Substituted pyrimidine compound as well as preparation method and application thereof

Abstract

The invention relates to a substituted pyrimidine compound and a preparation method and application thereof, the substituted pyrimidine compound has the following structural formula: # imgabs0 #, in the formula, R1 is one of hydrogen, methyl, ethyl, methoxyl, fluorine or chlorine; r2 is one of hydrogen, chlorine or methyl; r3 is hydrogen, ethyl, phenyl, benzyl, p-bromobenzyl or p-chlorobenzyl; the preparation method comprises the following steps: mixing azacycloalkane or a derivative thereof, isonitrile, alkali, a catalyst and a ligand in a reaction solvent, and reacting. Compared with the prior art, the invention provides the method for obtaining the 4, 5-Di-or 4, 5, 6-trisubstituted pyrimidine compound through the cascade 1, 3-dipole [3 + 2] cyclization / ring-opening / elimination reaction of the synthesized Cu (II) catalyzed 2H-azidene and 1-isocyano methylsulfonyl-4-methyl benzene or the derivative thereof, the diversified functional molecules with good to excellent yield can be obtained, and the method has the advantages of simple process, convenience in operation, low cost and the like. More selectivity is provided for synthesis of pyrimidine compounds, and the preparation method is simple and has a relatively good industrial application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemistry, and relates to a substituted pyrimidine compound, a preparation method and application thereof, and in particular to a 4,5-Di- or 4,5,6-trisubstituted pyrimidine compound, a preparation method for synthesizing a Cu(II)-catalyzed cascade 1,3-dipolar [3+2] cyclization / ring-opening / elimination reaction of 2H-azide and 1-isocyanatomethylsulfonyl-4-methylbenzene or a derivative thereof, and application thereof in medicine. Background Art

[0002] Nitrogen-containing heterocycles are one of the important core structural motifs in organic chemistry. Among them, pyrimidine compounds are often found in various natural products, bioactive molecules and functional materials, representing an important and valuable family of nitrogen-containing heterocycles. Many pyrimidine-containing compounds have been widely used in clinical medicine. Therefore, due to the unique and huge applications of pyrimidine-containing molecules, synthetic chemists have been working hard to explore new and effective synthetic strategies for constructing pyrimidine skeletons.

[0003] Since Pinner developed the first synthetic method for pyrimidines based on the condensation of amidines with 1,3-diketone rings, various methods involving the condensation of 1,3-dicarbonyl compounds or their synthetic equivalents with amidine rings to form pyrimidine rings have been reported. In addition, many protocols for constructing pyrimidine scaffolds using carbonyls or their derivatives as substrates or involving amidines and non-carbonyls as substrates have also been developed. However, many serious limitations, including high temperatures, long reaction times, relatively inaccessible catalysts, harsh reaction conditions, and substrate specificity, have hampered the further development of these protocols in the above literature. In order to expand the scope of substrates for the construction of pyrimidine scaffolds, numerous non-carbonyl or non-amidine synthetic strategies have been explored.

[0004] 2H-nitrogen heterocycles are the smallest strained nitrogen-containing three-membered rings and can be used as synthetically useful synthons in organic synthesis due to their inherent reactivity. Over the past few decades, these outstanding organic chemists have taken advantage of their inherent structural features to construct various nitrogen heterocycles such as indoles, pyrroles, pyridines, pyrazines, oxazoles, and imidazoles from 2H-nitrogen heterocycles through ring-opening reactions under certain conditions. Only recently, the use of pyrimidine drugs using 2H-nitrogen oxides as substrates has been gradually developed.

[0005] Literature analysis found that, except for a few successful reports of producing pyrimidine derivatives without substituents at the 2-position, the vast majority of the above methods demonstrated the synthesis of less or fully substituted pyrimidine derivatives with constant substituents at the 2-position of the skeleton. In 2024, the copper-catalyzed reaction of 2H-azines with α-isocyanates or α-isocyanoacetamides was developed to rapidly prepare only 4,5,6-trisubstituted pyrimidines. The paper reports the structure of this substituted pyrimidine, but the substituents at the 4-position of the pyrimidine skeleton are limited to electron-withdrawing substituents (-COOR, -CONR1R2, and -polyfluoroalkyl), and other types of substituents at this position have not been reported.

[0006] In addition, the above method has the technical problems of complex process and low yield. Summary of the invention

[0007] The purpose of the present invention is to provide a substituted pyrimidine compound and a preparation method and application thereof, which are used to synthesize substituted pyrimidines without a substituent at the 2-position, and to obtain some diversified functional molecules with good to excellent yields, which provides more selectivity for the synthesis of pyrimidine compounds and has the advantages of simple preparation method and convenient post-treatment.

[0008] The purpose of the present invention can be achieved by the following technical solutions:

[0009] The first aspect of the present invention provides a substituted pyrimidine compound, which is a disubstituted pyrimidine compound or a trisubstituted pyrimidine compound, each having the following structural formula:

[0010]

[0011] In the formula, R1 is one of hydrogen, methyl, ethyl, methoxy, fluorine or chlorine; R2 is one of hydrogen, chlorine or methyl; R3 is one of hydrogen, ethyl, phenyl, benzyl, p-bromobenzyl or p-chlorobenzyl.

[0012]

[0013] Furthermore, the disubstituted pyrimidine compound is a 4,5-disubstituted pyrimidine compound.

[0014] Furthermore, the 4,5-disubstituted pyrimidine compound is at least one of 4,5-diphenylpyrimidine (structural formula is shown in Formula 3), 4-phenyl-5-(p-tolyl)pyrimidine, 5-(4-ethylphenyl)-4-phenylpyrimidine, 5-(4-methoxyphenyl)-4-phenylpyrimidine, 5-(4-fluorophenyl)-4-phenylpyrimidine or 4-phenyl-5-(thiophene-2-yl)pyrimidine.

