Acetamido-substituted amide ester compound and preparation method and application thereof

Abstract

The invention discloses an acetamido-substituted amide ester compound as well as a preparation method and application thereof, the compound takes amino-acid ester hydrochloride and isatoic anhydride as raw materials, and the raw materials react in acetonitrile under the action of potassium carbonate to generate the amide ester compound; and reacting the amide ester compound with acetyl chloride under the action of triethylamine to obtain the acetamido substituted amide ester compound. The raw materials for synthesis of the compound are cheap and easy to obtain, and the synthesis method is simple. Meanwhile, the compound has a good inhibition effect on the activity of crop germs, and particularly has remarkable inhibition activity on fusarium graminearum, phytophthora capsici, pyricularia grisea, sclerotinia sclerotiorum, cucumber botrytis cinerea and rhizoctonia solani.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicines and pharmaceuticals, and in particular, relates to an acetylamino-substituted amide ester compound and a preparation method and use thereof. Background Art

[0002] Substituted amide compounds and amide ester compounds are one of the hot topics in the field of drug and pesticide research. They have attracted much attention due to their wide range of biological activities and diverse structures, and are widely used in the fields of medicine, pesticides, fine chemicals, etc. In terms of pesticides, they can be used as highly effective insecticides, fungicides, and herbicides, etc., and play a vital role in ensuring the healthy growth of crops and increasing agricultural yields. For example, in 2013, Sun et al. reported that benzoyl urea compounds showed good insecticidal activity against the larvae of the diamondback moth, and could effectively control the damage of this type of pest to crops; in 2022, The new diamide derivatives synthesized by et al. show excellent antibacterial activity against Bacillus cereus, which helps to deal with the problem of bacterial infection of crops. In the field of medicine, it also has considerable application potential. For example, in 2008, Hsu-Shan Huang et al. reported amide-substituted anthraquinone derivatives, which are effective telomerase inhibitors and provide new ideas and directions for related research such as cancer treatment. In 2023, Huibin Yang et al. synthesized a new type of anthranilamide derivative containing a 3,5-dichloropyridylpyrazole group, in which tetrachlorfenapyr showed considerable activity against beet armyworms and had a very low toxicity to mammals, highlighting the advantages of this type of compound in ensuring insecticidal effects while taking into account safety.

[0003] However, with the increasing demand for practical applications and the increasing requirements for compound performance, the existing substituted amide compounds still have some limitations. As far as we know, amide ester compounds containing acetylamino substitution are rare in the literature reported in the past. Therefore, the present invention mainly studies the synthesis and antibacterial activity of amide ester compounds substituted with acetylamino, and provides new ideas and solutions for solving the pain points in the application of existing compounds. 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 an acetylamino-substituted amide ester compound and a preparation method and use thereof. The preparation method of the compound is simple and the raw materials are readily available. The compound has good antibacterial activity against crop pathogens, especially against wheat fusarium sphaeroides, pepper phytophthora, rice blast, rapeseed sclerotinia, cucumber gray mold, rice sheath blight and other pathogens, thereby ensuring the yield of crops.

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

[0006] In one aspect, the present invention provides an acetylamino-substituted amide ester compound having a general structural formula (I):

[0007]

[0008] Where R 1 is one of H, halogen atom or methoxy; R 3 is a C1-C6 alkyl group or a hydrogen atom; R 2 is one of H, alkyl or halogen atoms.

[0009] Preferably, R 1 is one of H, chlorine, bromine or methoxy; R 3 is a methyl group or H; R 2 It is one of H or a halogen atom.

[0010] Preferably, the compound having the general structural formula (I) is selected from one or more of the following compounds:

[0011] Benzyl (2-acetylaminobenzoyl) alanine ester

[0012]

[0013] Benzyl (2-acetylamino-5-chlorobenzoyl) glycinate

[0014]

[0015] Benzyl (2-acetylamino-5-chlorobenzoyl) alaninate

[0016]

[0017] Benzyl (2-acetylamino-5-bromobenzoyl) alaninate

[0018]

[0019] Benzyl (2-acetylamino-5-bromobenzoyl) glycinate

[0020]

[0021] Benzyl (2-acetylamino-5-methoxybenzoyl) glycinate

[0022]

[0023] Benzyl (2-acetylamino-5-methoxybenzoyl) alanine ester

[0024]

[0025] 4-Chlorobenzyl (2-acetylaminobenzoyl) glycine ester

[0026]

[0027] Another aspect of the present invention provides a method for preparing an acetylamino-substituted amide ester compound, the method specifically comprising the following steps:

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

[0029]

[0030] S2) reacting an amide ester compound having the general structural formula (III) with acetyl chloride in the presence of triethylamine to prepare an acetylamino-substituted amide ester compound having the general structural formula (I):

[0031]

[0032] Where R 1 is one of H, halogen atom or methoxy; R 3 is a C1-C6 alkyl group or a hydrogen atom; R 2 is one of H, alkyl or halogen atom.

