阅读说明：本技术 一类萘醌类化合物及其制备与杀螨、杀菌用途 (Naphthoquinone compounds and preparation and acaricidal and bactericidal application thereof ) 是由 郝双红 王红梅 林琎 余海涛 于 2021-10-05 设计创作，主要内容包括：本发明(名称为：一类萘醌类化合物及其制备与杀螨、杀菌用途)涉及15种2,3-取代的萘醌衍生物及其制备方法,以及在杀螨、抑菌方面的用途。15种2,3-取代的萘醌衍生物,通过2-羟基-1,4萘醌与不同醛加成得化合物1-6,再与不同酰氯或磺酰氯在碱催化下缩合成得化合物7-15。这些化合物可作为杀螨剂防治作物害螨,也可作为杀菌剂防治番茄灰霉病菌、苹果腐烂病菌、黄瓜枯萎病菌、小麦全蚀病菌。(The invention relates to 15 kinds of 2, 3-substituted naphthoquinone derivatives, a preparation method thereof and application thereof in mite killing and bacteriostasis, in particular to naphthoquinone compounds and preparation and mite killing and bactericidal application thereof. 15 kinds of 2, 3-substituted naphthoquinone derivatives, which are prepared through adding 2-hydroxy-1, 4 naphthoquinone and different aldehydes to obtain compounds 1-6, and condensation with different acyl chlorides or sulfonyl chlorides under the catalysis of alkali to obtain compounds 7-15. The compounds can be used as acaricide to prevent and treat crop pest mites, and can also be used as bactericide to prevent and treat botrytis cinerea, apple rot pathogen, cucumber fusarium wilt pathogen and wheat take-all pathogen.)

1. The structure of a naphthoquinone compound is shown as a general formula:

when R is¹When it is dodecyl, R²Selected from H, 4-methylbenzoyl, 4-trifluoromethylbenzoyl, 4-methylbenzenesulfonyl;

when R is¹In the case of 4-trifluoromethylphenyl, R²Selected from 4-methylbenzoyl, 4-trifluoromethylbenzoyl, 4-methylbenzenesulfonyl;

when R is¹When it is 2,4, 5-trimethoxyphenyl, R²Selected from H, 2-pyridinesulfonyl;

when R is¹In the case of 4-cyanophenyl, R²Selected from H, 4-methylbenzoyl;

when R is¹When is, R²Selected from H, 6-chloro-3-pyridinesulfonyl;

when R is¹When is, R²Is selected from H.

2. The compound of claim 1, wherein:

when R is¹When it is dodecyl, R²Selected from H, 4-methylbenzoyl, 4-trifluoromethylbenzoyl, 4-methylbenzenesulfonyl;

when R is¹In the case of 4-trifluoromethylphenyl, R²Selected from H, 4-methylbenzoyl, 4-trifluoromethylbenzoyl, 4-methylbenzenesulfonyl;

when R is¹When it is 2,4, 5-trimethoxyphenyl, R²Selected from 2-pyridinesulfonyl;

when R is¹In the case of 4-cyanophenyl, R²Is selected from 4-methylbenzoyl.

3. The compound of claim 1, wherein:

when R is¹In the case of 4-trifluoromethylphenyl, R²Is selected from H;

when R is¹When it is 2,4, 5-trimethoxyphenyl, R²Is selected from H;

when R is¹In the case of 4-cyanophenyl, R²Is selected from H;

when R is¹When is, R²Selected from H, 6-chloro-3-pyridinesulfonyl;

when R is¹When is, R²Is selected from H.

4. Use of a compound according to claim 2 for controlling pest mites.

5. The use of a compound according to claim 3 for controlling plant diseases such as botrytis cinerea, apple rot, cucumber fusarium wilt, and wheat take-all.

Technical Field

The invention relates to naphthoquinone compounds and preparation, acaricidal and bactericidal applications thereof, and particularly relates to the field of agricultural acaricides and bactericides.