[0015] Furthermore, the tri-substituted pyrimidine compound is a 4,5,6-tri-substituted pyrimidine compound.

[0016] Further, the 4,5,6-trisubstituted pyrimidine compound is 4-ethyl-5,6-diphenylpyrimidine, 4-(4-bromobenzyl)-5,6-diphenylpyrimidine, 4-benzyl-6-phenyl-5-(p-tolyl)pyrimidine, 4-(4-chlorobenzyl)-6-phenyl-5-(p-tolyl)pyrimidine, 4,5,6-triphenylpyrimidine, 5-(4-methoxyphenyl)-4,6-diphenylpyrimidine, 5-(4-chlorophenyl)-4,6-diphenylpyrimidine, 5-(4-fluorophenyl)-4,6-diphenylpyrimidine, 4,5-diphenyl-6-tolylpyrimidine, 5-(4-ethylphenyl)-4-phenyl-6-tolylpyrimidine, 5-(4-methoxyphenyl)-4-phenyl-6-tolylpyrimidine, -(4-methoxyphenyl)-6-phenyl-4-toluenesulfonyl-1,4-dihydropyrimidine, 5-(4-methoxyphenyl)-4,6-diphenyl-4-toluenesulfonyl-1,4-dihydropyrimidine, 4,6-diphenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine, 5-(4-chlorophenyl)-4,6-diphenyl-4-toluenesulfonyl-1,4-dihydropyrimidine, 4-phenyl-5,6-di-p-tolyl-4-toluenesulfonyl-1,4-dihydropyrimidine, 4-ethyl-6-phenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine or at least one of 4-allyl-6-phenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine.

[0017] The second aspect of the present invention provides a method for preparing a substituted pyrimidine compound, comprising: mixing azacycloalkane or a derivative thereof, 1-isocyanatomethylsulfonyl-4-methylbenzene or a derivative thereof, a base, a catalyst and a ligand in a reaction solvent, and reacting.

[0018] Further, the azacycloalkane or its derivative is selected from at least one of 2,3-diphenyl-2H-azine, 3-phenyl-2-p-tolyl-2H-azine, 2-(4-ethylphenyl)-3-phenyl-2H-azine, 2-(4-methoxyphenyl)-3-phenyl-2H-azine, 2-(4-fluorophenyl)-3-phenyl-2H-azine, 3-phenyl-2-thiophen-2-yl-2H-azine, 2-(4-chlorophenyl)-3-phenyl-2H-azine or 2,3-di-p-tolyl-2H-azine and the like.

[0019] Further, the 1-isocyanatomethylsulfonyl-4-methylbenzene or its derivative is selected from at least one of 1-isocyanatomethylsulfonyl-4-methylbenzene, 2-(toluene-4-sulfonyl)-butyronitrile, 3-(4-bromophenyl)-2-(toluene-4-sulfonyl)-propionitrile, 3-phenyl-2-(toluene-4-sulfonyl)propionitrile, 3-(4-chlorophenyl)-2-(toluene-4-sulfonyl)-propionitrile, phenyl-(toluene-4-sulfonyl)-acetonitrile, 1-isocyanatomethylsulfonyl-4-methylbenzene, 1-(isocyanatophenylmethylsulfonyl)-4-methylbenzene, 1-(1-isocyanopropane-1-sulfonyl)-4-methylbenzene and 1-(1-isocyanato-3-ene-1-sulfonyl)-4-methylbenzene.

[0020] Further, the base is selected from at least one of cesium carbonate, triethylamine, potassium hydroxide, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicycloundec-7-ene (DBU);

[0021] The catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous oxide, silver acetate or di(trifluoromethanesulfonyl) cuprous (copper trifluoromethanesulfonate, Cu(OTf)2);

[0022] The ligand is selected from one of L-proline, 1,10-phenanthroline or bipyridine;

[0023] The reaction solvent is selected from at least one of N,N-dimethylformamide, 1,4-dioxane, dichloromethane, tetrahydrofuran (THF) or acetonitrile.

[0024] Furthermore, the molar ratio of aziridine or its derivative, 1-isocyanatomethylsulfonyl-4-methylbenzene or its derivative, base, catalyst and ligand is (1-1.5):1:1:0.1:0.1.

[0025] Furthermore, in the reaction, the reaction temperature is room temperature to 80°C.

[0026] Furthermore, during the reaction, the reaction progress was monitored by thin layer chromatography (TLC).

[0027] Furthermore, after the reaction, the product mixture is diluted with a saturated sodium chloride solution and continued to be stirred; the organic layer is separated and the aqueous layer is extracted with a solvent; the organic layer is then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum; the obtained crude product is purified by silica gel flash column chromatography and concentrated to obtain a pyrimidine compound.

[0028] Furthermore, in the extraction, the organic phase obtained by the extraction separation is washed with saturated brine, and the aqueous layer is washed with dichloromethane.

[0029] Furthermore, in the flash column chromatography, petroleum ether / ethyl acetate (v / v=5:1) is used as the eluent.

[0030] As a preferred technical solution, the preparation method comprises:

[0031] Aziridine or its derivative, 1-isocyanatomethylsulfonyl-4-methylbenzene or its derivative (e.g., 1-isocyanatomethylsulfonyl-4-methylbenzene), a base (e.g., 1,8-diazabicycloundec-7-ene), a catalyst (e.g., cuprous bis(trifluoromethanesulfonyl)) and a ligand (L-proline) are stirred in a reaction solvent (e.g., tetrahydrofuran) at 80°C. After the reaction is complete (monitored by thin layer chromatography), the mixture is diluted with a saturated sodium chloride solution and continued to be stirred. The organic layer is separated and extracted with dichloromethane using the aqueous layer. The combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product is purified by flash column chromatography on silica gel with petroleum ether / ethyl acetate as the eluent and concentrated to give the desired product 3.