[0033] As a preference, R 1 is one of H, chlorine, bromine or methoxy; R 3 is a methyl group or H; R 2 It is one of H or a halogen atom.

[0034] Preferably, step S1) is specifically as follows: weighing the amino acid ester hydrochloride of the general structural formula (IV), the isatoic anhydride of the general structural formula (V), K 2 CO 3 The mixture was added to a 100 mL round-bottom flask, and 30 mL of acetonitrile was added to dissolve the mixture. The reaction solution was heated to react to obtain an amide ester compound having the structural formula (III).

[0035] In step S1) of the present invention, the preferred reaction molar ratio of the amino acid ester hydrochloride having the general structural formula (IV) and the isatoic anhydride and potassium carbonate having the general structural formula (V) 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 III (0.284 g, 1 mmol), triethylamine (0.152 g, 1.5 mmol) and add them to a 100 mL round-bottom flask, and add 30 mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102 g, 1.3 mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath, and after all the dripping is completed, transfer to a 25°C oil bath and continue to react for 2 hours. After the reaction is completed, extract with water (50 mL×2 times), and extract the aqueous phase with DCM (50 mL×3 times). Combine the organic phases and use anhydrous Na 2 SO 4 After drying, the solvent is removed by rotary evaporation under reduced pressure, and the substituted amide ester compound having the general structural formula (I) is obtained by column chromatography.

[0037] In the present invention, the role of adding triethylamine is to remove the acidic components (such as hydrochloric acid, etc.) that may exist in the reactants, and to neutralize the hydrochloric acid generated by the reaction of acetyl chloride and the reactants to promote the reaction.

[0038] Preferably, the solvent is an organic solvent, preferably dichloromethane (DCM).

[0039] Preferably, the molar ratio of the amount of acetyl chloride added to the key reactant (such as III-1) is 0.8-1.5:1, preferably 1-1.4:1, and more preferably 1.1-1.3:1.

[0040] Preferably, the molar ratio of the amount of triethylamine added to the key reactant (such as III-1) is 1-2:1, preferably 1.2-1.8:1, and more preferably 1.3-1.5:1.

[0041] Preferably, in a mixed solution containing a reactant (such as glycine benzyl ester hydrochloride, etc.), the reactant and K 2 CO 3 The molar ratio is 1:0.5-1.5, preferably 1:0.8-1.3, and more preferably 1:1-1.2.

[0042] Preferably, the reaction solvent has different preferences in different steps. For the synthesis step of compound I, dichloromethane is used as the main solvent; for the synthesis step of compound III, acetonitrile is used as the main solvent.

[0043] Preferably, the acetyl chloride mixture is added to the mixed solution containing the reactants (such as III-1) so that the molar ratio of the reactants to the acetyl chloride is 1:1-1.5, preferably 1:1.1-1.3, for example 1:1.2.

[0044] In the present invention, the reaction temperature for obtaining the acetyl chloride mixed solution 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 0.5-5h, preferably 1-3h, more preferably 1.5-2.5h.

[0045] In the present invention, before adding the acetyl chloride mixed solution to the mixed solution containing the reactants, the solution containing the reactants is first cooled to a suitable low temperature (such as ice-water bath cooling in the synthesis of compound I), and the reaction temperature of the acetyl chloride mixed solution and the mixed solution containing the reactant III is -5 to 30° C., preferably 0 to 20° C. The reaction time is 0.5-2.5 h, preferably 1.0-2.5 h, and more preferably 1.5-2.0 h.

[0046] In the present invention, the separation is filtration, suction filtration or extraction; preferably, water and dichloromethane are used for multiple alternating extraction separations.

[0047] Preferably, the present invention further comprises drying the extracted organic phase, preferably using anhydrous Na 2 SO 4 dry.

[0048] Preferably, the present invention further comprises a step of removing solvent from the dried product, preferably by vacuum rotary evaporation.

