Novel coumarin derivative containing quinazoline unit as well as preparation method and application of novel coumarin derivative

Abstract

The invention discloses a novel coumarin derivative (as shown in a structural formula I) containing a quinazoline unit. A preparation method of the novel coumarin derivative comprises the following steps: heating coumarin molecules A treated by a sodium hydroxide solution and 4-chloroquinazoline molecules B in acetonitrile to carry out etherification reaction, and heating an obtained intermediate product C and benzyl chloride or bromoethane in acetonitrile to carry out reaction, so as to obtain the novel coumarin derivative containing the quinazoline unit. The novel coumarin derivative I containing the quinazoline unit is obtained; the novel coumarin derivative containing the quinazoline unit is a novel compound, has an obvious inhibition 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 candidate molecule of a novel antitumor drug. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a novel coumarin derivative containing a quinazoline unit, and a preparation method and application thereof. Background Art

[0002] At present, drug treatments for cancer mainly include chemotherapy, targeted therapy and immunotherapy. Targeted therapy drugs interfere with the growth and spread of cancer cells by inhibiting signal pathways such as EGFR and VEGF, and immunotherapy drugs inhibit 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 costs, and easy recurrence. Therefore, it is very necessary to develop new anti-tumor drugs with better efficacy and fewer toxic side effects. Summary of the invention

[0003] Purpose of the invention: The first purpose of the present invention is to provide a novel coumarin derivative containing a quinazoline unit having anti-tumor activity. The second purpose of the present invention is to provide a method for preparing the novel coumarin derivative containing a quinazoline unit; the third purpose of the present invention is to provide the application of the novel coumarin derivative containing a quinazoline unit in anti-tumor cells.

[0004] Technical solution: The novel coumarin derivative containing a quinazoline unit described in the present invention has a structural formula as shown in Formula I:

[0005]

[0006] Among them, 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 quinazoline unit of the present invention comprises heating a coumarin molecule A treated with sodium hydroxide solution and a 4-chloroquinazoline molecule B in acetonitrile to cause an etherification reaction, and then heating the obtained intermediate product C with different benzyl chlorides or ethyl bromide in acetonitrile to react to obtain the novel coumarin derivative I containing quinazoline unit. The synthesis route is as follows:

[0008]

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

[0010] The invention discloses an application of the novel coumarin derivative containing quinazoline unit in anti-tumor cell. The tumor cells are human pancreatic cancer cells (PANC-1), human gastric cancer cells (SGC7901) and human breast cancer cells (MDA-MB-231).

[0011] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The novel coumarin derivative containing a quinazoline unit described in the present invention is a new type of compound; (2) The preparation method of the novel coumarin derivative containing a quinazoline unit described in the present invention has a novel and efficient reaction, simple operation, and readily available raw materials; (3) The novel coumarin derivative containing a quinazoline unit described in the present invention has a strong inhibitory activity against tumor cells, can effectively inhibit the proliferation of tumor cells, and has potential application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the novel coumarin derivative containing quinazoline unit prepared in Example 1;

[0013] Figure 2 The carbon NMR spectrum of the novel coumarin derivative containing quinazoline unit prepared in Example 1;

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

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

[0016] Example 1

[0017] The novel coumarin derivative containing 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, the structural formula is as follows;

[0018]

[0019] Step 1: Synthesis of intermediate compound B

[0020] (1) Synthesis of Quinazolin-4(3H)-one

[0021]

[0022] To a three-necked round-bottom flask containing methyl anthranilate (10 g) was added formamide (15 mL) and formic acid (3 mL), and the reaction was carried out under the condition that the monitoring temperature was not lower than 135°C. After TLC monitoring showed no obvious change in the reaction, the reaction was stopped, and the product in the reaction flask was directly poured into a beaker containing 300 mL of water while hot, stirred and allowed to stand for precipitation, and filtered, the filter cake was dissolved with dichloromethane, and filtered again, and the filter cake obtained was quinazoline-4(3H)-one (3.8 g).

