7-halogenated dihydroisoquinoline compound and application of 7-halogenated dihydroisoquinoline compound in preparation of bactericide for resisting plant pathogenic fungi

Abstract

The invention relates to a novel 7-halogenated dihydroisoquinoline compound and application of the novel 7-halogenated dihydroisoquinoline compound in preparation of a bactericide for resisting plant pathogenic fungi. The structure of the isoquinoline compound is shown as a formula (I): # imgabs0 #, wherein R1 is selected from halogen; r2-R6 are selected from the group consisting of hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkoxy carbon groups. The compound disclosed by the invention has obvious inhibitory activity on various plant pathogenic fungi, and can be used for preparing a bactericide for preventing and treating crop diseases.

Description

Technical Field

[0001] The invention relates to the field of pesticide fungicides, in particular to 7-halogenated dihydroisoquinoline compounds and applications thereof in preparing anti-plant pathogenic fungicide fungicides. Background Art

[0002] Isoquinoline alkaloids are a class of organic compounds containing an isoquinoline skeleton in nature. They have significant biological activity and are one of the important active ingredients in traditional Chinese medicine. Among them, berberine, sanguinarine, chelerythrine, etc. are a very special class of isoquinoline alkaloids, containing a quaternary ammonium salt structure (C=N + ), also known as quaternary ammonium isoquinoline alkaloids. Although quaternary ammonium alkaloids account for a very small proportion in nature, they have shown excellent biological activities in the fields of medicine and agriculture, such as anti-tumor, bactericidal, insecticidal, acaricidal, antiviral, etc., and their development and application have attracted much attention from drug researchers. Zhou Le et al. reported a series of N-aryl-3,4-dihydroisoquinoline salt derivatives containing unique pharmacophores of quaternary ammonium alkaloids, which have good biological activity against pathogens and mites of animals and plants (CN 101759637B). The applicant also reported two types of 3-aryl isoquinoline compounds and their use as anti-plant pathogenic fungicides (CN 115353488 B).

[0003] Based on the previous research results, the applicant used quaternary ammonium isoquinoline alkaloids as the lead, adopted the biomimetic pesticide design strategy, simplified the lead structure, combined with the pharmacophore splicing principle, designed and synthesized a series of novel 7-halogenated dihydroisoquinoline compounds, and studied their anti-plant pathogenic fungi activity. The results show that the novel 7-halogenated dihydroisoquinoline compounds involved in the present invention have good antibacterial activity against a variety of plant pathogenic fungi.

[0004] The novel 7-halogenated dihydroisoquinoline compounds involved in the present invention are new compounds that have not been reported in the literature. Previously, existing literature reported structures similar to those of the present invention, but did not clearly list the compounds protected by the present invention and their physical and chemical properties. Summary of the invention

[0005] The present invention aims to provide novel 7-halogenated dihydroisoquinoline compounds and their application in preparing anti-plant pathogenic fungicide.

[0006] The novel 7-halogenated dihydroisoquinoline compound of the present invention has a structure as shown in formula (I):

[0007] In formula (I), R 1Halogen; R 2 -R 6 Selected from hydrogen, halogen, hydroxy, trifluoromethyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxycarbonyl.

[0008] The present invention provides a general preparation method for the novel 7-halogenated dihydroisoquinoline compound, and its typical synthesis route is shown in Reaction Formula 1.

[0009] Reaction 1

[0010] Compound I is used for preparing anti-plant pathogenic fungi drugs. It has significant inhibitory activity against wheat sheath blight (Rhizotonia cerealis), apple ring rot fungus (Physalospora piricola), wheat fusarium (Fusarium graminearum), watermelon anthracnose fungus (Colletotrichum lagenarium), barley smut fungus (Ustilagohordei) and corn leaf spot fungus (Helminthosporium maydis).

[0011] Compared with the prior art, the present invention has the following advantages and effects:

[0012] The present invention uses a natural quaternary ammonium salt type isoquinoline alkaloid lead compound and adopts a biomimetic design strategy to design and synthesize a series of novel 7-halogenated dihydroisoquinoline compounds with novel structures. The in vitro antibacterial activity test proves that the anti-plant pathogenic fungi activity of the compounds is significant, and some target compounds are equivalent to the commercial fungicides chlorothalonil and boscalid, which provides a basis for the synthesis of 7-halogenated dihydroisoquinoline derivatives and a wider range of biological activity studies. DETAILED DESCRIPTION

[0013] In the present invention, the structural formula of the novel 7-halogenated dihydroisoquinoline compounds designed and synthesized is as follows:

[0014] In formula (I), R 1 is selected from halogen; R 2 -R 6 Selected from hydrogen, halogen, hydroxy, trifluoromethyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C1 -C 6 Alkoxycarbonyl.

