CN111004215B - 2, 4-substituted pyrimidine derivatives, preparation method thereof and application thereof in preparing antitumor drugs - Google Patents

Abstract

The invention belongs to the field of medical compounds, and particularly relates to 2, 4-substituted pyrimidine derivatives, a preparation method thereof and application thereof in preparing antitumor drugs. The derivative has a structure shown in a general formula I, and when the compound is applied as an anti-tumor medicament, the compound has stronger anti-tumor activity and smaller toxic and side effects, is easier to use as the anti-tumor medicament, and particularly has excellent activity on non-small cell lung cancer A549, colorectal cancer cell HCT-116, liver cancer cell HepG2 and the like.

Description

2,4-Substituted pyrimidine derivatives and preparation method thereof and application in preparation of antitumor drugs

technical field

The invention belongs to the field of medicinal compounds, in particular to a class of 2,4-substituted pyrimidine derivatives, a preparation method thereof, and an application in the preparation of antitumor drugs.

Background technique

Cancer is a malignant tumor originating from epithelial tissue, characterized by rapid proliferation and metastasis of cells, and the mortality rate ranks first among all diseases. In recent decades, with the change of human living habits and living environment, the incidence of cancer has been showing an upward trend. According to the World Health Statistics Report 2018 released by the World Health Organization, about 40 million people worldwide die from non-communicable diseases every year, of which 8.8 million die from cancer, accounting for 22% of the death toll. There are 4.29 million new cancer cases in China every year, accounting for 20% of the global new cancer cases, and 2.81 million deaths. Cancer prevention and treatment has become one of the most important public health issues in our country.

At present, the clinical methods for the treatment of malignant tumors mainly include radiotherapy, surgery and chemotherapy. With the continuous development of tumor molecular biology technology and the further understanding of tumor pathogenesis, a variety of molecular targeted therapy drugs have been developed. Molecular targeted therapy refers to the use of specific drugs or inhibitors to target possible carcinogenic sites, such as cell signaling pathways, cytokines and receptors, and tumor angiogenesis, to suppress them at the molecular level and inhibit tumor cells. grow. Molecular targeted therapy for tumors is highly selective. Drugs or inhibitors will bind to the corresponding oncogenic sites to play a role in the body, causing specific apoptosis of tumor cells without affecting other normal tissue cells. Angiogenesis is a key factor in tumor growth, which not only delivers nutrients for tumor growth, but also plays an important role in tumor cell growth and metastasis. Vascular endothelial growth factor receptor VEGFR-2 is mainly distributed in vascular endothelial cells and plays an important role in the process of angiogenesis. In view of the important role of VEGFR-2 in angiogenesis, the research on antitumor drugs targeting VEGFR-2 has received more and more attention, and a variety of VEGFR-2 inhibitors have been reported. In short, with the continuous development of molecular biology, cancer treatment has entered the era of molecular targeted therapy, and further research and development of new anti-tumor drugs with strong targeting, high efficiency and low toxicity has become one of the important directions of current drug research.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a class of 2,4-substituted pyrimidine derivatives and their preparation method and application in the preparation of antitumor drugs. Such compounds are novel VEGFR-2 tyrosine kinase inhibitors, which can inhibit VEGFR in vitro -2 overexpressed tumor cells showed good inhibitory activity.

The present invention adopts the following technical scheme: the 2,4-substituted pyrimidine derivatives have the structure of general formula I.

The preparation method of 2,4-substituted pyrimidine derivatives with the structure of general formula I comprises the following steps:

Step 1: 2-(4-nitrostyryl) pyridine (3) adopts the following steps for each preparation of one unit of 2.04 g: 10 mmol 2-methylpyridine (1), 10 mmol 4-nitrobenzaldehyde (2) Mix 20mmol of acetic anhydride and 2mmol of acetic acid into a single-necked flask, connect to an anhydrous calcium chloride drying tube, heat to vigorous reflux, continue reflux reaction for about 24h, TLC monitoring reaction is completed, concentrated under reduced pressure, the residue is dissolved in 30mL of dichloromethane , the reaction solution was washed successively with 20% aqueous sodium bicarbonate solution and distilled water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from ethanol to obtain 2.04 g of a yellow solid with a yield of 90%;