Background

Naphthoquinone compounds are an important class of natural quinone compounds, have various biological activities, and have applications in the fields of insect killing, bacteriostasis, tumor resistance and the like; the naphthoquinone derivative has high activity and low toxicity to mammals, and has insecticidal and bacteriostatic effects which are worthy of deep research.

The acaricidal quinone is a commercial acaricidal agent, and the research on the action mechanism of the deacetyl metabolite of the acaricidal quinone shows that: the metabolite can inhibit mitochondrial respiration of compound III in an electron transfer chain, and a bonding point is a coenzyme oxidation point of the compound III.

Naphthoquinone compounds have been proved to be effective antifungal drugs, wherein dithianon is a commercial excellent fungicide variety and has the advantages of broad spectrum, low toxicity and low resistance; can be used for preventing and treating various diseases of pome fruit and stone fruit, and can be used for treating scab of apple and pear; leaf spot of cherry; peach and apricot leaf shrinkage disease, especially longan, lichee brown spot and downy mildew.

In summary, the patent takes natural active 2-hydroxy-1, 4-naphthoquinone as a lead, introduces different substituents into 2-position and 3-position of the lead to carry out structural modification, designs and synthesizes naphthoquinone compounds, and screens the acaricidal and bactericidal activities of the naphthoquinone compounds.

Disclosure of Invention

The invention aims to provide naphthoquinone compounds and a preparation method thereof, and the naphthoquinone compounds can be applied to crop acaricidal and disease control.

The technical scheme of the invention is as follows:

the naphthoquinone compound provided by the invention has the following structural general formula:

1--6：R¹selected from dodecyl, 4-trifluoromethylphenyl, 2,4, 5-trimethoxyphenyl, 4-cyanophenyl,、；

7--12：R¹Selected from dodecyl, 4-trifluoromethylphenyl, 4-cyanophenyl,，R²Selected from 4-methyl-phenyl, 4-trifluoromethyl-phenyl, 6-chloro-3-pyridyl;

13--15：R¹selected from dodecyl, 4-trifluoromethylphenyl, 2,4, 5-trimethoxyphenyl, R²Selected from 4-methyl-phenyl and 2-pyridyl.

The synthetic reaction formula of the naphthoquinone compound is as follows:

in the formula R¹、R²And R³As defined above;

a process for the preparation of a compound of formula (la): in a proper solvent and at a proper temperature, 2-hydroxy-1, 4-naphthoquinone reacts with different aldehydes by using a proper catalyst to generate compounds 1-6. Then, in a proper solvent, using a proper catalyst at a proper temperature, reacting the compounds 1, 2,4 and 5 with different acyl chlorides to obtain compounds 7-12, and reacting the compounds 1, 2 and 3 with different sulfonyl chlorides to obtain compounds 13-15;

suitable solvents may be selected from dichloromethane, trichloromethane, and the like;

the appropriate temperature is 0 ℃ to the boiling point of the solvent;

suitable catalysts are N-methylmorpholine, hanster, L-proline, 2-methylpyridine, etc.;

the reaction time is 2 to 30 hours;

the compound has excellent acaricidal effect on tetranychus cinnabarinus, and partial compounds also have good inhibition effect on botrytis cinerea, fusarium oxysporum, apple rot pathogen and wheat take-all pathogen.

