7-Halogenated dihydroisoquinoline compounds and their application in the preparation of fungicides against plant pathogenic fungi.

Abstract

This invention relates to novel 7-halodihydroisoquinoline compounds and their application in the preparation of fungicides against plant pathogenic fungi. The structures of these isoquinoline compounds are as shown in formula (I): wherein R1 is selected from halogens; R2-R6 are selected from hydrogen, halogens, hydroxyl groups, trifluoromethyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, and C1-C6 alkoxycarbon groups. The compounds of this invention exhibit significant inhibitory activity against a variety of plant pathogenic fungi and can be used to prepare fungicides for the prevention and control of crop diseases.

Description

Technical Field

[0001] This invention relates to the field of pesticides and fungicides, particularly 7-halodihydroisoquinoline compounds and their application in the preparation of fungicides against plant pathogenic fungi. Background Technology

[0002] Isoquinoline alkaloids are a class of organic compounds in nature containing an isoquinoline skeleton. They possess significant biological activity and are among the important active ingredients in traditional Chinese medicine. Berberine, sanguinarine, and chelerythrine are particularly unique isoquinoline alkaloids, containing a quaternary ammonium salt structure (C=N). + 3-aryl-3,4-dihydroisoquinoline alkaloids, also known as quaternary ammonium isoquinoline alkaloids, are present in small quantities in nature but exhibit excellent biological activities in medicine and agriculture, such as antitumor, bactericidal, insecticidal, acaricidal, and antiviral effects. Their development and application are of great interest to 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 showed good biological activity against pathogenic fungi and mites in animals and plants (CN 101759637B). The applicant also reported two classes of 3-aryl isoquinoline compounds and their application in the preparation of fungicides against plant pathogenic fungi (CN 115353488 B).

[0003] Based on previous research, the applicant used quaternary ammonium salt-type isoquinoline alkaloids as a lead compound, adopted a biomimetic pesticide design strategy to simplify the lead compound's structure, and combined this with the principle of pharmacophore splicing to design and synthesize a series of novel 7-halodihydroisoquinoline compounds. Their activity against plant pathogenic fungi was then studied. The results demonstrate that the novel 7-halodihydroisoquinoline compounds involved in this invention exhibit good antifungal activity against a variety of plant pathogenic fungi.

[0004] The novel 7-halodihydroisoquinoline compounds involved in this invention are new compounds not previously reported in the literature. Previous literature has reported structures similar to those of this invention, but did not explicitly list the compounds protected by this invention and their physicochemical properties. Summary of the Invention

[0005] The purpose of this invention is to provide novel 7-halodihydroisoquinoline compounds and their application in the preparation of fungicides against plant pathogenic fungi.

[0006] The novel 7-halodihydroisoquinoline compound described in this invention has the structure shown in formula (I).

[0007]

[0008] In formula (I), R1 is a halogen; R2-R6 are selected from hydrogen, halogen, hydroxyl, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkoxycarbonyl.

[0009] This invention provides a general method for preparing the novel 7-halodihydroisoquinoline compounds, and its typical synthetic route is shown in reaction formula 1.

[0010]

[0011] Reaction 1

[0012] Compound I was used in the preparation of drugs against plant pathogenic fungi. It exhibited significant inhibitory activity against Rhizotonia cerealis (wheat sheath blight), Physalospora piricola (apple ring rot), Fusarium graminearum (wheat scab), Colletotrichum lagenarium (watermelon anthracnose), Ustilago hordei (barley smut), and Helminthosporium maydis (corn leaf spot).

[0013] Compared with the prior art, the present invention has the following advantages and effects:

[0014] This invention utilizes natural quaternary ammonium salt-type isoquinoline alkaloids as lead compounds and employs a biomimetic design strategy to design and synthesize a series of novel 7-halodihydroisoquinoline compounds. In vitro antibacterial activity tests demonstrate that these compounds exhibit significant activity against plant pathogenic fungi, with some target compounds showing comparable activity to commercial fungicides such as chlorothalonil and boscalid. This provides a foundation for the synthesis of 7-halodihydroisoquinoline derivatives and broader bioactivity studies. Detailed Implementation

[0015] In this invention, the novel 7-halodihydroisoquinoline compounds designed and synthesized have the following general structural formula:

[0016]

[0017] In formula (I), R1 is selected from halogens; R2-R6 are selected from hydrogen, halogens, hydroxyl groups, trifluoromethyl groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, and C1-C6 alkoxycarbon groups.

[0018] The application of novel 7-halodihydroisoquinoline compounds in the preparation of fungicides against plant pathogenic fungi is known. Isoquinoline compounds are known to have significant inhibitory activity against a variety of plant pathogenic fungi, including Rhizotonia cerealis (wheat sheath blight), Physalospora piricola (apple ring rot), Fusarium graminearum (wheat scab), Colletotrichum lagenarium (watermelon anthracnose), Ustilago hordei (barley smut), and Helminthosporium maydis (corn leaf spot).

[0019] The general synthetic method for 7-halodihydroisoquinoline compound I described in this invention is carried out according to reaction formula 1. Compound I-1 is used as an example for detailed explanation.

[0020]

[0021] Example 1, Synthesis of compound I-1.

[0022] The synthetic route of compound I-1 is shown in reaction formula 2.

