CN107056713A - 4 ((pyrimidine radicals of 4 substituted aryl 2) amino) benzoyl hydrazine derivatives and its preparation method and application - Google Patents

Abstract

4‑((4‑substituted aryl‑2‑pyrimidinyl) amino) benzoylhydrazine derivatives and their preparation methods and applications relate to tumor drugs. Preparation method: prepare intermediate p-guanidine ethyl benzoate nitrate; prepare intermediate 1-(substituted aryl)-3-(dimethylamino)-2-propene-1-ketone; prepare intermediate 4-(( 4-substituted aryl-2-pyrimidinyl) amino) ethyl benzoate; preparation of intermediate 4-((4-substituted aryl-2-pyrimidinyl) amino) benzohydrazide; preparation of 4-((4- Substituted aryl-2-pyrimidinyl) amino) benzohydrazide derivatives. Use of a class of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives in the preparation of medicines for treating or preventing tumor-related diseases. The invention has significant effects of inhibiting tumor cell growth and inducing tumor cell apoptosis, and can be used for preparing medicines for treating or preventing tumor-related diseases.

Description

4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives and their preparation Methods and Applications

technical field

The invention relates to tumor drugs, in particular to 4-((4-substituted aryl-2-pyrimidinyl)amino)benzoylhydrazine derivatives and their preparation methods and applications.

Background technique

Tumor drug therapy began in the 1940s. After 70 years of development, there are currently about 100 anti-tumor drugs in clinical use worldwide. In the 21st century, with the development of modern medicine, the in-depth study of the molecular mechanism of tumors, and the maturity of modern biomedical technology, the research and development of anti-tumor drugs worldwide has achieved fruitful results. According to incomplete statistics, there are more than 450 new anti-tumor drug candidates currently in the clinical research stage in the world, involving more than 2,850 clinical studies, including 223 phase III clinical studies, involving more than 80 new drugs. There are many kinds of anticancer drugs, but there are few ideal tumor drugs, and the existing anticancer drugs more or less have the disadvantages of low bioavailability, high toxicity and side effects. Therefore, designing and synthesizing antitumor drugs with high bioavailability, obvious anticancer activity and low toxicity is still a research hotspot.

Contents of the invention

The first object of the present invention is to provide 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives.

The second object of the present invention is to provide a preparation method of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives.

The third object of the present invention is to provide a class of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives for the preparation of drugs for treating or preventing tumor-related diseases.

The structural formula of the 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivative is:

Among them, R ₁ represents C ₁ ~ C ₄ linear alkyl, C ₅ or C ₆ cycloalkyl, unsubstituted aralkyl, substituted phenyl; R ₂ represents Cl or H; X represents O or S; Y stands for N or C.

The preparation method of the 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivative comprises the following steps:

1) preparation of intermediate p-guanidinobenzoic acid ethyl ester nitrate;

2) Preparation of intermediate 1-(substituted aryl)-3-(dimethylamino)-2-propen-1-one;

3) Preparation of intermediate ethyl 4-((4-substituted aryl-2-pyrimidinyl)amino)benzoate;

4) Preparation of intermediate 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide;

5) Preparation of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives.

In step 1), the specific method for the preparation of the intermediate p-guanidinobenzoic acid ethyl ester nitrate can be: add p-aminobenzoic acid ethyl ester, cyanamide and dehydrated alcohol successively in a dry reaction flask; After adding hydrochloric acid in the state, the temperature was raised to reflux, and the reaction was carried out for 22-24 hours; after the reaction was detected by thin-layer chromatography (TLC), the reaction was stopped; Heat preservation reaction, filter, collect filter cake, dry to obtain white solid product p-guanidinobenzoic acid ethyl nitrate, yield 75%～80%; The described p-aminobenzoic acid ethyl ester, cyanamide, hydrochloric acid, ammonium nitrate The molar ratio may be 1:(2.5-3):(1.2-1.5):(2-2.5).