[0049] Another aspect of the present invention provides a use of an acetylamino-substituted amide ester compound having a general structural formula (I):

[0050] (1) Used for inhibiting fungi in crops; specifically, used for inhibiting one or more of Fusarium fusiformis, Rice blast, Phytophthora, Sclerotinia sclerotiorum, Botrytis cinerea and Sheath blight.

[0051] Preferably, the acetylamino-substituted amide ester compound having the general structural formula (I) is used to inhibit Sclerotinia sclerotiorum.

[0052] (2) Used for preparing drugs for inhibiting fungi of crops; specifically used for preparing drugs for inhibiting one or more pathogens selected from the group consisting of wheat fusarium head blight, pepper phytophthora, rice blast, rapeseed sclerotinia, cucumber gray mold, and rice sheath blight.

[0053] Preferably, the acetylamino-substituted amide esters having the general structural formula (I) are used to prepare drugs for inhibiting rice blast fungus, sclerotinia sclerotiorum and sheath blight fungus.

[0054] After adopting the above technical scheme, the present invention has the following beneficial effects compared with the prior art.

[0055] 1. The acetylamino-substituted amide ester compound having the general structural formula (I) prepared by the present invention is a brand-new compound, and the compound has very good antibacterial activity; in particular, it has a significant inhibitory effect on the activity of pathogens such as wheat fusarium, pepper phytophthora, rice blast, rapeseed sclerotinia, cucumber gray mold, and rice sheath blight.

[0056] 2. In the preparation method of the acetylamino-substituted amide ester compound having the general structural formula (I) provided by the present invention, the synthetic raw materials are cheap and readily available, the synthetic method is simple, the yield is high, and the product is easy to separate and purify.

[0057] The specific implementation modes of the present invention are further described in detail below in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] The accompanying drawings are part of this application and are used to provide a further understanding of the present invention. The illustrative embodiments of the present invention and their descriptions are used to explain the present invention, but do not constitute an improper limitation of the present invention. Obviously, the drawings described below are only some embodiments. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work. In the drawings:

[0059] Figure 1 is the general structural formula of the acetylamino-substituted amide ester compound having the general structural formula (I) of the present invention;

[0060] Figure 2 The invention discloses a synthetic route diagram of the acetylamino-substituted amide ester compound having the general structural formula (I) of the present invention.

[0061] It should be noted that these drawings and textual descriptions are not intended to limit the conceptual scope of the present invention in any way, but are intended to illustrate the concept of the present invention for those skilled in the art by referring to specific embodiments. DETAILED DESCRIPTION

[0062] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments will be clearly and completely described below in conjunction with the 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.

[0063] The structural formula of the intermediate product of the present invention is shown in Table 1 below.

[0064] Table 1 Structural formula of intermediate products

[0065]

[0066]

[0067] The sources of the chemical reagents used in the embodiments of the present invention are as follows:

[0068] Shanghai Myrel Chemical Technology Co., Ltd.: Glycine benzyl ester hydrochloride (CAS: 1738-68-7), isatoic anhydride (CAS: 118-48-9), acetyl chloride (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), 5OCH3-isatoic anhydride (CAS: 37795-77-0), 4-chlorophenylglycine (CAS: 67336-19-0), benzaldehyde (CAS: 100-52-7).

[0069] Xilong Chemical Co., Ltd.: Triethylamine (CAS: 121-44-8).

[0070] Guangdong Guanghua Science and Technology Co., Ltd.: anhydrous methanol (CAS: 67-56-1), dichloromethane (CAS: 75-09-2), ethyl acetate (CAS: 141-78-6).

[0071] Hunan Huihong Reagent Co., Ltd.: Anhydrous ethanol (CAS: 64-17-5).

[0072] Example 1

[0073] Synthesis of benzyl (2-acetylaminobenzoyl) alanine ester:

[0074]

[0075] Weigh L-alanine benzyl ester hydrochloride (0.259 g, 1.2 mmol), isatoic anhydride (0.163 g, 1 mmol), K 2 CO 3 (0.166 g, 1.2 mmol) was added to a 100 mL round-bottom flask, and 30 mL of acetonitrile was added to dissolve. The mixture was transferred to a 50 °C oil bath and the reaction was continued for 18 h. After the reaction was completed, the solvent was removed by decompression, and the obtained solid was extracted with water (50 mL × 2 times), and the aqueous phase was extracted with DCM (50 mL × 3 times). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure, and white solid benzyl (2-aminobenzoyl) alanine ester was obtained by column chromatography.

