Preparation method of polysubstituted quinazolinone compound initiated by ultraviolet light

Abstract

The invention provides a preparation method of a multi-substituted quinazolinone compound initiated by ultraviolet light, which comprises the following step of: reacting a benzaldehyde compound with an anthranilamide compound in an organic solvent under the action of a reaction atmosphere, a free radical initiator and ultraviolet irradiation to obtain the multi-substituted quinazolinone compound. The preparation method is cheap in substrate, simple in step, mild in condition, relatively low in reaction cost and wide in application range, the problem of metal residues in drug synthesis is avoided, and the obtained product is the quinazolinone compound which can be used as potential new material molecules and biomedical active molecules.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of ultraviolet light-initiated polysubstituted quinazolinone compounds. Background Art

[0002] Quinazolinone derivatives are a class of heterocyclic compounds with a wide range of biological and pharmacological activities, including significant anti-tumor, antibacterial, anti-inflammatory and antiviral properties, and these compounds have also been widely used in the fields of pesticides and materials science (Li, S.; Ma, J,-A. Chem. Soc. Rev. 2015, 44, 7439; Chen, Y.; Sun, S.-N.; Chen, X.-H.; Chen, M.-L.; Lin, J.-M.; Niu, Q.; Li, S.-L.; Liu, J.; Lan, Y.-Q. Adv. Mater. 2025, 37, 2413638; Dong, L.-L.; Shen, S.-Q.; Jiang, X.; Ding, B.-L.; Yang, M.-L.; Chen, W.; Liu, Y.-X.; Chen, Z.-Y.; Cao, Q.-N.; Gao, Y.-M.; Ma, S.-J.; Zhang, L.-H.; Dong, J.-G.; Yang, Q. J. Agric. Food Chem. 2023, 71, 17410.). Therefore, the research on the synthesis methods of quinazolinone has received increasing attention from synthetic chemists. Traditional synthesis methods mainly involve the cyclization reaction of anthranilic acid and its derivatives to construct the core structure of quinazolinone (Borah, B.; Swain, S.; Patat, M.; Chowhan, L.R. Front. Chem. 2022, 10, 991026.). However, the emergence of transition metal-catalyzed C-H bond activation reactions has introduced new strategies for the synthesis of quinazolinone (Zou, J.-Y.; Yang, Y.-Y.; Gu, J.; Liu, F.; Ye, Z.-W.; Yi, W.-B.; He, Y. Angew. Chem., Int. Ed. 2023, 62, e202310320; Thrilokraj R.; J.G.; Budagumpi, S.; Kshirsagar, U.A.; Dateer, R.B. Green Chem. 2024, 26, 4723.). In particular, palladium- and copper-catalyzed coupling reactions have shown unique advantages in constructing complex quinazolinone derivatives (Lv, X.-Y.; Abrams, R.; Martin, R. Angew. Chem., Int. Ed. 2023, 62, e202217386; He, L.; Li, H.-Q.; Neumann, H.; Beller, M.; Wu, X.-F. Angew. Chem., Int. Ed. 2014, 53, 1420; Teng, F.; Yu, T.; Peng, Y.; Hu, W.-M.; Hu, Z.; He, Y.-M.; Luo, S.; Zhu, Q. J. Am. Chem. Soc. 2021, 143, 2722.; Sheetal.; Sharma, P.; Kumar, A.; Sharma, N.; Giri, K.; Das, P. Chem. Commun. 2024, 60, 6043.). A method for synthesizing quinazolinone derivatives (Patent - CN106518789A) has been disclosed, which uses a water-soluble iridium metal complex as a catalyst to obtain quinazolinone compounds through cyclization and dehydrogenation of o-aminobenzamide and aldehydes as raw materials. However, this method uses the precious metal iridium as a catalyst, which is not economical and green, and at the same time, metal residues will also affect the synthesis purity of drug molecules. The research team of the inventors of this application has long been committed to developing green, efficient and simple methods for the synthesis and functionalization of quinazolinone. For example, we have explored a copper-catalyzed, oxygen-mediated oxidative ring expansion reaction using inexpensive metal, and synthesized multi-substituted quinazolinone derivatives in one step through the reaction of indole and amine (Feng, Y.-D.; Li, Y.-D.; Cheng, G.-L.; Wang, L.-H.; Cui, X.-L. J. Org. Chem. 2015, 80, 7099.).In addition, we also studied the palladium-catalyzed sequential [4+2] and [3+2] cycloaddition reactions between quinazolinones and alkynes to generate tetrahydropyrano[3,2-c]furan-fused ring systems. Meanwhile, other methods for the synthesis and modification of quinazolinones were developed, including iridium-catalyzed mono- and disulfonamidation of quinazolinones, palladium-catalyzed oxidative self-coupling reactions of quinazolinones to form diaryl compounds, and rhodium-catalyzed [4+2] tandem cycloaddition reactions to obtain polysubstituted isoquinazolinone derivatives (Feng, Y.-D.; Zhang, Z.-Y.; Fu, Q.; Yao, Q.-H.; Huang, H.-B.; Shen, J.-H.; Cui, X.-L. Chin. Chem. Lett. 2020, 31, 58; Feng, Y.-D.; Li, Y.-D.; Yu, Y.-L.; Wang, L.-H.; Cui, X.-L. RSC Adv. 2018, 8, 8450; Feng, Y.-D.; Wu, Z.-P.; Chen, T.; Fu, Q.; Yao, Q.-H.; Shen, J.-H; Cui, X.-L. Chin. Chem. Lett. 2020, 31, 3263; Yue, X.-L; Gao, Y.-J.; Huang, J.-W.; Feng, Y.-D.; Cui, X.-L. Org. Lett. 2023, 25, 2923.). Although the synthetic strategies of quinazolinones are becoming increasingly diverse, the development of greener, more efficient, and simpler methods remains a focus of current research. Therefore, the development of green, simple, and efficient methods for the synthesis of quinazolinone compounds will greatly promote the application of such compounds in biomedicine, new materials, and other fields. Summary of the Invention