In step 2), the specific method for preparing the intermediate 1-(substituted aryl)-3-(dimethylamino)-2-propen-1-one can be: add 2- Acetylpyridine (or 3-acetylpyridine, 4-acetylpyridine, 4-chloroacetophenone), N,N-dimethylformamide dimethyl acetal, heated to 110°C, reflux reaction for 18-20h, TLC detection After the reaction, stop the reaction, add ethyl acetate after the reaction solution is concentrated under reduced pressure, stir, filter with suction, collect the filter cake, and dry to obtain the solid product 1-(substituted aryl)-3-(dimethylamino)-2-propene -1-ketone, yield 56%～60%; said 2-acetylpyridine (or 3-acetylpyridine, 4-acetylpyridine, 4-chloroacetophenone), N,N-dimethylformamide dimethyl The molar ratio of acetal can be 1:(1.1～1.2).

In step 3), the specific method for preparing the intermediate 4-((4-substituted aryl-2-pyrimidinyl) amino) ethyl benzoate can be: add p-guanidinobenzene in a dry reaction flask successively Ethyl formate nitrate, 1-(substituted aryl)-3-(dimethylamino)-2-propen-1-one, solid sodium hydroxide, absolute ethanol, heated to reflux, reacted for 18-22h, detected by TLC After the reaction, the reaction was stopped, cooled to room temperature, suction filtered, the filter cake was collected, and dried to obtain the solid product 4-((4-substituted aryl-2-pyrimidinyl)amino)ethyl benzoate, with a yield of 84%～ 90%; The mol ratio of described ethyl p-guanidine benzoate nitrate, 1-(substituted aryl)-3-(dimethylamino)-2-propene-1-one, sodium hydroxide can be 1: (1～1.1): (1.2～1.5).

In step 4), the specific method for preparing the intermediate 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide can be: add 4-((( 4-substituted aryl-2-pyrimidinyl) amino) ethyl benzoate, hydrazine hydrate, absolute ethanol, heated to reflux, reacted for 18-20h, after TLC detected the reaction, stopped the reaction, cooled to room temperature, suction filtered, collected The filter cake is dried to obtain the solid product 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide, with a yield of 66%～70%; the 4-((4-substituted aryl -2-pyrimidinyl) amino) ethyl benzoate and hydrazine hydrate molar ratio can be 1: (18 ~ 20).

In step 5), the specific method for preparing 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives can be: add 4-(( 4-substituted aryl-2-pyrimidinyl) amino) benzohydrazide solid, N,N-dimethylformamide, heat to 100°C, wait until the solid dissolves completely, cool down to 70°C, add isocyanate (can be aliphatic Isocyanate, substituted or unsubstituted phenyl isocyanate, substituted or unsubstituted phenyl thioisocyanate, unsubstituted aralkyl isocyanate, unsubstituted aralkyl thioisocyanate), heat preservation reaction 3 ~ 4h; TLC detection reaction Afterwards, stop the reaction, add water after cooling to room temperature, filter with suction, collect the filter cake, and dry, the obtained crude product is separated by silica gel column chromatography (eluent is dichloromethane:methanol=50:1 by volume) to obtain a solid Product 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives, yield 56%～60%; the 4-((4-substituted aryl-2-pyrimidinyl) The molar ratio of amino)benzohydrazide to isocyanate can be 1: (1～1.1).

Use of the 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives in the preparation of medicines for treating or preventing tumor-related diseases.

The class of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives has a significant effect of inhibiting tumor cell growth and inducing tumor cell apoptosis, and can be used to prepare therapeutic or preventive tumor cell Drugs for related diseases.

A class of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives of the present invention has low synthesis reaction cost, simple and easy-to-control reaction process, and is suitable for industrial production. The compound has significant effects of inhibiting tumor cell growth and inducing tumor cell apoptosis, and can be widely used in the preparation of antitumor drugs.

Description of drawings

Figure 1 is a graph showing the growth inhibitory effect of N-cyclohexyl-2-(4-((4-(4-pyridyl)-2-pyrimidinyl)amino)benzoyl)hydrazine-1-carboxamide on tumor cell HepG2 . In Fig. 1, the abscissa is the action time of the compound (h), and the ordinate is the growth inhibition rate (%). The concentration gradient is set as follows: curve a is 5 μM/L, b is 10 μM/L, and c is 20 μM/L. The time points were 24h, 48h, 72h and 96h.

