anhydrous ethanol (35 mL) and the reaction was allowed to proceed at room temperature. The reaction was monitored by TLC and was stopped when no further change was observed. The residue was distilled under reduced pressure to obtain intermediate compound A (4.2 g). This was then added to intermediate B (2.8 g) in refluxing acetonitrile (35 mL). The reaction was monitored by TLC and was stopped when no further change was observed. The residue was distilled under reduced pressure and extracted with dichloromethane and water. The aqueous phase was retained and the pH of the system was adjusted to 3 using hydrochloric acid (1 M). The precipitate that separated was intermediate C (1.86 g). Intermediate C (500 mg), potassium carbonate (710 mg) and 3-methylbenzyl chloride (345 mg) were added to 20 mL of acetonitrile and the reaction was allowed to proceed at 90 °C. The reaction was monitored by TLC and was stopped when no further change was observed. The residue was distilled under reduced pressure and column chromatography was performed using silica gel (eluent: petroleum ether: ethyl acetate = 8: 1) to obtain the target product W14 as a white solid.

[0134] The target compound W14 was a white solid and was obtained in 72% yield; m.p. 79 °C; 1 H NMR (400 MHz, CDC13) δ 8.66 (s, 1H), 8.09 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.24 (s, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.05 (s, 2H), 6.95 (d, J = 12.3 Hz, 1H), 5.94 (d, J = 12.3 Hz, 1H), 5.11 (s, 2H), 2.57 (s, 3H), 2.33 (s, 3H); 13C NMR (101 MHz, CDC13) δ 165.46, 153.45, 150.11, 138.42-137.91, 136.30, 135.50, 130.70, 130.14, 129.12-128.77, 128.41, 127.67, 125.73, 125.36, 122.45-122.08, 116.05, 66.32, 21.79, 21.36; HRMS (ESI) m / z [M+H] + calcd for C 26 H 22 N2O3: 411.1703, found: 411.1699.

[0135] Example 15

[0136] The novel coumarin derivative containing quinazoline unit described in the present application, R 1 = 6-methyl, R 2 = 3-methoxybenzyl, chemical name 3-methoxybenzyl-(Z)-3-(2-(6-methylquinazolin-4- yloxy)phenyl)acrylate, English name 3-methoxybenzyl-(Z)-3-(2-((6-methylquinazolin-4- yl)oxy)phenyl)acrylate, structural formula as follows:

[0137]

[0138] Synthesis of 3-methoxybenzyl-(Z)-3-(2-(6-methylquinazoline-4-oxo)phenyl)acrylate

[0139]

[0140] The intermediate C in Example 15 (500 mg), potassium carbonate (710 mg) and 3- methoxybenzyl chloride (410 mg) were added into acetonitrile (20 mL), heated to reflux at 90 °C, the reaction was stopped after TLC monitoring showed no obvious change. Distillation under reduced pressure, silica gel column chromatography separation (eluent was petroleum ether: ethyl acetate = 10: 1) to obtain white solid target product W15.

[0141] The target compound W15 is a white solid, the yield is 80%; m.p. 67 °C; 1 H NMR (400MH z, CDCl3) δ 8.71 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 8.6Hz, 1H), 7.78 (d, J = 8.6Hz, 1H), 7.69 (d, J = 7.6Hz, 1H), 7.49 (t, J = 7.7Hz, 1H), 7.33 (d, J = 7 .5Hz, 1H), 7.29 (d, J = 7.6Hz, 2H), 7.00 (d, J = 12.3Hz, 1H), 6.91-6.85 (m, 3H), 5.99 (d, J = 12.3Hz, 1H), 5.16 (s, 2H), 3.82 (s, 3H), 2.61 (s, 3H); 13 CNMR (101MHz, CDCl3) δ166.03, 165.37, 159.69, 153.45, 150.13, 138.37, 138.02, 137.12, 136.31, 130.70, 130.19, 1 29.57, 128.80, 127.68, 125.72, 122.30, 122.04, 120.50, 116.04, 113.75, 66.09, 55.26, 21.79; HRMS(ESI)m / z[M+H] + calcd for C 26 H 22 N2O4: 427.1652, found: 427.1648.