[0003] The object of the present invention is to provide a method for preparing polysubstituted quinazolinone compounds initiated by ultraviolet light. The preparation method has simple steps, mild conditions, a wide range of substrate applicability, and the obtained products are quinazolinone compounds and derivatives containing various substituents.

[0004] To achieve the above object, the present invention adopts the following technical scheme:

[0005] A method for preparing polysubstituted quinazolinone compounds initiated by ultraviolet light, comprising the following steps:

[0006] Under the action of a reaction atmosphere, a radical initiator, and ultraviolet light irradiation, benzaldehyde compounds (II) react with anthranilamide compounds (III) in an organic solvent, and after the reaction is completed, the polysubstituted quinazolinone compounds (I) are obtained through post-treatment:

[0007] The reaction formula is as follows:

[0008]

[0009] Among them, R 1 is hydrogen, alkyl, halogen, methoxy or N,N-dimethyl;

[0010] R 2 is hydrogen, alkyl, halogen or methoxy.

[0011] Preferably, the R 1 is hydrogen, methyl, fluorine, chlorine, bromine, tert-butyl, methoxy, N,N-dimethyl.

[0012] Preferably, the R 2 is hydrogen, methyl, fluorine, chlorine, bromine, tert-butyl or methoxy.

[0013] Preferably, the reaction atmosphere is one of air and oxygen, preferably oxygen.

[0014] Preferably, the radical initiator is one of tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP), benzoyl peroxide (BPO), tert-butyl peroxide (TBPO), tert-butyl perbenzoate (TBPB) and benzoyl peroxide (BP), preferably tert-butyl hydroperoxide (TBHP).

[0015] Preferably, the light source is ultraviolet light with different powers and wavelengths, preferably with a power of 250 W and a maximum wavelength of 365 nm.

[0016] Preferably, the organic solvent is one of acetonitrile, methanol, dichloromethane, 1,2-dichloroethane, toluene, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, preferably acetonitrile.

[0017] Preferably, in terms of molar amount, benzaldehyde compound: o-aminobenzamide compound: radical initiator = 1.5-5.0: 1.0: 1.0-4.0, preferably 3.0: 1.0: 2.0.