[0076] Weigh the prepared benzyl (2-aminobenzoyl) alanine ester (0.298g, 1mmol), triethylamine (0.152g, 1.5mmol) into a 100mL round-bottom flask, and add 30mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102g, 1.3mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25°C oil bath and continue the reaction for 2h. After the reaction is completed, extract with water (50mL×2 times), and extract the aqueous phase with DCM (50mL×3 times). Combine the organic phases and use anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a white solid was obtained by column chromatography.

[0077] 1 H NMR (400 MHz, DMSO-d 6 )δ10.88(s,1H),9.09(d,J=6.8Hz,1H),8.36(d,J=8.3Hz,1H),7.77(dd,J=7.9,1.6Hz,1H),7.57-7.25(m,6H ),7.16(td,J=7.6,1.2Hz,1H),5.18(d,J=1.7Hz,2H),4.63-4.50(m,1H),2.06(s,3H),1.45(d,J=7.3Hz,3H).

[0078] 13 C NMR (100 MHz, DMSO-d 6 )δ172.79,168.81,168.67,139.18,136.49,132.48,128.90,128.87,128.50,128.12,123.02,121.24,121.02,66.48,48.93,25.21,16.90.

[0079] Example 2

[0080] Synthesis of benzyl (2-acetylamino-5-chlorobenzoyl) glycine ester:

[0081]

[0082] Weigh glycine benzyl ester hydrochloride (0.242 g, 1.2 mmol), 5-Cl isatoic anhydride (0.198 g, 1 mmol), K 2 CO 3(0.166 g, 1.2 mmol) was added to a 100 mL round-bottom flask, and 30 mL of acetonitrile was added to dissolve. The mixture was transferred to a 50 °C oil bath and the reaction was continued for 18 h. After the reaction was completed, the solvent was removed by decompression, and the obtained solid was extracted with water (50 mL × 2 times), and the aqueous phase was extracted with DCM (50 mL × 3 times). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure, and white solid benzyl (2-amino-5-chlorobenzoyl) glycine ester was obtained by column chromatography.

[0083] Weigh the prepared benzyl (2-amino-5-chlorobenzoyl) glycine ester (0.319 g, 1 mmol) and triethylamine (0.152 g, 1.5 mmol) into a 100 mL round-bottom flask, and add 30 mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102 g, 1.3 mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25 ° C oil bath and continue to react for 2 hours. After the reaction is completed, extract with water (50 mL × 2 times), and extract the aqueous phase with DCM (50 mL × 3 times). Combine the organic phases and use anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a white solid was obtained by column chromatography.

[0084] 1 H NMR (400 MHz, DMSO-d 6 )δ10.93(s,1H),9.37(s,1H),8.41(d,J=9.0Hz,1H),7.81(d,J=2.6Hz,1H),7.58(dd,J =9.0, 2.5Hz, 1H), 7.45-7.30 (m, 5H), 5.19 (s, 2H), 4.12 (d, J = 5.8Hz, 2H), 2.08 (s, 3H).

[0085] 13 C NMR (100 MHz, DMSO-d 6 )δ169.88,168.88,167.92,138.18,136.29,132.29,128.90,128.61,128.42,128.21,126.88,122.86,122.56,66.59,41.82,39.95,25.18.

[0086] Example 3

[0087] Synthesis of Benzyl (2-Acetylamino-5-Chlorobenzoyl) Alanine Ester

[0088]

[0089] Take L-alanine benzyl ester hydrochloride (0.259 g, 1.2 mmol), 5-Cl isatoic anhydride (0.198 g, 1 mmol), K 2 CO 3 (0.166 g, 1.2 mmol) was added to a 100 mL round-bottom flask, and 30 mL of acetonitrile was added to dissolve. The mixture was transferred to a 50 °C oil bath and the reaction was continued for 18 h. After the reaction was completed, the solvent was removed by decompression, and the obtained solid was extracted with water (50 mL × 2 times), and the aqueous phase was extracted with DCM (50 mL × 3 times). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure, and yellow solid benzyl (2-amino-5-chlorobenzoyl) alanine ester was obtained by column chromatography.

[0090] Weigh the prepared benzyl (2-amino-5-chlorobenzoyl) alanine ester (0.333 g, 1 mmol) and triethylamine (0.152 g, 1.5 mmol) into a 100 mL round-bottom flask, and add 30 mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102 g, 1.3 mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25°C oil bath and continue the reaction for 2 hours. After the reaction is completed, extract with water (50 mL × 2 times), and extract the aqueous phase with DCM (50 mL × 3 times). Combine the organic phases and use anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a yellow solid was obtained by column chromatography.

