3-ester-1, 3-quinazoline-2, 4-diketone compound as well as preparation method and application thereof

Abstract

The invention discloses a 3-ester-1, 3-quinazoline-2, 4-diketone compound and a preparation method and application thereof.The 3-ester-1, 3-quinazoline-2, 4-diketone compound is prepared by the steps that amino-acid ester hydrochloride and isatoic anhydride serve as raw materials and react in acetonitrile under the action of potassium carbonate to generate an amide ester compound; and then reacting the amide ester compound with triphosgene under the action of triethylamine to obtain the 3-ester-1, 3-quinazoline-2, 4-diketone compound. Raw materials for synthesis of the compound are cheap and easy to obtain, the synthesis method is simple, meanwhile, the compound has good bacteriostatic activity on crop germs, especially has a remarkable activity inhibition effect on germs such as gibberellic disease bacteria, phytophthora germs, pyricularia grisea, sclerotinia sclerotiorum, botrytis cinerea and rhizoctonia solani, and the yield of crops is well guaranteed.

Description

Technical Field

[0001] The present invention belongs to the technical field of pesticide drugs. Specifically, it relates to a 3-esteryl-1,3-quinazoline-2,4-dione compound, a preparation method thereof, and uses thereof. Background Art

[0002] Quinazoline dione compounds are one of the hotspots in the fields of drug and pesticide research due to their wide range of biological activities and diverse structures. In terms of pesticides, they can be used as highly efficient insecticides, fungicides, herbicides, etc., playing a crucial role in ensuring the healthy growth of crops and increasing agricultural yields. In 2014, Ji et al. synthesized a series of quinazoline dione compounds and evaluated their inhibitory effects on chitin synthase (CHS) and antifungal activities in vitro. The results showed that the compounds had strong inhibitory ability against CHS, with a half-inhibitory concentration (IC50) of 0.08 mmol / L. In 2016, Pan Dingwu et al. designed and synthesized quinazoline dione compounds. The antibacterial test results showed that the compounds had an inhibition rate of 100% against Xanthomonas oryzae pv. oryzae at a concentration of 100 μg / mL. In addition, they also had certain inhibitory activities against Xanthomonas citri subsp. citri. In 2020, El-Naggar et al. synthesized a series of quinazoline-2,4-dione compounds. These compounds had strong interactions and good binding affinities with the outer membrane protein OmpU of Gram-negative bacteria, showing effective antibacterial activities against Gram-negative bacterial strains. In 2022, Boshta et al. reported the design and synthesis of a series of quinazoline-2,4(1H,3H)-dione derivatives. These compounds had a wide range of biological activity spectra against Gram-positive and Gram-negative strains. In 2024, Ibrahim et al. reported that quinazoline-2,4-dione analog compounds showed high antibacterial efficacy against two Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, and two Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus, at low doses, exceeding the traditional drug ciprofloxacin.

[0003] It can be seen that quinazoline dione compounds have wide biological activities and diverse structures, but esteryl-substituted quinazoline dione compounds are rarely reported in the previously published literature. Therefore, the present invention designs and synthesizes esteryl-substituted quinazoline dione compounds and studies their antibacterial activities. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a 3-ester-1,3-quinazoline-2,4-dione compound, a preparation method and uses thereof. This type of compound is prepared by reacting an amino acid ester hydrochloride with isatoic anhydride as raw materials in acetonitrile under the action of potassium carbonate to form an amide ester compound; then reacting the amide ester compound with triphosgene under the action of triethylamine to obtain a 3-ester-1,3-quinazoline-2,4-dione compound. The raw materials used in the synthesis of this type of compound are cheap and easily available, the synthesis method is simple, and it has good antibacterial activity against crop pathogens, especially significant inhibitory effects on pathogens such as Gibberella zeae, Phytophthora infestans, Magnaporthe oryzae, Sclerotinia sclerotiorum, Botrytis cinerea, and Rhizoctonia solani, which well guarantees the yield of crops.

[0005] To solve the above technical problems, the basic concept of the technical solution adopted by the present invention is:

[0006] On the one hand, the present invention provides a 3-ester-1,3-quinazoline-2,4-dione compound, which is a compound having the general structural formula (Ⅰ),

[0007]

[0008] wherein R 1 is an alkyl group with 1 - 6 carbon atoms or a hydrogen atom; R 2 is one of an alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, and a substituted benzyl group; R 3 is one of H, a halogen atom, or a methoxy group;

[0009] Preferably, R 1 is one of H or methyl; R 2 is one of an ethyl group, a benzyl group, or a 4-chlorobenzyl group; R 3 is one of H, chlorine, or bromine.

