Substituted tetrahydro-beta-carboline derivative as well as synthesis method and application thereof

Abstract

The invention relates to a substituted tetrahydro-beta-carboline derivative as well as a synthesis method and application thereof. The preparation method comprises the following steps: by taking different carboxylic acids as raw materials, adding a solvent anhydrous dichloromethane for dissolving, reacting with thionyl chloride under the condition of oil bath heating to prepare a corresponding acyl chloride substrate, then carrying out amidation reaction with a tetrahydro-beta-carboline compound, adding a quenching agent for quenching reaction, and finally obtaining the tetrahydro-beta-carboline compound. And carrying out reduced pressure concentration to remove dichloromethane to obtain the substituted tetrahydro-beta-carboline derivative. The compound has the application of inhibiting phytopathogen. The phytopathogen is pythium aphanidermatum, cotton verticillium wilt, alternaria alternata, botrytis cinerea, curvularia maize, eggplant verticillium wilt, fusarium oxysporum, cucumber target leaf spot, tomato alternaria solani, watermelon fusarium wilt, cucumber brown spot, apple alternaria leaf spot and sclerotinia sclerotiorum. The synthesis process is simple, and the product purity is high.

Description

Technical Field

[0001] The invention belongs to the field of pesticide synthesis, and specifically relates to a substituted tetrahydro-β-carboline derivative, a synthesis method thereof, and use and application of the derivative for inhibiting plant pathogens. Background Art

[0002] Plant pathogens can cause local or whole-plant diseases after infecting crops, threatening global food security and causing significant economic losses. Therefore, the use of pesticides is an indispensable factor in the agricultural production process. Although traditional chemical control can control pests to a certain extent and thus achieve a good control effect, due to the inherent defects and long-term abuse of chemical synthetic pesticides, they will have a negative impact on human health and the environment, and cause harmful pests and diseases to develop resistance.

[0003] Botanical pesticides refer to compounds and their derivatives that are synthesized by chemical means based on the unique active ingredients contained in certain plants or their active structures. Botanical pesticides developed from natural products have the advantages of low toxicity, high efficiency, easy degradation, and low resistance, which has aroused people's strong interest in development. Therefore, looking for biologically active substances from plant secondary compounds as lead compounds and designing and synthesizing their derivatives is one of the effective ways to develop new green pesticides and solve or reduce the occurrence of resistance. β-Carboline alkaloids are natural products with a wide range of sources in nature and have significant biological activity. Botanical green pesticides developed with β-carboline alkaloids as lead compounds have great potential.

[0004] Tetrahydro-β-carboline compounds are indole alkaloids widely distributed in nature. They exist not only in plants, but also in some marine organisms, especially those sea squirts and invertebrates. They have multiple biological activities such as anti-tumor, anti-bacterial, anti-hypertensive and treatment of Alzheimer's disease. In recent years, tetrahydro-β-carboline compounds have attracted more and more attention due to their unique properties and structures. Current research has made it clear that the tetrahydro-β-carboline nucleus is the most basic structure that exhibits biological activity, and the magnitude of biological activity depends on the presence, position and properties of substituents. Summary of the invention

[0005] In order to overcome the shortcomings of the prior art, the present invention aims to provide a substituted tetrahydro-β-carboline derivative, a synthesis method and use thereof. The substituted tetrahydro-β-carboline derivative has the advantages of high efficiency, low toxicity, low residue and no environmental pollution, and has good inhibitory activity against walnut pythium, cotton verticillium dahliae, tobacco brown spot pathogen, tomato gray mold, corn curvature, eggplant verticillium dahliae, oxysporum fusarium, cucumber target spot pathogen, tomato early blight pathogen, watermelon wilt pathogen, cucumber brown spot pathogen, apple leaf spot pathogen and rapeseed sclerotinia pathogen.

[0006] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0007] Substituted tetrahydro-β-carboline derivatives having the general formula (I):

[0008]

[0009] The synthetic route of the substituted tetrahydro-β-carboline derivatives having the formula (I) is as follows:

[0010]

[0011] The substituent R1 is any one of the following groups:

[0012]

[0013] Specifically, the synthesis process of the substituted tetrahydro-β-carboline derivative having formula (I) comprises the following steps:

[0014] Step 1: Prepare the corresponding acid chlorides from ready-made acid chlorides or from carboxylic acids according to the following method: different carboxylic acids are used as raw materials, dissolved in anhydrous dichloromethane, and reacted with thionyl chloride under heating in an oil bath to prepare a series of acid chlorides;

[0015] Wherein, the readily available acyl chloride is selected from any one of the following: 4-chlorobenzoyl chloride, 4-fluorobenzoyl chloride, 4-methylbenzoyl chloride, phenylacetyl chloride, phenylpropionyl chloride, 2-chlorobenzoyl chloride;

[0016] Or the acyl chloride substrate is prepared based on any of the following carboxylic acids: 5-methylnicotinic acid, 3-chloropyridine-4-carboxylic acid, 6-methylnicotinic acid, 2-chloropyridine-6-carboxylic acid, 5-chloropyrazine-2-carboxylic acid, pyrazine-2-carboxylic acid, nicotinic acid, isonicotinic acid, 2-chloronicotinic acid, 6-chloronicotinic acid, 2-pyridinecarboxylate, 5,6-dichloronicotinic acid, 2-fluoronicotinic acid, 4-methoxybenzoic acid, 1-naphthoic acid.

[0017] Step 2: Weigh the reaction substrate VI (tetrahydro-β-carboline compound) and place it in a round-bottom flask, add anhydrous dichloromethane and stir to dissolve, add triethylamine dropwise thereto, stir and react at room temperature for 30 minutes, and then transfer to an ice-water bath;

[0018] Step 3: dissolving the acyl chloride substrate obtained in step 1 in anhydrous dichloromethane under ultrasonic conditions, and adding the resulting solution dropwise to the reaction system of step 2 to undergo amidation reaction with the substrate tetrahydro-β-carboline compound, and performing TLC tracking detection. After the reaction is complete, adding a saturated sodium bicarbonate solution dropwise to the reaction solution to quench the reaction, extracting with dichloromethane, combining the organic phases, and concentrating under reduced pressure. The crude product is separated by column chromatography to obtain a substituted tetrahydro-β-carboline derivative.