[0032]

[0033] In the above reaction equation, R 1 is free of substituents, methyl, ethyl, methoxy, fluorine or chlorine, R 2 is free of substituents, chlorine and methyl, R 3 It is free of substituents, ethyl, phenyl, benzyl, p-bromobenzyl and p-chlorobenzyl.

[0034] As a preferred technical solution, the preparation method comprises:

[0035] Aziridine or its derivative, 1-isocyanatomethylsulfonyl-4-methylbenzene or its derivative (e.g., 1-isocyanatomethylsulfonyl-4-methylbenzene), a base (e.g., 1,8-diazabicycloundec-7-ene), a catalyst (e.g., cuprous iodide), and a ligand (e.g., 1,10-phenanthroline) are stirred in acetonitrile at room temperature for 16 hours. The organic phase is quenched with water and extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent and concentrated to give product 4 or 5.

[0036]

[0037] In the above reaction equation, R 1 is hydrogen or methyl, R 2 is hydrogen, methyl, methoxy, chlorine or ethyl, R 3 It is p-toluenesulfonyl, phenyl, benzyl, p-bromobenzyl or p-chlorobenzyl.

[0038] The third aspect of the present invention provides an application of a substituted pyrimidine compound, including using the substituted pyrimidine compound to prepare a medical anticancer drug or an antiviral drug (such as fluorouracil, lamivudine).

[0039] Compared with the prior art, the present invention has the following characteristics:

[0040] The present invention provides a method for synthesizing a Cu(II)-catalyzed cascade 1,3-dipolar [3+2] cyclization / ring-opening / elimination reaction of 2H-azide and 1-isocyanatomethylsulfonyl-4-methylbenzene or its derivatives: obtaining a 4,5-Di- or 4,5,6-trisubstituted pyrimidine compound, and utilizing the copper-catalyzed reaction of 2H-azide and 1-isocyanatomethylsulfonyl-4-methylbenzene or its derivatives to rapidly prepare a 4,5-di- or 4,5,6-trisubstituted pyrimidine having a non-electron-withdrawing substituent at the 6- or 4-position. As a novel and practical method, the method of the present invention expands the synthesis route of nitrogen-containing heterocyclic compounds, obtains more structurally rich compounds, provides more selectivity for the synthesis of pyrimidine compounds, and the preparation method is simple, with good prospects for industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of 4,5-diphenylpyrimidine prepared in Example 1.

[0042] Figure 2 This is the carbon NMR spectrum of 4,5-diphenylpyrimidine prepared in Example 1.

[0043] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of 4-phenyl-5-(p-tolyl)pyrimidine prepared in Example 2.

[0044] Figure 4 This is the carbon NMR spectrum of 4-phenyl-5-(p-tolyl)pyrimidine prepared in Example 2. DETAILED DESCRIPTION

[0045] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0046] The following are more detailed implementation cases, which further illustrate the technical solutions of the present invention and the technical effects that can be obtained.

[0047] In the following examples, unless otherwise specified, raw materials, reagents or processing techniques are all conventional commercial products or conventional processing techniques in the art.

[0048] Example 1

[0049]

[0050] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0051] In a 10 mL sealed tube, 2,3-diphenyl-2H-azine (0.5 mmol), 1-isocyanatomethylsulfonyl-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl)copper (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 ° C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 4,5-diphenylpyrimidine with a yield of 84%.

[0052] 1 H NMR (400MHz,CDCl3)δ9.29(s,1H),8.77(s,1H),7.48(d,J=7.5Hz,2H),7.41–7.28(m,6H),7.25(dd,J=6.4,3.1Hz,2H). The spectrum is shown in Figure 1 shown.

[0053] 13 C NMR (100MHz, CDCl3)δ163.54,158.24,157.53,137.39,136.21,133.35,129.81,129.54,129.37,128.85,128.27,128.19. The spectrum is shown in Figure 2 shown.

[0054] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 16 H 12 N2H 233.1073; Found 233.1081.

[0055] Example 2

[0056]

[0057] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0058] In a 10 mL sealed tube, 3-phenyl-2-p-tolyl-2H-azacyclohexane (0.5 mmol), 1-isocyanatomethylsulfonyl-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl)copper (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 ° C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 4-phenyl-5-(p-tolyl)pyrimidine with a yield of 80%.

[0059] 1 H NMR (400MHz,CDCl3)δ9.27(s,1H),8.76(s,1H),7.52–7.45(m,2H),7.41–7.28(m,3H),7.19(d,J=7.9Hz,2H),7.13(d,J=8.0Hz,2H),2.40(s,3H). The spectrum is shown in Figure 3 shown.

[0060] 13 C NMR (100MHz, CDCl3) δ163.48, 158.25, 157.31, 138.11, 133.33, 133.18, 129.77, 129.57, 129.46, 129.22, 128.25, 21.26. The spectrum is shown in Figure 4 shown.

[0061] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 17 H 14 N2H 247.1229; Found 247.1237.

[0062] Example 3

[0063]

[0064] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0065] In a 10 mL sealed tube, 2-(4-ethylphenyl)-3-phenyl-2H-azine (0.5 mmol), 1-isocyanatomethylsulfonyl-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl)copper (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 ° C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 5-(4-ethylphenyl)-4-phenylpyrimidine with a yield of 60%.

[0066] 1 H NMR (400MHz, CDCl3) δ9.28 (d, J=4.1Hz, 1H), 8.76 (dd, J=10.0, 4.2Hz, 1H), 7.54–7.46 (m, 1H ),7.45–7.19(m,6H),7.16(dt,J=8.8,4.5Hz,2H),2.69(p,J=7.8Hz,2H),1.37–1.17(m,3H).