[0010] A 3-ester-1,3-quinazoline-2,4-dione compound having the general structural formula (Ⅰ) is specifically selected from one or more of the following compounds:

[0011] 3-(Benzyloxycarbonylmethyl)quinazoline-2,4-dione:

[0012]

[0013] 3-(Benzyloxycarbonylmethyl)-6-chloroquinazoline-2,4-dione:

[0014]

[0015] 3-(Benzyloxycarbonylmethyl)-7-chloroquinazoline-2,4-dione:

[0016]

[0017] 3-(1-(Benzyloxycarbonyl)-1-methylethyl)quinazoline-2,4-dione:

[0018]

[0019] 3-(1-(Benzyloxycarbonyl)-1-methylethyl)-6-chloroquinazoline-2,4-dione:

[0020]

[0021] 3-(1-(Benzyloxycarbonyl)-1-methylethyl)-6-bromoquinazoline-2,4-dione:

[0022]

[0023] 3-(Ethoxycarbonylmethyl)quinazoline-2,4-dione:

[0024]

[0025] 3-((4-Chlorobenzyloxy)carbonylmethyl)quinazoline-2,4-dione:

[0026]

[0027] On the other hand, the present invention provides a method for synthesizing 3-ester-1,3-quinazoline-2,4-dione compounds with the structural general formula (I), which specifically includes the following steps:

[0028] S1) React an amino acid ester hydrochloride with the structural formula (IV) and isatoic anhydride with the structural formula (V) in acetonitrile under the action of potassium carbonate to obtain an amide ester compound with the structural formula (III):

[0029]

[0030] S2) React the amide ester compound with the structural general formula (III) with triphosgene under the action of triethylamine to prepare 3-ester-1,3-quinazoline-2,4-dione compounds with the structural general formula (I):

[0031]

[0032] wherein R 1 is an alkyl group with 1-6 carbon atoms or a hydrogen atom; R 2 is one of an alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, and a substituted benzyl group; R 3 is one of H, a halogen atom, and a methoxy group;

[0033] Preferably, R 1 is one of H or methyl; R 2 is one of ethyl, benzyl or 4-chlorobenzyl; R 3 is one of H, chlorine or bromine;

[0034] Preferably, step S1) is specifically as follows: Weigh the amino acid ester hydrochloride of structural general formula (IV), isatoic anhydride of structural general formula (V), and K2CO3 and add them into a 100 mL round-bottom flask, add 30 mL of acetonitrile to dissolve, and heat the reaction solution to react to obtain the amide ester compound of formula (III).

[0035] In the present invention, in step S1), the preferred reaction molar ratio of the amino acid ester hydrochloride having structural general formula (IV), isatoic anhydride of structural general formula (V), and potassium carbonate is 1.2:1:1.2, the preferred temperature is 50 °C, and the preferred reaction time is 18 h.

[0036] Preferably, step S2) is specifically as follows: Weigh compound III (0.853 g, 3 mmol) and triethylamine (0.607 g, 6 mmol) and add them into a 100 mL round-bottom flask, and add 30 mL of tetrahydrofuran to dissolve. Triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran is slowly added dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is completed, it is transferred to an oil bath at 65 °C for reaction for 4 h. After the reaction is completed, it is cooled, and the solvent is removed under reduced pressure. The obtained solid is extracted with DCM and water, the organic phase is separated, and the aqueous phase is extracted with DCM (30 mL × 3 times). The organic phases are combined, dried with anhydrous Na2SO4, and the solvent is removed by rotary evaporation under reduced pressure. The 3-esteryl-1,3-quinazoline-2,4-dione compound of structural general formula (I) is obtained through column chromatography separation.

[0037] In the present invention, the function of adding triethylamine is, firstly, to remove the possible acidic components (such as hydrochloric acid, etc.) in the reactants, and secondly, to neutralize the hydrochloric acid generated by the reaction of triphosgene and the reactants to promote the reaction.

[0038] Preferably, the solvent is an organic solvent, preferably tetrahydrofuran.

[0039] Preferably, the molar ratio of the amount of triphosgene added to the key reactant (such as compound III-1) is 1-3:3, preferably 1.5-2.5:3, more preferably 1.8-2:3.

[0040] Preferably, the molar ratio of the amount of triethylamine added to the key reactant (such as compound III-1) is 1-3:1, preferably 1.5-2.5:1, more preferably 1.9-2.1:1.

[0041] Preferably, the reaction solvent has different preferences in different steps. For the synthesis step of compound I, tetrahydrofuran is used as the solvent; for the synthesis step of compound III, acetonitrile is used as the solvent.

[0042] In the present invention, the reaction temperature for obtaining the triphosgene mixture is 0 - 10°C, preferably 0 - 5°C, more preferably 0 - 2°C; for example, the temperature range of an ice-water bath. The reaction time is 1 - 7 h, preferably 3 - 5 h, more preferably 3.5 - 4.5 h.

[0043] In the present invention, before adding the triphosgene mixture to the mixed solution containing reactant III, the solution containing reactant III is first cooled to an appropriate low temperature. The reaction temperature between the triphosgene mixture and the mixed solution containing reactant III is -5 to 30°C, preferably 0 to 20°C. The reaction time is 1 - 7 h, preferably 3 - 5 h, more preferably 3.5 - 4.5 h.

[0044] In the present invention, the separation is filtration, suction filtration or extraction; preferably, multiple alternating extractions with water and tetrahydrofuran are used for separation.

[0045] Preferably, the present invention also includes drying the extracted organic phase, preferably using anhydrous Na2SO4 for drying.