Step 2: 1.53 g per unit of 2-(4-aminostyryl)pyridine (4) was prepared by the following steps: 9 mmol of 2-(4-nitrostyryl)pyridine (3) was dissolved in 20 mL of ethanol , add 20 mL of 4mol/L ammonium chloride solution, then add 40 mmol of iron powder, heat to 50 ° C, TLC monitoring the completion of the reaction, filter, concentrate the filtrate, repeatedly extract with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure. , recrystallized from ethanol to obtain 1.53 g of a yellow solid with a yield of 86%;

Step 3: 1.73g of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine (5) was prepared per unit by the following steps: Styryl) pyridine (4) and 7mmol of 2,4-dichloropyrimidine were added to the single-necked flask, then 14mmol of triethylamine and 30mL of ethanol were added, heated to reflux, continued reflux reaction for about 4h, TLC monitored the completion of the reaction, and concentrated under reduced pressure , add 10 mL of ethyl acetate to make slurry, filter, rinse with distilled water, repeat this operation twice to obtain 1.73 g of brown solid with a yield of 80%;

Step 4: 570 mg per unit of solid, 2,4-substituted pyrimidine derivatives (I) were prepared as follows: 2 mmol 2-chloro-4-(4-(2-(2-pyridyl)vinyl)aniline base) pyrimidine (5) and 2.4 mmol of amine compounds were dissolved in 20 mL of ethanol, and the reaction was carried out under microwave conditions at 120 ° C for about 20 min. The reaction was monitored by TLC, concentrated under reduced pressure, diluted with 20 mL of ethyl acetate, and the reaction solution was saturated brine. Washed, dried over anhydrous sodium sulfate, filtered, and recrystallized from ethyl acetate/petroleum ether to obtain 570 mg of a brown solid with a yield of 78%.

Further: R in the general formula I is selected from unsubstituted aryl, substituted aryl, unsubstituted benzyl, substituted benzyl, and alkyl. The unsubstituted aryl group is phenyl. The substituted aryl group is a phenyl group substituted by a group selected from the group consisting of halogen and alkoxy. The unsubstituted benzyl group is benzyl. The substituted benzyl group is a benzyl group substituted by the following groups, including: alkoxy group and halogen; the alkyl group is selected from cyclopropyl group and cyclohexyl group.

Further application of the 2,4-substituted pyrimidine derivatives having the structure of general formula I in the preparation of antitumor drugs. The anti-tumor drug is an anti-tumor drug suitable for liver cancer, kidney cancer, lung cancer, thyroid cancer and colon cancer.

Beneficial effects of the present invention: The inhibitory effect of the above compounds on non-small cell lung cancer A549 and liver cancer cells HepG2 was determined by the CCK-8 method, and the results showed that the above compounds had a better inhibitory rate on tumor cells, and the inhibitory activity of some compounds was higher than that of the positive control. The drug Sorafenib is better and provides an experimental basis for the research and development of new anti-tumor drugs.

Description of drawings

Figure 1: Diagram of the preparation process of 2,4-substituted pyrimidine derivatives;

In the figure: 1, 2-methylpyridine; 2, 4-nitrobenzaldehyde; 3, 2-(4-nitrostyryl) pyridine; 4, 2-(4-aminostyryl) pyridine; 5 , 2-chloro-4-(4-(2-(2-pyridyl) vinyl) anilino) pyrimidine; I, 2,4-substituted pyrimidine derivatives.

Detailed ways

In order to understand the specific content of the present invention more clearly, the present invention will be further described below with reference to the examples, but the present invention is not limited to the following examples.

