A method for synthesizing quinazolinone derivatives

Abstract

The present invention discloses a method for synthesizing quinazolinone derivatives, which belongs to the field of organic chemistry. This method uses aryl urea and aryl sulfonamide as reactants, a commercially available and inexpensive high-valent iodine reagent such as iodobenzene acetate as an oxidant, and hexafluoroisopropanol as a solvent. The reaction is carried out at 20-30°C to obtain quinazolinone derivatives. The method is simple to operate, uses readily available raw materials, has a short reaction process, is highly efficient, and has a reaction yield of up to 76%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and particularly relates to a method for synthesizing a quinazolinone derivative. Background Art

[0002] Dearomatization, a classic strategy for converting planar molecules into three-dimensional molecules, is widely used in modern organic synthesis. Compared to phenolic hydroxyl groups and heteroaromatic compounds (indole, pyridine, pyrrole, and furan), benzene-based non-activated aromatic hydrocarbons have higher resonance stabilization energies, making their dearomatization difficult to achieve. Therefore, efficiently achieving dearomatization of non-activated aromatic hydrocarbons has been a hot topic among organic chemists. Currently, dearomatization of non-activated aromatic hydrocarbons relies primarily on: 1) hydrogenation reduction reactions under high temperature and high pressure; 2) oxidation reactions of non-activated aromatic hydrocarbons mediated by transition metals or light; 3) cycloaddition reactions of non-activated aromatic hydrocarbons as dienes; and 4) direct addition reactions of metal reagents (such as alkyl lithium reagents) to non-activated aromatic hydrocarbons. These dearomatization reactions typically require very demanding reaction conditions, such as high temperature, high pressure, transition metal catalysis, and visible light regulation. Therefore, developing efficient and mild dearomatization reactions for non-activated aromatic hydrocarbons is a significant research challenge.

[0003]

[0004] Traditional non-activated aromatic dearomatization strategy

[0005] In recent years, hypervalent iodine reagents have been widely used in organic synthesis due to their low cost, easy handling, low toxicity, and environmental friendliness. Currently, the dearomatization of aromatic hydrocarbons using hypervalent iodine oxidation strategies relies on the introduction of hydroxyl groups onto the aromatic rings of aromatic compounds, thereby activating the substrates through a ligand exchange process. Consequently, the dearomatization of phenolic hydroxyl compounds promoted by hypervalent iodine has developed rapidly, resulting in the construction of a series of ortho- and para-substituted dearomatization target molecules. Compared to these chemical transformations, the dearomatization of non-activated aromatic hydrocarbons mediated by hypervalent iodine remains largely unexplored. To expand the application of hypervalent iodine reagents in dearomatization chemistry, we developed and designed diarylurea reaction substrates to achieve electrophilic dearomatization of aromatic rings via hypervalent iodine oxidative coupling reactions.

[0006]

[0007] Design of a hypervalent iodine-promoted dearomatization reaction for non-activated aromatics Summary of the Invention

[0008] The present invention aims to provide a method for synthesizing quinazolinone derivatives, which uses a commercially available and inexpensive high-valent iodine reagent to oxidize the aromatic ring of an aryl urea derivative through an electrophilic dearomatization reaction to construct the final quinazolinone derivative in high yield.

[0009] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0010] A method for synthesizing a quinazolinone derivative, the reaction formula of which is shown below:

[0011]

[0012] where R 1 、R 2 、R 3 、R 4 、R 5 Each is independently an electron-withdrawing group or an electron-donating group.

[0013] Furthermore, R 1 is halogen, methyl, isopropyl, tert-butyl, R 2 is methyl, ethyl, R 3 is methyl, ethyl, isopropyl, R 4 is hydrogen, halogen, methyl, ethyl, R 5 For methyl and ethyl.

[0014] Specifically, the aryl urea derivative shown in formula a is used as a reactant, the aryl sulfonamide shown in formula b is used as a nucleophilic reagent, and a high-valent iodine reagent is used as an oxidant. The reaction is carried out in an organic solvent at 20-30° C. to obtain the quinazolinone derivative shown in formula c.

[0015] Furthermore, the aryl urea derivatives are 1-(2',6'-dimethyl-1,1'-diphenyl)-3-methoxy-1-methylurea, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-isopropoxy-1-methylurea, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-ethylurea, 3-ethoxy Any one of 1-(2',4,6'-trimethyl-1,1'-diphenyl)urea, 1-(4-tert-butyl-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, 1-(4-chloro-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, and 3-ethoxy-1-(5-isopropyl-2',6'-dimethyl-1,1'-diphenyl)-1-methylurea.