[0046] Preferably, the present invention also includes a desolvation process for the dried product, preferably using vacuum desolvation.

[0047] On the other hand, the present invention provides a 3 - ester - 1,3 - quinazoline - 2,4 - dione compound having the structural general formula (Ⅰ), or the use of a 3 - ester - 1,3 - quinazoline - 2,4 - dione compound having the structural general formula (Ⅰ) prepared by the above method, and the 3 - ester - 1,3 - quinazoline - 2,4 - dione compound having the structural general formula (Ⅰ) is used for antibacterial of crops; specifically used for inhibiting one or more of Gibberella zeae, Magnaporthe oryzae, Phytophthora infestans, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani.

[0048] Preferably, the 3 - ester - 1,3 - quinazoline - 2,4 - dione compound having the structural general formula (Ⅰ) is used for inhibiting Sclerotinia sclerotiorum.

[0049] On the other hand, the present invention provides a 3-ester-1,3-quinazoline-2,4-dione compound having the structural general formula (I), or the use of a 3-ester-1,3-quinazoline-2,4-dione compound having the structural general formula (I) prepared by the above method. The 3-ester-1,3-quinazoline-2,4-dione compound having the structural general formula (I) is used to prepare a drug for inhibiting bacteria in crops, specifically for preparing a drug for inhibiting one or more of Gibberella zeae, Magnaporthe oryzae, Phytophthora infestans, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani.

[0050] Preferably, the 3-ester-1,3-quinazoline-2,4-dione compound having the structural general formula (I) is used for preparing a drug for inhibiting Magnaporthe oryzae, Sclerotinia sclerotiorum and Rhizoctonia solani.

[0051] In the present invention, an amide ester compound solution having the structural general formula (III) is obtained by reacting an amino acid ester hydrochloride with isatoic anhydride. This type of compound has good inhibitory effects on crop disease-causing bacteria and can be used for directly inhibiting bacteria in crops or for preparing drugs for inhibiting bacteria in crops; through further experiments, the amide ester compound having the structural general formula (III) is used as an intermediate product. Further, triphosgene is dissolved in tetrahydrofuran to obtain a triphosgene solution of tetrahydrofuran, and then the amide ester compound solution having the structural general formula (III) is reacted with the triphosgene solution of tetrahydrofuran to obtain a 3-ester-1,3-quinazoline-2,4-dione compound having a brand-new structure and the structural general formula (I). This type of compound has good inhibitory effects on crop disease-causing bacteria and can be used for directly inhibiting bacteria in crops or for preparing drugs for inhibiting bacteria in crops;

[0052] After adopting the above technical solution, the present invention has the following beneficial effects compared with the prior art.

[0053] 1. The 3-ester-1,3-quinazoline-2,4-dione compound having the structural general formula (I) prepared in the present invention is a brand-new compound, and this compound has very good antibacterial activity; especially, the inhibitory effect on the activity of Gibberella zeae, Phytophthora infestans, Magnaporthe oryzae, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani is remarkable.

[0054] 2. In the preparation method of the 3-ester-1,3-quinazoline-2,4-dione compound having the structural general formula (I) provided by the present invention, the synthetic raw materials are cheap and easily available, the synthesis method is simple, the yield is relatively high, and the product is easy to separate and purify.

[0055] The following further describes in detail the specific embodiments of the present invention with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The accompanying drawings, as part of this application, are used to provide a further understanding of the present invention. The schematic embodiments and descriptions thereof of the present invention are used to explain the present invention, but do not unduly limit the present invention. Obviously, the accompanying drawings in the following description are only some embodiments, and those of ordinary skill in the art can obtain other drawings based on these drawings without creative efforts. In the accompanying drawings:

[0057] Figure 1 It is a structural diagram of the 3-ester-1,3-quinazoline-2,4-dione compound with the structural general formula (Ⅰ) according to the present invention.

[0058] Figure 2 It is a synthetic route diagram of the 3-ester-1,3-quinazoline-2,4-dione compound with the structural general formula (Ⅰ) according to the present invention.

[0059] It should be noted that these accompanying drawings and textual descriptions are not intended to limit the scope of the concept of the present invention in any way, but to illustrate the concept of the present invention to those skilled in the art by referring to specific embodiments. Detailed Embodiments

[0060] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. The following embodiments are used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0061] The structural formulas of the intermediate products of the present invention are as shown in Table 1 below:

[0062] Table 1 Structural Formulas of Intermediate Products

[0063]

[0064] The sources of the chemical reagents used in the embodiments of the present invention are as follows:

[0065] Shanghai Merck Chemical Technology Co., Ltd.: Glycine benzyl ester hydrochloride (CAS: 1738-68-7), Isatoic anhydride (CAS: 118-48-9), Triphosgene (CAS: 75-36-5), Anhydrous sodium sulfate (CAS: 7757-82-6), Acetonitrile (CAS: 75-05-8), L-Alanine benzyl ester hydrochloride (CAS: 5557-83-5, 5Cl-Isatoic anhydride (CAS: 4743-17-3), 5Br-Isatoic anhydride (CAS: 4692-98-2), 4-Chlorophenylglycine (CAS: 67336-19-0)

[0066] Xilong Chemical Co., Ltd.: Triethylamine (CAS: 121-44-8)

[0067] Guangdong Guanghua Sci-Tech Co., Ltd.: anhydrous methanol (CAS: 67-56-1), tetrahydrofuran (CAS:

[0068] 109-99-9), ethyl acetate (CAS: 141-78-6).