[0015] The novel 7-halogenated dihydroisoquinoline compounds are used as fungicides for the preparation of anti-plant pathogenic fungi. It is known that the isoquinoline compounds have significant inhibitory activity against the following plant pathogenic fungi: wheat leaf blight (Rhizotonia cerealis), apple ring rot fungus (Physalospora piricola), wheat head blight fungus (Fusarium graminearum), watermelon anthracnose fungus (Colletotrichum lagenarium), barley smut fungus (Ustilagohordei) and corn leaf spot fungus (Helminthosporium maydis), etc.

[0016] The general synthesis method of the 7-halogenated dihydroisoquinoline compound I of the present invention is carried out according to Reaction Scheme 1. Compound I-1 is used for specific description.

[0017]

[0018] Example 1, Synthesis of Compound I-1.

[0019] The synthesis route of compound I-1 is shown in Reaction Scheme 2.

[0020] Reaction 2

[0021] Synthesis of intermediate 3: Take intermediate 3a as an example. Add p-fluorophenylethanol (10mmol, 1.40g), paraformaldehyde (12mmol, 0.36g), and concentrated hydrochloric acid (12mol / L, 3mL) into a 25mL reaction bottle in sequence, heat and stir to react, and monitor with a thin layer chromatography (TLC) plate until the reaction is complete. After cooling, add 100mL of ethyl acetate to the residue, and then use saturated NaHCO 3 The solution (25 mL × 3) was washed with saturated brine (25 mL × 2) and distilled water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by column chromatography (PE: EA) to obtain 3a. The synthesis method of other intermediates 3 is the same as that of 3a.

[0022] Synthesis of intermediate 4: Take intermediate 4a as an example. Add 3a (10mmol, 1.52g), copper bromide (12mmol, 2.68g), and 20mL of anhydrous acetonitrile into a 50mL single-mouth bottle, heat to reflux, and monitor by TLC until the reaction is complete. After cooling, remove the solvent under reduced pressure, add 100mL of ethyl acetate to the residue, wash with saturated brine (25mL×2) and distilled water (25mL×3) in turn, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate the residue by column chromatography (PE:EA) to obtain 4a. The synthesis method of other intermediates 4 is the same as 4a.

[0023] Synthesis method of target compound I-1: Dissolve methyl 2-aminobenzoate (1mmol, 0.209g) in 10mL acetonitrile, add dropwise 4a (1.5mmol, 0.330g) dissolved in 1,4-dioxane (5mL), stir overnight at room temperature after addition, and monitor by TLC until the reaction is complete. Remove the solvent under reduced pressure, wash the solid with ethyl acetate, and centrifuge to obtain target compound I-1.

[0031] Compound I-1: white powder, yield 51%, mp 186–187°C. 1 H NMR(600MHz,Chloroform-d)δ9.80(s,1H),8.70(d,J=7.2Hz,1H),8.21(d,J=7.8Hz,1H),8.07(d,J=5.5Hz,1H),7.87(t,J=7 .5Hz,1H),7.69(t,J=7.7Hz,1H),7.44(t,J=7.2Hz,1H),7.38(dd,J=8.3,4.8Hz,1H),4.43(s,2H),3.92(s,3H),3.60(s,2H). 13 C NMR (150MHz, DMSO-d6) δ169.30,164.30,161.22(d,J=245.2Hz),142.52,135.20,133.75(d,J=3.1Hz),132.37,132.14,131 .36 (d, J = 7.7Hz), 127.51, 126.74 (d, J = 8.9Hz), 125.91 (d, J = 21.7Hz), 124.77, 120.80 (d, J = 23.4Hz), 53.62, 53.50, 25.04.

[0024] The synthesis methods of the remaining compounds I are the same as I-1, and the structural formulas of some representative compounds are shown in Table 1.

[0025] The physicochemical data of some representative compounds are as follows:

[0026] Compound I-2: white powder, yield 54%, mp 198–199°C. 1 H NMR (400 MHz, DMSO-d 6 )δ9.79(s,1H),8.46(s,1H),8.20(d,J=7.1Hz,2H),7.94(d,J=7.1Hz,1H),7.86(t,J=7.9Hz, 1H),7.78(d,J=7.7Hz,1H),7.70–7.64(m,1H),4.63(s,2H),3.93(s,3H),3.45–3.41(m,2H). 13 C NMR (150 MHz, DMSO-d 6 )δ167.52,165.50,161.98,160.36,143.63,133.94,131.67,131.09,130.96(d,J=7 .8Hz), 128.13, 127.53, 125.49, 124.16, 120.75 (d, J = 23.3Hz), 53.20, 51.62, 24.79.