[0018] Preferably, the reaction temperature is 80-160 °C, preferably 140 °C, and the reaction time is 18-54 h, preferably 48 h.

[0019] Preferably, the structure of the polysubstituted quinazolinone compound includes the following:

[0020]

[0021] The advantages of the present invention are as follows:

[0022] Compared with the prior art, the present invention starts from inexpensive o-aminobenzamide and aryl aldehyde, and under metal-free conditions, uses ultraviolet light, a radical initiator and oxygen to generate polysubstituted quinazolinone derivatives in one step. The invention has inexpensive substrates, simple steps, mild conditions, low reaction costs, a wide range of applications, avoids the problem of metal residues in drug synthesis, and the obtained products, quinazolinone compounds, can be used as potential new material molecules and bio-medically active molecules. Detailed implementation mode

[0023] To make the above features and advantages of the present invention more obvious and understandable, specific examples are given below for detailed description. Unless otherwise specified, the methods of the present invention are all conventional methods in the art.

[0024] Example 1

[0025] 2-Phenyl-4(3H)-quinazolinone, whose structural formula is:

[0026]

[0027] In a 5.0 mL reaction vessel, 0.3 mmol of benzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane and extracted with water three times. The organic phase was dried over anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 20 mg of the target product with a yield of 90%. The NMR characterization of this compound is as follows: 1 HNMR(400MHz,DMSO-d6)δ12.52(s,1H),8.16(m,3H),7.83(m,1H),7.74(m,1H),7.62–7.45(m,4H). 13 C NMR(100MHz,DMSO-d6)δ162.7,152.8,149.2,135.1,133.2,131.9,129.1,128.2,128.0,127.0,126.3,121.5.

[0028] Example 2

[0029] 6-Fluoro-2-phenyl-4(3H)-quinazolinone, whose structural formula is:

[0030]

[0031] In a 5.0 mL reaction vessel, 0.3 mmol of benzaldehyde, 0.1 mmol of 2-amino-5-fluorobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under irradiation with a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (18.7 mg) was obtained by column chromatography separation with a yield of 78%. The NMR characterization of this compound is as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 8.47–8.00 (m, 2H), 7.86–7.78 (m, 2H), 7.71 (td, J = 8.7, 3.0 Hz, 1H), 7.62–7.44 (m, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.1, 161.7, 159.2, 152.3, 146.1, 133.0, 131.9, 130.8 (d, J = 8.3 Hz), 129.1, 128.2, 123.5 (d, J = 24.1 Hz), 122.7 (d, J = 8.2 Hz), 111.0 (d, J = 23.3 Hz).

[0032] Example 3

[0033] 6-Isopropyl-2-phenyl-4(3H)-quinazolinone, and its structural formula is:

[0034]

[0035] In a 5.0 mL reaction vessel, 0.3 mmol of benzaldehyde, 0.1 mmol of 2-amino-5-isopropylbenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under irradiation with a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (23.2 mg) was obtained by column chromatography separation with a yield of 88%. The NMR characterization of this compound is as follows: 11H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.23–8.08 (m, 2H), 8.05–7.95 (m, 1H), 7.78–7.40 (m, 5H), 3.06 (p, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.8, 152.0, 147.5, 134.0, 133.2, 131.7, 129.0, 128.2, 128.1, 128.0, 127.0, 122.8, 121.2, 33.7, 24.2.

[0036] Example 4

[0037] 6-Methoxy-2-phenyl-4(3H)-quinazolinone, and its structural formula is:

[0038]

[0039] In a 5.0 mL reaction vessel, 0.3 mmol of benzaldehyde, 0.1 mmol of 2-amino-5-methoxybenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (21.4 mg) was obtained by column chromatography separation with a yield of 85%. The NMR characterization of this compound is as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.17 (dd, J = 8.0, 1.7 Hz, 3H), 7.72 (s, 1H), 7.60–7.52 (m, 4H), 7.45 (dd, J = 8.9, 3.0 Hz, 1H), 3.90 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.5, 158.2, 150.6, 143.7, 133.2, 131.5, 129.7, 129.0, 128.0, 124.6, 122.2, 106.3, 56.1.