[0069] Hunan Huihong Reagent Co., Ltd.: absolute ethanol (CAS: 64-17-5).

[0070] Example A1

[0071] Synthesis of 3-(benzyloxycarbonylmethyl)quinazoline-2,4-dione

[0072]

[0073] Weigh benzyl glycinate hydrochloride (0.242 g, 1.2 mmol), isatoic anhydride (0.163 g, 1 mmol), and K2CO3 (0.166 g, 1.2 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of acetonitrile to dissolve. Transfer to an oil bath at 50 °C and react for 18 h. After the reaction is completed, remove the solvent under reduced pressure. The obtained solid is extracted with water (30 mL × 2 times), and the aqueous phase is extracted with DCM (30 mL × 3 times). Combine the organic phases, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the yellow solid 2-((2-aminobenzoyl)amino)benzyl acetate.

[0074] Weigh 2-((2-aminobenzoyl)amino)benzyl acetate (0.853 g, 3 mmol) and triethylamine (0.607 g, 6 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of tetrahydrofuran to dissolve. Slowly add triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is complete, transfer to an oil bath at 65 °C and react for 4 h. After the reaction is completed, cool and remove the solvent under reduced pressure. The obtained solid is added with DCM and water, and the organic phase is separated. The aqueous phase is extracted with DCM (30 mL × 3 times). Combine the organic phases and dry with anhydrous Na2SO4, then remove the solvent under reduced pressure. Separate by column chromatography to obtain a white solid.

[0075] 1 H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 7.98 (dd, J = 8.0, 1.5 Hz, 1H), 7.74 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 7.41 (d, J = 4.6 Hz, 5H), 7.32 - 7.22 (m, 2H), 5.23 (s, 2H), 4.77 (s, 2H).

[0076] 1313C NMR(101MHz, DMSO-d6) δ 168.99, 162.57, 150.74, 140.35, 136.60, 136.46, 129.42, 129.13, 128.87, 128.41, 123.86, 116.36, 114.26, 67.33, 42.37.

[0077] Example A2

[0078] Synthesis of 3-(Benzyloxycarbonylmethyl)-6-chloroquinazoline-2,4-dione

[0079]

[0080] Weigh glycine benzyl ester hydrochloride (0.242 g, 1.2 mmol), 5-Cl isatoic anhydride (0.198 g, 1 mmol), and K2CO3 (0.166 g, 1.2 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of acetonitrile to dissolve. Transfer it to an oil bath at 50 °C and react for 18 h. After the reaction is completed, remove the solvent under reduced pressure. The obtained solid is extracted with water (30 mL × 2 times), and the aqueous phase is extracted with DCM (30 mL × 3 times). Combine the organic phases, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the yellow solid 2-((2-Amino-5-chlorobenzoyl)amino)benzyl acetate.

[0081] Weigh 2-((2-Amino-5-chlorobenzoyl)amino)benzyl acetate (0.957 g, 3 mmol) and triethylamine (0.607 g, 6 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of tetrahydrofuran to dissolve. Slowly add triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is completed, transfer it to an oil bath at 65 °C and react for 4 h. After the reaction is over, cool it down and remove the solvent under reduced pressure. Add DCM and water to the obtained solid, separate the organic phase, and extract the aqueous phase with DCM (30 mL × 3 times). Combine the organic phases and dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain a white solid.

[0082] 1 1H NMR(400MHz, DMSO-d6) δ 11.82(s, 1H), 7.88(d, J = 2.4 Hz, 1H), 7.75(dd, J = 8.7, 2.5 Hz, 1H), 7.38(d, J = 4.6 Hz, 5H), 7.25(d, J = 8.7 Hz, 1H), 5.20(s, 2H), 4.74(s, 2H).

[0083] 1313C NMR(101MHz, DMSO-d6) δ 168.29, 161.11, 149.94, 138.72, 136.07, 135.88, 128.92, 128.64, 128.37, 127.36, 126.81, 118.14, 115.10, 66.90, 42.01.

[0084] Example A3

[0085] Synthesis of 3-(Benzyloxycarbonylmethyl)-7-chloroquinazoline-2,4-dione

[0086]

[0087] Weigh glycine benzyl ester hydrochloride (0.242 g, 1.2 mmol), 4-Cl isatoic anhydride (0.198 g, 1 mmol), and K2CO3 (0.166 g, 1.2 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of acetonitrile to dissolve. Transfer it to an oil bath at 50 °C and react for 18 h. After the reaction is completed, remove the solvent under reduced pressure. The obtained solid is extracted with water (50 mL × 2 times), and the aqueous phase is extracted with DCM (50 mL × 3 times). Combine the organic phases, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the yellow solid benzyl 2-((2-amino-4-chlorobenzoyl)amino)acetate.