[0023] (2) Synthesis of 4-chloroquinazoline

[0024]

[0025] Add 12 drops of N,N-dimethylformamide, dichloroethane (18 mL) and thionyl chloride (25 mL) to a flask containing quinazolin-4(3H)-one (3 g), and react at 90°C. After TLC monitoring shows no significant change, stop the reaction. After vacuum distillation, dissolve the residue with petroleum ether, filter, and vacuum distill the filtrate to obtain 4-chloroquinazoline (2.8 g).

[0026] Step 2: Synthesis of benzyl-(Z)-3-(2-(quinazoline-4-oxy)phenyl)acrylate

[0027]

[0028] Add 4 mL of sodium hydroxide (1.86 g) aqueous solution and anhydrous ethanol (35 mL) to a 100 mL flask containing coumarin (3 g), stir at room temperature, and stop the reaction after the reaction is monitored by TLC. Distill under reduced pressure to obtain intermediate compound A (4.2 g). Then, add it and intermediate B (2.8 g) to refluxing acetonitrile (35 mL). After the reaction is monitored by TLC, stop the reaction. Distill under reduced pressure, add dichloromethane and water to extract, retain the aqueous phase, adjust the system pH to 3 with hydrochloric acid (1 M), and the precipitate is intermediate C (1.8 g). Add intermediate C (500 mg), potassium carbonate (710 mg), and benzyl chloride (325 mg) to 20 mL of acetonitrile, heat under reflux at 90 ° C, and stop the reaction after the reaction is monitored by TLC. Distill under reduced pressure and separate by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 12:1) to obtain the target product W1.

[0029] The target compound W1 is a white solid with a yield of 82%; mp 96°C; 1H NMR (400MHz, CDCl3) δ8.75 (s, 1H), 8.31 (d, J = 7.7Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.95 (t, J = 7.7Hz, 1H), 7.66 (t, J = 8.9Hz, 2H), 7.49 (t, J=8.4Hz, 1H), 7.37-7.33 (m, 3H), 7.31 (d, J=11.0Hz, 4H), 6.97 (d, J=12.3Hz, 1H), 5.96 (d, J=12.3Hz, 1H), 5.16 (s, 2H); 13 C NMR (101MHz, CDCl3) δ166.52, 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] + Calculate 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, the English name is 3-methoxybenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the structural formula is as follows;

[0032]

[0033] Synthesis of 3-methoxybenzyl-(Z)-3-(2-(quinazoline-4-oxy)phenyl)acrylate

[0034]

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

[0036] The target compound W2 is a white solid with a yield of 76%; mp 65°C; 1 H NMR (400MHz, CDCl3) δ8.74 (s, 1H), 8.30 (d, J=8.2Hz, 1H), 8.02 (d, J=8.4Hz, 1H), 7.93 (t, J=7.7Hz, 1H), 7.65 (t, J=7.4Hz, 2H), 7.47 (t, J=7. 7Hz, 1H), 7.32 (d, J = 7.6Hz, 2H), 7.24 (s, 1H), 6.96 (d, J = 12.3Hz, 1H), 6.88-6.82 (m, 3H), 5.95 (d, J = 12.3Hz, 1H), 5.12 (s, 2H), 3.80 (s, 3H); 13 C NMR (101MHz, CDCl3) δ166.48, 165.34, 159.68, 154.26, 151.72, 149.85, 138.34, 137.10, 134.27, 130.62, 13 0.17, 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] + Calculate 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, the English name is 3-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the structural formula is as follows;

[0039]

[0040] Synthesis of 3-Methylbenzyl-(Z)-3-(2-(quinazoline-4-oxy)phenyl)acrylate

[0041]

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

[0043] The target compound W3 is a white solid with a yield of 81%; mp 72°C; 1 H NMR (400MHz, CDCl3) δ8.75 (s, 1H), 8.31 (d, J = 7.6Hz, 1H), 8.04 (d, J = 8.4Hz, 1 H), 7.98-7.91 (m, 1H), 7.66 (t, J=8.0Hz, 2H), 7.49 (t, J=7.1Hz, 1H), 7.31 (dd , J=14.9, 7.4Hz, 2H), 7.24 (d, J=7.8Hz, 1H), 7.15 (d, J=7.4Hz, 1H), 7.08 (s, 2 H), 6.96 (d, J=12.3Hz, 1H), 5.96 (d, J=12.3Hz, 1H), 5.13 (s, 2H), 2.36 (s, 3H); 13 C NMR (101MHz, CDCl3) δ166.52, 165.43, 154.36, 151.68, 149.85, 138.19, 135.48, 134.26, 130.62, 130.12, 12 9.24-128.82, 128.42, 127.96, 127.75, 125.84, 125.43, 123.59, 122.30, 116.15, 66.25; HRMS(ESI)m / z[M+H] + Calculation for C25H 20 N2O3: 397.1547, found: 397.1549.