[0023]

[0024] Reaction 2

[0025] Synthesis of Intermediate 3: Taking Intermediate 3a as an example, p-fluorophenylethanol (10 mmol, 1.40 g), paraformaldehyde (12 mmol, 0.36 g), and concentrated hydrochloric acid (12 mol / L, 3 mL) were added sequentially to a 25 mL reaction flask. The mixture was heated and stirred, and the reaction was monitored by thin-layer chromatography (TLC) until complete. After cooling, 100 mL of ethyl acetate was added to the residue, and the mixture was washed sequentially with saturated NaHCO3 solution (25 mL × 3), saturated saline solution (25 mL × 2), and distilled water (25 mL × 2). The residue was 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 methods of other intermediates 3 are the same as those for 3a.

[0026] Synthesis of intermediate 4: Taking intermediate 4a as an example. 3a (10 mmol, 1.52 g), copper bromide (12 mmol, 2.68 g), and 20 mL of anhydrous acetonitrile were added to a 50 mL single-necked flask and heated to reflux. The reaction was monitored by TLC until complete. After cooling, the solvent was removed under reduced pressure. 100 mL of ethyl acetate was added to the residue, and the mixture was washed successively with saturated brine (25 mL × 2) and distilled water (25 mL × 3). The residue was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by column chromatography (PE:EA) to obtain 4a. The synthesis methods for other intermediates 4 are the same as for 4a.

[0027] Synthesis of target compound I-1: Methyl 2-aminobenzoate (1 mmol, 0.209 g) was dissolved in 10 mL of acetonitrile, and a solution of 1,4-dioxane (5 mL) containing 4a (1.5 mmol, 0.330 g) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature, and the reaction was monitored by TLC until complete. The solvent was removed under reduced pressure, and the solid was washed with ethyl acetate and centrifuged to obtain target compound I-1.

[0028] 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.

[0029] The synthesis methods for the remaining compounds I are the same as those for I-1. The structural formulas of some representative compounds are shown in Table 1.

[0030] The physicochemical data of some representative compounds are as follows:

[0031] Compound I-2: white powder, yield 54%, mp 198–199 °C. 1H NMR (400MHz, DMSO-d6) 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(150MHz,DMSO-d6)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.

[0032] Compound I-3: white powder, yield 48%, mp 207–208℃. 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). 13 C 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.

[0033] Compound I-4: white powder, yield 45%, mp 190–192 °C.1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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 = 7.7Hz), 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.

[0034] 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). 13 CNMR(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.

[0035] 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.

[0036] Compound I-7: yellow powder, yield 41%, mp 193–195 °C. 1 H 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).

[0037] Compound I-8: yellow powder, yield 56%, mp 220–221℃. 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). 13C 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.

[0038] 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.

[0039] 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.

[0040] Compound I-11: white powder, yield 50%, mp 220–221℃. 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.

[0041] Compound I-12: white powder, yield 57%, mp 164–165 °C. 1 H 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.

[0042] Compound I-13: white powder, yield 38%, mp 241–242℃. 1H 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.

[0043] Compound I-14: white powder, yield 40%, mp 201–202℃. 1 H 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.

[0044] Compound I-15: white powder, yield 45%, mp 211–212℃. 1H 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.

[0045] Example 2: Experimental methods and results of the antifungal activity of target compound I against plant pathogenic fungi.

[0046] This invention utilizes the mycelial growth rate method to test the in vitro activity of some target compounds I-1—I-15 against six common crop pathogens: *Rhizotonia cerealis* (RC), *Physalospora piricola* (PP), *Fusarium graminearum* (FG), *Colletotrichum lagenarium* (CL), *Ustilago hordei* (UH), and *Helminthosporium maydis* (HM). Chlorothalonil and Boscalid were used as control agents. The compounds were dissolved in dimethyl sulfoxide to prepare a concentration of 10 mg·L⁻¹. -1 The mother liquor was diluted with Tween solution to a concentration of 50 mg·L⁻¹. -1 The test solution was prepared by adding 1 mL of the above solution to 9 mL of potato dextrose agar (PDA) medium. After the medium had completely solidified, the test strain was inoculated, with dimethyl sulfoxide as a blank control. The experiment was repeated three times. After incubating at 25°C in the dark for 3-4 days, the culture dish was removed, and the colony diameter was measured using the cross-crossing method. The results of the anti-plant pathogenic fungal test are shown in Table 2.

[0047] The results showed that the novel 7-halodihydroisoquinoline compounds exhibited moderate to significant in vitro antifungal activity against six common plant pathogenic fungi, comparable to that of commercially available drugs chlorothalonil and cyazofamid. Therefore, the novel 7-halodihydroisoquinoline compounds of this invention can be used to prepare fungicides against plant pathogenic fungi. Table 1 shows the structural formulas of some target compounds I-1–I-15.

[0048]

[0049] Table 2. Experimental data on the antifungal activity of target compounds I-1–I-15 against plant pathogenic fungi.

[0050]

Claims

1.7-Halodihydroisoquinoline compounds in the preparation of drugs against plant pathogenic fungi, wherein the plant pathogenic fungus is *Ustilago hordei*, and the specific structure of the 7-halodihydroisoquinoline compound is as follows:

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