[0088] Weigh benzyl 2-((2-amino-4-chlorobenzoyl)amino)acetate (0.957 g, 3 mmol) and triethylamine (0.607 g, 6 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of tetrahydrofuran to dissolve. Slowly add triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is complete, transfer it to an oil bath at 65 °C and react for 4 h. After the reaction is over, cool it down, remove the solvent under reduced pressure. Add DCM and water to the obtained solid, separate the organic phase, and extract the aqueous phase with DCM (30 mL × 3 times). Combine the organic phases and dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the yellow solid.

[0089] 1 1H NMR(400MHz, DMSO-d6) δ 11.81(s, 1H), 7.95(d, J = 8.4 Hz, 1H), 7.44 - 7.32(m, 5H), 7.28(dd, J = 8.5, 1.9 Hz, 1H), 7.23(d, J = 2.0 Hz, 1H), 5.20(s, 2H), 4.73(s, 2H).

[0090] 1313C NMR (101 MHz, DMSO-d6) δ 168.32, 161.35, 150.10, 140.89, 140.35, 136.07, 130.01, 128.92, 128.64, 128.37, 123.60, 115.27, 112.69, 66.88, 41.91.

[0091] Example A4

[0092] Synthesis of 3-(1-(Benzyloxycarbonyl)-1-methylmethyl)quinazoline-2,4-dione

[0093]

[0094] Take L-alanine benzyl ester hydrochloride (0.259 g, 1.2 mmol), isatoic anhydride (0.163 g, 1 mmol), and K2CO3 (0.166 g, 1.2 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of acetonitrile to dissolve. Transfer it to an oil bath at 50 °C and react for 18 h. After the reaction is completed, remove the solvent under reduced pressure. The obtained solid is extracted with water (30 mL × 2 times), and the aqueous phase is extracted with DCM (30 mL × 3 times). Combine the organic phases, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain benzyl 2-((2-aminobenzoyl)amino)propionate.

[0095] Weigh benzyl 2-((2-aminobenzoyl)amino)propionate (0.894 g, 3 mmol) and triethylamine (0.607 g, 6 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of tetrahydrofuran to dissolve. Slowly add triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is complete, transfer it to an oil bath at 65 °C and react for 4 h. After the reaction is over, cool it down, remove the solvent under reduced pressure. Add DCM and water to the obtained solid, separate the organic phase, and extract the aqueous phase with DCM (30 mL × 3 times). Combine the organic phases and dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain a white solid.

[0096] 1 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.68 (ddd, J = 8.5, 7.3, 1.5 Hz, 1H), 7.29 (s, 5H), 7.25 - 7.16 (m, 2H), 5.57 (q, J = 6.9 Hz, 1H), 5.12 (s, 2H), 1.53 (d, J = 6.9 Hz, 3H).

[0097] 13 C NMR(101MHz, DMSO-d6) δ 170.25, 161.86, 149.96, 139.81, 136.42, 135.91, 128.79, 128.38, 128.04, 127.97, 123.32, 115.75, 113.93, 66.54, 49.24, 14.74.

[0098] Example A5

[0099] Synthesis of 3-(1-(Benzyloxycarbonyl)-1-methylmethyl)-6-chloroquinazoline-2,4-dione

[0100]

[0101] Take L-alanine benzyl ester hydrochloride (0.259 g, 1.2 mmol), 5-chloro isatoic anhydride (0.198 g, 1 mmol), and K2CO3 (0.166 g, 1.2 mmol) and add them to a 100 mL round-bottom flask, then add 30 mL of acetonitrile to dissolve. Transfer it to an oil bath at 50 °C and react for 18 h. After the reaction is completed, remove the solvent by distillation under reduced pressure. The obtained solid is extracted with water (30 mL × 2 times), and the aqueous phase is extracted with DCM (30 mL × 3 times). Combine the organic phases, dry with anhydrous Na2SO4, remove the solvent by distillation under reduced pressure, and separate by column chromatography to obtain the white solid 2-((2-amino-5-chlorobenzoyl)amino)propionic acid benzyl ester.

[0102] Weigh 2-((2-amino-5-chlorobenzoyl)amino)propionic acid benzyl ester (0.999 g, 3 mmol) and triethylamine (0.607 g, 6 mmol) and add them to a 100 mL round-bottom flask, then add 30 mL of tetrahydrofuran to dissolve. Slowly add triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is complete, transfer it to an oil bath at 65 °C and react for 4 h. After the reaction is completed, cool it down, remove the solvent by distillation under reduced pressure. Add DCM and water to the obtained solid, separate the organic phase, and extract the aqueous phase with DCM (30 mL × 3 times). Combine the organic phases and dry with anhydrous Na2SO4, remove the solvent by distillation under reduced pressure, and separate by column chromatography to obtain a yellow solid.

[0103] 1 H NMR(400MHz, DMSO-d6) δ 11.81(s, 1H), 7.88(d, J = 2.5Hz, 1H), 7.74(dd, J = 8.8, 2.5Hz, 1H), 7.30(t, J = 2.2Hz, 5H), 7.23(d, J = 8.7Hz, 1H), 5.58(q, J = 6.9Hz, 1H), 5.14(s, 2H), 1.54(d, J = 7.0Hz, 3H).