Example 1

The preparation method of 2-anilino-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine Ⅰ-1:

Step 1: Preparation of 2-(4-nitrostyryl)pyridine 3: 2.04g per unit prepared,

2-picoline 1 (0.93g, 10mmol), 4-nitrobenzaldehyde 2 (1.51g, 10mmol) mixed acetic anhydride (2.04g, 20mmol) and acetic acid (0.12g, 2mmol) were added to the single-neck flask, and then Put into anhydrous calcium chloride drying tube, heat to vigorous reflux, continue reflux reaction for about 24h, TLC monitoring reaction is completed, concentrated under reduced pressure, the residue is dissolved in dichloromethane (30mL), the reaction solution is successively added with 20% aqueous sodium bicarbonate solution (30 mL) and distilled water (20 mL×2), washed with distilled water (20 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and recrystallized from ethanol to obtain 2.04 g of a yellow solid with a yield of 90%.

Preparation of step 2 2-(4-aminostyryl)pyridine 4: 1.53g per unit prepared,

Dissolve 2-(4-nitrostyryl)pyridine 3 (2.04g, 9mmol) in ethanol (20mL), add 4mol/L ammonium chloride solution (20mL), then add iron powder (2.24g, 40mmol) ), heated to 50°C, TLC monitored the completion of the reaction, filtered, concentrated the filtrate, repeatedly extracted with ethyl acetate (20 mL×3), dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from ethanol to obtain 1.53 g of a yellow solid, Yield 86%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 8.48(d,1H), 7.70(t,1H), 7.49(d,1H), 7.42(d,1H), 7.33(d,2H), 7.14( dd,1H),6.94(d,1H),6.59(d,2H),5.42(s,2H).

Step 3 Preparation of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5: 2-(4-aminostyryl)pyridine was prepared for each unit of 1.73g. 4 (1.37g, 7mmol) and 2,4-dichloropyrimidine (1.04g, 7mmol) were added to the single-necked flask, then triethylamine (1.42g, 14mmol) and ethanol (30mL) were added, heated to reflux, and the reflux reaction was continued. After about 4 h, the reaction was monitored by TLC, concentrated under reduced pressure, added ethyl acetate (10 mL) to make slurry, filtered, rinsed with distilled water, and repeated this operation twice to obtain 1.73 g of brown solid with a yield of 80%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 10.17(s,1H), 8.56(d,1H), 8.19(d,1H), 7.78-7.74(m,1H), 7.67-7.63(m,5H) ),7.51(d,1H),7.26-7.21(m,2H),6.80(d,1H).

Step 4: Preparation of 2-anilino-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-1: 570 mg per unit of solid prepared,

2-Chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5 (618 mg, 2 mmol) and aniline (224 mg, 2.4 mmol) were dissolved in ethanol (20 mL) at 120 The reaction was carried out under microwave conditions for about 20 min, and the reaction was monitored by TLC, concentrated under reduced pressure, diluted with ethyl acetate (20 mL), washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, ethyl acetate/petroleum Recrystallization from ether gave 570 mg of a brown solid in 78% yield.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 9.52(s, 1H), 9.22(s, 1H), 8.56(d, 1H), 8.05(d, 1H), 7.81-7.75(m, 5H), 7.68-7.60(m, 3H), 7.53(d, 1H), 7.28(t, 2H), 7.24-7.19(m, 2H), 6.94(t, 1H), 6.27(d, 1H).

Example 2

The preparation method of 2-(4-methoxyanilino)-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine Ⅰ-2:

The preparation of step one 2-(4-nitrostyryl) pyridine 3:

Synthesize 2-(4-nitrostyryl)pyridine according to step 1 of Example 1.

The preparation of step two 2-(4-aminostyryl) pyridine 4:

Synthesize 2-(4-aminostyryl)pyridine according to step 2 of Example 1.

Step 3 Preparation of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5:

2-Chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine was synthesized according to step 3 of Example 1.

Step 4 Preparation of 2-(4-methoxyanilino)-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-2:

According to step 4 of Example 1, aniline (224 mg, 2.4 mmol) was replaced with 4-methoxyaniline (296 mg, 2.4 mmol) to obtain 593 mg of white solid with a yield of 75%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 9.47(s, 1H), 9.03(s, 1H), 8.56(d, 1H), 8.01(d, 1H), 7.80-7.74(m, 3H), 7.68-7.51(m, 6H), 7.24-7.18(m, 2H), 6.89(d, 2H), 6.21(d, 1H), 3.75(s, 3H).