[0016] Furthermore, the arylsulfonamide is 4-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonamide, 4-fluorobenzenesulfonamide, 3-methylbenzenesulfonamide, N ,4-dimethylbenzenesulfonamide, N -ethyl-4-methylbenzenesulfonamide.

[0017] Furthermore, the hypervalent iodine reagent is one or more of iodobenzene acetate, iodosobenzene, and iodobenzene di(trifluoroacetate). Preferably, the hypervalent iodine reagent is iodobenzene acetate.

[0018] Furthermore, the organic solvent is one or more of hexafluoroisopropanol, trifluoroethanol, and acetonitrile. Preferably, the organic solvent is hexafluoroisopropanol.

[0019] Furthermore, the molar ratio of the reactants is: aryl urea: aryl sulfonamide: iodobenzene acetate = 2: 1: (2.0~4.0).

[0020] Furthermore, the molar concentration of the aryl urea in the organic solvent is 0.1-0.2 mol / L.

[0021] Furthermore, the reaction time is 12-24 hours.

[0022] Furthermore, the method further comprises extracting the organic phase after the reaction is complete, and separating and purifying the organic phase by column chromatography.

[0023] The method of the present invention is simple to operate, has readily available raw materials, short reaction steps, high efficiency, and a reaction yield of up to 76%.

[0024] This method is not only efficient, requires mild conditions, but also exhibits high chemoselectivity. The reaction produces only para-substituted dearomatization products, successfully achieving 1,4-functionalization of non-activated aromatic hydrocarbons and constructing quinazolinone derivatives with two C–N bonds in a single step. Furthermore, the development of oxidation strategies using hypervalent iodine reagents to efficiently synthesize such derivatives is of great significance for the development of pharmaceutical intermediates. DETAILED DESCRIPTION

[0025] The use of chemical synthesis methods to synthesize quinazolinone derivatives as pharmaceutical intermediates is of great significance, but rapid and efficient synthesis using current chemical methods is difficult to achieve. After extensive research, the inventors discovered that using iodobenzene acetate as an oxidant can efficiently convert aryl urea derivatives into quinazolinones.

[0026] The quinazolinone synthesis method of the present invention is shown in the following formula:

[0027]

[0028] where R 1 、R2 、R 3 、R 4 、R 5 The group can be an electron-withdrawing group or an electron-donating group.

[0029] The molar ratio of the reactants is: aryl urea: aryl sulfonamide: iodobenzene acetate = 2: 1: (2.0~4.0).

[0030] Furthermore, the following methods may be selected:

[0031] (1) Place 1-(2',6'-dimethyl-1,1'-diphenyl)-3-methoxy-1-methylurea in a reaction flask, add 4-methylbenzenesulfonamide and iodobenzene acetate as an oxidant, and use hexafluoroisopropanol as a solvent. React for 16 hours to obtain the product in high yield. N -(3'-methoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide product; the molar ratio of the reactants is: 1-(2',6'-dimethyl-1,1'-diphenyl)-3-methoxy-1-methylurea: 4-methylbenzenesulfonamide: iodobenzene acetate = 2:1:(2.0~3.0).

[0032] (2) Place 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea in a reaction flask, add iodobenzene acetate and 4-methylbenzenesulfonamide as oxidants, and hexafluoroisopropanol as the reaction solvent, and react for 15 hours to obtain the product. N -(3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide derivative; the molar ratio of the reactants is: 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea: 4-methylbenzenesulfonamide: iodobenzene acetate = 2:1:(2.5~3.0).

[0033] (3) 1-(2',6'-dimethyl-1,1'-diphenyl)-3-isopropoxy-1-methylurea, 4-methylbenzenesulfonamide and iodobenzene acetate as an oxidant were placed in a reaction flask, hexafluoroisopropanol was added as a solvent, and the reaction was carried out for 20 hours to obtain the product in high yield. N -(3'-isopropoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide product; 1-(2',6'-dimethyl-1,1'-diphenyl)-3-isopropoxy-1-methylurea: 4-methylbenzenesulfonamide: iodobenzene acetate = 2:1:(2.8~3.2).

[0034] (4) 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-ethylurea was placed in a reaction flask, iodobenzene acetate and 4-methylbenzenesulfonamide were added, and hexafluoroisopropanol was used as a solvent. The reaction was continued for 18 hours to obtain the product in high yield. N -(3'-ethoxy-1'-ethyl-2,6-dimethylquinazolinone)-4-methylbenzenesulfonamide derivative; 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-ethylurea: 4-methylbenzenesulfonamide: iodobenzene acetate = 2:1:(2.2~2.5).