[0104] 13 C NMR (101 MHz, DMSO-d6) δ 170.05, 160.91, 149.69, 138.68, 136.36, 135.79, 128.78, 128.40, 128.07, 127.29, 126.86, 118.01, 115.30, 66.60, 49.46, 14.62.

[0105] Example A6

[0106] Synthesis of 3-(1-(Benzyloxycarbonyl)-1-methylmethyl)-6-bromoquinazoline-2,4-dione

[0107]

[0108] Weigh L-alanine benzyl ester hydrochloride (0.259 g, 1.2 mmol), 5-bromo isatoic anhydride (0.242 g, 1 mmol), and K2CO3 (0.166 g, 1.2 mmol), add them into a 100 mL round-bottom flask, and dissolve with 30 mL of acetonitrile. Transfer it to an oil bath at 50 °C and react for 18 h. After the reaction is completed, remove the solvent under reduced pressure. The obtained solid is extracted with water (30 mL × 2 times), and the aqueous phase is extracted with DCM (30 mL × 3 times). Combine the organic phases, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the white solid 2-((2-amino-5-bromobenzoyl)amino)propionic acid benzyl ester.

[0109] Weigh 2-((2-amino-5-bromobenzoyl)amino)propionic acid benzyl ester (1.131 g, 3 mmol) and triethylamine (0.607 g, 6 mmol), add them into a 100 mL round-bottom flask, and dissolve with 30 mL of tetrahydrofuran. Slowly add triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is completed, transfer it to an oil bath at 65 °C and react for 4 h. After the reaction is over, cool it down, remove the solvent under reduced pressure. Add DCM and water to the obtained solid, separate the organic phase, and extract the aqueous phase with DCM (30 mL × 3 times). Combine the organic phases and dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the white solid.

[0110] 11H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 8.7, 2.3 Hz, 1H), 7.36 - 7.25 (m, 5H), 7.17 (d, J = 8.7 Hz, 1H), 5.57 (q, J = 6.9 Hz, 1H), 5.13 (s, 2H), 1.53 (d, J = 7.0 Hz, 3H).

[0111] 13 13C NMR (101 MHz, DMSO-d6) δ 170.05, 160.82, 149.69, 139.02, 138.49, 136.36, 129.86, 128.79, 128.40, 128.07, 118.23, 115.71, 114.81, 66.60, 49.46, 14.63.

[0112] Example A7

[0113] Synthesis of 3-(Ethoxycarbonylmethyl)quinazoline-2,4-dione

[0114]

[0115] Weigh glycine ethyl ester hydrochloride (0.168 g, 1.2 mmol), isatoic anhydride (0.163 g, 1 mmol), and K2CO3 (0.166 g, 1.2 mmol), add them into a 100 mL round-bottom flask, and dissolve with 30 mL of acetonitrile. Transfer to an oil bath at 50 °C and react for 18 h. After the reaction is completed, remove the solvent under reduced pressure. The obtained solid is extracted with water (30 mL × 2 times), and the aqueous phase is extracted with DCM (30 mL × 3 times). Combine the organic phases, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the yellow solid ethyl 2-((2-aminobenzoyl)amino)acetate.

[0116] Weigh ethyl 2-((2-aminobenzoyl)amino)acetate (0.666 g, 3 mmol) and triethylamine (0.607 g, 6 mmol), add them into a 100 mL round-bottom flask, and dissolve with 30 mL of tetrahydrofuran. Slowly add triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is completed, transfer to an oil bath at 65 °C and react for 4 h. After the reaction is completed, cool down, remove the solvent under reduced pressure. Add DCM and water to the obtained solid, separate the organic phase, and extract the aqueous phase with DCM (30 mL × 3 times). Combine the organic phases and dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain a white solid.

[0117] 11H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.93 (dd, J = 7.9, 1.5 Hz, 1H), 7.72 - 7.66 (m, 1H), 7.26 - 7.20 (m, 2H), 4.65 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H).

[0118] 13 13C NMR (101 MHz, DMSO-d6) δ 168.95, 162.51, 150.69, 140.33, 136.39, 128.37, 123.79, 116.31, 114.25, 61.98, 42.29, 14.94.

[0119] Example A8

[0120] Synthesis of 3-(4-chlorobenzyloxycarbonylmethyl)quinazoline-2,4-dione

[0121]

[0122] Weigh glycine-4-chlorobenzyl ester p-toluenesulfonate (0.372 g, 1.2 mmol), isatoic anhydride (0.163 g, 1 mmol), and K2CO3 (0.166 g, 1.2 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of acetonitrile to dissolve. Transfer it to an oil bath at 50 °C and react for 18 h. After the reaction is completed, remove the solvent under reduced pressure. The obtained solid is extracted with water (30 mL × 2 times), and the aqueous phase is extracted with DCM (30 mL × 3 times). Combine the organic phases, dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the yellow solid 2-((2-aminobenzoyl)amino)acetic acid (2-chlorobenzyl) ester.