[0027] Compound I-3: white powder, yield 48%, mp 207–208 °C. 1 H NMR(400MHz,Chloroform-d)δ9.26(d,J=8.8Hz,1H),9.11(d,J=9.4Hz,1H),8.82(d,J =8.0Hz,1H),7.95(dd,J=9.0,2.5Hz,1H),7.63(d,J=8.0Hz,1H),7.51(dd,J=8.5,5.2H z,1H),7.47(s,1H),5.55(t,J=6.9Hz,2H),4.39(t,J=6.7Hz,2H),3.57(t,J=6.9Hz,2 H), 1.79 (dt, J = 14.4, 6.8 Hz, 2H), 1.49 (dq, J = 14.7, 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR(100MHz,Chloroform-d)δ164.16,152.47,148.17,141.11,135.86,132.80(d,J=2.9Hz),132.25,131.71,130.73(d,J=7.7 Hz), 128.42, 122.62, 121.30 (q, J = 210.6Hz), 121.56, 120.73, 116.11 (d, J = 24.6Hz), 66.33, 49.66, 30.72, 26.23, 19.32, 13.83.

[0028] Compound I-4: white powder, yield 45%, mp 190–192 °C. 1 H NMR (400 MHz, DMSO-d 6 )δ9.60(s,1H),8.06(d,J=1.1Hz,1H),7.88(d,J=8.1,5.3,2.5Hz,2H),7.83(dd,J=8.7,2.8Hz,1H),7.80(dd,J=8 .1,1.2Hz,1H),7.72(dd,J=8.5,5.1Hz,1H),4.51–4.43(m,2H),3.86(s,3H),3.47(t,J=8.0Hz,2H),2.50(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ168.30,163.38,160.25(d,J=245.1Hz),141.40,139.31,134.40,132.74(d,J=3.0Hz),131.59,130.37(d,J=7.7H z), 126.29, 125.72 (d, J = 9.0Hz), 124.90 (d, J = 21.1Hz), 123.47, 119.69 (d, J = 23.5Hz), 52.66, 52.45, 24.04, 20.07.

[0029] Compound I-5: brown powder, yield 58%, mp 184–185°C. 1 H NMR(400MHz,Chloroform-d)δ10.05(s,1H),8.74(dd,J=8.8,4.7Hz,1H),8.05(dd,J=7.8,2.6Hz,1H ),7.84(dd,J=8.4,2.9Hz,1H),7.48–7.34(m,3H),4.42(s,2H),3.90(s,3H),3.58(t,J=8.0Hz,2H). 13CNMR(100MHz,Chloroform-d)δ168.26(d,J=2.8Hz),163.34(d,J=2.1Hz),163.15(d,J=255 .2Hz),161.62(d,J=249.7Hz),138.55(d,J=3.6Hz),132.36(d,J=3.4Hz),130.34(d,J=8.7 Hz), 130.03 (d, J = 7.5Hz), 126.89 (d, J = 9.0Hz), 126.47 (d, J = 8.2Hz), 125.64 (d, J = 22.0Hz) ,122.31(d,J=23.4Hz), 122.06(d,J=22.6Hz), 119.37(d,J=25.3Hz), 54.48, 53.45, 25.71.

[0030] Compound I-6: white powder, yield 48%, mp 193–194 °C. 1 H NMR(400MHz,Chloroform-d)δ9.91(s,1H),9.20(d,J=1.9Hz,1H),8.19(dd,J=8.4,1.9Hz,1H),8.02(dd,J=7.8, 2.5Hz, 1H), 7.69 (d, J = 8.5Hz, 1H), 7.49–7.36 (m, 2H), 4.37 (t, J = 7.6Hz, 2H), 3.94 (s, 3H), 3.53 (t, J = 7.7Hz, 2H). 13 C NMR(100MHz,Chloroform-d)δ164.72,164.63,161.90(d,J=250.5Hz),140.57,133.18,132.93,131.64(d,J=3.5Hz),131.53, 131.15, 130.11 (d, J = 7.6Hz), 128.14 (d, J = 9.0Hz), 127.98, 125.47 (d, J = 22.1Hz), 122.23 (d, J = 23.5Hz), 53.17, 52.98, 25.74.