Figure 2 is a WB detection chart of PARP cleavage in HepG2 cells caused by N-cyclohexyl-2-(4-((4-(4-pyridyl)-2-pyrimidinyl)amino)benzoyl)hydrazine-1-carboxamide . In Figure 2, the concentration gradient of the compound is 5 μM/L, 10 μM/L and 20 μM/L, the corresponding DMSO is added to the control group as a control, and GAPDH is used as an internal reference.

detailed description

In order to facilitate the understanding of the present invention, the present invention will now be further described in conjunction with specific embodiments to further explain the present invention, but this does not constitute any limitation to the present invention.

Embodiment 1: the synthesis of ethyl p-guanidine benzoate nitrate

In a 200mL dry single-neck bottle, first add ethyl p-aminobenzoate (5.0g, 0.030mol), cyanamide (50%w/w, 7.6g, 0.091mol), absolute ethanol (20mL); Concentrated hydrochloric acid (3.8 mL, 0.045 mol) was added dropwise under stirring, and the temperature was raised to reflux after the dropwise addition. After 24 hours of reaction, TLC detected that the reaction was complete, and the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the solvent, then 50 mL of water was added, and then an aqueous solution of ammonium nitrate (4.8 g, 0.061 mol) was added dropwise at 0°C. After the addition was completed, the reaction was incubated for 1 hour, filtered, the filter cake was collected, and dried to obtain a white solid The product was 6.3 g of ethyl guanidine benzoate nitrate, and the yield was 78%.

Example 2: Synthesis of 1-(2-pyridyl)-3-(dimethylamino)-2-propene-1-one

Add 2-acetylpyridine (5.0g, 0.041mol) and N,N-dimethylformamide dimethyl acetal (5.4g, 0.045mol) sequentially into a dry 100mL single-necked bottle, heat to 110°C, and reflux After 18 hours of reaction, TLC detected that the reaction was complete, and the reaction was stopped. After the reaction solution was concentrated under reduced pressure, 5 mL of ethyl acetate was added, stirred at room temperature for 1 h, filtered with suction, the filter cake was collected, and dried to obtain 4.2 g of a yellow-green solid with a yield of 58%. Spectral data: ¹ H NMR (600MHz, DMSO-d ₆ ): 8.55～8.69 (m, 1H), 7.98 (d, J＝7.7Hz, 1H), 7.91 (dt, J＝1.7, 7.66Hz, 1H), 7.80(d,J=12.6Hz,1H),7.50(ddd,J=1.2,4.77,7.52Hz,1H),6.38(d,J=10.6Hz,1H),3.18(s,3H),2.92(s ,3H).

Embodiment 3: Synthesis of ethyl 4-((4-(2-pyridyl)-2-pyrimidinyl) amino)benzoate

Add 1-(2-pyridyl)-3-(dimethylamino)-2-propen-1-one (1.00 g, 0.0056 mol) and ethyl p-guanidinobenzoate nitric acid to a 50 mL dry single-necked bottle successively Salt (1.53g, 0.0056mol), sodium hydroxide solid (0.273g, 0.0068mol), absolute ethanol (10mL), heated to reflux, reacted for 18h, TLC detected that the reaction was complete, stop the reaction. After cooling to room temperature, it was filtered with suction, and the filter cake was collected and dried to obtain 1.52 g of off-white solid with a yield of 84%. Spectral data: ¹ HNMR (600MHz, CDCl ₃ ): 8.73(d, J=4.4Hz, 1H), 8.62(d, J=4.9Hz, 1H), 8.42(d, J=7.7Hz, 1H), 8.07( d, J=8.2 Hz, 2H), 7.89-7.91(m, 1H), 7.87(d, J=5.6Hz, 1H), 7.81(d, J=8.0Hz, 2H), 7.56(br.s., 1H), 7.40～7.45(m, 1H), 4.38(q, J＝7.0Hz, 2H), 1.41(t, J＝6.9Hz, 3H).