[0067] 13 C NMR (100MHz, CDCl3) δ158.21,157.38,157.30,144.44,133.37,129.87,129.48,129.29,128.85,128.36,127.80,27.70,16.06.

[0068] HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 18 H 16 N2Na 283.1205; Found 283.1215.

[0069] Example 4

[0070]

[0071] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0072] In a 10 mL sealed tube, 2-(4-methoxyphenyl)-3-phenyl-2H-azine (0.5 mmol), 1-isocyanatomethylsulfonyl-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl)copper (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 ° C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 5-(4-methoxyphenyl)-4-phenylpyrimidine with a yield of 83%.

[0073] 1 H NMR (400MHz, CDCl3) δ7.58 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8. 8Hz,2H),7.07–6.99(m,2H),6.99–6.92(m,2H),6.68–6.60(m,2H),3.71(s,3H).

[0074] 13 C NMR (100MHz, CDCl3) δ159.93,154.83,142.94,139.86,134.02,130.29,129.94,129.14,127.57,126.97,126.90,113.43,55.19.

[0075] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 17 H 14 N2OH 263.1178; Found 263.1188.

[0076] Example 5

[0077]

[0078] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0079] In a 10 mL sealed tube, 2-(4-fluorophenyl)-3-phenyl-2H-azine (0.5 mmol), 1-isocyanatomethylsulfonyl-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl)copper (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 ° C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 5-(4-fluorophenyl)-4-phenylpyrimidine with a yield of 40%.

[0080] 1H NMR (400MHz, CDCl3) δ9.19 (s, 1H), 8.64 (d, J = 7.7Hz, 1H), 7.39–7.34 (m, 2H), 7.27–7.22 (m, 2H), 7.18–7.08 (m, 4H), 6.98 (t, J = 8.6Hz, 2H).

[0081] 13C NMR (100MHz, CDCl3) δ163.77,161.50,157.82,157.34,137.05,133.81,133.73,132.42,132.04,13 2.00,131.11,131.03,129.74,128.38,116.13,115.92.19FNMR(376MHz, CDCl3)δ-113.15,-115.93.

[0082] HRMS(ESI-FT)m / z:[M+H]+Calcd for C16H11N2FH 251.0979; Found251.0988.

[0083] Example 6

[0084]

[0085] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0086] In a 10 mL sealed tube, 3-phenyl-2-thiophen-2-yl-2H-azacyclohexane (0.5 mmol), 1-isocyanatomethylsulfonyl-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl)copper (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 ° C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 4-phenyl-5-(thiophen-2-yl)pyrimidine with a yield of 53%.

[0087] 1 H NMR (400MHz, CDCl3) δ7.61(ddd,J=9.7,4.4,1.2Hz,2H),7.32–7.26(m,2H),7.24–7.21(m,1H),7.13(d,J=8.0Hz,2H),2.34(s,3H).

[0088] 13 C NMR (100MHz, CDCl3) δ145.18,143.32,135.83,133.77,133.55,130.44,130.37,129.64,129.05,128.75,128.51.

[0089] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 14 H 10 N2SH 239.0565; Found 239.0573.

[0090] Example 7

[0091]

[0092] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0093] In a 10 mL sealed tube, 2,3-diphenyl-2H-azine (0.5 mmol), 2-(toluene-4-sulfonyl)-butyronitrile (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl) cuprous (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 °C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 4-ethyl-5,6-diphenylpyrimidine in a yield of 65%.

[0094] 1 H NMR (400MHz, CDCl3) δ9.23 (s, 1H), 7.38–7.32 (m, 5H), 7.31–7.20 (m, 3H), 7.17–7.14 (m, 2H), 2.72 (q, J = 7.5Hz, 2H), 1.24 (t, J = 7.5Hz, 3H).

[0095] 13 C NMR (100MHz, CDCl3) δ170.85,168.75,156.67,130.02,129.71,128.77,128.59,127.86,127.78,29.49,13.06.

[0096] HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 18 H 16 N2Na 283.1205; Found 283.1215.

[0097] Example 8

[0098]

[0099] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0100] In a 10 mL sealed tube, 2,3-diphenyl-2H-azine (0.5 mmol), 3-(4-bromophenyl)-2-(toluene-4-sulfonyl)-propionitrile (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl) cuprous (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 °C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 4-(4-bromobenzyl)-5,6-diphenylpyrimidine in a yield of 38%.

[0101] 1 H NMR (400MHz, CDCl3) δ8.05–7.99(m,1H),7.56–7.45(m,3H),7.44–7.36(m,3H),7.35–7.28(m,1H),7 .25(s,5H),7.18(dd,J=20.4,7.9Hz,1H),7.04(d,J=8.2Hz,1H),6.97(d,J=8.1Hz,1H),5.29(s,2H).

[0102] 13 C NMR (100MHz, CDCl3) δ166.38,149.86,145.04,137.25,133.91,131.81,131. 64,130.32,130.10,129.27,129.21,128.78,128.59,128.35,127.18,53.44.

[0103] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 23 H 17 N2BrH 401.0575; Found 405.0585.

[0104] Example 9

[0105]

[0106] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0107] In a 10 mL sealed tube, 3-phenyl-2-p-tolyl-2H-azacyclohexane (0.5 mmol), 3-phenyl-2-(toluene-4-sulfonyl) propionitrile (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl) cuprous (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 ° C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 4-benzyl-6-phenyl-5-(p-tolyl) pyrimidine with a yield of 58%.