[0019] The use of the substituted tetrahydro-β-carboline derivatives in inhibiting plant pathogens. The plant pathogens are walnut rot, cotton Verticillium wilt, tobacco brown spot, tomato gray mold, corn curvature, eggplant Verticillium wilt, Fusarium oxysporum, cucumber target spot, tomato early blight, watermelon wilt, cucumber brown spot, apple leaf spot and rapeseed sclerotinia.

[0020] Beneficial effects: The substituted tetrahydro-β-carboline derivatives provided by the present invention have the characteristics of simple structure, readily available raw materials, mild reaction conditions, simple process, and have the activity of inhibiting plant pathogens. The synthesized compounds are derived from the skeleton of natural products and have the environmental protection characteristics of high efficiency, low toxicity and low residue.

[0021] The results of the activity test showed that the EC of W11 and W17 against Curvularia serrata of corn was 50 The values ​​were 32.46 mg / L and 58.54 mg / L respectively; the EC value of compound W11 against tomato gray mold 50 The inhibition rate of compound W20 on tomato early blight pathogen was greater than 60%, and its EC 50 The value was 35.95 mg / L; the inhibition rate of compounds W16 and W20 on tomato gray mold was greater than 60%, and their EC 50 The values ​​were 12.71 mg / L and 18.76 mg / L respectively; the inhibition rates of compounds W6, W16 and W20 against Sclerotinia sclerotiorum were all greater than 60%, and their EC 50 The values ​​are 16.43 mg / L, 12.71 mg / L and 12.72 mg / L respectively, which has excellent application prospects. DETAILED DESCRIPTION

[0022] The present invention is described in detail below in conjunction with embodiments.

[0023] Example 1 Synthesis

[0024] Step 1: Preparation of acyl chloride. The preparation method is as follows: weigh 246.9 mg (1.8 mmol) of 5-methylnicotinic acid into a dry 50 mL round-bottom flask, add 10 mL of anhydrous dichloromethane, add 0.20 mL (2.7 mmol, 2.3 eq.) of thionyl chloride dropwise therein during stirring, heat to 55°C and reflux for 2.5 h, remove dichloromethane and thionyl chloride by rotary evaporation, and obtain 5-methylnicotinic acid chloride for later use.

[0025] Step 2: Weigh 366.5 mg (1.5 mmol) of the reaction substrate VI (tetrahydro-β-carboline compound) and place it in a 100 mL round-bottom flask, add 15 mL of anhydrous dichloromethane and stir to dissolve, add 0.32 mL (2.3 mmol, 2.3 eq.) of triethylamine dropwise, stir at room temperature for 30 min, and then transfer to an ice-water bath;

[0026] Step 3: Dissolve the prepared 5-methylnicotinoyl chloride in 10 mL of anhydrous dichloromethane with the aid of an ultrasonic instrument, and add dropwise to the reaction system of the second step. After the addition is complete, transfer to room temperature for reaction, and TLC tracking detects that the reaction is complete. Add saturated sodium bicarbonate solution to the reaction solution in an ice-water bath to quench the reaction, extract the aqueous phase twice with dichloromethane (10 mL×2), combine the organic phases, wash with saturated sodium chloride solution (20 mL×2), and dry over anhydrous sodium sulfate. The obtained initial product is separated by silica gel column chromatography (ethyl acetate: petroleum ether=1:3), and finally 158.1 g of the target compound W1 (0.43 mmol, 29%) is obtained.

[0027] Property identification: white solid, 1 H NMR(400MHz,DMSO-d6)δ11.03(1H,s,H-7),8.53(1H,s,H-22),8.48(s,1H,H-24),7. 71(1H,s,H-26),7.45(1H,d,J=7.6Hz,H-6),7.34(1H,d,J=7.9Hz,H-3),7.08(1H,t,J =7.5Hz,H-2),6.99(1H,m,H-1),5.60(1H,q,J=6.4Hz,H-10),4.88(1H,d,J=5.3Hz),3 .58(3H,s,H-18),3.07(2H,m,H-13),2.36(3H,s,H-27),1.54(3H,d,J=6.4Hz,H-14). 13C NMR(101MHz,DMSO-d6)δ171.75(C,C-15),169.57(C,C-19),151.35(CH,C-24),144.66(CH,C-22),136.80 (C,C-4),134.90(C,C-8),133.95(CH,C-26),133.77(C,C-25),132.54(C,C-20),126.65(C,C-5),121.80 (CH,C-2),119.24(CH,C-1),118.45(CH,C-6),111.67(CH,C-3),104.52(C,C-9),56.00(CH3,C-18),52.8 2(CH,C-12),46.72(CH,C-10),22.56(CH2,C-13),19.78(CH3,C-14),18.32(CH3,C-27).MS(ESI(+))calcd forC 21 H 22 N3O3 + [M+H] + :364.2;found:364.5.

[0028] The difference between Examples 2 to 21 and Example 1 is that the carboxylic acids used in the first step to prepare the acyl chloride are different. The specific properties and yields of the obtained products and the information of the carboxylic acids used are shown in Table 1:

[0029] Table 1

[0030]

[0031] Example 2

[0032]

[0033] White solid, 1H NMR(400MHz,DMSO-d6)δ11.02(1H,s,H-7),7.56(2H,d,J=8.3Hz,H-26,H-22),7.50(2H, d,J=8.4Hz,H-23,H-25),7.44(1H,d,J=7.6Hz,H-6),7.34(1H,d,J=7.8Hz,H-3),7.08(1 H,t,J=7.4Hz,H-2),7.04-6.94(1H,m,H-1),5.58(1H,q,J=6.4Hz,H-10),4.85(1H,d,J= 4.6Hz,H-12),3.57(3H,s,H-18),3.33-2.86(2H,m,H-13),1.53(3H,d,J=6.1Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ171.80(C,C-15),170.60(C,C-19),136.78(C,C-4),135.85(C,C-24),134. 76(C,C-8),134.07(C,C-20),129.38(2CH,C-22,C-26),128.83(2CH,C-23,C-25),126.65(C,C-5), 121.70(CH,C-2),119.18(CH,C-1),118.43(CH,C-6),111.63(CH,C-3),104.48(C,C-9),55.94(CH3 ,C-18),52.84(CH,C-12),46.71(CH,C-10),22.56(CH2,C-13),19.76(CH3,C-14).MS(ESI(+))calcd for C 21 H 20 ClN2O3 + [M+H] + :383.1; found:381.7.