Example 4: Synthesis of 4-((4-(2-pyridyl)-2-pyrimidinyl)amino)benzohydrazide

Add 4-((4-(2-pyridyl)-2-pyrimidinyl) amino)ethyl benzoate (1.52g, 0.0047mol), hydrazine hydrate (5.00mL) successively into a 50mL dry single-necked bottle, without Water and ethanol (5 mL), heated to reflux, after 20 h of reaction, TLC detected that the reaction was complete, and the reaction was stopped. After cooling to room temperature, it was filtered with suction, and the filter cake was collected and dried to obtain 1.7 g of a pink solid product. Yield 70%. Spectral data: ¹ H NMR (600MHz, DMSO-d ₆ ): 10.06(br.s., 1H), 9.62(br.s., 1H), 8.77(d, J=2.9Hz, 1H), 8.70(d ,J=4.7Hz,1H),8.43(d,J=7.5Hz,1H),8.07(t,J=7.4Hz,1H),7.93(d,J=8.4Hz,2H),7.84(d,J ＝8.2Hz, 2H), 7.79(d, J＝4.7Hz, 1H), 7.54～7.64(m, 1H), 4.50(br.s., 2H).

Example 5: Preparation of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives: N-tert-butyl-2-(4–((4-(2-pyridyl )-2-pyrimidinyl)amino)benzoyl)hydrazine-1-carboxamide

Add 4-((4-(2-pyridyl)-2-pyrimidinyl)amino)benzohydrazide (0.100g, 0.00032mol) and N,N-dimethylformazide successively into a 50mL dry two-necked flask Amide (5mL) was heated to 100°C. After the solid was completely dissolved, the temperature was lowered to 70°C, tert-butyl isocyanate (0.032g, 0.00035mol) was added, and the reaction was kept for 3h. TLC detects that the reaction is complete, and the reaction is stopped. After cooling to room temperature, add 10 mL of water, filter with suction, collect the filter cake, and dry, the obtained crude product is separated by silica gel column chromatography (eluent is dichloromethane:methanol=50:1, v/v) to obtain a yellow solid product 0.090g, yield 68%. Spectral data: ¹ H NMR (600MHz, DMSO-d ₆ ): 10.10(s, 1H), 9.95(d, J=2.0Hz, 1H), 8.76(d, J=4.0Hz, 1H), 8.71(d, J＝4.9 Hz, 1H), 8.43(d, J＝7.8Hz, 1H), 8.07(dt, J＝1.6, 7.70Hz, 1H), 7.93～7.96(m, 2H), 7.87-7.90 (m, 2H ), 7.80(d, J＝4.9Hz, 1H), 7.58～7.61(m, 2H), 6.08(br.s., 1H), 1.27(s, 9H). ¹³ C NMR (151MHz, DMSO-d ₆ ): 166.3, _163.4 , _160.2 , _160.1 , 157.8, 153.9, 150.2, 144.1, 138.1, _128.7 , 126.3, 125.6, 121.6, 118.2, 109.2, 49.9, 29.6. ⁺ [M+H] ⁺ 406.1986, found 406.1982; calcd for C ₂₁ H ₂₃ N ₇ O ₂ Na ⁺ [M+Na] ⁺ 428.1805, found 428.1802.

Example 6: Preparation of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives: N-phenyl-2-(4–((4-(2-pyridyl) -2-pyrimidinyl)amino)benzoyl)hydrazine-1-thiocarboxamide

Add 4-((4-(2-pyridyl)-2-pyrimidinyl)amino)benzohydrazide (0.100g, 0.00032mol) and N,N-dimethylformazide successively into a 50mL dry two-necked flask Amide (5mL) was heated to 100°C. After the solid was completely dissolved, the temperature was lowered to 70°C, and phenylthioisocyanate (0.044g, 0.00035mol) was added, and the reaction was kept for 3h. TLC detects that the reaction is complete, and the reaction is stopped. After cooling to room temperature, add 10 mL of water, filter with suction, collect the filter cake, and dry, the obtained crude product is separated by silica gel column chromatography (eluent is dichloromethane:methanol=50:1, v/v) to obtain a white solid product 0.070g, yield 50%. Spectral data: ¹ H NMR (600MHz, DMSO-d ₆ ): 10.39(s, 1H), 10.13(s, 1H), 9.80(br.s., 1H), 9.68(s, 1H), 8.76～8.78( m, 1H), 8.72(d, J=4.9Hz, 1H), 8.43(d, J=7.8Hz, 1H), 8.07(dt, J=1.7, 7.7Hz, 1H), 7.98(s, 4H), 7.81(d, J=5.1Hz, 1H), 7.59(ddd, J=1.1, 4.7, 7.5Hz, 1H), 7.46(d, J=1.8Hz, 2H), 7.34(t, J=7.7Hz, 2H ),7.13～7.19(m,1H). ¹³ C NMR(151MHz,DMSO-d ₆ ):166.1,163.4,160.2,160.1,153.9,150.2,144.3,139.8,138.1,129.3,128.4,126.5,126.3,125.5 , 125.4, 121.6, 118.0, 109.3. HRMS(+): calcd for C ₂₃ H ₂₀ N ₇ OS ⁺ [M+H] ⁺ 442.1445, found 442.1444, calcd for C ₂₃ H ₁₉ N ₇ OSNa ⁺ [M+Na ] ⁺ 464.1264, found 464.1265.