[0108] 1 H NMR(400MHz,)δ7.95–7.86(m,1H),7.63–7.44(m,2H),7.43–7.16(m,7H),7.15–6 .85(m,3H),6.80–6.60(m,1H),3.86(s,1H),3.72(s,1H),2.42(d,J=14.1Hz,3H).

[0109] 13 C NMR (100MHz, CDCl3) δ155.05,145.11,144.97,138.97,134.00,133.57,130.44, 130.39,129.53,129.00,128.94,128.83,128.30,127.50,126.95,62.94,21.71.

[0110] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 24 H 20 N2H 337.1628; Found 336.1680.

[0111] Example 10

[0112]

[0113] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0114] In a 10 mL sealed tube, 3-phenyl-2-p-tolyl-2H-azacyclohexane (0.5 mmol), 3-(4-chlorophenyl)-2-(toluene-4-sulfonyl)-propionitrile (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl) cuprous (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 °C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and stirring was continued. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 4-(4-chlorobenzyl)-6-phenyl-5-(p-tolyl)pyrimidine in a yield of 53%.

[0115] 1 H NMR (400MHz, CDCl3) δ7.80–7.71(m,1H),7.52(dd,J=18.0,8.1Hz,2H),7.37–7.26(m,3H),7.24(d,J=7.8Hz,1H),7.21–7.14(m ,3H),7.10(d,J=8.2Hz,1H),7.05–6.94(m,3H),6.90(d,J=7.7Hz,2H),2.40(s,1H),2.36(d,J=4.2Hz,2H),2.21–2.16(m,1H).

[0116] 13 C NMR (100MHz, CDCl3) δ155.05,149.84,145.09,144.95,142.94,139.75,138.95,134. 00,133.96,133.60,130.44,130.39,129.10,128.94,128.81,128.72,31.41,21.70.

[0117] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 24 H 19 N2ClH 371.1238; Found 371.1254.

[0118] Embodiment 11

[0119]

[0120] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0121] In a 10 mL sealed tube, 2,3-diphenyl-2H-azine (0.5 mmol), phenyl-(toluene-4-sulfonyl)-acetonitrile (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl) cuprous (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 °C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 4,5,6-triphenylpyrimidine in a yield of 82%.

[0122] 1 H NMR (400MHz, CDCl3) δ9.36 (s, 1H), 7.37–7.32 (m, 4H), 7.31 (d, J = 7.6Hz, 2H), 7.28 (d, J=1.6Hz,1H),7.26(d,J=1.7Hz,1H),7.22–7.16(m,2H),7.00(dt,J=6.6,1.6Hz,2H).

[0123] 13 C NMR (100MHz, CDCl3) δ167.87,157.42,137.21,130.98,129.72,128.87,128.39,127.94,127.56,105.86,93.03.

[0124] HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 22 H 16 N2H 309.1386; Found 309.1395.

[0125] Example 12

[0126]

[0127] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0128] In a 10 mL sealed tube, 2-(4-methoxyphenyl)-3-phenyl-2H-azine (0.5 mmol), phenyl-(toluene-4-sulfonyl)-acetonitrile (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl) cuprous (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 °C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 5-(4-methoxyphenyl)-4,6-diphenylpyrimidine with a yield of 70%.

[0129] 1 H NMR (400MHz, CDCl3) δ8.27(s,1H),7.45–7.33(m,3H),7.33–7.24(m,2H),7.16–7.07(m,2H),7.00(d,J=4.9Hz,6H),6.93(s,1H),2.15(s,3H).

[0130] 13 C NMR (100MHz, CDCl3) δ146.24,144.46,140.06,138.22,130.18,129.53,129.35,129.24,127.73,126.60,53.45.

[0131] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 23 H 18 N2OH 339.1419; Found 339.1525.

[0132] Embodiment 13

[0133]

[0134] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0135] In a 10 mL sealed tube, 2-(4-chlorophenyl)-3-phenyl-2H-azine (0.5 mmol), phenyl-(toluene-4-sulfonyl)-acetonitrile (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl) cuprous (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 °C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 5-(4-chlorophenyl)-4,6-diphenylpyrimidine in a yield of 58%.

[0136] 1 H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 7.21 (qd, J=8.0, 6.0Hz, 10H), 7.09–7.03 (m, 2H), 6.85–6.79 (m, 2H).

[0137] 13 C NMR (100MHz, CDCl3) δ165.44,157.40,137.80,134.57,133.72,132.26,129.63,129.08,128.73,128.13.

[0138] HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 22 H 15 N2ClNa 365.0815; Found365.0821.

[0139] Embodiment 14

[0140]

[0141] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0142] In a 10 mL sealed tube, 2-(4-fluorophenyl)-3-phenyl-2H-azine (0.5 mmol), phenyl-(toluene-4-sulfonyl)-acetonitrile (0.5 mmol), 1,8-diazabicycloundec-7-ene (0.5 mmol), bis(trifluoromethanesulfonyl) cuprous (0.05 mmol) and L-proline (0.05 mmol) were stirred in tetrahydrofuran (2 mL) at 80 °C for 8 hours. After the reaction was completed (monitored by thin layer chromatography (TLC)), the mixture was diluted with saturated sodium chloride solution (5 mL) and continued to stir. The organic layer was separated and extracted with dichloromethane (3×15 mL) with the aqueous layer. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel flash column chromatography and concentrated to give the product 5-(4-fluorophenyl)-4,6-diphenylpyrimidine in a yield of 63%.

[0143] 1 H NMR (400MHz, CDCl3) δ9.26 (s, 1H), 7.25–7.15 (m, 15H).

[0144] 13 C NMR (100MHz, CDCl3) δ165.52,163.39,157.17,137.78,132.66,132.58,130.47,129.65,129.08,128.08,115.75,115.54.

[0145] 19 F NMR (376MHz,CDCl3)δ-113.66.