[0091] 1 H NMR (400 MHz, DMSO-d 6 )δ10.80(s,1H),9.20(d,J=6.8Hz,1H),8.37(d,J=8.9Hz,1H),7.82(d,J=2.5Hz,1H),7.57(dd,J=9.0 ,2.5Hz,1H),7.42-7.29(m,5H),5.18(s,2H),4.62-4.51(m,1H),2.07(s,3H),1.45(d,J=7.3Hz,3H).

[0092] 13 C NMR (100 MHz, DMSO-d 6)δ172.60,168.81,167.42,138.01,136.44,132.13,128.87,128.52,128.45,128.13,126.86,122.94,122.87,66.54,48.99,25.13,16.84.

[0093] Example 4

[0094] Synthesis of benzyl (2-acetylamino-5-bromobenzoyl) alanine ester:

[0095]

[0096] Take L-alanine benzyl ester hydrochloride (0.259 g, 1.2 mmol), 5-Br isatoic anhydride (0.242 g, 1 mmol), K 2 CO 3 (0.166 g, 1.2 mmol) was added to a 100 mL round-bottom flask, and 30 mL of acetonitrile was added to dissolve. The mixture was transferred to a 50 °C oil bath and the reaction was continued for 18 h. After the reaction was completed, the solvent was removed by decompression, and the obtained solid was extracted with water (50 mL × 2 times), and the aqueous phase was extracted with DCM (50 mL × 3 times). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure, and white solid benzyl (2-amino-5-bromobenzoyl) alanine ester was obtained by column chromatography.

[0097] Weigh the prepared benzyl (2-amino-5-bromobenzoyl) alanine ester (0.363g, 1mmol), triethylamine (0.152g, 1.5mmol) into a 100mL round-bottom flask, and add 30mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102g, 1.3mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25°C oil bath and continue the reaction for 2h. After the reaction is completed, extract with water (50mL×2 times), and extract the aqueous phase with DCM (50mL×3 times). Combine the organic phases and use anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a white solid was obtained by column chromatography.

[0098] 1 H NMR (400 MHz, DMSO-d 6)δ 10.93 (s, 1H), 9.36 (t, J = 5.8 Hz, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.9, 2.4 Hz, 1H), 7.39 (d, J = 2.3 Hz, 5H), 5.19 (s, 2H), 4.11 (d, J = 5.8 Hz, 2H), 2.08 (s, 3H).

[0099] 13 C NMR (100 MHz, DMSO-d 6 )δ 169.88, 168.87, 167.85, 138.60, 136.30, 135.19, 131.03, 128.90, 128.60, 128.40, 123.10, 122.82, 114.75, 66.58, 41.82, 39.99, 25.22.

[0100] Example 5

[0101] Synthesis of benzyl (2-acetamido-5-bromobenzoyl)glycinate:

[0102]

[0103] Weigh glycine benzyl ester hydrochloride (0.242 g, 1.2 mmol), 5-Br isatoic anhydride (0.242 g, 1 mmol), K 2 CO 3 (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 them with anhydrous Na 2 SO 4 and remove the solvent by rotary evaporation under reduced pressure. The yellow solid benzyl (2-amino-5-bromobenzoyl)glycinate is obtained by column chromatography separation.

[0104] Weigh the prepared benzyl (2-amino-5-bromobenzoyl) glycine ester (0.377 g, 1 mmol) and triethylamine (0.152 g, 1.5 mmol) into a 100 mL round-bottom flask, and add 30 mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102 g, 1.3 mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25 ° C oil bath and continue to react for 2 hours. After the reaction is completed, extract with water (50 mL × 2 times), and extract the aqueous phase with DCM (50 mL × 3 times). Combine the organic phases and use anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a yellow solid was obtained by column chromatography.

[0105] 1 H NMR (400 MHz, DMSO-d 6 )δ10.93(s,1H),9.36(t,J=5.8Hz,1H),8.35(d,J=8.9Hz,1H),7.93(d,J=2.4Hz,1H),7.70(d d,J=8.9,2.4Hz,1H),7.39(d,J=2.3Hz,5H),5.19(s,2H),4.11(d,J=5.8Hz,2H),2.08(s,3H).

[0106] 13 C NMR (100 MHz, DMSO-d 6 )δ169.88,168.87,167.85,138.60,136.30,135.19,131.03,128.90,128.60,128.40,123.10,122.82,114.75,66.58,41.82,39.99,25.22.