[0123] Weigh 2-((2-aminobenzoyl)amino)acetic acid (2-chlorobenzyl) ester (0.957 g, 3 mmol) and triethylamine (0.607 g, 6 mmol) and add them to a 100 mL round-bottom flask. Then add 30 mL of tetrahydrofuran to dissolve. Slowly add triphosgene (0.579 g, 1.95 mmol) dissolved in tetrahydrofuran dropwise through a constant pressure dropping funnel in an ice-water bath. After the addition is completed, transfer it to an oil bath at 65 °C and react for 4 h. After the reaction is over, cool it down, remove the solvent under reduced pressure. Add DCM and water to the obtained solid, separate the organic phase, and extract the aqueous phase with DCM (30 mL × 3 times). Combine the organic phases and dry with anhydrous Na2SO4, remove the solvent under reduced pressure, and separate by column chromatography to obtain the yellow solid.

[0124] 11H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.47 - 7.39 (m, 4H), 7.25 (ddd, J = 9.2, 7.7, 1.5 Hz, 2H), 5.20 (s, 2H), 4.75 (s, 2H).

[0125] 13 13C NMR (101 MHz, DMSO-d6) δ 168.47, 162.07, 150.23, 139.86, 135.97, 135.17, 133.29, 130.26, 128.92, 127.92, 123.36, 115.87, 113.77, 66.02, 41.87.

[0126] Test on the antibacterial activity effect of crops

[0127] In vitro antibacterial activity tests were carried out on 3-(benzyloxycarbonylmethyl)quinazoline-2,4-dione, 3-(benzyloxycarbonylmethyl)-6-chloroquinazoline-2,4-dione, 3-(benzyloxycarbonylmethyl)-7-chloroquinazoline-2,4-dione, 3-(1-(benzyloxycarbonyl)-1-methylmethyl)quinazoline-2,4-dione, 3-(1-(benzyloxycarbonyl)-1-methylmethyl)-6-chloroquinazoline-2,4-dione, 3-(1-(benzyloxycarbonyl)-1-methylmethyl)-6-bromoquinazoline-2,4-dione, 3-(ethoxycarbonylmethyl)quinazoline-2,4-dione, 3-(4-chlorobenzyloxycarbonylmethyl)quinazoline-2,4-dione.

[0128] Taking Gibberella zeae, Phytophthora capsici, Magnaporthe oryzae, Sclerotinia sclerotiorum, Botrytis cinerea and Rhizoctonia solani as test materials for bactericidal activity tests, the test agents were dissolved in acetone and then diluted with 200 g / ml sorpol - 144 emulsifier to a 500 g / mL liquid medicine. Under sterile operating conditions, 1 mL of the compound solution was pipetted into a sterilized petri dish, and then 9 mL of sterilized PDA culture medium was pipetted into the petri dish and mixed well to prepare a drug-containing plate with the corresponding concentration. The cultured pathogenic bacteria were cut into discs with a diameter of 4 mm using a sterilized puncher at the edge of the colony under sterile conditions. After the culture medium solidified, the discs were inoculated in the center of the drug-containing plate with an inoculator and placed in an incubator at an appropriate temperature for culture. The treatment without the agent was used as a blank control. Each treatment was cultured in an incubator at 24 ± 1 °C. After 72 hours, the colony diameter was observed and measured. The diameter of each colony was measured vertically once using the cross method, and the average value was taken.

[0129] Growth inhibition rate (%) = (control colony diameter - treated colony diameter) × 100 / (control colony diameter - 4 mm).

[0130] The drug concentration was 50 μg / mL. The antibacterial activity test results are shown in Table 2.

[0131] Table 2 Antibacterial activity results

[0132]

[0133] As can be seen from Table 2, the target compounds all have antibacterial activity against the tested pathogenic bacteria, and some have good antibacterial activity. Among them, the inhibition rate of 3-(benzyloxycarbonylmethyl)quinazoline-2,4-dione against Sclerotinia sclerotiorum is as high as 92.8%; the inhibition rate of 3-(benzyloxycarbonylmethyl)-7-chloroquinazoline-2,4-dione against Sclerotinia sclerotiorum is as high as 75.6%; the inhibition rate of 3-(1-(benzyloxycarbonyl)-1-methylmethyl)quinazoline-2,4-dione against Rhizoctonia solani is 78.9%.

[0134] The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art of this patent, without departing from the scope of the technical solution of the present invention, can make some changes or modifications using the technical content prompted above into equivalent embodiments of equivalent changes. However, as long as it does not depart from the content of the technical solution of the present invention, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention still fall within the scope of the present invention's solution.

Claims

1. A 3-ester-1,3-quinazoline-2,4-dione compound, characterized in that, The compound has a general structural formula (I). Wherein, R 1 is an alkyl group having 1 to 6 carbon atoms or a hydrogen atom; R 2 is one of an alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, and a substituted benzyl group; R 3 is one of H, a halogen atom, and a methoxy group.