[0146] HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 22 H 15 N2FNa 349.1111; Found349.1118.

[0147] Embodiment 15

[0148]

[0149] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0150] In a 5 mL round-bottom flask, 2-(4-ethylphenyl)-3-phenyl-2H-azine (0.75 mmol), 1-isocyanatomethylsulfonyl-4-methylbenzene (1-isocyanatomethylsulfonyl-4-methylbenzene or its derivatives, 0.5 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.5 mmol), cuprous iodide (CuI, 0.05 mmol) and 1,10-phenanthroline (1,10-phen, 0.05 mmol) were stirred in acetonitrile (MeCN, 2 mL) at room temperature for 16 hours. The organic phase was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (volume ratio = 5:1) as the eluent, and the product 5-(4-ethylphenyl)-4-phenyl-6-tolylpyrimidine was obtained after concentration with a yield of 76%.

[0151] 1 H NMR(400MHz, CDCl3)δ9.25(s,1H),7.66–7.60(m,2H),7.34–7.19(m,7H),7. 16–7.07(m,4H),2.70(q,J=7.6Hz,2H),2.45(s,3H),1.29(t,J=7.6Hz,3H).

[0152] 13 C NMR (100MHz, CDCl3) δ168.79,164.87,156.41,145.00,144.89,136.92,135.27,131 .38,130.79,129.88,129.59,129.42,129.15,127.96,127.52,28.69,21.74,15.43.

[0153] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 25 H 22 N2O2SH 415.1474; Found415.1480.

[0154] Example 16

[0155]

[0156] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0157] In a 5 mL round-bottom flask, 2-(4-methoxyphenyl)-3-phenyl-2H-azine (0.75 mmol), 1-isocyanatomethylsulfonyl-4-methylbenzene (1-isocyanatomethylsulfonyl-4-methylbenzene or its derivatives, 0.5 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.5 mmol), cuprous iodide (CuI, 0.05 mmol) and 1,10-phenanthroline (1,10-phen, 0.05 mmol) were stirred in acetonitrile (MeCN, 2 mL) at room temperature for 16 hours. The organic phase was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using petroleum ether / ethyl acetate (volume ratio = 5:1) as the eluent, and concentrated to give the product 5-(4-methoxyphenyl)-6-phenyl-4-tosyl-1,4-dihydropyrimidine with a yield of 68%.

[0158] 1 H NMR (400MHz, CDCl3) δ7.96–7.86(m,2H),7.54(d,J=8.1Hz,2H),7.41–7.35(m,3H),7.31(d,J= 13.8Hz, 4H), 7.24 (d, J = 8.0Hz, 2H), 6.94–6.87 (m, 2H), 6.11 (s, 1H), 3.87 (s, 3H), 2.44 (s, 3H).

[0159] 13 C NMR (100MHz, CDCl3) δ134.02,129.93,129.14,129.00,127.57,126.97,126.91,126.14,113.43,55.19,21.56.

[0160] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 24 H 22 N2O3SH 419.1351; Found419.1356.

[0161] Embodiment 17

[0162]

[0163] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0164] In a 5 mL round-bottom flask, 2-(4-methoxyphenyl)-3-phenyl-2H-azine (0.75 mmol), 1-(isocyanophenylmethanesulfonyl)-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.5 mmol), cuprous iodide (CuI, 0.05 mmol) and 1,10-phenanthroline (1,10-phen, 0.05 mmol) were stirred in acetonitrile (MeCN, 2 mL) at room temperature for 16 hours. The organic phase was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (volume ratio = 5:1) as the eluent, and the product 5-(4-methoxyphenyl)-4,6-diphenyl-4-toluenesulfonyl-1,4-dihydropyrimidine was obtained after concentration with a yield of 73%.

[0165] 1 H NMR (400MHz, CDCl3) δ8.11(d,J=8.2Hz,2H),7.37(d,J=8.0Hz,2H),7.32–7.27(m,1H),7.27–7. 23(m,6H),7.23–7.16(m,4H),6.83–6.77(m,2H),6.73–6.67(m,2H),3.75(s,3H),2.45(s,3H).

[0166] 13 C NMR (100MHz, CDCl3) δ167.04,164.96,159.43,145.08,136.98,135.13,132.63, 131.82,130.04,129.99,129.62,129.45,127.97,127.01,114.25,55.21,21.79.

[0167] HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 30 H 26 N2O3SNa 517.1399; Found517.1393.

[0168] Embodiment 18

[0169]

[0170] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0171] In a 5 mL round-bottom flask, 3-phenyl-2-p-tolyl-2H-azacyclohexane (0.75 mmol), 1-(isocyanophenylmethanesulfonyl)-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.5 mmol), cuprous iodide (CuI, 0.05 mmol) and 1,10-phenanthroline (1,10-phen, 0.05 mmol) were stirred in acetonitrile (MeCN, 2 mL) at room temperature for 16 hours. The organic phase was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (volume ratio = 5:1) as the eluent, and the product 4,6-diphenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine was obtained after concentration with a yield of 79%.

[0172] 1 H NMR(600MHz, CDCl3)δ8.09–8.01(m,2H),7.31(d,J=8.0Hz,2H),7.23–7.16(m,8H),7.1 3(t,J=7.7Hz,4H),6.91(d,J=7.9Hz,2H),6.73–6.70(m,2H),2.39(s,3H),2.22(s,3H).

[0173] 13 C NMR (151MHz, CDCl3) δ166.95,165.05,138.08,136.97,135.18,132.90,131.98,130.43,130.05,130.00,129.58,129.42,127.88,21.76,21.27.

[0174] HRMS (ESI-FT) m / z: [M+Na] + Calcd for C 30 H 26 N2O2SNa 501.1450; Found501.1442.