[0044] Example 4

[0045] The novel coumarin derivative containing quinazoline unit of the present invention, R 1 =H, R2 = 3-chlorobenzyl, the chemical name is 3-chlorobenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the English name is 3-chlorobenzyl(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the structural formula is as follows;

[0046]

[0047] Synthesis of 3-Chlorophenyl-(Z)-3-(2-(quinazoline 4-oxy)phenyl)acrylate

[0048]

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

[0050] The target compound W4 is a white solid with a yield of 72%; mp 83°C; 1 H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 8.28 (d, J = 9.0Hz, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.93 (t , J=7.7Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 7.59 (d, J=6.9Hz, 1H), 7.48 (t, J=7.1Hz, 1H), 7.3 2 (d, J=8.5Hz, 1H), 7.28 (d, J=2.1Hz, 1H), 7.27 (s, 1H), 7.26 (d, J=4.0Hz, 1H), 7.21 (s, 1 H), 7.13 (d, J=7.1Hz, 1H), 6.99 (d, J=12.2Hz, 1H), 5.95 (d, J=12.2Hz, 1H), 5.10 (s, 2H); 13 C NMR (101MHz, CDCl3) δ166.44, 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 derivative containing quinazoline unit of the present invention, R 1 =H, R 2=2-methylbenzyl, the chemical name is 2-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the English name is 2-methylbenzyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the structural formula is as follows;

[0053]

[0054] Synthesis of 2-methylbenzyl-(Z)-3-(2-(quinazoline-4-oxy)phenyl)acrylate

[0055]

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

[0057] The target compound W5 is a white solid with a yield of 75%; mp 61°C; 1 H NMR (400MHz, CDCl3) δ8.74 (s, 1H), 8.33 (d, J = 8.2Hz, 1H), 8.04 (d, J = 8.4Hz, 1H), 7.98-7.91 (m, 1H), 7.66 (dd, J = 15.5, 7.4Hz, 2H), 7. 47 (t, J=7.8Hz, 1H), 7.34-7.26 (m, 2H), 7.25-7.15 (m, 4H), 6.97 (d, J=12.3Hz, 1H), 5.96 (d, J=12.3Hz, 1H), 5.18 (s, 2H), 2.27 (s, 3H); 13 C NMR (101MHz, CDCl3) δ166.48, 165.46, 154.27, 151.65, 149.84, 138.26, 137.09, 134.27, 133.59, 130.57, 130.2 2, 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] + Calculate for C 25 H 20 N2O3: 397.1547, found: 397.1549.

[0058] Example 6

[0059] The novel coumarin derivative containing quinazoline unit of the present invention, 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, the structural formula is as follows;

[0060]

[0061] Synthesis of 4-methoxybenzyl-(Z)-3-(2-(quinazoline-4-oxy)phenyl)acrylate

[0062]

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

[0064] The target compound W6 is a white solid with a yield of 78%; mp 70°C; 1 H NMR (400MHz, CDCl3) δ8.73 (s, 1H), 8.28 (d, J = 8.2Hz, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.95-7.89 (m, 1H), 7.63 (dd, J = 14.6, 7.7Hz, 2H), 7.46 (t, J = 7.1Hz, 1H) , 7.29 (dd, J=17.3, 5.3Hz, 2H), 7.22 (d, J=8.7Hz, 2H), 6.92 (d, J=12.3Hz, 1H ), 6.86 (d, J = 8.7Hz, 2H), 5.91 (d, J = 12.3Hz, 1H), 5.07 (s, 2H), 3.81 (s, 3H); 13CNMR (101MHz, CDCl3) δ165.44, 159.62, 154.27, 151.71, 149.83, 138.06, 134.26, 130.62, 130.19, 1 28.88, 128.04-127.64, 125.82, 123.59, 122.31, 116.18, 113.89, 66.04, 55.33; HRMS(ESI)m / z[M+H] + Calculate for C 25 H 20 N2O3: 413.1496, found: 413.1495.