[0107] Example 6

[0108] Synthesis of benzyl (2-acetylamino-5-methoxybenzoyl) glycine ester:

[0109]

[0110] Weigh glycine benzyl ester hydrochloride (0.242 g, 1.2 mmol), 5-CH3O-isatoic anhydride (0.193 g, 1 mmol), K 2 CO 3(0.166 g, 1.2 mmol) was added to a 100 mL round-bottom flask, and 30 mL of acetonitrile was added to dissolve. The mixture was transferred to a 50 °C oil bath and the reaction was continued for 18 h. After the reaction was completed, the solvent was removed by decompression, and the obtained solid was extracted with water (50 mL × 2 times), and the aqueous phase was extracted with DCM (50 mL × 3 times). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a white solid was obtained by column chromatography.

[0111] Weigh the prepared benzyl (2-amino-5-methoxybenzoyl) glycine ester (0.314 g, 1 mmol) and triethylamine (0.152 g, 1.5 mmol) into a 100 mL round-bottom flask, and add 30 mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102 g, 1.3 mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25°C oil bath and continue the reaction for 2 hours. After the reaction is completed, extract with water (50 mL × 2 times), and extract the aqueous phase with DCM (50 mL × 3 times). Combine the organic phases and use anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a white solid was obtained by column chromatography.

[0112] 1 H NMR (400 MHz, DMSO-d 6 )δ10.68(s,1H),9.20(t,J=5.9Hz,1H),8.24(d,J=9.1Hz,1H),7.47-7.22(m,6H),7.11 (dd,J=9.1,2.9Hz,1H),5.19(s,2H),4.11(d,J=5.8Hz,2H),3.78(s,3H),2.04(s,3H).

[0113] 13 C NMR (100 MHz, DMSO-d 6 )δ170.03,168.85,168.29,154.84,136.34,132.49,128.89,128.58,128 .40,123.08,122.65,118.22,113.22,66.52,55.93,41.81,39.97,25.01.

[0114] Example 7

[0115] Synthesis of benzyl (2-acetylamino-5-methoxybenzoyl) alanine ester:

[0116]

[0117] Weigh L-alanine benzyl ester hydrochloride (0.259 g, 1.2 mmol), 5-CH3O-isatoic anhydride (0.193 g, 1 mmol), K 2 CO 3 (0.166 g, 1.2 mmol) was added to a 100 mL round-bottom flask, and 30 mL of acetonitrile was added to dissolve. Transfer to a 50 ° C oil bath and continue the reaction for 18 h. After the reaction was completed, the solvent was removed by decompression, and the obtained solid was extracted with water (50 mL × 2 times), and the aqueous phase was extracted with DCM (50 mL × 3 times). The organic phases were combined, dried over anhydrous Na2SO4, and the solvent was removed by vacuum rotary evaporation. White solid benzyl (2-amino-5-methoxybenzoyl) alanine ester was obtained by column chromatography.

[0118] Weigh the prepared benzyl (2-amino-5-methoxybenzoyl) alanine ester (0.328g, 1mmol), triethylamine (0.152g, 1.5mmol) into a 100mL round-bottom flask, and add 30mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102g, 1.3mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25°C oil bath and continue the reaction for 2h. After the reaction is completed, extract with water (50mL×2 times), and extract the aqueous phase with DCM (50mL×3 times). Combine the organic phases and use anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a white solid was obtained by column chromatography.

[0119] 1 H NMR (400 MHz, DMSO-d 6 )δ10.49(s,1H),9.04(d,J=6.9Hz,1H),8.18(d,J=9.1Hz,1H),7.41-7.29(m,5H),7.26(d,J=2.9Hz,1H),7.10 (dd,J=9.1,3.0Hz,1H),5.18(s,2H),4.56(p,J=7.2Hz,1H),3.78(s,3H),2.02(s,3H),1.44(d,J=7.3Hz,3H).

[0120] 13 C NMR (100 MHz, DMSO-d 6)δ172.77,168.33,168.29,154.88,136.48,132.10,128.87,128.50,128 .12,123.47,123.23,117.83,113.71,66.49,55.95,48.90,24.91,16.95.