[0175] Embodiment 19

[0176]

[0177] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0178] In a 5 mL round-bottom flask, 2-(4-chlorophenyl)-3-phenyl-2H-azine (0.75 mmol), 1-(isocyanophenylmethanesulfonyl)-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.5 mmol), cuprous iodide (CuI, 0.05 mmol) and 1,10-phenanthroline (1,10-phen, 0.05 mmol) were stirred in acetonitrile (MeCN, 2 mL) at room temperature for 16 hours. The organic phase was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (volume ratio = 5:1) as the eluent, and the product 5-(4-chlorophenyl)-4,6-diphenyl-4-toluenesulfonyl-1,4-dihydropyrimidine was obtained after concentration with a yield of 61%.

[0179] 1 H NMR (400MHz, CDCl3) δ8.14–8.09(m,2H),7.39(d,J=8.1Hz,2H),7.30–7.14(m,12H),6.95–6.89(m,2H),2.46(s,3H).

[0180] 13 C NMR (100MHz, CDCl3) δ167.21,165.63,165.27,145.28,136.56,135.99,135.19,134.85,1 32.73,131.46,130.47,130.06,130.01,129.69,128.98,128.48,128.29,127.99,21.83.

[0181] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 29 H 23 N2O2SClH 497.1085; Found497.1081.

[0182] Embodiment 20

[0183]

[0184] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0185] In a 5 mL round-bottom flask, 2,3-di-p-tolyl-2H-azacyclohexane (0.75 mmol), 1-(isocyanophenylmethanesulfonyl)-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.5 mmol), cuprous iodide (CuI, 0.05 mmol) and 1,10-phenanthroline (1,10-phen, 0.05 mmol) were stirred in acetonitrile (MeCN, 2 mL) at room temperature for 16 hours. The organic phase was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (volume ratio = 5:1) as the eluent, and the product 4-phenyl-5,6-di-p-tolyl-4-toluenesulfonyl-1,4-dihydropyrimidine was obtained after concentration with a yield of 58%.

[0186] 1 H NMR(400MHz,)δ8.12(d,J=8.2Hz,2H),7.41–7.36(m,2H),7.31–7.13(m,8H) ,6.99(dd,J=8.1,3.3Hz,4H),6.83–6.77(m,2H),2.46(s,3H),2.30(s,6H).

[0187] 13 C NMR (100MHz, CDCl3) δ166.92,166.78,164.96,145.00,139.83,138.01,137.08,135.17,134.02,132.66, 132.18,130.40,130.10,130.03,129.99,129.59,129.48,129.32,128.66,127.86,21.78,21.36,21.32.

[0188] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 31 H 28 N2O2SH 491.1787; Found491.1785.

[0189] Embodiment 21

[0190]

[0191] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0192] In a 5 mL round-bottom flask, 3-phenyl-2-p-tolyl-2H-azacyclohexane (0.75 mmol), 1-(1-isocyanopropane-1-sulfonyl)-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.5 mmol), cuprous iodide (CuI, 0.05 mmol) and 1,10-phenanthroline (1,10-phen, 0.05 mmol) were stirred in acetonitrile (MeCN, 2 mL) at room temperature for 16 hours. The organic phase was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (volume ratio = 5:1) as the eluent, and the product 4-ethyl-6-phenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine was obtained after concentration with a yield of 81%.

[0193] 1 H NMR (400MHz, CDCl3) δ8.10(d,J=8.2Hz,2H),7.37(d,J=8.0Hz,2H),7.32–7.24(m,5H),7.19–7.12(m ,4H),6.93(d,J=7.9Hz,2H),2.69(q,J=7.5Hz,2H),2.45(s,3H),2.36(s,4H),1.13(t,J=7.4Hz,3H).

[0194] 13 C NMR (100MHz, CDCl3) δ173.21,164.86,144.97,138.24,136.77,135.17,133.86,132.01,130 .15,129.94,129.59,129.53,129.48,129.41,129.00,127.87,28.92,21.77,21.31,12.64.

[0195] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 26 H 26 N2O2SH 431.1631; Found431.1635.

[0196] Embodiment 22

[0197]

[0198] A substituted pyrimidine compound, the structural formula of which is shown above, and the preparation method comprises:

[0199] In a 5 mL round-bottom flask, 3-phenyl-2-p-tolyl-2H-azacyclohexane (0.75 mmol), 1-(1-isocyano-3-ene-1-sulfonyl)-4-methylbenzene (0.5 mmol), 1,8-diazabicycloundec-7-ene (DBU, 0.5 mmol), cuprous iodide (CuI, 0.05 mmol) and 1,10-phenanthroline (1,10-phen, 0.05 mmol) were stirred in acetonitrile (MeCN, 2 mL) at room temperature for 16 hours. The organic phase was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (volume ratio = 5:1) as the eluent, and the product 4-allyl-6-phenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine was obtained after concentration with a yield of 62%.

[0200] 1 H NMR (400MHz, CDCl3) δ7.79–7.75(m,2H),7.49(d,J=8.3Hz,2H),7.36–7.26(m,4H),7.25(s,3 H),7.19(d,J=7.9Hz,4H),6.09(s,1H),5.29(s,2H),2.40(s,3H),2.36(s,4H),1.25(s,2H).

[0201] 13 C NMR (100MHz, CDCl3) δ145.09,144.95,133.96,133.60,130.44,130.39,129.53, 129.34,129.21,128.99,128.94,128.86,128.81,128.56,127.17,53.44,21.70.

[0202] HRMS (ESI-FT) m / z: [M+H] + Calcd for C 27 H 26 N2O2SH 443.1715; Found443.1726.