[0065] Example 7

[0066] The novel coumarin derivative containing quinazoline unit of the present invention, 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, the structural formula is as follows;

[0067]

[0068] Synthesis of 4-methylbenzyl (Z)-3-(2-(quinazoline-4-oxy)phenyl)acrylate

[0069]

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

[0071] The target compound W7 is a white solid with a yield of 89%; mp 67°C; 1H NMR (400MHz, CDCl3) δ8.75 (s, 1H), 8.30 (d, J = 8.9Hz, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.97-7.91 (m, 1H), 7.66 (t, J = 7.0Hz, 2H), 7.49 (t, J = 7. 8Hz, 1H), 7.31 (dd, J=14.8, 8.0Hz, 2H), 7.17 (d, J=2.2Hz, 4H), 6.95 (d, J=12.3Hz, 1H), 5.95 (d, J=12.3Hz, 1H), 5.12 (s, 2H), 2.37 (s, 3H); 13 C NMR (101MHz, CDCl3) δ166.60-166.40, 165.41, 154.30, 151.72, 149.84, 138.12, 134.26, 132.62, 130.64, 130.1 2, 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] + Calculate for C 25 H 20 N2O3: 397.1547, found: 397.1549.

[0072] Example 8

[0073] The novel coumarin derivative containing quinazoline unit of the present invention, 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 structural formula is as follows;

[0074]

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

[0076]

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

[0078] The target compound W8 is a white solid with a yield of 87%; mp 90°C; 1 H NMR (400MHz, CDCl3) δ8.74 (s, 1H), 8.29 (d, J = 8.2Hz, 1H), 8.04 (d, J = 8.4Hz, 1H), 7.97-7.91 (m, 1H), 7.68-7.59 (m, 2H), 7.49 (t, J=8.3Hz, 1H), 7.31 (dd, J=10.6, 4.6Hz, 4H), 7.19 (d, J=8.4Hz, 2H), 6.99 (d, J=12.2Hz, 1H), 5.95 (d, J=12.3Hz, 1H), 5.11 (s, 2H); 13 C NMR (101MHz, CDCl3) δ166.44, 165.30, 154.23, 151.73, 149.82, 138.60, 134.39-133.72, 130.53, 130.18, 129.7 1, 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] + Calculate for C 24 H 17 ClN2O3: 417.1001, found: 417.1032.

[0079] Example 9

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

[0081]

[0082] Synthesis of 2-chlorobenzyl-(Z)-3-(2-(quinazoline 4-oxy)phenyl)acrylate

[0083]

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

[0085] The target compound W9 is a white solid with a yield of 91%; mp 69°C; 1 H NMR (400MHz, CDCl3) δ 8.74 (s, 1H), 8.33 (d, J = 8.0Hz, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.94 (t, J = 7.7Hz, 1H), 7.67 (t, J = 7.9Hz, 2H), 7.46 (t, J = 7.7Hz, 1H), 7.38 (d, J=7.8Hz, 1H), 7.33-7.27 (m, 2H), 7.23 (t, J=6.2Hz, 3H), 7.00 (d, J=12.3Hz, 1H), 5.98 (d, J=12.3Hz, 1H), 5.26 (s, 2H); 13 C NMR (101MHz, CDCl3) δ166.48, 165.19, 154.25, 151.70, 149.86, 138.71, 134.28, 133.42, 130.57, 130.19, 12 9.76, 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] + Calculate for C 24 H 17 ClN2O3: 417.1001, found: 417.1032.

[0086] Example 10

[0087] The novel coumarin derivative containing quinazoline unit of the present invention, R 1 =H, R 2= ethyl, the chemical name is ethyl-(Z)-3-(2-(quinazolin-4-oxy)phenyl)acrylate, the English name is ethyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the structural formula is as follows;

[0088]

[0089] Synthesis of Ethyl-(Z)-3-(2-(Quinazolin-4-oxy)phenyl)acrylate

[0090]

[0091] The intermediate C (500 mg) in Example 1, potassium carbonate (710 mg) and bromoethane (260 mg) were added to acetonitrile (20 mL), and the mixture was heated to reflux at 90°C for reaction. After no obvious change was observed by TLC monitoring, the reaction was stopped. The mixture was distilled under reduced pressure and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 9:1) to obtain the target product W10 as a light yellow oil.