[0121] Example 8

[0122] 4-Chlorobenzyl (2-acetylaminobenzoyl) glycine ester:

[0123]

[0124] Weigh 4-chlorophenylglycine ester (0.223 g, 1.2 mmol), isatoic anhydride (0.163 g, 1 mmol), K 2 CO 3 (0.166 g, 1.2 mmol) was added to a 100 mL round-bottom flask, and 30 mL of acetonitrile was added to dissolve. The mixture was transferred to a 50 °C oil bath and the reaction was continued for 18 h. After the reaction was completed, the solvent was removed by decompression, and the obtained solid was extracted with water (50 mL × 2 times), and the aqueous phase was extracted with DCM (50 mL × 3 times). The organic phases were combined and washed with anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure, and 4-chlorophenyl (2-methylbenzoyl) glycine ester was obtained as a white solid by column chromatography.

[0125] Weigh the prepared 4-chlorophenyl (2-methylbenzoyl) glycine ester (0.303g, 1mmol), triethylamine (0.152g, 1.5mmol) into a 100mL round-bottom flask, and add 30mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102g, 1.3mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25°C oil bath and continue the reaction for 2h. After the reaction is completed, extract with water (50mL×2 times), and extract the aqueous phase with DCM (50mL×3 times). Combine the organic phases and purify with anhydrous Na 2 SO 4 After drying, the solvent was removed by rotary evaporation under reduced pressure and a white solid was obtained by column chromatography.

[0126] 1 H NMR (400 MHz, DMSO-d 6)δ11.04(s,1H),9.23(t,J=5.9Hz,1H),8.44-8.38(m,1H),7.76(dd,J=8.0,1.6Hz,1H),7.51(ddd,J=8.6,7.4,1 .5Hz,1H),7.43(d,J=1.0Hz,4H),7.17(td,J=7.6,1.2Hz,1H),5.19(s,2H),4.11(d,J=5.8Hz,2H),2.08(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ170.00,169.27,168.69,139.46,135.41,133.23,132.66,130.28,128.88,128.54,123.08,121.00,120.68,65.70,41.82,25.25.

[0127] Antibacterial activity test of crops

[0128] Using the in vitro method, benzyl (2-acetylaminobenzoyl) alaninate, benzyl (2-acetylamino-5-chlorobenzoyl) glycine ester, benzyl (2-acetylamino-5-chlorobenzoyl) alaninate, benzyl (2-acetylamino-5-chlorobenzoyl) alaninate, benzyl (2-acetylamino-5-bromobenzoyl) alaninate, benzyl (2-acetylamino-5-bromobenzoyl) glycine ester, benzyl (2-acetylamino-5-methoxybenzoyl) alaninate, benzyl (2-acetylamino-5-methoxybenzoyl) glycine ester and 4-chlorobenzyl (2-acetylaminobenzoyl) glycine ester were tested for their antibacterial activity.

[0129] Wheat fusarium head blight, pepper phytophthora, rice blast, rape sclerotinia, cucumber gray mold and rice sheath blight were used as test materials for fungicidal activity test. The test agent was dissolved in acetone and then diluted to 500 g / mL solution with 200 g / mL sorporl-144 emulsifier. Under aseptic operating conditions, 1 mL of compound solution was pipetted into a sterilized plate with a pipette, and then 9 mL of sterilized PDA culture medium was added to the plate with a pipette, mixed, and a drug-containing plate of corresponding concentration was prepared. The cultured pathogens were cut from the edge of the colony with a sterile puncher with a diameter of 4 mm under aseptic conditions. After the culture medium solidified, the bacterial cake was inoculated in the center of the drug-containing plate with an inoculator and placed in an incubator at a suitable temperature for culture. A blank control was used without adding the agent. 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.

[0130] Growth inhibition rate (%): (control colony diameter - treated colony diameter) × 100 / (control colony diameter - 4 mm).

[0131] The drug concentration was 50 μg / mL. The antibacterial activity test results are shown in Table 2.

[0132] Table 2 Antibacterial activity results

[0133]

[0134] As shown in Table 2, the target compounds all have antibacterial activity against the tested pathogens, and some have good antibacterial activity. Among them, benzyl (2-amino-5-chlorobenzoyl) glycine ester has an inhibition rate of up to 86.8% against rice blast fungus, an inhibition rate of 82.7% against sclerotinia sclerotiorum, and an inhibition rate of 79.8% against rice sheath blight fungus, and has a broad-spectrum antibacterial activity; 4-chlorobenzyl (2-acetylaminobenzoyl) glycine ester has an inhibition rate of 86.5% against sclerotinia sclerotiorum.

[0135] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. Any technician familiar with this patent can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims

1. An acetylamino-substituted amide ester compound, characterized in that: The compound has the general structural formula (I): Where R 1 is one of H, halogen atom or methoxy; R 3 is a C1-C6 alkyl group or a hydrogen atom; R 2 is one of H, alkyl or halogen atom.