[0035] (5) 3-ethoxy-1-methyl-1-(2',4,6'-trimethyl-1,1'-diphenyl)urea, iodobenzene acetate and 4-methylbenzenesulfonamide were placed in a reaction flask, hexafluoroisopropanol was added as solvent, and the reaction was carried out for 12 hours to obtain the product in high yield. N -(3'-ethoxy-1',2,6,7'-tetramethylquinazolinone)-4-methylbenzenesulfonamide target product; 3-ethoxy-1-methyl-1-(2',4,6'-trimethyl-1,1'-diphenyl)urea: 4-methylbenzenesulfonamide: iodobenzene acetate = 2:1:(2.5~3.0).

[0036] (6) 1-(4-tert-butyl-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, iodobenzene acetate as an oxidant, and 4-methylbenzenesulfonamide were placed in a reaction flask, and hexafluoroisopropanol was added as a solvent. The reaction was continued for 22 hours to obtain the product in high yield. N -(7'-tert-butyl-3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide derivative; 1-(4-tert-butyl-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea: 4-methylbenzenesulfonamide: iodobenzene acetate = 2:1:(2.6~3.0).

[0037] (7) 1-(4-chloro-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea was placed in a reaction flask, iodobenzene acetate and 4-methylbenzenesulfonamide were added, and hexafluoroisopropanol was used as a solvent. The reaction was continued for 20 hours to obtain the product in high yield. N -(7'-chloro-3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide target product; 1-(4-chloro-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea: 4-methylbenzenesulfonamide: iodobenzene acetate = 2:1:(2.8~3.5).

[0038] (8) 3-Ethoxy-1-(5-isopropyl-2',6'-dimethyl-1,1'-diphenyl)-1-methylurea, iodobenzene acetate as an oxidant, and 4-methylbenzenesulfonamide were placed in a reaction flask, and hexafluoroisopropanol was added as a solvent. The reaction was continued for 24 hours to obtain the product in high yield. N -(3'-ethoxy-6'-isopropyl-1',2,6-trimethylquinazolinone) - 4-Methylbenzenesulfonamide derivatives; N -Ethoxy-2,2-diphenylacetamide: iodobenzene: m-chloroperbenzoic acid = 2:1: (3.0~3.5).

[0039] (9) 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea was placed in a reaction flask, iodobenzene acetate and 4-ethylbenzenesulfonamide were added as oxidants, and hexafluoroisopropanol was used as solvent. The reaction was continued for 18 hours to obtain the product in high yield. N -(3'-ethoxy-1',2,6-trimethylquinazolinone)-4-ethylbenzenesulfonamide target product; 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea: 4-ethylbenzenesulfonamide: iodobenzene acetate = 2:1:(2.0~2.5).

[0040] (10) 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, iodobenzene acetate as an oxidant, and 4-fluorobenzenesulfonamide were placed in a reaction flask, and hexafluoroisopropanol was added as a solvent. The reaction was continued for 22 hours to obtain the product in high yield. N -(3'-ethoxy-6'-isopropyl-1',2,6-trimethylquinazolinone) - 4-Fluorobenzenesulfonamide derivative; 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea: 4-fluorobenzenesulfonamide: iodobenzene acetate = 2:1:(3.5~4.0).

[0041] (11) 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea was placed in a reaction flask, iodobenzene acetate and 3-methylbenzenesulfonamide were added as oxidants, and hexafluoroisopropanol was used as solvent. The reaction was continued for 20 hours to obtain the product in high yield. N -(3'-ethoxy-1',2,6-trimethylquinazolinone)-3-methylbenzenesulfonamide target product; 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea: 3-methylbenzenesulfonamide: iodobenzene acetate = 2:1:(3.0~3.5).

[0042] (12) 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, oxidizing agent iodobenzene acetate and 4-fluorobenzenesulfonamide were added. N ,4-Dimethylbenzenesulfonamide was placed in a reaction flask, hexafluoroisopropanol was added as a solvent, and the reaction was carried out for 24 hours to obtain a high yield. N -(3'-ethoxy-1',2,6-trimethylquinazolinone) -N ,4-dimethylbenzenesulfonamide derivatives; 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea: N ,4-dimethylbenzenesulfonamide: iodobenzene acetate = 2:1: (3.2~3.6).