[0092] The target compound W10 was a light yellow oil with a yield of 70%; 1 H NMR (500MHz, CDCl3) δ8.75 (s, 1H), 8.34 (d, J = 8.8Hz, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.92 (t, J = 7.7Hz, 1H), 7.67 (d, J = 4.1Hz, 2H), 7.46 (t, J = 7.8Hz, 1H), 7.33 (t, J=7.6Hz, 1H), 7.27 (d, J=8.5Hz, 1H), 6.92 (d, J=12.3Hz, 1H), 5.90 (d, J=12.3Hz, 1H), 4.15 (q, J=7.1Hz, 2H), 1.20 (t, J=7.1Hz, 3H); 13 CNMR (126MHz, CDCl3) δ166.44, 165.54, 154.22, 151.71, 149.96, 137.57, 134.18, 130.62, 129.99, 1 28.95, 127.94, 127.67, 125.66, 123.53, 122.58, 122.17, 116.19, 60.30, 14.03; HRMS(ESI)m / z[M+H] + Calculate for C 19 H 16 N2O3: 321.1234, found: 321.1235.

[0093] Embodiment 11

[0094] The novel coumarin derivative containing quinazoline unit of the present invention, R 1 =H, R 2 =4-phenyl-1-butyl, the chemical name is 4-phenylbutyl-(Z)-3-(2-(quinazolin-4-oxy)phenyl)acrylate, the English name is 4-phenylbutyl-(Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylate, the structural formula is as follows;

[0095]

[0096] Synthesis of 4-phenylbutyl-(Z)-3-(2-(quinazoline-4-oxy)phenyl)acrylate

[0097]

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

[0099] The target compound W11 was a light yellow oil with a yield of 88%; 1 H NMR (400MHz, CDCl3) δ 8.77 (s, 1H), 8.36 (d, J = 8.9Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.95 (t, J = 7.7Hz, 1H), 7.67 (dd, J = 14.6, 7.5Hz, 2H), 7.46 (t, J = 7. 8Hz, 1H), 7.36-7.28 (m, 4H), 7.21 (dd, J=19.9, 7.2Hz, 3H), 6.95 (d, J=12. 3Hz, 1H), 5.92 (d, J=12.3Hz, 1H), 4.14 (s, 2H), 2.62 (s, 2H), 1.62 (s, 4H); 13 C NMR (101MHz, CDCl3) δ166.47, 165.78, 154.27, 151.71, 142.03, 137.77, 134.31, 130.57, 130.05, 129.05, 1 28.40, 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] +Calculate for C 27 H 24 N2O3: 425.1860, found: 425.1860.

[0100] Example 12

[0101] The novel coumarin derivative containing quinazoline unit of the present invention, R 1 =8-methyl, R 2 =3-methylbenzyl, the chemical name is 3-methylbenzyl-(Z)-3-(2-(8-methylquinazolin-4-yl)oxy)phenyl)acrylate, the English name is 3-methylbenzyl-(Z)-3-(2-((8-methylquinazolin-4-yl)oxy)phenyl)acrylate, the structural formula is as follows;

[0102]

[0103] Step 1: Synthesis of intermediate compound B

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

[0105]

[0106] To 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 monitoring temperature was not lower than 135°C. After no obvious change was observed in the reaction monitored by TLC, the reaction was stopped, and the product in the reaction flask was directly poured into a beaker containing 300 mL of water while hot, stirred and allowed to stand for precipitation, and filtered, the filter cake was dissolved with dichloromethane, and filtered again, and the filter cake obtained was 8-methylquinazolin-4(3H)-one (3.6 g).

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

[0108]

[0109] Add 12 drops of N,N-dimethylformamide, dichloroethane (18 mL) and thionyl chloride (25 mL) to a flask containing 8-methylquinazolin-4(3H)-one (3 g), and react at 90°C. After TLC monitoring shows no significant change, stop the reaction. After vacuum distillation, dissolve the residue with petroleum ether, filter, and vacuum distill the filtrate to obtain 4-chloro-8-methylquinazoline (2.4 g).