[0034] Example 3

[0035]

[0036] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ11.03(1H,s,H-7),7.55(2H,dd,J=8.6,5.5Hz,H-26,H-22), 7.45(1H,d,J=7.6Hz,H-6),7.35-7.29(3H,m,H-23,H-25,H-3),7.11-7.05(1H,m,H-2 ),7.03-6.95(1H,m,H-1),5.61(1H,q,J=4.8Hz,H-10),4.91-4.83(1H,d,J=7.6Hz,H -12),3.57(3H,s,H-18),3.36-2.87(2H,m,H-13),1.58-1.53(3H,d,J=5.2Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ171.87(C,C-15),170.76(C,C-19),165.62(C,d,J=267.2Hz,C-24),161.84(C,C-20) ,136.79(C,C-4),134.17(C,C-8),133.50(2CH,d,J=3.4Hz,C-22,C-26),129.37(2CH,d,J=8.7Hz,C-23,C-25 ),126.67(C,C-5),121.49(CH,C-2),118.41(CH,C-1),116.06(CH,C-6),111.67(CH,C-3),104.47(C,C-9),5 5.89(CH3,C-18),52.75(CH,C-12),46.64(CH,C-10),22.56(CH2,C-13),19.66(CH3,C-14).MS(ESI(+))calcd for C 21 H 20 FN2O3 + [M+H] + :367.2; found:367.4.

[0037] Example 4

[0038]

[0039] Yellow oily, 11H NMR (400 MHz, DMSO-d6) δ 11.06 (1H, s, H-7), 8.78 (1H, d, J = 8.0 Hz, H-23), 8.66 (1H, d, J = 4.8 Hz, H-25), 7.51 (1H, d, J = 4.9 Hz, H-26), 7.45 (1H, d, J = 7.8 Hz, H-6), 7.34 (1H, d, J = 8.1 Hz, H-3), 7.09 (1H, t, J = 7.5 Hz, H-2), 6.99 (1H, t, J = 7.3 Hz, H-1), 5.61 (1H, q, J = 6.5 Hz, H-10), 4.70 (1H, d, J = 5.6 Hz, H-12), 3.59 (3H, s, H-18), 3.37 - 2.84 (2H, m, H-13), 1.53 (3H, d, J = 6.8 Hz, H-14). 13 13C NMR (101 MHz, DMSO-d6) δ 171.24 (C, C-15), 166.34 (C, C-19), 149.94 (CH, C-23), 149.09 (CH, C-25), 143.33 (C, C-4), 142.82 (C, C-20), 136.82 (C, C-8), 133.56 (C, C-22), 126.50 (C, C-5), 123.00 (CH, C-26), 121.86 (CH, C-2), 119.24 (CH, C-1), 118.53 (CH, C-6), 111.67 (CH, C-3), 104.43 (CH, C-9), 55.47 (CH3, C-18), 52.95 (CH, C-12), 46.61 (CH, C-10), 22.73 (CH2, C-13), 19.73 (CH3, C-14). MS (ESI(+)) calcd for C 20 H 19 ClN3O3 + [M + H] + : 384.1; found: 384.8.

[0040] Example 5

[0041]

[0042] Yellow oil, 1H NMR(400MHz,DMSO-d6)δ11.01(1H,s,H-7),8.55(1H,s,H-22),7.78(1H,d,J=7.4Hz,H-26),7.4 5(1H,d,J=7.6Hz,H-6),7.37(1H,d,J=7.9Hz,H-25),7.33(1H,d,J=7.9Hz,H-3),7.08(1H,t,J=7 .9Hz,H-2),7.04-6.94(1H,m,H-1),5.65-5.50(1H,q,J=6.0Hz,H-10),4.89(1H,d,J=4.4Hz,H-1 2),3.57(3H,s,H-18),3.34-2.88(2H,m,H-13),2.53(3H,s,H-27),1.52(3H,d,J=5.9Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ171.78(C,C-15),169.75(C,C-19),159.71(C,C-24),146.88(CH,C-22),136.77( C,C-4),135.03(C,C-8),133.99(CH,C-26),130.18(C,C-20),126.64(C,C-5),123.53(CH,C-25),121.70 (CH,C-2),119.18(CH,C-1),118.44(CH,C-6),111.63(CH,C-3),104.52(C,C-9),55.94(CH3,C-18),52.8 5(CH,C-12),46.74(CH,C-10),24.54(CH3,C-27),22.53(CH2,C-13),19.78(CH3,C-14).MS(ESI(+))calcd for C 21 H 22 N3O3 + [M+H] + :364.2; found:364.5.