[0043] (13) Place 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea in a reaction flask, add iodobenzene acetate as an oxidant and N -ethyl-4-methylbenzenesulfonamide, hexafluoroisopropanol as solvent, react for 24 hours to obtain high yield N -(3'-ethoxy-1',2,6-trimethylquinazolinone)- N -ethyl-4-methylbenzenesulfonamide target product; 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea: N -Ethyl-4-methylbenzenesulfonamide: iodobenzene acetate = 2:1: (3.6~4.0).

[0044] In the above reaction, the reaction temperature range is 20-30°C.

[0045] In the above reaction, the synthesis method of aryl urea derivatives is referenced by: Y. Wang, Y.-Y. Sun, Y.-M.Cui, Y.-X. Yu, Z.-G. Wu, J. Org. Chem. 2022, 87 , 3234. Example 1

[0046] N Synthesis of -(3'-methoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide

[0047]

[0048] To a 10 mL reaction tube, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-methoxy-1-methylurea (56.8 mg, 0.2 mmol), 4-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (64.4 mg, 0.2 mmol) were added. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a light yellow solid. N -(3'-methoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide (25.4 mg, 56% yield).

[0049] mp 242–243 o C; 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.2 Hz, 2H),7.33 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 6.9 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H),6.82 (d, J = 8.2 Hz, 1H), 6.76 (d, J = 9.4 Hz, 1H), 5.57 (s, 2H), 4.57 (d, J = 9.8 Hz, 1H), 4.40 – 4.33 (m, 1H), 3.77 (s, 3H), 3.36 (s, 3H), 2.44 (s, 3H), 1.53 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 154.7, 143.7, 138.4, 138.0, 137.5,129.9, 129.2, 127.2, 126.8, 125.1, 123.0, 122.7, 113.2, 68.8, 63.6, 47.9,30.1, 21.7, 18.9; ESI FTMS exact mass calcd for (C 24 H 27 N3O4S+Na) +requires m / z476.1620, found m / z 476.1611. Example 2

[0050] N Synthesis of -(3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide

[0051]

[0052] 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea (59.6 mg, 0.2 mmol), 4-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (96.6 mg, 0.3 mmol) were added to a 10 mL reaction tube. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a yellow solid. N -(3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide (35.5 mg, 76% yield).

[0053] mp 172–173 o C; 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 2H),7.30 (d, J = 7.9 Hz, 2H), 7.19 (t, J = 7.9 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H),6.79 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 5.54 (s, 2H), 4.65 (d, J = 9.4 Hz, 1H), 4.33 (s, 1H), 4.00 – 3.92 (m, 2H), 3.31 (s, 3H), 2.40 (s, 3H), 1.49 (s, 6H), 1.22 – 1.11 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 154.6, 143.5,138.2, 137.8, 137.5, 129.8, 129.0, 127.0, 126.7, 124.8, 122.8, 122.4, 113.0,71.3, 68.7, 47.7, 29.9, 21.5, 18.7, 13.8; ESI FTMS exact mass calcd for(C 25 H 29 N3O4S+Na) + requires m / z 490.1777, found m / z 490.1770. Example 3

[0054] N Synthesis of -(3'-Isopropoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide

[0055]

[0056] To a 10 mL reaction tube, add 1-(2',6'-dimethyl-1,1'-diphenyl)-3-isopropoxy-1-methylurea (62.4 mg, 0.2 mmol), 4-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (90.2 mg, 0.28 mmol). Finally, add 1 mL of hexafluoroisopropanol (HFIP) to dissolve the mixture and stir at room temperature overnight. After the reaction is complete, add 5 mL of saturated NaHCO3 solution and extract with dichloromethane three times. The organic phases are combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product is separated and purified by column chromatography to obtain a yellow solid. N -(3'-Isopropoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide (19.7 mg, 41% yield).

[0057] mp 180–181 o C; 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.2 Hz, 2H),7.33 (d, J = 8.0 Hz, 2H), 7.25 – 7.18 (m, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.81(d, J = 8.2 Hz, 1H), 6.75 (d, J= 7.7 Hz, 1H), 5.56 (s, 2H), 4.44 – 4.30 (m,2H), 4.15 – 4.04 (m, 1H), 3.35 (s, 3H), 2.44 (s, 3H), 1.52 (s, 6H), 1.23 (d, J = 6.2 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ 156.3, 143.7, 138.2, 138.2, 138.1,130.0, 129.1, 127.2, 127.1, 124.8, 123.0, 122.5, 113.2, 69.6, 48.0, 30.5,21.7, 21.6, 19.1; ESI FTMS exact mass calcd for (C 26 H 31 N3O4S+Na) + requires m / z504.1933, found m / z 504.1931. Example 4

[0058] N Synthesis of -(3'-ethoxy-1'-ethyl-2,6-dimethylquinazolinone)-4-methylbenzenesulfonamide

[0059]

[0060] 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-ethylurea (62.4 mg, 0.2 mmol), 4-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (74.1 mg, 0.23 mmol) were added to a 10 mL reaction tube. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a yellow solid. N -(3'-ethoxy-1'-ethyl-2,6-dimethylquinazolinone)-4-methylbenzenesulfonamide (24.1 mg, 50% yield).