[0040] Example 5

[0041] 2-(2-Methylphenyl)-4(3H)-quinazolinone, and its structural formula is:

[0042]

[0043] In a 5.0 mL reaction vessel, 0.3 mmol of 2-methylbenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under irradiation with a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (19.4 mg) was obtained by column chromatography separation with a yield of 82%. The NMR characterization of this compound is as follows: 1 H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.15(dd,J=8.0,1.6Hz,1H),7.82(ddd,J=8.5,7.0,1.6Hz,1H),7.67(dd,J=8.3,1.1Hz,1H),7.57–7.46(m,2H),7.42(td,J=7.5,1.5Hz,1H),7.37–7.27(m,2H),2.37(s,3H). 13 C NMR(100MHz,DMSO-d6)δ162.3,154.9,149.2,136.6,134.9,134.7,131.0,130.4,129.6,127.8,127.1,126.3,126.2,121.4,20.0.

[0044] Example 6

[0045] 2-(3-Methylphenyl)-4(3H)-quinazolinone, and its structural formula is:

[0046]

[0047] In a 5.0 mL reaction vessel, 0.3 mmol of 3-methylbenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under irradiation with a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (20.7 mg) was obtained by column chromatography separation with a yield of 88%. The NMR characterization of this compound is as follows: 11H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.14 (dd, J = 7.9, 1.6 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 7.2, 1.9 Hz, 1H), 7.82 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 7.73 (dd, J = 8.1, 1.2 Hz, 1H), 7.51 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.46–7.34 (m, 2H), 2.40 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.7, 152.9, 149.2, 138.4, 135.1, 133.1, 132.5, 129.0, 128.8, 128.0, 127.0, 126.3, 125.4, 121.4, 21.4.

[0048] Example 7

[0049] 2-(4-Methylphenyl)-4(3H)-quinazolinone, and its structural formula is:

[0050]

[0051] In a 5.0 mL reaction vessel, 0.3 mmol of 4-methylbenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (21.2 mg) was obtained by column chromatography separation with a yield of 90%. The NMR characterization of this compound is as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 8.15 (dd, J = 7.9, 1.5 Hz, 1H), 8.12–8.01 (m, 2H), 7.83 (ddd, J = 8.4, 7.1, 1.6 Hz, 1H), 7.73 (dd, J = 8.3, 1.1 Hz, 1H), 7.51 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 2.40 (s, 4H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.8, 152.8, 141.9, 135.0, 130.3, 129.7, 128.2, 127.8, 126.9, 126.3, 121.3, 21.5.

[0052] Example 8

[0053] 2-(2-Fluorophenyl)-4(3H)-quinazolinone, and its structural formula is:

[0054]

[0055] In a 5.0 mL reaction vessel, 0.3 mmol of 2-fluorobenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (17.3 mg) was obtained by column chromatography separation, with a yield of 72%. The NMR characterization of this compound is as follows: 1 HNMR(400MHz,DMSO-d6)δ12.59(s,1H),8.18(dd,J=8.0,1.5Hz,1H),7.86(t,J=7.6Hz,1H),7.79(t,J=7.7Hz,1H),7.74(d,J=8.0Hz,1H),7.60(dt,J=19.0,7.1Hz,2H),7.44–7.33(m,2H). 13 CNMR(100MHz,DMSO-d6)δ161.9,150.4,149.1,135.1,133.3(d,J=8.5Hz),131.49(d,J=2.2Hz),128.0,127.5,126.3,125.1(d,J=3.4Hz),122.7(d,J=13.0Hz),121.6,116.6(d,J=21.3Hz).