[0043] Example 6

[0044]

[0045] Yellow oily, 11H NMR (400 MHz, Chloroform-d) δ 8.53 (1H, s, H-7), 7.78 (1H, t, J = 7.7 Hz, H-26), 7.72 (1H, dd, J = 7.6, 1.0 Hz, H-25), 7.50 (1H, d, J = 7.6 Hz, H-24), 7.41 (1H, dd, J = 7.8, 1.0 Hz, H-6), 7.29 (1H, d, J = 7.6 Hz, H-3), 7.16 (1H, td, J = 8.1, 7.6, 1.4 Hz, H-2), 7.11 (1H, td, J = 7.4, 1.1 Hz, H-1), 5.72 (1H, q, J = 5.4 Hz, H-10), 5.26 (1H, d, J = 7.6 Hz, H-12), 3.65 (3H, s, H-18), 3.50 - 3.05 (2H, m, H-13), 1.74 (3H, d, J = 6.7 Hz, H-14). 13 13C NMR (101 MHz, Chloroform-d) δ 171.90 (C, C-15), 167.65 (C, C-19), 154.49 (C, C-23), 154.21 (C, C-20), 150.24 (C, C-4), 150.00 (C, C-8), 140.10 (CH, C-25), 136.51 (CH, C-26), 133.30 (C, C-5), 132.71 (CH, C-24), 126.60 (CH, C-2), 122.91 (CH, C-1), 118.36 (CH, C-6), 105.87 (CH, C-3), 104.59 (C, C-9), 56.21 (CH3, C-18), 52.55 (CH, C-12), 47.45 (CH, C-10), 19.63 (CH2, C-13), 19.39 (CH3, C-14). MS (ESI(+)) calcd for C 20 H 19 ClN3O3 + [M + H] + : 384.1; found: 384.7.

[0046] Example 7

[0047]

[0048] Yellow oil, 1H NMR(400MHz,Chloroform-d)δ8.09(1H,s,H-7),6.77(1H,d,J=7.0Hz,H-6),6.67(2H,d,J=8.0Hz,H-26,H-22),6.54(2H, d,J=8.9Hz,H-23,H-25),6.46(1H,d,J=7.2Hz,H-3),6.43-6.40(1H,m,H-2),6.40-6.35(1H,m,H-1),5.12(1H,q,J=4.8Hz H-10),4.30-4.11(1H,m,H-12),2.91(3H,s,H-18),2.81-2.17(2H,m,H-13),1.70(3H,s,H-27),0.98(3H,d,J=5.4Hz,H-14). 13 C NMR(101MHz,Chloroform-d)δ172.69(C,C-15),171.82(C,C-19),140.09(C,C-24),136.56(C,C-4),133. 71(C,C-8),130.26(C,C-20),129.63(2CH,C-23,C-25),129.27(C,C-5),126.60(CH,C-2),126.43(2CH,C- 22,C-26),121.90(CH,C-1),119.51(CH,C-6),118.26(CH,C-3),111.18(C,C-9),56.51(CH3,C-18),52.6 1(CH,C-12),46.82(CH,C-10),21.85(CH2,C-13),21.55(CH3,C-27),19.80(CH3,C-14).MS(ESI(+))calcd for C 22 H 23 N2O3 + [M+H] + :363.2; found:363.4.

[0049] Example 8

[0050]

[0051] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ11.03(1H,s,H-7),8.85(1H,d,J=1.3Hz,H-26),8.79(1H,d, J=1.3Hz,H-23),7.46(1H,d,J=7.5Hz,H-6),7.34(1H,d,J=8.0Hz,H-3),7.12-7.05(1 H,m,H-2),6.99(1H,t,J=7.4Hz,H-1),5.56(1H,q,J=6.8Hz,H-10),5.20(1H,d,J=3. 6Hz,H-12),3.56(3H,s,H-18),3.34-2.89(2H,m,H-13),1.60(3H,d,J=6.7Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ171.78(C,C-15),166.76(C,C-19),149.35(C,C-20),148.45(C,C-24), 144.54(CH,C-26),143.86(CH,C-23),136.78(C,C-4),133.75(C,C-8),126.59(C,C-5),121.74 (CH,C-2),119.18(CH,C-1),118.50(CH,C-6),111.65(CH,C-3),104.14(C,C-9),55.56(CH3,C- 18),52.73(CH,C-12),47.31(CH,C-10),22.72(CH2,C-13),19.61(CH3,C-14).MS(ESI(+))calcd for C 19 H 18 ClN4O3 + [M+H] + :385.1; found:385.8.

[0052] Example 9

[0053]

[0054] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ10.93(1H,s,H-7),7.43(1H,d,J=8.1Hz,H-6),7.34-7.27(5H,m,H-21,H- 22,H-23,H-24,H-25),7.26-7.19(1H,m,H-3),7.11-7.01(1H,t,J=7.0Hz,H-2),7.01-6.94(1H,m, H-1),5.45(1H,q,J=6.4Hz,H-10),5.35(1H,d,J=6.5Hz,H-12),4.11-3.78(2H,m,H-19),3.95(2H, dd,J=69.9,5.8Hz,H-20)3.53(3H,s,H-18),3.37-2.58(2H,m,H-12),1.41(3H,d,J=6.7Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ172.09(C,C-19),171.39(C,C-15),136.74(C,C-4),136.07(C,C-8),134.58(C, C-21),129.61(2CH,C-22,C-26),128.87(2CH,C-23,C-25),127.01(CH,C-24),126.60(C,C-5),121.58(C H,C-2),119.07(CH,C-1),118.42(CH,C-6),111.54(CH,C-3),104.14(C,C-9),54.06(CH3,C-18),52.64 (CH,C-12),52.50(CH,C-10),46.31(CH2,C-20),21.99(CH2,C-13),19.72(CH3,C-14).MS(ESI(+))calcd for C 22 H 23 N2O3 + [M+H] + :363.2; found:363.7.

[0055] Example 10

[0056]

[0057] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ10.99(1H,s,H-7),7.44(1H,d,J=2.1Hz,H-6),7.42(1H,s,H-26),7.32 (1H,d,J=7.7Hz,H-3),7.10-7.05(1H,m,H-2),7.04(1H,d,J=2.0Hz,H-24),7.02(1H,d,J=2.0Hz ,H-23),6.99(1H,ddd,J=8.0,7.2,1.0Hz,H-1),5.65-5.48(1H,q,J=6.8Hz,H-10),4.96(1H,d,J =3.8Hz,H-12),3.81(3H,s,H-18),3.34-2.88(2H,m,H-13),1.52-1.51(3H,d,J=5.3Hz,,H-14). 13 C NMR(101MHz,DMSO-d6)δ171.86(C,C-15),171.40(C,C-19),165.59(CH,C-24),149.11(C,C-20) ,136.83(CH,C-26),133.71(CH,C-23),126.59(C,C-4),123.13(C,C-8),121.77(C,C-5),119.60 (CH,C-2),119.20(CH,C-1),118.48(CH,C-6),111.65(CH,C-3),104.45(C,C-9),55.62(CH3,C- 18),52.78(CH,C-12),46.95(CH,C-10),22.47(CH2,C-13),19.65(CH3,C-14).MS(ESI(+))calcd forC 19 H 19 N4O3 + [M+H] + :351.2; found:351.4.