Detailed Description

Example 1 preparation of compounds 6 and 12:

under dry conditions, 0.17 g (1 mmoL) of 2-hydroxy-1, 4-naphthoquinone, 0.35 g (2 mmoL) of chromone-3-carbaldehyde, 0.28 g (1.1 mmoL) of hans' ester, 0.023 g (0.2 mmoL) of L-proline, 10 mL of dichloromethane were reacted at 30 ℃ for 17 h, after TLC detection, the column chromatography was performed on silica gel, and the chromatography solution was extracted with ethyl acetate: petroleum ether = 1:3 to obtain a reddish brown solid intermediate, namely a compound 6;

under dry conditions, 0.066 g (0.2 mmol) of intermediate 1, 0.070 g (0.4 mmol) of 6-chloro-nicotinoyl chloride, 33.7 ul (0.3 mmol) of N-methylmorpholine, 10 mL of chloroform, reacted at 50 ℃ for 12 h, and after TLC detection, purified by silica gel column chromatography, the chromatography solution was purified with ethyl acetate: petroleum ether = 1:2, to obtain a yellow solid target product, i.e. a target compound 12;

compounds 1-5 were synthesized in a manner similar to that of 6, and compounds 7-12 and 13-15 were synthesized in a manner similar to that of 12.

Synthesis of compounds¹H NMR、¹³C NMR and mass spectral data are as follows;

1. ¹HNMR (500 MHz, CDCl₃) δ 8.09 (dd, 2H), 7.70 (dt, 2H), 7.39 (s, 1H), 2.60 (t, 2H), 1.53 (d, 2H), 1.25 (s, 18H), 0.87 (t, 3H). ¹³CNMR (126 MHz, CDCl3) δ 145.17, 140.17, 134.01, 133.77, 132.23, 131.07, 130.61, 129.57, 126.59, 125.42, 31.94, 30.06, 29.56, 29.56, 29.34, 29.24, 29.16, 28.55, 24.41, 22.70, 21.84, 14.12. HRMS (ESI): calcd for C₂₂H₂₉O₃, ([M-H]⁺), 341.2117, found, 341.2122.

2. ¹HNMR (500 MHz, CDCl₃) δ 8.10 (dd, 2H), 7.76 (td, 1H), 7.69 (td, 1H), 7.50 (s, 4H), 7.48 (s, 1H), 4.00 (s, 2H). ¹³CNMR (126 MHz, CDCl3)δ 184.00, 177.80, 162.52, 151.85, 141.11, 137.19, 134.53, 134.26, 131.86 (d,J = 272.52 Hz),130.94, 130.87 (d,J = 3.65 Hz), 129.32 (d,J = 3.69 Hz), 127.08, 126.90, 125.89, 125.64 (d,J = 32.56 Hz), 125.62, 30.19. HRMS (ESI): calcd for C₁₈H₁₀F₃O₃, ([M-H]⁺), 331.0590, found, 331.0588.

3. ¹HNMR (500 MHz, CDCl₃) δ 8.1 (m, 2H), 7.88 (s, 1H), 7.70 (t, 2H), 6.87 (s, 1H), 6.51 (d, 1H), 3.90 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H). ¹³CNMR (126 MHz, CDCl3)δ 184.53, 181.43, 153.88, 150.89, 148.33, 143.35, 134.67, 132.93, 132.71, 129.80, 126.75, 126.12, 123.18, 118.26, 114.64, 97.95, 56.95, 56.73, 56.20, 22.60. HRMS (ESI): calcd for C₂₀H₁₇O₆, ([M-H]⁺),353.1034, found, 353.1039.

4. ¹HNMR (500 MHz, CDCl₃) δ 8.10 (dd, 2H), 7.77 (td, 1H), 7.72 (d, 1H), 7.55 (d, 2H), 7.49 (d, 2H), 3.99 (s, 2H). ¹³CNMR (126 MHz, CDCl3) δ 184.12, 181.35, 153.36, 144.47, 135.25, 133.25, 132.65, 132.27, 129.98, 129.34, 127.01, 126.36, 121.49, 118.94, 110.29, 29.32. HRMS (ESI): calcd for C₁₈H₁₀NO₃, ([M-H]⁺), 288.0668, found, 288.0666.