[0142] Example 16

[0143] The novel coumarin derivative containing a quinazoline unit described in this invention, R 1 =6,7-dimethoxy, R 2 = 3-Methoxybenzyl, chemical name is 3-methoxybenzyl-(Z)-3-(2-(6,7-dimethoxyquinazolin-4-oxo)phenyl)acrylate, English name is 3-methoxybenzyl(Z)-3-(2-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)acrylate, structural formula is as follows;

[0144]

[0145] Step 1: Synthesis of intermediate compound B

[0146] (1) Synthesis of 6,7-dimethoxyquinazolin-4(3H)-one

[0147]

[0148] To a three-necked round bottom flask containing methyl 2-amino-4,5-dimethoxybenzoate (10 g) was added formamide (15 mL) and formic acid (3 mL) and the reaction was carried out at a temperature not less than 135°C. After TLC monitoring, the reaction was stopped when no obvious change was observed. The product in the reaction flask was directly poured into a beaker containing 300 mL of water while hot. After stirring, the product was allowed to settle and was filtered under suction. The filter cake was dissolved in dichloromethane and filtered again under suction. The filter cake obtained was 6,7-dimethoxyquinazolin-4(3H)-one (3.75 g).

[0149] (2) Synthesis of 4-chloro-6,7-dimethoxyquinazoline

[0150]

[0151] To a flask containing 6,7-dimethoxyquinazolin-4(3H)-one (3 g) was added 12 drops of N,N-dimethylformamide, dichloroethane (18 mL) and sulphurous chloride (25 mL) and the reaction was carried out at 90°C. After TLC monitoring, the reaction was stopped when no obvious change was observed. The residue was dissolved in petroleum ether and filtered under suction. The filtrate was distilled under reduced pressure to obtain 4-chloro-6,7-dimethoxyquinazoline (2.7 g).

[0152] Second step: Synthesis of 3-methoxybenzyl-(Z)-3-(2-(6,7-dimethoxyquinazolin-4- yloxy)phenyl)acrylate

[0153]

[0154] To a 100 mL flask containing coumarin (3 g) was added 4 mL of an aqueous solution of sodium hydroxide (1.86 g) and anhydrous ethanol (35 mL) and stirred at room temperature. After TLC monitoring, the reaction was stopped when the reaction was completed. Distillation under reduced pressure gave intermediate compound A (4.2 g). Then, intermediate compound A was added to refluxing acetonitrile (35 mL) along with intermediate B (2.8 g). After TLC monitoring, the reaction was stopped when the reaction was completed. Distillation under reduced pressure, extraction with dichloromethane and water, adjustment of the pH of the aqueous phase to 3 with hydrochloric acid (1 M) and the precipitation of the intermediate C (1.65 g). Intermediate C (500 mg), potassium carbonate (710 mg) and 3-methoxybenzyl chloride (410 mg) were added to 20 mL of acetonitrile and the reaction was carried out at 90°C under reflux. After TLC monitoring, the reaction was stopped when the reaction was completed. Distillation under reduced pressure and column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 12:1) gave the target product W16 as a white solid.

[0155] The target compound W16 was a white solid with a yield of 83% and a melting point of 69°C. 1H NMR (400 MHz, CDC13) δ 8.58 (s, 1H), 7.85 (d, J = 16.1 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.36-7.32 (m, 2H), 7.24 (s, 1H), 7.20 (d, J = 9.2 Hz, 1H), 6.84 (t, J = 9.1 Hz, 3H), 6.55 (d, J = 16.1 Hz, 1H), 5.11 (s, 2H), 4.07 (s, 3H), 4.04 (s, 3H), 3.75 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 165.30-165.10, 159.69, 152.80, 138.71, 131.51, 129.61, 127.96, 127.65, 126.41, 123.43, 120.25, 119.89, 113.74, 113.53, 110.53, 106.93, 100.75, 66.25, 56.43, 55.21; HRMS (ESI) m / z [M+H] + calcd for C 27 H 24 N2O6: 473.1707, found: 473.1707.

[0156] Application performance test

[0157] In vitro anti-tumor activity test method:

[0158] The inhibitory effect of the target compound on human pancreatic cancer cells (PANC-1), human breast cancer cells (MDA-MB-231), and human gastric cancer cells (SGC7901) at a concentration of 100 μmol / L was determined by MTT method. Cells in the logarithmic phase were collected and seeded in a 96-well plate at a density of 7000 cells per well, and the edge wells of the 96-well plate were filled with PBS. Incubate for 24 h at 37°C, 5% CO2, and 90% humidity until the monolayer covers the bottom of the 96-well plate. Add the drug synthesized by the application, dilute it to 100 μmol / L with DMEM medium containing 10% serum, 100 μL per well, set 3 replicate wells, incubate for 48 h, add 10 μL CCK8 solution per well, and continue to incubate for 2 h. Measure the absorbance of each well at 450 nm using a microplate reader. Calculate the cell inhibition rate according to the absorbance, inhibition rate = (negative control group OD - drug group OD) / (negative control group OD - blank group OD) * 100%. The test results are shown in Table 1.