Example 7: Preparation of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives: N-(3-chloro-4-methylbenzene

Base)-2-(4–((4-(4-pyridyl)-2-pyrimidinyl)amino)benzoyl)hydrazine-1-carboxamide

Add 4-((4-(4-pyridyl)-2-pyrimidinyl)amino)benzoic hydrazide (0.150g, 0.00048mol), N,N-dimethylformazide successively in a 50mL dry two-necked flask Amide (7mL) was heated to 100°C. After the solid was completely dissolved, the temperature was lowered to 70°C, and 3-chloro-4-methylphenylisocyanate (0.090g, 0.00054mol) was added, and the reaction was kept for 3h. TLC detects that the reaction is complete, and the reaction is stopped. After cooling to room temperature, add 10 mL of water, filter with suction, collect the filter cake, and dry, the obtained crude product is separated by silica gel column chromatography (eluent is dichloromethane:methanol=50:1, v/v) to obtain a yellow solid product 0.120g, yield 51%. Spectral data: ¹ H NMR (600MHz, DMSO-d ₆ ): 10.18(s,1H), 10.15(s,1H), 8.97(br.s.,1H), 8.81(br.s.,2H), 8.73 (d,J=5.1Hz,1H),8.23(br.s.,1H),8.12(d,J=5.8Hz,2H),7.95～7.98(m,2H),7.91～7.94(m,2H) ,7.68(d,J=1.6Hz,1H),7.62(d,J=4.9Hz,1H),7.29(br.s.,1H),7.22(d,J=8.2Hz,1H),2.25(s ,3H). ¹³ C NMR (151MHz, DMSO-d ₆ ): 166.7, 162.0, 160.5, 160.4, 151.0, 144.3, 144.1, 139.4, 133.4, 131.5, 128.9, 128.7, 125.6, 121.5, 118.3, 109.8, 19. HRMS(+): calcd for C ₂₄ H ₂₁ ClN ₇ O ₂ ⁺ [M+H] ⁺ 474.1440, found 474.1440; calcd for C ₂₄ H ₂₀ ClN ₇ O ₂ Na ⁺ [M+Na] ⁺ 496.1259, found 496.1259.

Example 8: Preparation of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives: N-cyclohexyl-2-(4–((4-(4-pyridyl) -2-pyrimidinyl)amino)benzoyl)hydrazine-1-carboxamide

Add 4-((4-(4-pyridyl)-2-pyrimidinyl)amino)benzohydrazide (0.100g, 0.00033mol) and N,N-dimethylformazide successively into a 50mL dry double-necked flask Amide (5mL) was heated to 100°C. After the solid was completely dissolved, the temperature was lowered to 70°C, 3-chloro-4-methylphenylisocyanate (0.045g, 0.00036mol) was added, and the reaction was kept for 3h. TLC detects that the reaction is complete, and the reaction is stopped. After cooling to room temperature, add 10 mL of water, filter with suction, collect the filter cake, and dry, the obtained crude product is separated by silica gel column chromatography (eluent is dichloromethane:methanol=50:1, v/v) to obtain a white solid product 0.070g, yield 50%. Spectral data: 10.18(s, 1H), 10.15(s, 1H), 8.97(br.s., 1H), 8.81(br.s., 2H), 8.73(d, J=5.1Hz, 1H), 8.23 (br. s., 1H), 8.12(d, J＝5.8Hz, 2H), 7.95～7.98(m, 2H), 7.91～7.94(m, 2H), 7.68(d, J＝1.6Hz, 1H) , 7.62(d, J=4.9Hz, 1H), 7.29(br.s., 1H), 7.22(d, J=8.2Hz, 1H), 2.25(s, 3H). ¹³ C NMR (151 MHz, DMSO -d ₆ ):166.4, 162.0, 160.4, 158.2, 151.1, 144.2, 143.9, 128.8, 125.7, 121.4, 118.3, 109.8, 48.6, 33.5, 25.7, 25.1.HRMS(+): calcd for C ₂₃ H ₂₆ N ₇ O ₂ ⁺ [M+H] ⁺ 432.2142, found 432.2141; calcd for C ₂₃ H ₂₅ N ₇ O ₂ Na ⁺ [M+Na] ⁺ 454.1962, found 454.1960.