[0058] Embodiment 11

[0059]

[0060] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ11.02(1H,s,H-7),8.70(1H,d,J=1.6Hz,H-22),8.69(1H,d,J=1.6Hz,H-24) ,7.89(1H,d,J=7.7Hz,H-26),7.51(1H,dd,J=7.7Hz,H-6),7.40(1H,dd,J=7.7Hz,H-25),7.35(1H,d, J=8.0Hz,H-3),7.07(1H,t,J=7.4Hz,H-2),7.01-6.95(1H,m,H-1),5.72-5.62(1H,q,J=6.4Hz,H-10 ),4.77-4.73(1H,m,H-12),3.76-3.45(2H,m,H-13),3.42(3H,s,H-18),1.57(3H,d,J=6.6Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ167.73(C,C-15),151.01(C,C-19),147.77(CH,C-24),147.34(CH,C-22),13 6.51(C,C-4),135.54(CH,C-26),134.96(C,C-8),132.94(C,C-20),126.79(C,C-5),124.19(CH,C-25 ),121.56(CH,C-2),119.14(CH,C-1),118.31(CH,C-6),111.63(CH,C-3),106.55(C,C-9),50.97(CH 3,C-18),46.09(CH,C-12),42.12(CH,C-10),22.28(CH2,C-13),19.40(CH3,C-14).MS(ESI(+))calcd for C 20 H 20 N3O3 + [M+H] + :351.2; found:351.6.

[0061] Example 12

[0062]

[0063] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ11.04(1H,s,H-7),8.71(2H,d,J=5.6Hz,H-23,H-25),7.47(2H, d,J=5.8Hz,H-22,H-26),7.44(1H,d,J=8.0Hz,H-6),7.35(1H,d,J=8.1Hz,H-3),7.09(1H ,t,J=7.5Hz,H-2),7.00(1H,t,J=7.4Hz,H-1),5.60(1H,q,J=6.8Hz,H-10),4.77(1H,d,J =5.6Hz,H-12),3.58(3H,s,H-18),3.32-2.86(2H,m,H-13),1.54(3H,d,J=6.6Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ171.54(C,C-15),169.47(C,C-19),150.79(2CH,C-23,C-25),144.39( C,C-20),136.81(C,C-4),133.78(C,C-8),126.63(C,C-5),121.73(2CH,C-22,C-26),121.27(C H,C-2),119.19(CH,C-1),118.43(CH,C-6),111.65(CH,C-3),104.47(C,C-9),55.75(CH3,C-1 8),52.90(CH,C-12),46.70(CH,C-10),22.43(CH2,C-13),19.73(CH3,C-14).MS(ESI(+))calcd for C 20 H 20 N3O3 + [M+H] + :350.2; found:350.6.

[0064] Example 13

[0065]

[0066] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ11.01(1H,s,H-7),8.54(1H,d,J=4.0Hz,H-24),7.97(1H,d,J= 8.0Hz,H-26)7.65(1H,d,J=8.1Hz,H-25),7.46(1H,d,J=7.7Hz,H-6),7.33(1H,d,J=8. 1Hz,H-3),7.11-7.06(1H,m,H-2),6.99(1H,t,J=7.4Hz,H-1),5.59(1H,q,J=5.7Hz,H- 10), 4.92 (1H, d, J = 5.4Hz, H-12), 3.32-2.85 (2H, m, H-13), 1.51 (3H, d, J = 6.5Hz, H-14). 13 C NMR(101MHz,DMSO-d6)δ171.71(C,C-15),168.54(C,C-19),151.47(C,C-24),148.11(C,C-22),147. 84(C,C-4),138.40(CH,C-26),136.79(C,C-20),133.78(C,C-8),132.43(C,C-5),126.63(CH,C-25) ,125.11(CH,C-2),118.96(CH,C-1),118.49(CH,C-6),111.69(CH,C-3),104.61(C,C-9),60.31(CH3 ,C-18),56.05(CH,C-12),46.96(CH,C-10),19.87(CH2,C-13),14.62(CH3,C-14).MS(ESI(+))calcd for C 20 H 19 ClN3O3 + [M+H] + :384.1; found:384.8.

[0067] Embodiment 14

[0068]

[0069] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ11.01(1H,s,H-7),8.54(1H,s,H-22),7.97(1H,d,J=8.0Hz,H-26) ,7.65(1H,d,J=8.1Hz,H-6),7.46(1H,d,J=7.7Hz,H-25),7.33(1H,d,J=8.1Hz,H-3),7.08 (1H,t,J=7.2Hz,H-2),6.99(1H,t,J=7.4Hz,H-1),5.58(1H,q,J=6.7Hz,H-10),4.92(1H,d ,J=5.5Hz,H-12),3.58(3H,s,H-18),3.31-2.90(2H,m,H-13),1.51(3H,d,J=6.5Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ171.71(C,C-15),170.89(C,C-19),168.54(C,C-24),151.47(CH,C-22),14 8.11(C,C-4),147.84(CH,C-26),138.40(C,C-8),136.79(C,C-20),133.80(C,C-5),132.43(CH,C- 25),126.63(C,C-2),125.11(C,C-1),118.49(C,C-6),111.69(C,C-3),104.61(C,C-9),60.31(CH3 ,C-18),56.05(CH,C-12),46.76(CH,C-10),19.87(CH2,C-13),14.62(CH3,C-14).MS(ESI(+))calcd for C 20 H 19 ClN3O3 + [M+H] + :384.1; found:384.5.