[0159] Table 1 Inhibitory effect of compounds W1-W16 on tumor cells at a concentration of 100 μmol / L

[0160] Compound PANC-1 MDA-MB-231 SGC7901 W1 9.83±1.42 15.83±0.83 18.75±0.97 W2 67.23±0.88 69.58±2.38 68.86±0.59 W3 51.77±2.98 64.83±2.57 63.45±4.25 W4 76.39±1.29 67.01±3.94 82.54±2.47 W5 64.19±1.25 43.32±2.79 79.59±3.56 W6 35.33±3.26 23.42±2.09 39.24±2.19 W7 77.43±1.36 42.23±3.98 86.99±1.78 W8 76.65±2.03 16.10±0.42 75.64±2.14 W9 73.58±1.69 53.59±3.51 74.48±3.56 W10 65.77±1.72 85.58±1.38 69.57±1.53 W11 64.44±1.97 53.15±3.89 77.34±0.84 W12 69.47±2.39 12.86±1.45 69.73±3.45 W13 58.79±2.95 1.26±0.75 62.37±4.65 W14 68.26±2.84 43.93±2.87 63.27±5.79 W15 52.28±3.28 0±0.09 71.68±1.49 W16 69.26±2.38 42.70±2.38 48.15±3.94 5-fluorouracil 66.94±3.92 60.16±1.59 67.35±2.48

[0161] From Table 1, it can be seen that most of the compounds exhibit obvious inhibitory effect on the three kinds of tumor cells at a concentration of 100 μmol / L. Compared with the positive control drug 5-fluorouracil, compounds W2, W4, W7, W8, W9, W12, W14 and W16 exhibit significantly stronger inhibitory activity on pancreatic cancer cells than 5-fluorouracil at a concentration of 100 μmol / L; compounds W2, W3, W4 and W10 exhibit significantly stronger inhibitory activity on breast cancer cells than 5-fluorouracil; compounds W2, W4, W5, W7, W8, W9, W10, W11, W12 and W15 exhibit significantly stronger inhibitory activity on gastric cancer cells than 5-fluorouracil; among them, compounds W2 and W4 have stronger inhibitory effect on human pancreatic cancer cells, human breast cancer cells and human gastric cancer cells than 5-fluorouracil.

[0162] The above activity data fully demonstrate that the novel coumarin derivatives containing quinazoline unit have significant inhibitory activity on human pancreatic cancer cells, human breast cancer cells and human gastric cancer cells, and can be developed as new anti-tumor drug candidate molecules.

Claims

1. Coumarin derivatives containing a quinazoline unit, characterized in that, The structural formula is shown as formula I: wherein R is selected from the group consisting of hydrogen, 8-methyl, 6-methyl, or 6,7-dimethoxy; R 1 is selected from the group consisting of hydrogen, 8-methyl, 6-methyl, or 6,7-dimethoxy; R 2 is selected from the group consisting of phenyl, 3-methoxyphenyl, 3-methylphenyl, 3-chlorophenyl, 2-methylphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, 2-chlorophenyl, or methyl.

2. A method for preparing the coumarin derivative containing a quinazoline unit according to claim 1, characterized by, The coumarin molecule is hydrolyzed by 5% sodium hydroxide solution, and then reacts with 4-chloroquinazoline molecule B in hot acetonitrile, and the obtained intermediate product C reacts with different benzyl chloride or bromoethane in acetonitrile solution containing potassium carbonate to obtain the coumarin derivative I containing quinazoline unit, and the synthetic route is as follows:

3. The production method according to claim 2, characterized by, The structural formula of 4-chloroquinazoline molecule B is shown as follows:

4. The production method according to claim 2, characterized by, The structural formula of intermediate product C is shown as follows:

5. The coumarin derivative containing quinazoline unit according to claim 1 is applied to the preparation of a drug for inhibiting the proliferation of pancreatic cancer or gastric cancer cells.

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