Example 3

The preparation method of 2-(4-chloroanilino)-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine Ⅰ-3:

The preparation of step one 2-(4-nitrostyryl) pyridine 3:

Synthesize 2-(4-nitrostyryl)pyridine according to step 1 of Example 1.

The preparation of step two 2-(4-aminostyryl) pyridine 4:

Synthesize 2-(4-aminostyryl)pyridine according to step 2 of Example 1.

Step 3 Preparation of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5:

2-Chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine was synthesized according to step 3 of Example 1.

Step 4 Preparation of 2-(4-chloroanilino)-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-3:

According to step 4 of Example 1, aniline (224 mg, 2.4 mmol) was replaced with 4-chloroaniline (306 mg, 2.4 mmol) to obtain 664 mg of yellow solid with a yield of 83%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 9.55(s, 1H), 9.37(s, 1H), 8.56(d, 1H), 8.07(d, 1H), 7.83-7.75(m, 5H), 7.69-7.62(m, 3H), 7.53(d, 1H), 7.31(d, 2H), 7.23-7.19(m, 2H), 6.29(d, 1H).

Example 4

The preparation method of 2-benzylamino-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-4:

The preparation of step one 2-(4-nitrostyryl) pyridine 3:

Synthesize 2-(4-nitrostyryl)pyridine according to step 1 of Example 1.

The preparation of step two 2-(4-aminostyryl) pyridine 4:

Synthesize 2-(4-aminostyryl)pyridine according to step 2 of Example 1.

Step 3 Preparation of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5:

2-Chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine was synthesized according to step 3 of Example 1.

Step 4 Preparation of 2-benzylamino-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-4:

According to step 4 of Example 1, aniline (224 mg, 2.4 mmol) was replaced with benzylamine (257 mg, 2.4 mmol) to obtain 615 mg of yellow solid with a yield of 81%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 8.78(s, 1H), 8.54(d, 1H), 8.05(d, 1H), 7.80-7.67(m, 5H), 7.52(d, 1H), 7.26-7.05(m, 9H), 6.18(s, 1H), 4.32(d, 2H).

Example 5

The preparation method of 2-(4-methoxybenzylamino)-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine Ⅰ-5:

The preparation of step one 2-(4-nitrostyryl) pyridine 3:

Synthesize 2-(4-nitrostyryl)pyridine according to step 1 of Example 1.

The preparation of step two 2-(4-aminostyryl) pyridine 4:

Synthesize 2-(4-aminostyryl)pyridine according to step 2 of Example 1.

Step 3 Preparation of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5:

2-Chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine was synthesized according to step 3 of Example 1.

Step 4 Preparation of 2-(4-methoxybenzylamino)-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-5:

According to step 4 of Example 1, aniline (224 mg, 2.4 mmol) was replaced with 4-methoxybenzylamine (329 mg, 2.4 mmol) to obtain 598 mg of yellow solid with a yield of 73%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 8.67(d,1H), 8.54(d,1H), 8.94(d,1H), 7.77-7.67(m,5H), 7.51(d,1H), 7.32-7.17(m, 5H), 6.90-6.72(m, 3H), 6.04(d, 1H), 4.25(d, 2H), 3.72(s, 3H).

Example 6

The preparation method of 2-(4-fluorobenzylamino)-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine Ⅰ-6:

The preparation of step one 2-(4-nitrostyryl) pyridine 3:

Synthesize 2-(4-nitrostyryl)pyridine according to step 1 of Example 1.

The preparation of step two 2-(4-aminostyryl) pyridine 4:

Synthesize 2-(4-aminostyryl)pyridine according to step 2 of Example 1.

Step 3 Preparation of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5:

2-Chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine was synthesized according to step 3 of Example 1.