2. The 3-ester-1,3-quinazoline-2,4-dione compound according to claim 1, characterized in that, R 1 is one of H or methyl; R 2 is one of alkyl, benzyl or 4-chlorobenzyl; R 3 is one of H, chlorine or bromine.

3. A 3-ester-1,3-quinazoline-2,4-dione compound, characterized in that, The compound is selected from one or more of the following compounds: 3-(Benzyloxycarbonylmethyl)quinazoline-2,4-dione: 3-(Benzyloxycarbonylmethyl)-6-chloroquinazoline-2,4-dione: 3-(Benzyloxycarbonylmethyl)-7-chloroquinazoline-2,4-dione: 3-(1-(Benzyloxycarbonyl)-1-methylethyl)quinazoline-2,4-dione: 3-(1-(Benzyloxycarbonyl)-1-methylethyl)-6-chloroquinazoline-2,4-dione: 3-(1-(Benzyloxycarbonyl)-1-methylethyl)-6-bromoquinazoline-2,4-dione: 3-(Ethoxycarbonylmethyl)quinazoline-2,4-dione: 3-((4-Chlorobenzyloxy)carbonylmethyl)quinazoline-2,4-dione:

4. A method for preparing a 3-ester-1,3-quinazoline-2,4-dione compound with the structural general formula (Ⅰ), characterized in that, The general structural formula (I) is: The preparation method specifically includes the following steps: S1. React the amino acid ester hydrochloride with the structural formula (IV) and isatoic anhydride with the structural formula (V) in acetonitrile under the action of potassium carbonate to obtain an amide ester compound with the structural formula (III): S2. React the amide ester compound with the general structural formula (III) with triphosgene under the action of triethylamine to prepare a 3-esteryl-1,3-quinazoline-2,4-dione compound with the general structural formula (I): Wherein, R 1 is an alkyl group having 1 to 6 carbon atoms or a hydrogen atom; R 2 is one of an alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, and a substituted benzyl group; R 3 is one of H, a halogen atom, and a methoxy group.

5. The preparation method according to claim 4, characterized in that, R 1 is one of H or methyl; R 2 is one of ethyl, benzyl or 4-chlorobenzyl; R 3 is one of H, chlorine or bromine.

6. The preparation method according to claim 4, wherein Step S1 is specifically: Weigh the amino acid ester hydrochloride with the general structural formula (IV), isatoic anhydride with the general structural formula (V), and K2CO3 and add them to a 100 mL round-bottom flask, and add 30 mL of acetonitrile to dissolve. Then heat the reaction solution to react to obtain an amide ester compound with the structural formula (III); Step S2 is specifically: Weigh the amide ester compound with the structural formula (III) and triethylamine and add them to a 100 mL round-bottom flask, and add 30 mL of tetrahydrofuran to dissolve. Slowly drop the triphosgene dissolved in tetrahydrofuran through a constant pressure dropping funnel in an ice-water bath. After the dropping is completed, transfer it to an oil bath at 65 °C and react for 4 h. After the reaction is completed, cool it, remove the solvent under reduced pressure. The obtained solid is extracted with DCM and water, and the organic phase is separated. The aqueous phase is extracted with DCM three times, and the organic phases are combined, dried with anhydrous Na2SO4, and the solvent is removed by rotary evaporation under reduced pressure. The 3-esteryl-1,3-quinazoline-2,4-dione compound with the general structural formula (I) is obtained through column chromatography separation.

7. The preparation method according to claim 6, wherein In step S1, the molar ratio of the amino acid ester hydrochloride with the general structural formula (IV), isatoic anhydride with the general structural formula (V), and potassium carbonate is 1.2:1:1.2; In step S2, the addition amount of triphosgene and the molar ratio of the amide ester compound with the structural formula (III) is 1-3:

3.

8. The preparation method according to claim 6, wherein In step S2, before adding the triphosgene mixed solution to the mixed solution containing the amide ester compound of the reactant structural formula (Ⅲ), the mixed solution is first cooled to a low temperature. The reaction temperature of the triphosgene mixed solution and the mixed solution containing the amide ester compound of the reactant structural formula (Ⅲ) is -5 to 30 °C, and the reaction time is 1 - 7 h; The ice-water bath temperature range for obtaining the triphosgene mixed solution is 0 - 10 °C, and the reaction time is 1 - 7 h.

9. Use of the 3-ester-1,3-quinazoline-2,4-dione compound with structural general formula (I) according to any one of claims 1-3 or the 3-ester-1,3-quinazoline-2,4-dione compound with structural general formula (I) prepared by the method according to any one of claims 4-8, characterized in that, For inhibiting bacteria in crops or for preparing drugs for inhibiting bacteria in crops.

10. The use according to claim 9, characterized in that, For inhibiting bacteria in crops includes inhibiting one or more of Sclerotinia sclerotiorum, Phytophthora infestans, Gibberella zeae, Magnaporthe oryzae, Botrytis cinerea, and Rhizoctonia solani; For preparing drugs for inhibiting bacteria in crops includes preparing drugs for inhibiting one or more of Sclerotinia sclerotiorum, Phytophthora infestans, Gibberella zeae, Magnaporthe oryzae, Botrytis cinerea, and Rhizoctonia solani.

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