[0070] Embodiment 15

[0071]

[0072] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ11.03(1H,s,H-7),8.65-8.57(1H,m,H-23),7.99(1H,dd,J=4.1,1.7Hz,H- 26),7.71(1H,d,J=7.8Hz,H-25),7.58-7.50(1H,m,H-24),7.45(1H,d,J=7.7Hz,H-6),7.34(1H,d, J=8.0Hz,H-3),7.09(1H,t,J=7.0Hz,H-2),7.02-6.95(1H,m,H-1),5.56(1H,q,J=6.7Hz,H-10),5. 24(1H,d,J=5.6Hz,H-12),3.53(3H,s,H-18),3.34-2.92(2H,m,H-13),1.60(3H,d,J=6.4Hz,H-14). 13 C NMR(101MHz,DMSO-d6)δ171.99(C,C-15),169.10(C,C-19),154.69(C,C-20),154.50(CH,C-23),148 .90(C,C-4),138.22(CH,C-25),136.77(C,C-8),134.14(C,C-5),133.84(CH,C-24),126.64(CH,C-26 ),125.54(CH,C-2),124.23(CH,C-1),118.44(CH,C-6),104.80(CH,C-3),104.11(C,C-9),55.51(CH 3,C-18),52.63(CH,C-12),47.04(CH,C-10),21.95(CH2,C-13),19.58(CH3,C-14).MS(ESI(+))calcd for C 20 H 20 N3O3 + [M+H] + :350.2; found:350.6.

[0073] Example 16

[0074]

[0075] Yellow oily, 1H NMR(400MHz,DMSO-d6)δ10.97(1H,s,H-7),8.46(1H,s,H-22),8.22(1H,s,H-26) ,7.43(1H,d,J=7.6Hz,H-6),7.30(1H,d,J=7.9Hz,H-3),7.04(1H,t,J=7.5Hz,H- 2),6.95(1H,t,J=7.4Hz,H-1),5.53(1H,q,J=6.0Hz,H-10),4.96(1H,d,J=4.7Hz ,H-12),3.55(3H,s,H-18),3.28-2.84(2H,m,H-13),1.47(3H,d,J=5.9Hz,H-14). 13 CNMR(101MHz,DMSO-d6)δ171.68(C,C-15),167.12(C,C-19),148.77(C,C-24),145.75(CH,C-22),13 8.00(C,C-4),136.79(C,C-8),133.72(C,C-20),133.62(CH,C-26),130.13(C,C-25),126.63(C,C-5 ),121.74(CH,C-2),119.19(CH,C-1),118.49(CH,C-6),111.64(C,C-3),104.67(C,C-9),55.78(CH3 ,C-18),52.89(CH,C-12),46.91(CH,C-10),22.23(CH2,C-13),19.77(CH3,C-14).MS(ESI(+))calcd for C 20 H 18 Cl2N3O3 + [M+H] + :418.1; found:418.8.

[0076] Embodiment 17

[0077]

[0078] Yellow oily, 11H NMR (400 MHz, DMSO-d6) δ 11.03 (1H, s, H-7), 8.37 (1H, d, J = 4.6 Hz, H-24), 8.09 (1H, t, J = 8.0 Hz, H-26), 7.52 - 7.48 (1H, m, H-25), 7.46 (1H, d, J = 7.8 Hz, H-6), 7.35 (1H, d, J = 8.0 Hz, H-3), 7.12 - 7.07 (1H, m, H-2), 7.02 - 6.98 (1H, m, H-1), 5.60 (1H, q, J = 6.4 Hz, H-10), 4.88 (1H, d, J = 5.8 Hz, H-12), 3.56 (3H, s, H-18), 3.38 - 2.94 (2H, m, H-13), 1.54 (3H, d, J = 6.6 Hz, H-14). 13 13C NMR (101 MHz, DMSO-d6) δ 171.40 (C, C-15), 165.61 (C, d, J = 4.0 Hz, C-19), 149.17 (CH, d, J = 16.1 Hz, C-24), 136.83 (C, C-4), 134.98 (C, d, J = 351.6 Hz, C-22), 133.71 (C, C-8), 126.56 (CH, d, J = 6.9 Hz, C-26), 123.13 (CH, C-5) 121.87 (C, d, J = 19.9 Hz, C-20), 119.60 (C, C-2), 119.29 (CH, d, J = 5.4 Hz, C-25), 119.20 (C, C-1), 118.48 (C, C-6), 111.65 (C, C-3), 104.45 (C, C-9), 55.62 (CH3, C-18), 52.78 (CH, C-12), 46.95 (CH, C-10), 22.47 (CH2, C-13), 19.65 (CH3, C-14). MS (ESI(+)) calcd for C 20 H 19 FN3O3 + [M + H] + : 368.1; found: 368.5.

[0079] Example 18

[0080]

[0081] Yellow oil, 1H NMR(400MHz,DMSO-d6)δ11.00(1H,s,H-7),7.46-7.42(3H,m,H-26,H-22,H-6),7.33(1 H,d,J=7.6Hz,H-3),7.11-7.05(1H,m,H-2),7.03(2H,d,J=8.8Hz,H-25,H-23),6.99(1H ,td,J=7.5Hz,1.0Hz,H-1),5.58(1H,q,J=6.4Hz,H-10),4.96(1H,d,J=3.6Hz,H-12),3. 81(3H,s,H-28),3.58(3H,s,H-18),3.35-2.87(2H,m,H-13),1.52(3H,d,J=6.8,H-14). 13 C NMR(101MHz,DMSO-d6)δ172.14(C,C-15),171.48(C,C-19),160.65(C,C-24),136.76(C,C-4),134.33(C ,C-8),129.12(2CH,C-22,C-26),128.76(C,C-20),126.69(2CH,C-23,C-25),121.71(C,C-5),119.20(C H,C-2),118.37(CH,C-1),114.47(CH,C-6),111.55(CH,C-3),104.49(C,C-9),55.78(CH3,C-28),55.73 (CH3,C-18),52.74(CH,C-12),46.63(CH,C-10),22.73(CH2,C-13),19.82(CH3,C-14).MS(ESI(+))calcd for C 22 H 23 N2O4 + [M+H] + :379.2; found:379.6.