Step 4 Preparation of 2-(4-fluorobenzylamino)-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-6:

According to step 4 of Example 1, aniline (224 mg, 2.4 mmol) was replaced with 4-fluorobenzylamine (300 mg, 2.4 mmol) to obtain 564 mg of yellow solid with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 8.91(s, 1H), 8.54(d, 1H), 7.99(d, 1H), 7.76-7.62(m, 5H), 7.45(d, 1H), 7.22-6.95(m, 8H), 6.05(d, 1H), 4.24(d, 2H).

Example 7

The preparation method of 2-cyclopropylamino-4-(4-(2-(2-pyridyl) vinyl) anilino) pyrimidine Ⅰ-7:

The preparation of step one 2-(4-nitrostyryl) pyridine 3:

Synthesize 2-(4-nitrostyryl)pyridine according to step 1 of Example 1.

The preparation of step two 2-(4-aminostyryl) pyridine 4:

Synthesize 2-(4-aminostyryl)pyridine according to step 2 of Example 1.

Step 3 Preparation of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5:

2-Chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine was synthesized according to step 3 of Example 1.

Step 4 Preparation of 2-cyclopropylamino-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-7:

According to step 4 of Example 1, aniline (224 mg, 2.4 mmol) was replaced with cyclopropylamine (137 mg, 2.4 mmol) to obtain 494 mg of yellow solid with a yield of 75%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 8.54(d, 1H), 8.37(s, 1H), 8.01(d, 1H), 7.79-7.66(m, 4H), 7.50(d, 1H), 7.31-7.15(m, 5H), 5.98(s, 1H), 2.60(s, 1H), 0.59-0.41(m, 4H).

Example 8

The preparation method of 2-cyclohexylamino-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine Ⅰ-8:

The preparation of step one 2-(4-nitrostyryl) pyridine 3:

Synthesize 2-(4-nitrostyryl)pyridine according to step 1 of Example 1.

The preparation of step two 2-(4-aminostyryl) pyridine 4:

Synthesize 2-(4-aminostyryl)pyridine according to step 2 of Example 1.

Step 3 Preparation of 2-chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine 5:

2-Chloro-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine was synthesized according to step 3 of Example 1.

Step 4 Preparation of 2-cyclohexylamino-4-(4-(2-(2-pyridyl)vinyl)anilino)pyrimidine I-8:

According to Step 4 of Example 1, aniline (224 mg, 2.4 mmol) was replaced with cyclohexylamine (238 mg, 2.4 mmol) to obtain 528 mg of yellow solid with a yield of 71%.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 8.53(d, 1H), 8.30(s, 1H), 7.92(d, 1H), 7.74-7.62(m, 4H), 7.42(d, 1H), 7.21-6.84(m, 5H), 5.88(s, 1H), 3.66(s, 1H), 1.77-1.49(m, 5H), 1.19-1.05(m, 5H).

Table 1 Compound number and corresponding structural formula

Example 9

In vitro tumor cell inhibitory activity test determination of the compounds of the present invention:

A549 (non-small cell lung cancer), HCT-116 (colorectal cancer cells) and HepG2 (liver cancer cells) were used to verify the inhibitory activity of the compounds, and Sorafenib was selected as the control drug. A549, HCT-116 and HepG2 cells were inoculated in 96-well plates respectively, and after culturing in a 37°C incubator for 24 hours, the test compound was added at a concentration of 50 μM, and after culturing for 48 hours, the cells were treated with PBS buffer, and CCK-8 solution was added. Continue to cultivate for 2h, and detect the OD value with a microplate reader. The inhibition rates of different compounds on cell proliferation were calculated, and the specific results are shown in Table 2.

Table 2. In vitro inhibitory activity of compounds on tumor cells

It can be seen from the above Table 2 that the compounds of the present invention show a good inhibitory effect on the proliferation of three tumor cell lines, and the antitumor activity of some compounds is better than that of the positive control drug Sorafenib. Test compounds I-1, I-3, I-7, I-8 have obvious inhibitory effect on the proliferation of non-small cell lung cancer cell A549, and its effect is better than Sorafenib; test compounds I-3, I-6, I-8 has obvious inhibitory effect on the proliferation of colorectal cancer cell HCT-116; the tested compounds I-3, I-5 and I-8 have obvious inhibitory effect on the proliferation of hepatoma cell HepG2. Among them, the test compounds I-3 and I-8 showed a good inhibitory effect on the proliferation of the three tumor cell lines, which was higher than that of the positive control drug Sorafenib.