Example 9: Preparation of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives: N-butyl-2-(4-((4-(4-pyridyl) -2-pyrimidinyl)amino)benzoyl)hydrazine-1-carboxamide

Add 4-((4-(4-pyridyl)-2-pyrimidinyl)amino)benzohydrazide (0.100g, 0.00033mol) and N,N-dimethylformazide successively into a 50mL dry double-necked flask Amide (5mL) was heated to 100°C. After the solid was completely dissolved, the temperature was lowered to 70°C, butyl isocyanate (0.035g, 0.00036mol) was added, and the reaction was kept for 3h. TLC detects that the reaction is complete, and the reaction is stopped. After cooling to room temperature, add 10 mL of water, filter with suction, collect the filter cake, and dry, the obtained crude product is separated by silica gel column chromatography (eluent is dichloromethane:methanol=50:1, v/v) to obtain a light yellow solid Product 0.080g, yield 60%. Spectral data: ¹ H NMR (600MHz, DMSO-d ₆ ):10.16(s,1H),9.96(s,1H),8.80～8.83(m,2H),8.73(d,J＝5.1Hz,1H), 8.12～8.14(m,2H),7.93～7.95(m,2H),7.89～7.92(m,2H),7.74(s,1H),7.62(d,J＝5.1Hz,1H), 6.45(br. s.,1H),3.03(q,J=6.7Hz,2H),1.38(quin,J=7.2Hz,2H),1.28(sxt,J=7.3Hz,2H), 0.87(t,J=7.3Hz ,3H). ¹³ C NMR (151MHz, DMSO-d ₆ ): 166.5, 161.9, 160.5, 159.0, 150.9, 144.4, 143.9, 128.9, 125.8, 121.5, 118.3, 109.8, 39.3, 32.5, 19.9, 14.2.HRMS ( +): calcd for C ₂₁ H ₂₄ N ₇ O ₂ ⁺ [M+H] ⁺ 406.1986, found 406.1985; calcd for C ₂₁ H ₂₃ N ₇ O ₂ Na ⁺ [M+Na] ⁺ 428.1805, found 428.1806.

Example 10: Preparation of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives: N-phenethyl-2-(4–((4-(3-pyridyl )-2-pyrimidinyl)amino)benzoyl)hydrazine-1-carboxamide

Add 4-((4-(3-pyridyl)-2-pyrimidinyl)amino)benzohydrazide (0.150g, 0.00049mol) and N,N-dimethylformazide successively into a 50mL dry double-necked flask Amide (7mL) was heated to 100°C. After the solid was completely dissolved, the temperature was lowered to 70°C, and phenylethyl isocyanate (0.079g, 0.00054mol) was added, and the reaction was kept for 3h. TLC detects that the reaction is complete, and the reaction is stopped. After cooling to room temperature, add 10 mL of water, filter with suction, collect the filter cake, and dry, the obtained crude product is separated by silica gel column chromatography (eluent is dichloromethane:methanol=50:1, v/v) to obtain a yellow solid product 0.126g, yield 57%. Spectral data: ¹ H NMR (600MHz, DMSO-d ₆ ): 10.09(s, 1H), 9.99(br.s., 1H), 9.35(d, J＝2.0Hz, 1H), 8.74(dd, J＝ 1.4, 4.7Hz, 1H), 8.66(d, J＝5.1Hz, 1H), 8.52(td, J＝1.9, 7.9Hz, 1H), 7.92～7.95(m, 2H), 7.88～ 7.90(m, 2H ),7.86(s,1H),7.61(dd,J＝4.8,7.9Hz,1H),7.58(d,J＝5.1Hz,1H),7.26～7.30(m, 2H),7.20～7.23(m, 2H), 7.17～7.19(m, 1H), 6.53(br.s., 1H), 3.22～3.29(m, 2H), 2.71(t, J＝7.3 Hz, 2H). ¹³ C NMR (151MHz, DMSO -d ₆ ):166.6,162.2,160.3,160.0,159.0,152.1,148.6,144.1, 140.0,135.0,132.5,129.1,128.9,128.8,126.5,125.6,124.5,118.2,109.3.5,44.4, ): calcd for C ₂₅ H ₂₄ N ₇ O ₂ ⁺ [M+H] ⁺ 454.1986,found454.1981; calcd for C ₂₅ H ₂₃ N ₇ O ₂ Na ⁺ [M+Na] ⁺ 476.1805,found 476.1801.