[0061] mp 188–189 o C; 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J= 8.0 Hz, 2H),7.33 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1H), 6.91 – 6.83 (m, 2H), 6.76(d, J = 7.8 Hz, 1H), 5.57 (s, 2H), 4.46 (d, J = 9.7 Hz, 1H), 4.37 – 4.30 (m,1H), 4.01 – 3.94 (m, 4H), 2.44 (s, 3H), 1.52 (s, 6H), 1.24 – 1.19 (m, 6H); 13 CNMR (100 MHz, CDCl3) δ 154.5, 143.7, 138.3, 137.8, 136.7, 130.0, 129.1,129.0, 127.3, 127.2, 125.1, 123.3, 122.5, 113.2, 71.6, 68.7, 47.9, 37.6,21.7, 18.9, 13.9, 12.4; ESI FTMS exact mass calcd for (C 26 H 31 N3O4S+Na) + requires m / z 504.1933, found m / z 504.1922. Example 5

[0062] N Synthesis of -(3'-ethoxy-1',2,6,7'-tetramethylquinazolinone)-4-methylbenzenesulfonamide

[0063]

[0064] To a 10 mL reaction tube, add 3-ethoxy-1-methyl-1-(2',4,6'-trimethyl-1,1'-diphenyl)urea (62.4 mg, 0.2 mmol), 4-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (96.6 mg, 0.3 mmol). Finally, add 1 mL of hexafluoroisopropanol (HFIP) to dissolve the mixture and stir at room temperature overnight. After the reaction is complete, add 5 mL of saturated NaHCO3 solution, extract with dichloromethane three times, combine the organic phases, dry over anhydrous Na2SO4, and spin dry. Finally, separate and purify the product by column chromatography to obtain a light yellow solid. N-(3'-ethoxy-1',2,6,7'-tetramethylquinazolinone)-4-methylbenzenesulfonamide (24.1 mg, 50% yield).

[0065] mp 207–208 o C; 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H),7.33 (d, J = 8.0 Hz, 2H), 6.72 (d, J = 7.9 Hz, 1H), 6.65 – 6.59 (m, 2H), 5.56(s, 2H), 4.43 (d, J = 9.6 Hz, 1H), 4.37 – 4.28 (m, 1H), 3.98 (q, J = 7.1 Hz,2H), 3.34 (s, 3H), 2.43 (s, 3H), 2.31 (s, 3H), 1.51 (s, 6H), 1.21 (t, J = 7.1Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 154.9, 143.7, 139.1, 138.4, 137.9, 129.9,127.2, 126.8, 124.9, 123.4, 120.1, 113.8, 71.5, 68.6, 47.9, 30.0, 21.7, 21.6,18.9, 13.9; ESI FTMS exact mass calcd for (C 26 H 31 N3O4S+Na) + requires m / z504.1933, found m / z 504.1923. Example 6

[0066] N Synthesis of -(7'-tert-butyl-3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide

[0067]

[0068] 1-(4-tert-butyl-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea (70.8 mg, 0.2 mmol), 4-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (96.6 mg, 0.3 mmol) were added to a 10 mL reaction tube. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a light yellow solid. N -(7'-tert-Butyl-3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide (19.9 mg, 38% yield).

[0069] mp 207–208 o C; 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H),7.33 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 6.79 (s, 1H), 6.66 (d, J = 8.2 Hz, 1H), 5.56 (s, 2H), 4.44 – 4.30 (m, 2H), 4.04 – 3.94 (m, 2H), 3.37(s, 3H), 2.44 (s, 3H), 1.52 (s, 6H), 1.28 (s, 9H), 1.22 (t, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 155.1, 152.5, 143.7, 138.4, 138.0, 137.6, 129.9,127.2, 126.5, 124.9, 120.1, 119.8, 110.2, 71.5, 68.6, 48.0, 34.9, 31.4, 30.0,21.7, 19.0, 14.0; ESI FTMS exact mass calcd for (C 29 H 37 N3O4S+Na) + requires m / z546.2403, found m / z 546.2395. Example 7

[0070] N Synthesis of -(7'-chloro-3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide

[0071]

[0072] To a 10 mL reaction tube, 1-(4-chloro-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea (66.4 mg, 0.2 mmol), 4-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (106.3 mg, 0.33 mmol) were added. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a light yellow solid. N -(7'-chloro-3'-ethoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide (21.0 mg, 42% yield).