[0056] Example 9

[0057] 2-(4-Fluorophenyl)-4(3H)-quinazolinone, and its structural formula is:

[0058]

[0059] In a 5.0 mL reaction vessel, 0.3 mmol of 4-fluorobenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under irradiation with a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (17.8 mg) was obtained by column chromatography separation with a yield of 74%. The NMR characterization of this compound is as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 8.26 (dd, J = 9.0, 5.4 Hz, 2H), 8.16 (dd, J = 7.9, 1.5 Hz, 1H), 7.84 (ddd, J = 8.4, 7.1, 1.6 Hz, 1H), 7.74 (dd, J = 8.2, 1.1 Hz, 1H), 7.53 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.40 (t, J = 8.9 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6) δ 165.7, 163.3, 162.7, 151.9, 149.0, 135.1, 130.8 (d, J = 9.0 Hz), 129.7 (d, J = 2.9 Hz), 127.8, 127.1, 126.3, 121.3, 116.1 (d, J = 21.9 Hz).

[0060] Example 10

[0061] 2-(4-chlorophenyl)-4(3H)-quinazolinone, and its structural formula is:

[0062]

[0063] In a 5.0 mL reaction vessel, 0.3 mmol of 4-chlorobenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under irradiation with a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted three times with water, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (16.6 mg) was obtained by column chromatography separation with a yield of 65%. The NMR characterization of this compound is as follows: 1HNMR(400MHz,DMSO-d6)δ8.20(d,J=8.6Hz,2H),8.16(d,J=9.3Hz,1H),7.89–7.80(m,1H),7.74(d,J=7.9Hz,1H),7.62(d,J=8.6Hz,2H),7.54(t,J=7.0Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ162.7,151.8,149.0,136.8,135.1,132.0,130.1,129.1,127.9,127.2,126.3,121.4. This compound is a very effective class of α-glucosidase inhibitors, with an IC 50 value of 12.5±0.1 μM. The results of spectroscopic analysis show that this compound can statically quench the fluorescence spectrum by forming an inhibitor-α-glucosidase complex, and its interaction with α-glucosidase depends on hydrogen bonds, electrostatic and hydrophobic forces. (Wei M, Chai W M, Wang R, et al. Quinazolinone derivatives: Synthesis and comparison of inhibitory mechanisms on α-glucosidase[J]. Bioorganic & medicinal chemistry, 2016, 25(4). DOI: 10.1016 / j.bmc.2016.09.042.).

[0064] Example 11

[0065] 2-(4-Bromophenyl)-4(3H)-quinazolinone, and its structural formula is:

[0066]

[0067] In a 5.0 mL reaction vessel, 0.3 mmol of 4-bromobenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. Then, 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to build a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (21.1 mg) was obtained by column chromatography separation with a yield of 70%. The NMR characterization of this compound is as follows: 1HNMR(400MHz,DMSO-d6)δ12.62(s,1H),8.14(tt,J=9.3,2.0Hz,3H),7.85(ddd,J=8.5,7.1,1.6Hz,1H),7.81–7.70(m,3H),7.54(ddd,J=8.1,7.1,1.2Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ162.6,151.9,149.0,135.1,132.4,132.1,130.37,128.0,127.3,126.3,125.7,121.5. This compound is a class of effective α-glucosidase inhibitors, with an IC 50 value of 15.6 ± 0.2 μM. The results of spectroscopic analysis show that this compound can statically quench the fluorescence spectrum by forming an inhibitor-α-glucosidase complex. The binding driving force between it and α-glucosidase is hydrophobic and the interaction is weak. (Wei M, Chai W M, Wang R, et al. Quinazolinone derivatives: Synthesis and comparison of inhibitory mechanisms on α-glucosidase[J]. Bioorganic & medicinal chemistry, 2016, 25(4). DOI: 10.1016 / j.bmc.2016.09.042.).

[0068] Example 12

[0069] 2-(4-tert-Butylphenyl)-4(3H)-quinazolinone, and its structural formula is:

[0070]

[0071] In a 5.0 mL reaction vessel, 0.3 mmol of 4-tert-butylbenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to build a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane and extracted with water three times. The organic phase was dried over anhydrous Na2SO4, filtered, and the target product (22.8 mg) was obtained by column chromatography separation, with a yield of 82%. The NMR characterization of this compound is as follows: 11H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.31–8.06 (m, 3H), 7.83 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.73 (dd, J = 8.3, 1.1 Hz, 1H), 7.60–7.46 (m, 3H), 1.32 (s, 9H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.7, 154.8, 152.62, 149.3, 135.0, 130.4, 128.0, 127.9, 126.9, 126.3, 125.9, 121.4, 35.1, 31.4.