The embodiments of the present invention have been described in detail above, but the above contents are only preferred embodiments of the present invention, and should not be considered to limit the scope of the present invention. All equivalent changes and improvements made according to the scope of the application of the present invention should still belong to the scope of the patent of the present invention.

Claims (5)

1.2, 4-substituted pyrimidine derivatives, which are characterized in that the derivatives have a structure shown in a general formula I,

(ii) a R is selected from unsubstituted aryl; halogen or alkoxy substituted phenyl; an unsubstituted benzyl group; alkoxy or halogen substituted benzyl; cyclopropyl and cyclohexyl.

2. A process for the preparation of 2, 4-substituted pyrimidine derivatives having the structure of formula i as claimed in claim 1, which comprises the steps of:

the method comprises the following steps: preparation of 2- (4-nitrostyryl) pyridine:

adding 10mmol of 2-methylpyridine, 10mmol of 4-nitrobenzaldehyde, 20mmol of mixed acetic anhydride and 2mmol of acetic acid into a single-neck bottle, connecting an anhydrous calcium chloride drying tube, heating to violently reflux, continuously refluxing for 24 hours, monitoring the reaction by TLC, concentrating under reduced pressure, adding 30mL of dichloromethane into residues for dissolving, washing the reaction solution by 20% sodium bicarbonate aqueous solution and distilled water in sequence, drying by anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and recrystallizing by ethanol to obtain yellow solid;

step two: preparation of 2- (4-aminostyryl) pyridine:

dissolving 9mmol of 2- (4-nitrostyryl) pyridine in 20mL of ethanol, adding 20mL of 4mol/L ammonium chloride solution, adding 40mmol of iron powder, heating to 50 ℃, after TLC monitoring reaction is finished, filtering, concentrating filtrate, repeatedly extracting ethyl acetate, drying organic phase anhydrous sodium sulfate, concentrating under reduced pressure, and recrystallizing ethanol to obtain yellow solid;

step three: preparation of 2-chloro-4- (4- (2- (2-pyridyl) vinyl) anilino) pyrimidine:

adding 7mmol of 2- (4-aminostyryl) pyridine and 7mmol of 2, 4-dichloropyrimidine into a single-mouth bottle, adding 14mmol of triethylamine and 30mL of ethanol, heating to reflux, continuously refluxing for 4 hours, monitoring by TLC (thin layer chromatography), concentrating under reduced pressure, adding 10mL of ethyl acetate, pulping, filtering, eluting with distilled water, and repeating the operation twice to obtain a brown solid;

step four: preparing 2, 4-substituted pyrimidine derivatives:

dissolving 2mmol of 2-chloro-4- (4- (2- (2-pyridyl) vinyl) anilino) pyrimidine and 2.4mmol of R-NH2 in 20mL of ethanol, reacting for 20min under the microwave condition of 120 ℃, monitoring by TLC after the reaction is finished, concentrating under reduced pressure, adding 20mL of ethyl acetate for dilution, washing the reaction liquid with saturated saline, drying with anhydrous sodium sulfate, filtering, and recrystallizing ethyl acetate/petroleum ether to obtain the 2, 4-substituted pyrimidine derivatives as claimed in claim 1, wherein R is defined in claim 1.

3. The 2, 4-substituted pyrimidine derivative according to claim 1, wherein: the unsubstituted aryl group is phenyl.

4. The use of the 2, 4-substituted pyrimidine derivatives as claimed in claim 1 in the preparation of anti-tumor drugs.

5. Use according to claim 4, characterized in that: the anti-tumor medicine is suitable for liver cancer, kidney cancer, lung cancer, thyroid cancer and colorectal cancer.

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