[0073] mp 186–187 o C; 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.0 Hz, 2H),7.34 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.81 (s, 1H), 6.68 (d, J = 8.3 Hz, 1H), 5.59 (s, 2H), 4.42 – 4.30 (m, 2H), 4.04 – 3.94 (m, 2H), 3.33(s, 3H), 2.44 (s, 3H), 1.52 (s, 6H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (100MHz, CDCl3) δ 154.3, 143.8, 139.3, 138.3, 137.3, 134.8, 130.0, 128.2, 127.2,122.5, 121.5, 113.4, 71.6, 68.6, 47.8, 30.2, 21.7, 18.8, 13.9; ESI FTMS exactmass calcd for (C 25 H 28 ClN3O4S+Na) + requires m / z 524.1387, found m / z 524.1378. Example 8

[0074] N -(3'-ethoxy-6'-isopropyl-1',2,6-trimethylquinazolinone) - Synthesis of 4-methylbenzenesulfonamide

[0075]

[0076] 3-Ethoxy-1-(5-isopropyl-2',6'-dimethyl-1,1'-diphenyl)-1-methylurea (68.0 mg, 0.2 mmol), 4-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (103.0 mg, 0.32 mmol) were added to a 10 mL reaction tube. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a light yellow solid. N -(3'-ethoxy-6'-isopropyl-1',2,6-trimethylquinazolinone) - 4-Methylbenzenesulfonamide (26.0 mg, 51% yield).

[0077] mp 155–156 o C; 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.8 Hz, 2H),7.33 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 6.75 (d, J= 8.4 Hz, 1H),6.57 (s, 1H), 5.59 (s, 2H), 4.45 – 4.33 (m, 2H), 4.03 – 3.93 (m, 2H), 3.33(s, 3H), 2.81 – 2.70 (m, 1H), 2.44 (s, 3H), 1.51 (s, 6H), 1.23 (t, J = 7.2Hz, 3H), 1.14 (d, J = 6.9 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ 154.9, 143.7,143.4, 138.5, 137.8, 136.0, 129.9, 127.2, 126.7, 125.0, 122.7, 113.2, 71.6,68.8, 47.9, 33.3, 30.1, 24.1, 21.7, 18.9, 13.9; ESI FTMS exact mass calcd for(C 28 H 35 N3O4S+Na) + requires m / z 532.2246, found m / z 532.2239. Example 9

[0078] N Synthesis of -(3'-ethoxy-1',2,6-trimethylquinazolinone)-4-ethylbenzenesulfonamide

[0079]

[0080] To a 10 mL reaction tube, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea (59.6 mg, 0.2 mmol), 4-ethylbenzenesulfonamide (18.5 mg, 0.1 mmol), and iodobenzene acetate (80.5 mg, 0.25 mmol) were added. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a light yellow solid. N -(3'-ethoxy-1',2,6-trimethylquinazolinone)-4-ethylbenzenesulfonamide (16.4 mg, 34% yield).

[0081] mp 147–148o C; 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.1 Hz, 2H),7.35 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H),6.82 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 7.7 Hz, 1H), 5.57 (s, 2H), 4.43 (d, J = 9.7 Hz, 1H), 4.39 – 4.32 (m, 1H), 4.04 – 3.95 (m, 2H), 3.35 (s, 3H), 2.76 –2.69 (m, 2H), 1.52 (s, 6H), 1.28 – 1.21 (m, 6H); 13 C NMR (100 MHz, CDCl3) δ154.8, 149.9, 138.5, 138.0, 137.7, 129.1, 128.8, 127.3, 126.9, 125.1, 123.0,122.6, 113.2, 71.6, 68.8, 47.9, 30.1, 29.0, 18.9, 15.4, 14.0; ESI FTMS exactmass calcd for (C 26 H 31 N3O4S+Na) + requires m / z 504.1933, found m / z 504.1927. Example 10

[0082] N -(3'-ethoxy-6'-isopropyl-1',2,6-trimethylquinazolinone) - Synthesis of 4-fluorobenzenesulfonamide

[0083]

[0084] 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea (59.6 mg, 0.2 mmol), 4-fluorobenzenesulfonamide (17.5 mg, 0.1 mmol), and iodobenzene acetate (128.8 mg, 0.40 mmol) were added to a 10 mL reaction tube. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a yellow solid. N -(3'-ethoxy-6'-isopropyl-1',2,6-trimethylquinazolinone) - 4-Fluorobenzenesulfonamide (12.7 mg, 27% yield).