[0110] Step 2: Synthesis of 3-methylbenzyl-(Z)-3-(2-(8-methylquinazoline-4-oxy)phenyl)acrylate

[0111]

[0112] Add 4 mL of sodium hydroxide (1.86 g) aqueous solution and anhydrous ethanol (35 mL) to a 100 mL flask containing coumarin (3 g), stir at room temperature, and stop the reaction after the reaction is completed by TLC monitoring. Distill under reduced pressure to obtain intermediate compound A (4.2 g). Then, add it and intermediate B (2.8 g) to refluxing acetonitrile (35 mL). After the reaction is completed by TLC monitoring, stop the reaction. Distill under reduced pressure, add dichloromethane and water to extract, retain the aqueous phase, adjust the system pH to 3 with hydrochloric acid (1 M), and the precipitate is intermediate C (1.65 g). Add intermediate C (500 mg), potassium carbonate (710 mg), and 3-methylbenzyl chloride (345 mg) to 20 mL of acetonitrile, heat under reflux at 90 ° C for reaction, and stop the reaction after the reaction is completed by TLC monitoring. Distill under reduced pressure, separate by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 8:1) to obtain the white solid target product W12.

[0113] The target compound W12 is a white solid with a yield of 85%; mp 58°C; 1 H NMR (400MHz, CDCl3) δ8.77 (s, 1H), 8.14 (d, J = 8.1Hz, 1H), 7.75 (d, J = 7.1Hz, 1H), 7.6 3(d, J=7.4Hz, 1H), 7.53-7.49 (m, 1H), 7.46 (t, J=7.8Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.24 (d, J=8.1Hz, 1H), 7.21 (d, J=7.8Hz, 1H), 7.12 (d, J=7.5Hz, 1H), 7.06 (s, 2H), 6. 93(d,J=12.3Hz,1H), 5.92(d,J=12.3Hz,1H), 5.10(s,2H), 2.76(s,3H), 2.33(s,3H); 13 C NMR (101MHz, CDCl3) δ153.22, 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] + Calculate for C 26 H 22 N2O3: 411.1703, found: 411.1699.

[0114] Embodiment 13

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

[0116]

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

[0118]

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

[0120] The target compound W13 is a white solid with a yield of 79%; mp 76°C; 1 H NMR (400MHz, CDCl3) δ8.79 (s, 1H), 8.16 (d, J = 8.2Hz, 1H), 7.76 (d, J = 7.1Hz, 1H), 7.66 (d, J=7.6Hz, 1H), 7.53 (t, J=7.7Hz, 1H), 7.47 (t, J=7.2Hz, 1H), 7.31 (d, J=7. 6Hz, 1H), 7.27 (d, J = 3.7Hz, 1H), 7.24 (d, J = 3.8Hz, 1H), 6.97 (d, J = 12.3Hz, 1H), 6 .89-6.83 (m, 3H), 5.95 (d, J=12.3Hz, 1H), 5.13 (s, 2H), 3.80 (s, 3H), 2.78 (s, 3H); 13C NMR (101MHz, CDCl3) δ166.75, 165.35, 159.69, 153.21, 150.80, 150.04, 138.37, 137.13, 136.35, 134.33, 130.62, 130.18, 1 29.57, 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] + Calculate for C 26 H 22 N2O4: 427.1652, found: 427.1651.

[0121] Embodiment 14

[0122] The novel coumarin derivative containing quinazoline unit of the present invention, R 1 =6-methyl, R 2 =3-methylbenzyl, the chemical name is 3-methylbenzyl-(Z)-3-(2-(6-methylquinazolin-4-yl)oxy)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] Step 1: Synthesis of intermediate compound B

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

[0126]

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

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

[0129]

[0130] Add 12 drops of N,N-dimethylformamide, dichloroethane (18 mL) and thionyl chloride (25 mL) to a flask containing 6-methylquinazolin-4(3H)-one (3 g), and react at 90°C. After TLC monitoring shows no significant change, stop the reaction. After vacuum distillation, dissolve the residue with petroleum ether, filter, and vacuum distill the filtrate to obtain 4-chloro-6-methylquinazoline (2.8 g).