[0072] Example 13

[0073] 2-(4-Methoxyphenyl)-4(3H)-quinazolinone, and its structural formula is:

[0074]

[0075] In a 5.0 mL reaction vessel, 0.3 mmol of 4-methoxybenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and separated by column chromatography to obtain 20.2 mg of the target product with a yield of 80%. The NMR characterization of this compound is as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.17 (dd, J = 24.3, 8.8 Hz, 3H), 7.82 (t, J = 8.3 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.3, 135.0, 129.9, 128.7, 127.7, 126.6, 126.3, 125.3, 121.1, 117.5, 114.5, 114.1, 55.9. This compound has strong β-glucuronidase inhibitory activity, and the IC 50 value is 1.1 ± 0.05 μM, compared with the standard d-sucrose 1,4-lactone (IC 50= 45.75 ± 2.16 μM) for comparison, indicating that this compound has higher activity than the standard. (Khan M K, Saad M S, Shaikh N N, et al. Synthesis and β-glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-ones [J]. Bioorganic & Medicinal Chemistry, 2014, 22(13): 3449-3454.).

[0076] Example 14

[0077] 2-(4-N,N-dimethylphenyl)-4(3H)-quinazolinone, and its structural formula is:

[0078]

[0079] In a 5.0 mL reaction vessel, 0.3 mmol of 4-N,N-dimethylbenzaldehyde, 0.1 mmol of o-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. Then, 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (19.1 mg) was obtained by column chromatography separation with a yield of 72%. The NMR characterization of this compound is as follows: 1 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.11 (td, J = 7.7, 1.8 Hz, 3H), 7.77 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.65 (dd, J = 8.3, 1.1 Hz, 1H), 7.42 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 6.96–6.61 (m, 2H), 3.01 (s, 6H). 13 13C NMR (100 MHz, DMSO-d6) δ 162.9, 152.7, 134.9, 129.3, 127.3, 126.3, 125.9, 120.8, 119.2, 111.7, 40.1. This compound has strong β-glucuronidase inhibitory activity, and the IC 50 value is 5.5 ± 0.14 μM, compared with the standard d-sucrose 1,4-lactone (IC 50Compared with the standard (=45.75±2.16 μM), it was shown that this compound had higher activity than the standard. (Khan M K, Saad M S, Shaikh N N, et al. Synthesis and β - glucuronidase inhibitory activity of 2 - arylquinazolin - 4(3H) - ones[J]. Bioorganic & Medicinal Chemistry, 2014, 22(13): 3449 - 3454.).

[0080] Example 15

[0081] 2 - (1 - naphthyl) - 4(3H) - quinazolinone, whose structural formula is:

[0082]

[0083] In a 5.0 mL reaction vessel, 0.3 mmol of 1 - naphthaldehyde, 0.1 mmol of o - aminobenzamide, and 0.2 mmol of tert - butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under the irradiation of a high - pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane and extracted with water three times. The organic phase was dried over anhydrous Na2SO4, filtered, and the target product (19.0 mg) was obtained by column chromatography separation with a yield of 70%. The NMR characterization of this compound is as follows: 1 H NMR(400 MHz, DMSO - d6) δ12.68(s, 1H), 8.23(dd, J = 7.9, 1.5 Hz, 1H), 8.20–8.15(m, 1H), 8.15–8.10(m, 1H), 8.09–8.01(m, 1H), 7.88(ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.81(dd, J = 7.1, 1.3 Hz, 1H), 7.74(dd, J = 8.2, 1.1 Hz, 1H), 7.69–7.53(m, 4H). 13 C NMR(100 MHz, DMSO - d6) δ162.3, 154.5, 148.8, 135.0, 133.6, 132.2, 130.9, 130.7, 128.8, 128.2, 127.9, 127.5, 127.3, 126.8, 126.3, 125.7, 125.6, 121.7.