[0082] Embodiment 19

[0083]

[0084] Yellow oily, 1H NMR (400MHz, CDCl3) δ8.37(1H,s,H-7),7.51(1H,d,J=7.6Hz,H-6),7.33-7.30(2H,m,H-26,H -3),7.30-7.26(4H,m,H-25,H-27,H-24,H-28),7.18-7.12(1H,m,H-2),7.14-7.09(1H,m,H- 1),5.70(1H,q,J=6.8Hz,H-10),4.94(1H,d,J=5.6Hz,H-12),3.64(3H,s,H-18),3.56-2.92( 2H,m,H-13),3.19-3.07(2H,m,H-21),2.88-2.83(2H,m,H-22),1.54(3H,d,J=6.8Hz,H-14). 13 C NMR(101MHz, CDCl3)δ172.35(C,C-19),171.57(C,C-15),141.14(C,C-23),136.46(C,C-4),133.85(C,C -8),128.72(2CH,C-24,C-28),128.57(2CH,C-25,C-27),126.58(C,C-5),126.42(CH,C-26),122.04(CH ,C-2),119.62(CH,C-1),118.35(CH,C-6),111.06(CH,C-3),104.58(C,C-9),52.67(CH3,C-18),49.53( CH,C-12),46.31(CH,C-10),36.31(CH2,C-21),31.47(CH2,C-22),22.75(CH2,C-13),19.71(CH3,C-14).

[0085] Embodiment 20

[0086]

[0087] Yellow oily, 1H NMR (400MHz, CDCl3) δ8.60 (1H, s, H-7), 7.50 (1H, d, J = 2.4Hz, H-22), 7.49-7.45 (3 H,m,H-6,H-25,H-24),7.40-7.36(2H,m,H-23,H-3),7.18-7.13(1H,m,H-2),7.10 (1H,td,J=7.5,1.1Hz,H-1),5.85(1H,q,J=8.7,7.8Hz,H-12),4.62(1H,d,J=5.1H z,H-10),3.61(3H,s,H-18),3.55-3.09(2H,m,H-13),1.71(3H,d,J=6.8Hz,H-14). 13 C NMR(101MHz, CDCl3)δ171.30(C,C-15),169.17(C,C-19),136.57(C,C-4),136.00(C,C-8),133.41(C ,C-22),130.63(C,C-20),130.09(CH,C-24),129.82(CH,C-23),128.27(CH,C-26),127.51(CH,C-25 ),126.46(C,C-5),122.08(CH,C-2),119.65(CH,C-1),118.33(CH,C-6),111.20(CH,C-3),104.96(C ,C-9),56.27(CH3,C-18),52.69(CH,C-12),46.73(CH,C-10),23.09(CH2,C-13),19.72(CH3,C-14).

[0088] Embodiment 21

[0089]

[0090] Yellow oily, 1H NMR(400MHz, CDCl3)δ9.06(1H,s,H-7),7.99-7.94(2H,m,H-22,H-25),7.83-7.80(1H,m,H-27) ,7.69(1H,dd,J=7.0,1.2Hz,H-30),7.59-7.55(2H,m,H-26,H-28),7.48-7.41(2H,m,H-6,H-29) ,7.13-7.02(2H,m,H-3,H-2),7.02-6.98(1H,m,H-1),6.19-6.08(1H,q,J=6.9Hz,H-10),4.67( 1H,d,J=5.2Hz,H-12),3.65(3H,s,H-18),3.41-2.79(2H,m,H-13),1.85(3H,d,J=6.8Hz,H-14). 13 C NMR (101MHz, CDCl3) δ171.80(C,C-15),171.45(C,C-19),136.61(C,C-4),134.27(C,C-8),133.73(C,C-23),129.56(C,C-2 4),129.40(C,C-20),128.74(CH,C-22),128.37(CH,C-25),127.63(CH,C-30),126.89(CH,C-27),125.58(CH,C-28),125.21 (C,C-5),124.39(CH,C-29),124.27(CH,C-26),121.95(CH,C-2),119.51(CH,C-1),118.19(CH,C-6),111.31(CH,C-3),104 .70(C,C-9),56.35(CH3,C-18),52.69(CH,C-12),46.82(CH,C-10),23.25(CH2,C-13),19.99(CH3,C-14).MS(ESI(+))calcd for C 25 H 23 N2O3 + [M+H] + :399.2; found:399.5.

[0091] Embodiment 22

[0092] The inhibitory activity of the obtained compounds against plant pathogens was measured, and the results are shown in Tables 2.1 and 2.2. Wherein W1 to W21 correspond to the compounds obtained in Examples 1 to 21.

[0093] Table 2.1 Antibacterial activity of compounds W1-W21 against seven pathogenic fungi

[0094]

[0095]

[0096] Note: CJ: Cytospora juglandis is walnut rot fungus; VD: Verticillium dahliae is cotton Verticillium wilt pathogen; AA: Alternaria alternate is tobacco brown spot pathogen; BC: Botrytis cinerea is tomato gray mold pathogen; CL: Curvularia lunata is corn Curvularia lunata pathogen; EV: Eggplant verticillium is eggplant Verticillium wilt pathogen; FO: Fusarium oxysporum is Fusarium oxysporum. Each treatment was set up with three replicates, and carbendazim was used as the positive control.

[0097] As can be seen from the table, at a concentration of 100 mg / L, most of the compounds showed certain biological activity against 7 plant fungi, among which compounds W11 and W17 were significantly active, especially compound W11, which had good inhibitory activity against walnut rot, cotton Verticillium wilt, tobacco brown spot pathogen, tomato gray mold and corn Curvularia serrata, with inhibition rates of 49.65%, 48.29%, 45.86%, 60.28% and 72.23%, respectively. Compound W17 showed an inhibition rate of nearly 50% against walnut rot, cotton Verticillium wilt, corn Curvularia serrata and Fusarium oxysporum, specifically 41.31%, 53.01%, 65.23% and 45.27%, respectively. In addition, through longitudinal comparison, the series of compounds as a whole showed a significant inhibitory effect on corn Curvularia serrata, especially compounds W4, W5, W11, W13, W15 and W17, with inhibition rates of 51.28%, 59.21%, 72.23%, 50.45%, 58.06% and 65.23%, respectively.