[0031] Compound I-7: yellow powder, yield 41%, mp 193–195°C. 1H NMR(400MHz,Chloroform-d)δ9.84(s,1H),9.18(d,J=1.9Hz,1H),8.11(dd,J=8.4,1.7Hz,1H),8.02(dd,J= 7.7, 2.6Hz, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.50–7.36 (m, 2H), 4.36 (s, 2H), 3.96 (s, 3H), 3.54 (t, J = 7.7Hz, 2H).

[0032] Compound I-8: yellow powder, yield 56%, mp 220–221 °C. 1 H NMR(400MHz,Chloroform-d)δ10.19(s,1H),8.79(s,2H),8.77(s,1H),8.00(d,J=6.9Hz ,1H),7.40(d,J=6.2Hz,2H),4.57(t,J=7.7Hz,2H),3.96(s,6H),3.54(t,J=7.7Hz,2H). 13 C NMR(100MHz,Chloroform-d)δ164.65,163.05,162.92,160.57,143.39,133.03,132.43,131.94,1 30.06, 129.98, 128.07, 127.61, 125.41 (d, J = 22.5Hz), 122.01, 121.78, 53.20, 51.99, 25.61, 1.14.

[0033] Compound I-9: white powder, yield 55%, mp 181–182 °C. 1 H NMR(400MHz,Chloroform-d)δ9.82(s,1H),8.60(d,J=7.9Hz,1H),8.25(d,J=1.9Hz,1H),8.18(d,J=7.1Hz,1H),7. 80(t,J=7.4Hz,1H),7.66(t,J=7.6Hz,2H),7.37(d,J=8.2Hz,1H),4.44(s,2H),3.89(s,3H),3.61(t,J=7.8Hz,2H). 13 C NMR(100MHz,Chloroform-d)δ167.36,164.43,142.56,138.20,135.46,135.20,134 .82,134.46,132.26,131.66,129.72,127.79,126.95,124.00,54.16,53.17,25.89.

[0034] Compound I-10: white powder, yield 41%, mp 179–180°C. 1 H NMR(600MHz,Chloroform-d)δ10.27(s,1H),8.56(s,1H),8.35(s,1H),8.31(s,1H),8. 13(d,J=5.0Hz,1H),7.64(s,2H),7.38(s,1H),4.62(s,2H),3.93(s,3H),3.57(s,2H). 13 C NMR(150MHz,Chloroform-d)δ165.36,165.24,142.69,138.22,135.11,134.64,134 .50,132.04,132.02,131.16,129.77,128.20,127.55,123.39,53.06,52.48,25.99.

[0035] Compound I-11: white powder, yield 50%, mp 220–221 °C. 1 H NMR (400MHz, Chloroform-d) δ10.40(s,1H),8.31(s,1H),8.16(d,J=8.5Hz,2H),8.10(d,J=8.4Hz,2H),7.60(d,J=7.7Hz,1H),7.33(d,J=8.1Hz ,1H), 4.63(t,J=7.7Hz,2H), 4.31(t,J=6.6Hz,2H), 3.51(t,J=7.6Hz,2H), 1.73(p,J=6.8Hz,2H), 1.45(h,J=7.4Hz,2H), 0.97(t,J=7.4Hz,3H). 13 CNMR(100MHz,Chloroform-d)δ165.13,164.85,145.20,138.31,135.04,134.88,134.30,132.8 3,131.42,129.57,127.18,123.01,113.69,102.50,65.57,51.86,30.63,25.45,19.22,13.75.

[0036] Compound I-12: white powder, yield 57%, mp 164–165°C. 1H NMR(400MHz,Chloroform-d)δ9.76(s,1H),8.61(d,J=6.8Hz,1H),8.37(d,J=2.0Hz,1H),8.18(dd,J=7.9,1.5Hz,1H),7.81(td,J=7.2,6.3, 1.7Hz, 2H), 7.66 (t, J = 7.7Hz, 1H), 7.30 (d, J = 8.1Hz, 1H), 4.61 (t, J = 7.9Hz, 1H), 3.89 (s, 3H), 3.58 (t, J = 7.9Hz, 2H), 3.51 (t, J = 7.9Hz, 1H). 13 C NMR(100MHz,Chloroform-d)δ167.15,164.45,141.13,138.04,135.52,132.28,131 .69,130.36,129.92,127.79,124.82,122.05,120.36,118.92,54.07,53.18,25.96.