5. ¹HNMR (500 MHz, CDCl₃) δ 8.11 (dd, 2H), 7.75 (dt, 2H), 3.87 (s, 2H), 2.64 (m, 2H), 1.65(m, 2H), 1.36 (dd, 2H), 0.91 (t, 3H). ¹³CNMR (126 MHz, CDCl3) δ184.44, 181.57, 156.99, 134.96, 133.64, 132.60, 130.51, 126.31, 125.67, 121.51, 118.90, 118.74, 30.17, 27.59, 27.43, 22.01, 18.29, 14.38. HRMS (ESI): calcd for C₁₈H₁₇ClN₂O₃, ([M-H]⁺), 343.0856, found,343.0854.

6.¹HNMR (500 MHz, CDCl3) δ 11.05 (s, 1H), 8.34 (s, 1H), 8.26 (dd, 8.1, 1H), 8.08 (dd, 2H), 7.68 (m, 3H), 7.47 (m, 2H), 3.75 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 184.90, 181.11, 180.02, 156.71, 156.52, 155.91, 134.52, 134.07, 133.12, 132.25, 130.81, 126.39, 126.15, 125.96, 125.70, 122.75, 121.67,121.53, 118.25, 20.05. HRMS (ESI): calcd for C20H11O5, ([M-H]+), 331.0613, found, 331.0612.

7. ¹HNMR (500 MHz, CDCl₃) δ 8.2 (m, 4H), 7.79 (m, 2H), 7.37 (m, 2H), 2.62 (t, 2H), 2.46 (d, 3H), 1.56 (dd, 2H), 1.36 (m, 18H), 0.87 (t, 3H). ¹³CNMR (126 MHz, CDCl3)δ 182.27, 178.53, 177.70, 145.53, 144.24, 140.75, 134.46, 131.49, 129.53, 129.38, 129.12, 128.87, 127.33, 125.62, 125.17, 123.01, 120.85, 35.69, 33.77, 31.94, 30.25, 29.56, 28.55, 24.41, 22.70, 21.84, 19.98, 16.72, 16.61, 14.12. HRMS (ESI): calcd for C₃₀H₃₆O₄Na, ([M+Na]⁺), 483.2503, found, 483.2506.

8. ¹HNMR (500 MHz, CDCl₃) δ 8.15 (m, 2H), 7.77(m, 2H), 7.51 (dd, 4H), 4.23 (s, 2H), 1.26 (s, 10H), 1.20 (s, 13H). ¹³CNMR (126 MHz, CDCl3) δ 182.27, 178.53, 177.70, 145.53, 144.24, 140.75, 134.46, 134.23, 131.49, 131.28, 129.45 (d,J= 33.41 Hz), 129.45, 129.12, 128.87, 127.28, 125.62 (d,J = 3.7 Hz), 125.59 (d,J = 3.64 Hz)124.08 (d,J = 274.21 Hz), 123.01, 120.85, 35.69, 33.77, 31.43, 30.20, 29.71, 23.61, 22.69, 22.63, 19.98, 16.72, 16.67, 14.16. HRMS (ESI): calcd for C₃₀H₃₃F₃O₄Na, ([M+Na]⁺), 537.2321, found, 537.2323.

9. ¹HNMR (500 MHz, CDCl₃) δ 8.13(m, 2H), 8.04 (d, 2H), 7.75 (m, 2H), 7.50 (d, 2H), 7.42 (d, 2H), 7.34 (d, 2H), 4.03 (s, 2H), 2.48 (s, 3H). ¹³CNMR (126 MHz, CDCl3) δ 184.23, 178.15, 163.72, 152.24, 145.58, 141.42, 137.02, 134.31, 134.09, 131.91, 130.97, 130.65, 129.05 (d,J = 32.27 Hz), 129.60, 129.41, 129.18, 128.93, 126.87, 125.61 (d, J = 3.67 Hz), 125.57, 125.35 (d,J = 3.69 Hz), 125.22, 125.35 (d,J = 272.52 Hz), 124.99, 123.04, 123.12, 30.13, 21.87. HRMS (ESI): calcd for C₂₆H₁₆F₃O₄, ([M-H]⁺), 449.1009, found, 449.1006.