[0098] Table 2.2 Antibacterial activity of compounds W1-W21 against seven pathogenic fungi

[0099]

[0100]

[0101] Note: CC: Corynespora cassiicola is cucumber target spot pathogen; AS: Alternaria sonali is tomato early blight pathogen; FO: Fusarium oxysporum is watermelon wilt pathogen; CC: Corynespora cassicola is cucumber brown spot pathogen; AM: Alternaria mali is apple leaf spot pathogen; SS: Sclerotiniasclerotiorum is rapeseed sclerotinia pathogen; BC: Botrytis cinerea is tomato gray mold pathogen. Each treatment was set up with three replicates, and fluopyram, prothioconazole, boscalid, fluopyram, carbendazim and pyraclostrobin were used as positive controls.

[0102] As can be seen from the table, at a concentration of 30 mg / L, most of the compounds showed certain biological activity against 7 plant fungi, among which compounds W6, W16 and W20 were significantly active, especially compound W16, which showed good inhibitory activity against tomato early blight, rapeseed sclerotinia, tomato gray mold, cucumber brown spot and apple leaf spot pathogen, with inhibition rates of 51.03%, 72.33%, 61.56%, 46.46% and 45.49%, respectively. Compound W6 showed inhibition rates higher than 50% against rapeseed sclerotinia and tomato gray mold, which were 76.21% and 58.18%, respectively. Compound W20 also showed excellent inhibition rates against tomato early blight, rapeseed sclerotinia, tomato gray mold, tomato coryneformis, apple leaf spot pathogen and watermelon wilt pathogen, which were 62.76%, 67.48%, 66.23%, 44.88%, 45.96% and 41.25% respectively. In addition, a longitudinal comparison of this group of tests found that this series of compounds as a whole showed a significant inhibitory effect on rapeseed sclerotinia, especially compounds W16, W19 and W20, which inhibited 76.21%, 72.33%, 53.40% and 67.48% respectively, while the inhibition rate of compound W6 on rapeseed sclerotinia was comparable to that of the positive control boscalid, reaching 76.21%.

[0103] Compounds W6, W11, W16, W17 and W20 had good antifungal activity. Compounds W11 and W17 showed significant antifungal activity at a concentration of 100 mg / L. The EC value of compound W11 against Curvularia serrata and Botrytis cinerea was 0.0447. 50 The values ​​were 32.46 mg / L and 41.13 mg / L respectively. At a concentration of 30 mg / L, compounds W6, W16 and W20 showed high antibacterial activity against the seven tested plant fungi, among which compounds W16 and W20 had EC values ​​of 1.07 for Sclerotinia sclerotiorum. 50The values ​​are 12.71mg / L and 12.72mg / L.

[0104] The present invention is further described above in conjunction with the embodiments, but the present invention is not limited to the above-mentioned implementation modes, and various changes can be made within the knowledge scope of ordinary technicians in this field without departing from the purpose of the present invention.

Claims

1. A substituted tetrahydro- β -Carboline derivatives, as shown in formula (I): Formula (I); The substituent R1 is any one of the following groups: 。 2. The substituted tetrahydro- β - A method for preparing a carboline derivative, characterized in that: The process is as follows: 。 3. The substituted tetrahydro- β - A method for preparing a carboline derivative, characterized in that: The steps include: Step 1: prepare the corresponding acid chloride from the ready-made acid chloride or from the carboxylic acid according to the following method: using different carboxylic acids as raw materials, adding anhydrous dichloromethane to dissolve, and reacting with thionyl chloride under heating in an oil bath to prepare the corresponding acid chloride substrate; Step 2: The reaction substrate tetrahydro- β -Carboline compound was weighed and placed in a round-bottom flask, anhydrous dichloromethane was added and stirred to dissolve, triethylamine was added dropwise thereto, and the reaction was stirred at room temperature for 30 min and then transferred to an ice-water bath; Step 3: dissolve the acyl chloride substrate obtained in step 1 in anhydrous dichloromethane under ultrasonic conditions, and add the resulting solution dropwise into the reaction system of step 2 to react with the substrate tetrahydro- β -Carboline compound undergoes amidation reaction, followed by TLC detection. After the reaction is complete, saturated sodium bicarbonate solution is added dropwise to the reaction solution to quench the reaction, and the mixture is extracted with dichloromethane. The organic phases are combined and concentrated under reduced pressure. The crude product is separated by column chromatography to obtain substituted tetrahydro- β -Carboline derivatives.

4. The substituted tetrahydro- β - A method for preparing a carboline derivative, characterized in that: In the step 1, the ready-made acyl chloride is selected from any one of the following: 4-chlorobenzoyl chloride, 4-fluorobenzoyl chloride, 4-methylbenzoyl chloride, phenylacetyl chloride, phenylpropionyl chloride, 2-chlorobenzoyl chloride; or is prepared based on the following carboxylic acids: 5-methylnicotinic acid, 3-chloropyridine-4-carboxylic acid, 6-methylnicotinic acid, 2-chloropyridine-6-carboxylic acid, 5-chloropyrazine-2-carboxylic acid, pyrazine-2-carboxylic acid, nicotinic acid, isonicotinic acid, 2-chloronicotinic acid, 6-chloronicotinic acid, 2-carboxylic acid pyridine, 5,6-dichloronicotinic acid, 2-fluoronicotinic acid, 4-methoxybenzoic acid, 1-naphthoic acid.

5. The substituted tetrahydro- β - Use of carboline derivatives in inhibiting plant pathogens.

6. The use according to claim 5, characterized in that The plant pathogenic bacteria are any of walnut rot, cotton wilt, tobacco brown spot, tomato gray mold, corn curvature, eggplant wilt, Fusarium oxysporum, cucumber target spot, tomato early blight, watermelon wilt, cucumber brown spot, apple leaf spot and rapeseed sclerotinia.

Images