2. According to the claim 1 The acetylamino-substituted amide ester compound is characterized by: R 1 is one of H, chlorine, bromine or methoxy; R 3 is a methyl group or H; R 2 It is one of H or a halogen atom.

3. An acetylamino substituted amide ester compound according to claim 1, characterized in that: The compound is selected from one or more of the following compounds: Benzyl (2-acetylaminobenzoyl) alanine ester Benzyl (2-acetylamino-5-chlorobenzoyl) glycinate Benzyl (2-acetylamino-5-chlorobenzoyl) alaninate Benzyl (2-acetylamino-5-bromobenzoyl) alaninate Benzyl (2-acetylamino-5-bromobenzoyl) glycinate Benzyl (2-acetylamino-5-methoxybenzoyl) glycinate Benzyl (2-acetylamino-5-methoxybenzoyl) alanine ester 4-Chlorobenzyl (2-acetylaminobenzoyl) glycine ester 4. The method for preparing an acetylamino-substituted amide ester compound according to claim 1, characterized in that: The method specifically comprises the following steps: S1) reacting an amino acid ester hydrochloride having a structural formula (IV) with an isatoic anhydride having a structural formula (V) in acetonitrile under the action of potassium carbonate to obtain an amide ester compound having a structural formula (III): S2) reacting an amide ester compound having the general structural formula (III) with acetyl chloride in the presence of triethylamine to prepare an acetylamino-substituted amide ester compound having the general structural formula (I): Where R 1 is one of H, halogen atom or methoxy; R 3 is a C1-C6 alkyl group or a hydrogen atom; R 2 is one of H, alkyl or halogen atom.

5. The method for preparing an acetylamino-substituted amide ester compound according to claim 4, characterized in that: Step S1) is specifically: Weigh the amino acid ester hydrochloride of the general structural formula (IV), isatoic anhydride of the general structural formula (V), and K2CO3 into a 100 mL round-bottom flask, add 30 mL of acetonitrile to dissolve, and heat the reaction solution to react to obtain an amide ester compound having the structural formula (III).

6. The method for preparing an acetylamino-substituted amide ester compound according to claim 5, characterized in that: The preferred reaction molar ratio of the amino acid ester hydrochloride with the general structural formula (IV) and the isatoic anhydride and potassium carbonate with the general structural formula (V) is 1.2:1:1.2, the preferred temperature is 50° C., and the preferred reaction time is 18 hours.

7. The method for preparing an acetylamino-substituted amide ester compound according to claim 4, characterized in that: Step S2) is specifically: Weigh III (0.284 g, 1 mmol) and triethylamine (0.152 g, 1.5 mmol) into a 100 mL round-bottom flask, and add 30 mL of dichloromethane to dissolve. Slowly drip acetyl chloride (0.102 g, 1.3 mmol) dissolved in dichloromethane into the reaction bottle through a constant pressure dropping funnel under stirring in an ice-water bath. After all the dripping is completed, transfer to a 25°C oil bath and continue to react for 2 h. After the reaction is completed, extract with water (50 mL × 2 times), extract the aqueous phase with DCM (50 mL × 3 times), combine the organic phases, dry with anhydrous Na2SO4, remove the solvent by vacuum rotary evaporation, and separate by column chromatography to obtain an acetylamino-substituted amide ester compound with the general structural formula (Ⅰ).

8. The method for preparing an acetylamino-substituted amide ester compound according to claim 4, characterized in that: The molar ratio of acetyl chloride to the key reactant (such as III-1) is 0.8-1.5:1, preferably 1-1.4:1, and more preferably 1.1-1.3:1; The molar ratio of the amount of triethylamine added to the key reactant (such as III-1) is 1-2:1, preferably 1.2-1.8:1, and more preferably 1.3-1.5:

1.

9. The use of an acetylamino-substituted amide ester compound according to claim 1, characterized in that: Used for antibacterial effect on crops, or for preparing antibacterial effect drugs on crops.

10. The use according to claim 9, characterized in that Used for inhibiting fungi in crops, including inhibiting one or more of Gibberella, Rice Blast, Phytophthora, Sclerotinia, Botrytis Cinerea and Sheath Blight; The drug used for preparing antibacterial drugs for crops includes drugs used for preparing drugs for inhibiting one or more pathogens selected from the group consisting of wheat fusarium head blight, pepper phytophthora, rice blast, rapeseed sclerotinia, cucumber gray mold, and rice sheath blight.

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