[0084] Example 16

[0085] 2-(9-Anthryl)-4(3H)-quinazolinone, and its structural formula is:

[0086]

[0087] In a 5.0 mL reaction vessel, 0.3 mmol of 9-anthraldehyde, 0.1 mmol of 2-aminobenzamide, and 0.2 mmol of tert-butyl hydroperoxide were added. 2.0 mL of acetonitrile solvent was added, and oxygen was introduced to create a reaction atmosphere. Subsequently, under the irradiation of a high-pressure mercury lamp with a maximum wavelength of 365 nm and a power of 250 W, the reaction was carried out at 140 °C for 48 hours. The reaction was stopped and cooled to room temperature. The reaction solution was diluted with dichloromethane, extracted with water three times, the organic phase was dried over anhydrous Na2SO4, filtered, and the target product (20.9 mg) was obtained by column chromatography separation with a yield of 65%. The NMR characterization of this compound is as follows: 1 H NMR(400MHz,Chloroform-d)δ9.75(s,1H),8.58(s,1H),8.34(d,J=7.9Hz,1H),8.04(dd,J=6.8,3.4Hz,2H),7.93–7.79(m,3H),7.62(ddd,J=8.0,5.5,2.3Hz,1H),7.53–7.44(m,4H),7.28(d,J=1.4Hz,1H). 13 C NMR(100MHz,Chloroform-d)δ162.1,152.1,149.0,135.1,131.1,129.9,129.6,128.8,128.1,127.6,127.5,127.1,126.6,125.7,124.5,121.3.

[0088] The above are only the preferred embodiments of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope covered by the present invention.

Claims

1. A preparation method of an ultraviolet light-initiated multi-substituted quinazolinone compound, characterized in that, It includes the following steps: under the action of a reaction atmosphere, a radical initiator, and ultraviolet light irradiation, a benzaldehyde compound reacts with an anthranilamide compound in an organic solvent to obtain the poly-substituted quinazolinone compound described above; The structure of the benzaldehyde compound is as follows: The structure of the anthranilamide compound is as follows: The structure of the poly-substituted quinazolinone compound is as follows: Among them, R 1 is hydrogen, alkyl, halogen, methoxy or N,N -dimethyl; R 2 is hydrogen, alkyl, halogen or methoxy.

2. The preparation method of the multi-substituted quinazolinone compound according to claim 1, wherein R 1 is one of hydrogen, methyl, fluorine, chlorine, bromine, tert-butyl, methoxy, N,N -dimethyl.

3. The preparation method of the multi-substituted quinazolinone compound according to claim 1, wherein R 2 is one of hydrogen, methyl, fluorine, chlorine, bromine, tert-butyl, and methoxy.

4. The preparation method of the multi-substituted quinazolinone compound according to claim 1, characterized in that, The reaction atmosphere is one of air and oxygen.

5. The preparation method of the multi-substituted quinazolinone compound according to claim 1, wherein The radical initiator is one of tert-butyl hydroperoxide, di-tert-butyl peroxide, benzoyl peroxide, tert-butyl peroxide, tert-butyl perbenzoate, and benzoyl peroxide.

6. The preparation method of the multi-substituted quinazolinone compound according to claim 1, characterized in that, The light source is ultraviolet light with different powers and wavelengths.

7. The preparation method of the multi-substituted quinazolinone compound according to claim 1, characterized in that, The organic solvent described above is one of acetonitrile, methanol, dichloromethane, 1,2-dichloroethane, toluene, N-methylpyrrolidone, N,N -dimethylformamide, and dimethyl sulfoxide.

8. The preparation method of the multi-substituted quinazolinone compound according to claim 1, wherein In terms of molar amount, benzaldehyde compound: anthranilamide compound: radical initiator = 1.5 - 5.0: 1.0: 1.0 - 4.

0.

9. The preparation method of the multi-substituted quinazolinone compound according to claim 1, wherein, The reaction temperature is 80 - 160 °C, and the reaction time is 18 - 54 h.

10. The preparation method of the multi-substituted quinazolinone compound according to claim 1, characterized in that, The structure of the poly-substituted quinazolinone compound includes the following: 。

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