[0203] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A substituted pyrimidine compound, characterized in that It is a disubstituted pyrimidine compound or a trisubstituted pyrimidine compound, each having the following structural formula: In the formula, R1 is one of hydrogen, methyl, ethyl, methoxy, fluorine or chlorine; R2 is one of hydrogen, chlorine or methyl; R3 is one of hydrogen, ethyl, phenyl, benzyl, p-bromobenzyl or p-chlorobenzyl.

2. The substituted pyrimidine compound according to claim 1, characterized in that The disubstituted pyrimidine compound is at least one of 4,5-diphenylpyrimidine, 4-phenyl-5-(p-tolyl)pyrimidine, 5-(4-ethylphenyl)-4-phenylpyrimidine, 5-(4-methoxyphenyl)-4-phenylpyrimidine, 5-(4-fluorophenyl)-4-phenylpyrimidine or 4-phenyl-5-(thiophen-2-yl)pyrimidine.

3. The substituted pyrimidine compound according to claim 1, characterized in that The trisubstituted pyrimidine compound is 4-ethyl-5,6-diphenylpyrimidine, 4-(4-bromobenzyl)-5,6-diphenylpyrimidine, 4-benzyl-6-phenyl-5-(p-tolyl)pyrimidine, 4-(4-chlorobenzyl)-6-phenyl-5-(p-tolyl)pyrimidine, 4,5,6-triphenylpyrimidine, 5-(4-methoxyphenyl)-4,6-diphenylpyrimidine, 5-(4-chlorophenyl)-4,6-diphenylpyrimidine, 5-(4-fluorophenyl)-4,6-diphenylpyrimidine, 4,5-diphenyl-6-tolylpyrimidine, 5-(4-ethylphenyl)-4-phenyl-6-tolylpyrimidine, 5-(4-methoxyphenyl)-4-phenyl-6-tolylpyrimidine, 5-(4-methoxyphenyl)-4-phenyl-6-tolylpyrimidine, The invention further comprises at least one of 4-(4-methoxyphenyl)-6-phenyl-4-toluenesulfonyl-1,4-dihydropyrimidine, 5-(4-methoxyphenyl)-4,6-diphenyl-4-toluenesulfonyl-1,4-dihydropyrimidine, 4,6-diphenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine, 5-(4-chlorophenyl)-4,6-diphenyl-4-toluenesulfonyl-1,4-dihydropyrimidine, 4-phenyl-5,6-di-p-tolyl-4-toluenesulfonyl-1,4-dihydropyrimidine, 4-ethyl-6-phenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine and 4-allyl-6-phenyl-5-(p-tolyl)-4-tolyl-1,4-dihydropyrimidine.

4. A method for preparing a substituted pyrimidine compound according to any one of claims 1 to 3, characterized in that: The method comprises: mixing azacycloalkane or its derivative, 1-isocyanatomethylsulfonyl-4-methylbenzene or its derivative, a base, a catalyst and a ligand in a reaction solvent, and reacting.

5. The method for preparing a substituted pyrimidine compound according to claim 4, characterized in that: The azacycloalkane or its derivative is selected from at least one of 2,3-diphenyl-2H-azine, 3-phenyl-2-p-tolyl-2H-azine, 2-(4-ethylphenyl)-3-phenyl-2H-azine, 2-(4-methoxyphenyl)-3-phenyl-2H-azine, 2-(4-fluorophenyl)-3-phenyl-2H-azine, 3-phenyl-2-thiophen-2-yl-2H-azine, 2-(4-chlorophenyl)-3-phenyl-2H-azine or 2,3-di-p-tolyl-2H-azine.

6. The method for preparing a substituted pyrimidine compound according to claim 4, characterized in that: The 1-isocyanatomethylsulfonyl-4-methylbenzene or a derivative thereof is selected from at least one of 1-isocyanatomethylsulfonyl-4-methylbenzene, 2-(toluene-4-sulfonyl)-butyronitrile, 3-(4-bromophenyl)-2-(toluene-4-sulfonyl)-propionitrile, 3-phenyl-2-(toluene-4-sulfonyl)propionitrile, 3-(4-chlorophenyl)-2-(toluene-4-sulfonyl)-propionitrile, phenyl-(toluene-4-sulfonyl)-acetonitrile, 1-isocyanatomethylsulfonyl-4-methylbenzene, 1-(isocyanatophenylmethylsulfonyl)-4-methylbenzene, 1-(1-isocyanopropane-1-sulfonyl)-4-methylbenzene or 1-(1-isocyanato-3-ene-1-sulfonyl)-4-methylbenzene.

7. The method for preparing a substituted pyrimidine compound according to claim 4, characterized in that: The base is selected from at least one of cesium carbonate, triethylamine, potassium hydroxide, 1,4-diazabicyclo[2.2.2]octane or 1,8-diazabicycloundec-7-ene; The catalyst is selected from at least one of cuprous iodide, cuprous bromide, cuprous oxide, silver acetate or copper trifluoromethanesulfonate; The ligand is selected from one of L-proline, 1,10-phenanthroline or bipyridine; The reaction solvent is selected from at least one of N,N-dimethylformamide, 1,4-dioxane, dichloromethane, tetrahydrofuran or acetonitrile.

8. The method for preparing a substituted pyrimidine compound according to claim 4, characterized in that: The molar ratio of the azacycloalkane or its derivative, 1-isocyanatomethylsulfonyl-4-methylbenzene or its derivative, base, catalyst and ligand is (1-1.5):1:1:0.1:0.

1.

9. The method for preparing a substituted pyrimidine compound according to claim 4, characterized in that: In the reaction, the reaction temperature is room temperature to 80°C.

10. Use of a substituted pyrimidine compound according to any one of claims 1 to 3, characterized in that: The substituted pyrimidine compound is used for preparing anticancer drugs or antiviral drugs.

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