Example 11: Preparation of 4-((4-substituted aryl-2-pyrimidinyl)amino)benzohydrazide derivatives: N-benzyl-2-(4–((4-(4-chlorophenyl )-2-pyrimidinyl)amino)benzoyl)hydrazine-1-thiocarboxamide

Add 4-((4-(4-chlorophenyl)-2-pyrimidinyl)amino)benzohydrazide (0.100g, 0.00029mol), N,N-dimethyl Formamide (7mL) was heated to 120°C. After the solid was completely dissolved, the temperature was lowered to 70°C, and benzyl thioisocyanate (0.048g, 0.00032mol) was added, and the reaction was kept for 3.5h. TLC detects that the reaction is complete, and the reaction is stopped. After cooling to room temperature, add 10 mL of water, filter with suction, collect the filter cake, and dry, the obtained crude product is separated by silica gel column chromatography (eluent is dichloromethane:methanol=50:1, v/v) to obtain a white solid product 0.110 g, yield 76%. Spectral data: ¹ H NMR (600MHz, DMSO-d ₆ ): 10.26(s, 1H), 10.08(s, 1H), 9.42(s, 1H), 8.64(d, J=5.3Hz, 2H), 8.20- 8.23(m, 2H), 7.90～7.96(m, 4H), 7.63～7.67(m, 2H), 7.52(d, J=5.1Hz, 1H), 7.28～7.34(m, 4H), 7.19～7.24( m, 1H), 4.75 (d, J=6.0Hz, 2H). ¹³ C NMR (151MHz, DMSO-d ₆ ): 166.2, 163.0, 160.3, 159.9, 144.3, 140.0, 136.3, 135.8, 129.5, 129.2, 128.5 ,127.5,127.0,125.3,118.0,109.2,47.2.HRMS(+):calcd for C ₂₅ H ₂₂ ClN ₆ OS ⁺ [M+H] ⁺ 489.1259,found489.1259; calcd for C ₂₅ H ₂₁ ClN ₆ OSNa ⁺ [M+Na] ⁺ 511.1078, found 511.1075.

Claims (10)

1.4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative, it is characterised in that its structural formula is：

Wherein, R₁Represent C₁~C₄Straight chained alkyl, C₅Or C₆Cycloalkyl, unsubstituted aromatic alkyl, substituted-phenyl；R₂Represent Cl or H；X represents O or S；Y represents N or C.

2. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 1, its It is characterised by comprising the following steps：

1) intermediate p -guanidinobenzoic acid ethyl ester nitrate is prepared；

2) intermediate 1- (substituted aryl) -3- (dimethylamino) -2- propylene -1- ketone is prepared；

3) intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate is prepared；

4) intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine is prepared；

5) 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative is prepared.

3. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its Be characterised by step 1) in, it is described prepare intermediate p -guanidinobenzoic acid ethyl ester nitrate specific method be：Dry Ethylaminobenzoate, cyanamide and absolute ethyl alcohol are sequentially added in reaction bulb；Add after hydrochloric acid, be warming up under stirring Backflow, reacts 22~24h；After thin-layer chromatography detection reaction, stop reaction；Reaction solution is concentrated under reduced pressure except water is added after solvent, 0 DEG C plus ammonium nitrate the aqueous solution, insulation reaction after addition, filtering, collect filter cake, dry white solid product to guanidine radicals benzene first Acetoacetic ester nitrate；The ethylaminobenzoate, cyanamide, hydrochloric acid, ammonium nitrate mol ratio for 1 ︰ (2.5~3) ︰ (1.2~ 1.5) ︰ (2~2.5).

4. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its It is characterised by step 2) in, it is described to prepare the specific of intermediate 1- (substituted aryl) -3- (dimethylamino) -2- propylene -1- ketone Method is：2- acetylpyridines and DMF dimethylacetal, or 3- second are sequentially added in dry reaction bulb Acyl pyridine and DMF dimethylacetal, or 4- acetylpyridines and DMF dimethylacetal, Or 4- chloro-acetophenones and DMF dimethylacetal, it is heated to 110 DEG C, back flow reaction 18~20h, TLC detection After reaction, stop reaction, reaction solution adds ethyl acetate after being concentrated under reduced pressure, stirring, suction filtration collects filter cake, dries to obtain solid product 1- (substituted aryl) -3- (dimethylamino) -2- propylene -1- ketone；The 2- acetylpyridines and N,N-dimethylformamide dimethyl Acetal, or 3- acetylpyridines and DMF dimethylacetal, or 4- acetylpyridines and DMF Dimethylacetal, or the mol ratio of 4- chloro-acetophenones and DMF dimethylacetal is 1 ︰ (1.1~1.2).

5. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its It is characterised by step 3) in, the tool for preparing intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate Body method is：P -guanidinobenzoic acid ethyl ester nitrate, 1- (substituted aryl) -3- (diformazans are sequentially added in dry reaction bulb Amino) -2- propylene -1- ketone, sodium hydrate solid, absolute ethyl alcohol, be heated to backflow, react 18~22h, TLC detection reaction after, Stop reaction, be cooled to suction filtration after room temperature, collect filter cake, drying obtains solid product 4- ((4- substituted aryl -2- pyrimidine radicals) ammonia Base) ethyl benzoate；It is described state p -guanidinobenzoic acid ethyl ester nitrate, 1- (substituted aryl) -3- (dimethylamino) -2- propylene - 1- ketone, the mol ratio of sodium hydroxide are 1 ︰ (1~1.1) ︰ (1.2~1.5).

6. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its It is characterised by step 4) in, it is described to prepare the specific of intermediate 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine Method is：4- ((4- substituted aryl -2- pyrimidine radicals) amino) ethyl benzoate, hydration are sequentially added in dry reaction bulb Hydrazine, absolute ethyl alcohol, are heated to backflow, react 18~20h, after TLC detection reactions, stop reaction, be cooled to suction filtration after room temperature, receive Collect filter cake, drying obtains solid product 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine；4- ((the 4- substitution virtues Base -2- pyrimidine radicals) amino) mol ratio of ethyl benzoate and hydrazine hydrate is 1 ︰ (18~20).

7. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its It is characterised by step 5) in, it is described to prepare the specific of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative Method is：4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine solid, N, N- are sequentially added in dry reaction bulb Dimethylformamide, is heated to 100 DEG C, treats that solid dissolving completely, is cooled to 70 DEG C, and it (can be fatty isocyanide to add isocyanates Acid esters, substituted or unsubstituted phenyl isocyanate, substituted or unsubstituted phenyl isocyanates, unsubstituted fragrant alkane Based isocyanate, unsubstituted aromatic alkyl isothiocyanic acid ester), 3~4h of insulation reaction；After TLC detection reactions, stop anti- Should, it is cooled to after room temperature and adds water, suction filtration collects filter cake, dries, obtained crude product is through the isolated solid product of silica gel column chromatography 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative；The 4- ((4- substituted aryl -2- pyrimidine radicals) amino) Benzoyl hydrazine, the mol ratio of isocyanates are 1 ︰ (1~1.1).

8. the preparation method of 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative as claimed in claim 2, its It is characterised by step 5) in, the eluant, eluent is by volume the ︰ 1 of Er Lv Jia Wan ︰ methanol=50.

9. a class 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative, which is used to prepare, treats or prevents tumour phase Purposes in the medicine of related disorders.

10. a class 4- ((4- substituted aryl -2- pyrimidine radicals) amino) benzoyl hydrazine derivative has significant suppression tumour cell Growth and the effect of inducing apoptosis of tumour cell, the medicine of tumor-related illness is treated or prevented for preparing.