[0085] mp 218–220 o C; 1 H NMR (400 MHz, CDCl3) δ 7.99 – 7.92 (m, 2H), 7.22(t, J = 8.4 Hz, 3H), 6.92 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.76(d, J = 7.8 Hz, 1H), 5.59 (s, 2H), 4.49 (d, J = 9.7 Hz, 1H), 4.37 (s, 1H), 4.04 – 3.96 (m, 2H), 3.36 (s, 3H), 1.54 (s, 6H), 1.23 (t, J = 7.1 Hz, 3H); 13 CNMR (100MHz, CDCl3) δ 154.8, 138.1, 137.5, 129.9 (d, J = 9.2 Hz), 129.2,126.9, 124.9, 122.8 (d, J = 23.6 Hz), 116.6 (d, J = 22.5 Hz), 113.2, 71.6,68.8, 48.0, 30.1, 18.9, 14.1; 19F NMR (282 MHz, CDCl3) δ -105.1; ESI FTMSexact mass calcd for (C 24 H 26 FN3O4S+Na) + requires m / z 494.1526, found m / z494.1519. Example 11

[0086] N Synthesis of -(3'-ethoxy-1',2,6-trimethylquinazolinone)-3-methylbenzenesulfonamide

[0087]

[0088] To a 10 mL reaction tube, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea (59.6 mg, 0.2 mmol), 3-methylbenzenesulfonamide (17.1 mg, 0.1 mmol), and iodobenzene acetate (112.7 mg, 0.35 mmol) were added. Finally, 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve the mixture and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a light yellow solid. N -(3'-ethoxy-1',2,6-trimethylquinazolinone)-3-methylbenzenesulfonamide (10.7 mg, 23% yield).

[0089] mp 185–186 o C; 1 H NMR (400 MHz, CDCl3) δ 7.78 – 7.68 (m, 2H), 7.42 –7.37 (m, 2H), 7.22 (d, J = 7.3 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 5.58 (s, 2H), 4.46 – 4.33 (m, 2H), 4.05 – 3.95 (m, 2H), 3.35 (s, 3H), 2.45 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H);13 CNMR (100 MHz, CDCl3) δ 154.8, 141.2, 139.6, 138.1, 137.8, 133.7, 129.2,129.1, 127.5, 127.0, 124.2, 122.6, 113.2, 71.6, 68.8, 48.0, 30.1, 21.5, 18.9,14.0; ESI FTMS exact mass calcd for (C 25 H 29 N3O4S+Na) + requires m / z 490.1777,found m / z 490.1771. Example 12

[0090] N -(3'-ethoxy-1',2,6-trimethylquinazolinone) -N Synthesis of 4-dimethylbenzenesulfonamide

[0091]

[0092] 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea (59.6 mg, 0.2 mmol), 4-fluorobenzenesulfonamide N 4-Dimethylbenzenesulfonamide (18.5 mg, 0.1 mmol) and iodobenzene acetate (112.7 mg, 0.35 mmol) were added to a 10 mL reaction tube, and finally 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve them and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added, and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous Na2SO4, and then spun down to dryness. Finally, the product was separated and purified by column chromatography to obtain a yellow solid. N -(3'-ethoxy-1',2,6-trimethylquinazolinone) -N ,4-Dimethylbenzenesulfonamide (30.3 mg, 63% yield).