[0131] Step 2: Synthesis of 3-methylbenzyl-(Z)-3-(2-(6-methylquinazoline-4-oxy)phenyl)acrylate

[0132]

[0133] Add 4 mL of sodium hydroxide (1.86 g) aqueous solution and anhydrous ethanol (35 mL) to a 100 mL flask containing coumarin (3 g), stir at room temperature, and stop the reaction after the reaction is monitored by TLC. Distill under reduced pressure to obtain intermediate compound A (4.2 g). Then, add it and intermediate B (2.8 g) to refluxing acetonitrile (35 mL). After the reaction is monitored by TLC, stop the reaction. Distill under reduced pressure, add dichloromethane and water to extract, retain the aqueous phase, adjust the system pH to 3 with hydrochloric acid (1 M), and the precipitate is intermediate C (1.86 g). Add intermediate C (500 mg), potassium carbonate (710 mg), and 3-methylbenzyl chloride (345 mg) to 20 mL of acetonitrile, heat under reflux at 90 ° C for reaction, and stop the reaction after the reaction is monitored by TLC. Distill under reduced pressure and separate by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 8:1) to obtain the white solid target product W14.

[0134] The target compound W14 is a white solid with a yield of 72%; mp 79°C; 1 H NMR (400MHz, CDCl3) δ8.66 (s, 1H), 8.09 (s, 1H), 7.91 (d, J=8.6Hz, 1H), 7.75 (d, J =8.6Hz, 1H), 7.64 (d, J = 7.6Hz, 1H), 7.46 (t, J = 7.8Hz, 1H), 7.30 (d, J = 7.5Hz, 1H) , 7.24 (s, 1H), 7.21 (d, J = 7.9Hz, 1H), 7.12 (d, J = 7.5Hz, 1H), 7.05 (s, 2H), 6.95 (d , J=12.3Hz, 1H), 5.94 (d, J=12.3Hz, 1H), 5.11 (s, 2H), 2.57 (s, 3H), 2.33 (s, 3H); 13C NMR (101MHz, CDCl3) δ165.46, 153.45, 150.11, 138.42-137.91, 136.30, 135.50, 130.70, 130.14, 129.12-1 28.77, 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] + Calculate for C 26 H 22 N2O3: 411.1703, found: 411.1699.

[0135] Embodiment 15

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

[0137]

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

[0139]

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

[0141] The target compound W15 is a white solid with a yield of 80%; mp 67°C; 1 H NMR (400 MH 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] + Calculate for C 26 H 22 N2O4: 427.1652, found: 427.1648.

[0142] Example 16

[0143] The novel coumarin derivative containing quinazoline unit of the present invention, R 1 =6,7-dimethoxy, R 2 =3-methoxybenzyl, the chemical name is 3-methoxybenzyl-(Z)-3-(2-(6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)acrylate, the English name is 3-methoxybenzyl(Z)-3-(2-((6,7-dimethoxyquinazolin-4-yl)oxy)phenyl)acrylate, the 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 under the condition that the monitoring temperature was not lower than 135° C. After no obvious change was observed in the reaction monitored by TLC, the reaction was stopped, and the product in the reaction flask was directly poured into a beaker containing 300 mL of water while hot, stirred and allowed to stand for precipitation, and filtered with suction. The filter cake was dissolved with dichloromethane and filtered with suction again. The filter cake obtained was 6,7-dimethoxyquinazoline-4(3H)-one (3.75 g).

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

[0150]

[0151] Add 12 drops of N,N-dimethylformamide, dichloroethane (18 mL) and thionyl chloride (25 mL) to a flask containing 6,7-dimethoxyquinazoline-4(3H)-one (3 g), and react at 90°C. After TLC monitoring shows no significant change, stop the reaction. After vacuum distillation, dissolve the residue with petroleum ether, filter, and vacuum distill the filtrate to obtain 4-chloro-6,7-dimethoxyquinazoline (2.7 g).