[0037] Compound I-13: white powder, yield 38%, mp 241–242 °C. 1 H NMR(400MHz,Chloroform-d)δ10.34(s,1H),8.47–8.42(m,1H),8.16(d,J=8.7Hz,2H),8.11(d,J=8.6Hz,2H),7.76(dd,J=8.0,1.6Hz,1H),7.28(d,J= 8.2Hz,1H),4.63(t,J=7.8Hz,2H),4.31(t,J=6.6Hz,2H),3.49(t,J=7.8Hz ,2H), 1.74(p,J=6.7Hz,2H), 1.45(h,J=7.4Hz,2H), 0.97(t,J=7.4Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ164.87,145.22,141.20,137.91,135.37,132.85,13 1.45,129.80,127.49,123.00,121.91,65.59,51.79,30.64,25.52,19.23,13.75.

[0038] Compound I-14: white powder, yield 40%, mp 201–202 °C. 1H NMR(400MHz,Chloroform-d)δ9.77(s,1H),9.16(d,J=1.9Hz,1H),8.33(d,J=2.0Hz,1H),8.18(dd,J=8.5,1.9Hz,1H),7.83(d d,J=8.1,2.0Hz,1H),7.68(d,J=8.4Hz,1H),7.31(d,J=8.1Hz,1H),4.35(t,J=7.6Hz,2H),3.94(s,3H),3.51(t,J=7.6Hz,2H). 13 C NMR(100MHz,Chloroform-d)δ164.71,163.26,140.71,140.62,137.80,134.50,133 .11,132.97,131.51,131.13,129.93,128.61,127.92,122.34,53.17,52.62,25.94.

[0039] Compound I-15: white powder, yield 45%, mp 211–212 °C. 1 H NMR(400MHz,Chloroform-d)δ9.82(s,1H),8.39(s,1H),8.33(d,J=8.1Hz,1H),7.96(s,1H),7.82–7.76(m,1H),7.55(d,J=7.8 Hz, 1H), 7.31 (d, J = 8.1Hz, 1H), 4.40 (s, 2H), 4.06 (t, J = 8.0Hz, 2H), 3.86 (s, 3H), 3.56 (t, J = 7.8Hz, 2H), 1.34 (Q, J = 8.0Hz, 3H). 13 C NMR(100MHz,Chloroform-d)δ167.24,164.43,142.26,140.94,140.06,137.80,135.64,13 5.33,132.69,129.88,127.36,127.04,123.52,121.77,64.03,54.05,53.00,25.82,14.28.

[0040] Example 2, experimental method and results of the anti-plant pathogenic fungi activity of target compound I.

[0041] The present invention uses the hyphae growth rate method to test the in vitro activity of some target compounds I-1-I-15 against six common crop pathogens, including wheat sheath blight (Rhizotonia cerealis, RC), apple ring rot (Physalospora piricola, PP), wheat head blight (Fusarium graminearum, FG), watermelon anthracnose (Colletotrichum lagenarium, CL), barley smut (Ustilago hordei, UH) and corn leaf spot (Helminthosporium maydis, HM), with chlorothalonil (Chlorothalonil) and boscalid (Boscalid) as control drugs. The compound was dissolved in dimethyl sulfoxide to a concentration of 10 mg·L -1 The mother solution was diluted with Tween solution to a concentration of 50 mg·L -1 1 mL of the above solution was added to 9 mL of potato dextrose agar (PDA) medium. After the medium was completely solidified, the test bacteria were inoculated. Dimethyl sulfoxide was used as a blank control. The experiment was repeated 3 times. After culturing at 25°C in the dark for 3-4 days, the culture dish was removed and the colony diameter was measured by the cross method. The results of the anti-plant pathogenic fungi test are shown in Table 2.

[0042] The results showed that the novel 7-halogenated dihydroisoquinoline compounds had moderate to significant in vitro antibacterial activity against 6 common plant pathogenic fungi, which was comparable to the commercial drugs chlorothalonil and boscalid. Therefore, the novel 7-halogenated dihydroisoquinoline compounds of the present invention can be used to prepare antifungal fungicides against plant pathogenic fungi. Table 1 Structural formulas of some target compounds I-1 to I-15 Table 2 Experimental data of anti-plant pathogenic fungi activity of target compounds I-1-I-15

Claims

1. A novel 7-halogenated dihydroisoquinoline compound, the structure of which is shown in formula (I). In formula (I), R1 is selected from halogen; R2-R6 are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl.

2. Use of the novel 7-halogenated dihydroisoquinoline compound according to claim 1 in the preparation of an anti-plant pathogenic fungus drug.

3. The use of the novel 7-halogenated dihydroisoquinoline compound according to claim 2 in the preparation of an anti-plant pathogenic fungus drug, wherein the plant pathogenic fungus is selected from Rhizotonia cerealis, Physalospora piricola, Fusarium graminearum, Colletotrichum lagenarium, Ustilago hordei and Helminthosporium maydis, etc.

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