[0093] mp 218–219 o C; 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.8 Hz, 2H),7.33 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.9 Hz, 1H), 6.93 (t, J= 7.6 Hz, 1H),6.82 (d, J = 9.5 Hz, 2H), 5.38 (s, 2H), 5.04 (s, 1H), 4.04 – 3.97 (m, 2H), 3.35 (s, 3H), 2.70 (s, 3H), 2.44 (s, 3H), 1.57 (s, 6H), 1.12 (t, J = 7.2 Hz,3H); 13 C NMR (100 MHz, CDCl3) δ 154.9, 143.5, 139.7, 138.0, 137.1, 129.9,129.1, 127.3, 126.9, 123.8, 123.2, 122.6, 113.1, 71.2, 69.1, 52.2, 30.1,29.7, 21.7, 18.9, 13.7; ESI FTMS exact mass calcd for (C 26 H 31 N3O4S+Na) + requires m / z 504.1933, found m / z 504.1930. Example 13

[0094] N -(3'-ethoxy-1',2,6-trimethylquinazolinone)- N Synthesis of 4-ethyl-methylbenzenesulfonamide

[0095]

[0096] 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea (59.6 mg, 0.2 mmol) was added to a 10 mL reaction tube. N 4-ethyl-4-methylbenzenesulfonamide (19.9 mg, 0.1 mmol), iodobenzene acetate (122.4 mg, 0.38 mmol), and finally 1 mL of hexafluoroisopropanol (HFIP) was added to dissolve it and stirred at room temperature overnight. After the reaction was complete, 5 mL of saturated NaHCO3 solution was added, and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous Na2SO4, and then spin-dried. Finally, the product was separated and purified by column chromatography to obtain a light yellow solid. N -(3'-ethoxy-1',2,6-trimethylquinazolinone)- N -ethyl-4-methylbenzenesulfonamide (15.3 mg, 31% yield). Example 14

[0097] The product was obtained by replacing the iodobenzene acetate in Example 1 with iodosobenzene. N -(3'-methoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide 13.1 mg, yield 29%. Example 15

[0098] Substituting di(trifluoroacetic acid)iodobenzene for the iodobenzene acetate in Example 1, the product N -(3'-methoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide 3.6 mg, yield 8%. Example 16

[0099] The product was obtained by replacing the hexafluoroisopropanol in Example 1 with trifluoroethanol. N -(3'-methoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide 4.5 mg, yield 10%. Example 17

[0100] The hexafluoroisopropanol in Example 1 was replaced by acetonitrile to obtain the product N -(3'-methoxy-1',2,6-trimethylquinazolinone)-4-methylbenzenesulfonamide 5.9 mg, yield 13%.

[0101] The above description is only a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Any simple modification, equivalent replacement and improvement made by any technician familiar with the profession to the above embodiment without departing from the scope of the technical solution of the present invention and based on the technical essence of the present invention shall still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for synthesizing a quinazolinone derivative, characterized in that: In the presence of a hypervalent iodine reagent and an organic solvent, the aryl urea represented by formula a reacts with the aryl sulfonamide represented by formula b to obtain a quinazolinone derivative represented by formula c; the reaction formula is as follows: ， Among them, R 1 is methyl, isopropyl, tert-butyl, halogen, R 2 is ethyl, R 3 is methyl, ethyl or isopropyl, R 4 is methyl, ethyl, halogen, R 5 is methyl or ethyl; the high-valent iodine reagent is iodobenzene acetate; the organic solvent is hexafluoroisopropanol; and the reaction is carried out at 20-30° C. for 12-24 hours.

2. The method for synthesizing a quinazolinone derivative according to claim 1, wherein: The aromatic urea is 1-(2',6'-dimethyl-1,1'-diphenyl)-3-methoxy-1-methylurea, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-isopropoxy-1-methylurea, 1-(2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-ethylurea, 3-ethoxy-1- Any one of methyl-1-(2',4,6'-trimethyl-1,1'-diphenyl)urea, 1-(4-tert-butyl-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, 1-(4-chloro-2',6'-dimethyl-1,1'-diphenyl)-3-ethoxy-1-methylurea, and 3-ethoxy-1-(5-isopropyl-2',6'-dimethyl-1,1'-diphenyl)-1-methylurea.

3. The method for synthesizing a quinazolinone derivative according to claim 1, wherein: The aryl sulfonamides are 4-methylbenzenesulfonyl chloride, 4-ethylbenzenesulfonamide, 4-fluorobenzenesulfonamide, 3-methylbenzenesulfonamide, N ,4-dimethylbenzenesulfonamide, N -ethyl-4-methylbenzenesulfonamide.

4. The method for synthesizing a quinazolinone derivative according to claim 1, wherein: The molar ratio of the aryl urea, aryl sulfonamide, and hypervalent iodine reagent is 2:1:2-4.

5. The method for synthesizing a quinazolinone derivative according to claim 1, wherein: The molar concentration of the aryl urea in the organic solvent is 0.1-0.2 mol / L.

6. The method for synthesizing a quinazolinone derivative according to claim 1, wherein: The method also includes extracting the organic phase and performing column chromatography separation and purification after the reaction is complete.

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