[0152] Step 2: Synthesis of 3-methoxybenzyl-(Z)-3-(2-(6,7-dimethoxyquinazoline-4-oxo)phenyl)acrylate

[0153]

[0154] Add 4 mL of sodium hydroxide (1.86 g) aqueous solution and anhydrous ethanol (35 mL) to a 100 mL flask containing coumarin (3 g), stir at room temperature, and stop the reaction after the reaction is completed by TLC monitoring. Distill under reduced pressure to obtain intermediate compound A (4.2 g). Then, add it and intermediate B (2.8 g) to refluxing acetonitrile (35 mL). After the reaction is completed by TLC monitoring, stop the reaction. Distill under reduced pressure, add dichloromethane and water to extract, retain the aqueous phase, adjust the system pH to 3 with hydrochloric acid (1 M), and the precipitate is intermediate C (1.65 g). Add intermediate C (500 mg), potassium carbonate (710 mg), and 3-methoxybenzyl chloride (410 mg) to 20 mL of acetonitrile, heat under reflux at 90 ° C, and stop the reaction after the reaction is completed by TLC monitoring. Distill under reduced pressure, separate by silica gel column chromatography (eluent is petroleum ether: ethyl acetate = 12:1) to obtain the white solid target product W16.

[0155] The target compound W16 is a white solid with a yield of 83%; mp 69°C; 1H NMR (400MHz, CDCl3) δ8.58 (s, 1H), 7.85 (d, J=16.1Hz, 1H), 7.74 (d, J=7.6Hz, 1H), 7.56 (s, 1H), 7.49 (t, J=7.7Hz, 1H), 7.36-7.32 (m, 2H) ; 13 C NMR (101MHz, CDCl3) δ165.30-165.10, 159.69, 152.80, 138.71, 131.51, 129.61, 127.96, 127.65, 126.41, 1 23.43, 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] + Calculate for C 27 H 24 N2O6: 473.1707, found: 473.1707.

[0156] Application performance testing

[0157] In vitro antitumor 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 the MTT method. Cells in the logarithmic phase were collected and inoculated in a 96-well plate at a density of 7000 cells / well, and the edge wells of the 96-well plate were filled with PBS. Incubate for 24 hours under 5% CO2, 37°C, and 90% humidity until the cell monolayer covers the bottom of the 96-well plate. Add the drug synthesized by the present invention, dilute it to 100 μmol / L with DMEM culture medium containing 10% serum, 100 μL per well, set 3 replicates, incubate for 48 hours, add 10 μL CCK8 solution to each well, and continue to culture for 2 hours. Use an enzyme marker to measure the absorbance of each well at 450nm. Calculate the cell inhibition rate based on 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 effects 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] As shown in Table 1, most compounds showed significant inhibitory effects on the three tumor cells at a concentration of 100 μmol / L. Compared with the positive control drug 5-fluorouracil, under the condition of 100 μmol / L, compounds W2, W4, W7, W8, W9, W12, W14, and W16 showed significantly stronger inhibitory activity against pancreatic cancer cells than 5-fluorouracil; compounds W2, W3, W4, and W10 showed significantly stronger inhibitory activity against breast cancer cells than 5-fluorouracil; compounds W2, W4, W5, W7, W8, W9, W10, W11, W12, and W15 showed significantly stronger inhibitory activity against gastric cancer cells than 5-fluorouracil; among them, compounds W2 and W4 showed stronger inhibitory effects 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 new coumarin derivatives containing quinazoline units have significant inhibitory activity against 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. A novel coumarin derivative containing a quinazoline unit, characterized in that: The structural formula is shown in Formula I: Among them, 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.

2. A method for preparing a novel coumarin derivative containing a quinazoline unit according to claim 1, characterized in that: Coumarin molecule A treated with sodium hydroxide solution and 4-chloroquinazoline molecule B are heated in acetonitrile to undergo etherification reaction, and the obtained intermediate product C is then heated with different benzyl chlorides or ethyl bromides in acetonitrile to obtain the novel coumarin derivative I containing a quinazoline unit. The synthetic route is as follows:

3. Use of the novel coumarin derivative containing quinazoline unit as claimed in claim 1 in anti-tumor cell aspects.

4. The use according to claim 3, characterized in that The tumor cells are pancreatic cancer cells, gastric cancer cells and breast cancer cells.

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