10. ¹HNMR (500 MHz, CDCl₃) δ 8.25 (d, 2H), 8.14 (m, 2H), 7.81 (m, 4H), 7.50 (d, 2H), 7.40 (d, 2H), 4.05 (s, 2H). ¹³CNMR (126 MHz, CDCl3)δ 184.00, 177.80, 162.52, 151.85, 141.11, 137.19, 136.01, 135.86 (q,J= 30.69 Hz), 134.53, 134.26, 131.86, 131.02, 130.94, 130.81, 130.60, 129.34, 129.23 (q,J = 32.84 Hz), 129.09, 127.08, 126.90, 125.96 (q,J= 3.57 Hz), 125.91 (q,J = 3.66 Hz), 125.69 (q,J = 3.66 Hz), 125.64 (d,J = 3.81 Hz), 125.15, 124.51, 124.05 (q,J = 271.8 Hz), 123.39 (q,J = 277.28 Hz), 122.98, 122.34, 30.19. HRMS (ESI): calcd for C₂₆H₁₃F₆O₄, ([M-H]⁺), 503.0726, found, 503.0724.

11. ¹HNMR (500 MHz, CDCl₃) δ 8.11 (d, 2H), 8.03 (d, 2H), 7.75(m, 2H), 7.53 (d, 2H), 7.41 (d, 2H), 7.34 (d, 2H), 4.02 (s, 2H), 2.48 (s, 3H). ¹³CNMR (126 MHz, CDCl3)δ 184.11, 177.99, 163.67, 152.38, 145.69, 142.86, 136.50, 134.37, 134.17, 132.41, 131.75, 130.87, 130.62, 129.85, 129.62, 126.87,126.84, 124.81 , 118.74, 110.63, 30.36, 21.88. HRMS (ESI): calcd for C₂₆H₁₆NO₄, ([M-H]⁺), 406.1086, found, 406.1085.

12. ¹HNMR (500 MHz, CDCl₃) δ9.15(d,1H), 8.41(dd, 1H), 8.14(dd,1H), 8.09 (dd, 2H), 8.05(s, 1H), 7.78 (m, 2H), 7.62 (t, 1H), 7.49(d,1H), 7.35 (dd,2H), 3.87(s, 2H). ¹³CNMR (126 MHz, CDCl3)δ 184.31, 177.68, 176.58, 161.85, 156.70, 156.22, 154.56, 152.01, 151.32, 140.32, 136.49, 134.40, 134.19, 133.63, 131.93, 130.79, 126.95, 126.82, 125.85, 125.18, 124.45, 123.62,123.48, 120.27, 118.02, 20.27. HRMS (ESI): calcd for C₂₆H₁₃ClNO₆,([M-H]⁺), 470.0440 , found, 470.0437.

13. ¹HNMR (500 MHz, CDCl₃) δ 8.12 (m, 2H), 8.02 (d, 2H), 7.76 (m, 2H), 7.43 (d, 2H), 2.64 (t, 2H), 2.50 (s, 3H), 1.5 (m, 2H), 1.25 (m, 18H), 0.88 (t, 3H). ¹³CNMR (126 MHz, CDCl3)δ184.59, 178.66, 149.26, 145.69, 142.98,134.29, 134.21,134.05, 133.99, 132.01, 130.78, 129.80, 128.68, 128.52, 126.89, 126.69, 32.56, 30.95, 29.82, 29.70, 29.64,29.56, 29.39, 29.07, 28.62, 25.34, 22.73, 21.85, 14.16. HRMS (ESI): calcd for C₂₉H₃₆O₅SNa, ([M+Na]⁺), 519.2177, found, 519.2176.

14. ¹HNMR (500 MHz, CDCl₃) δ 8.09 (m, 2H), 8.03 (d, 2H), 7.75 (m, 2H), 7.50 (d, 2H), 7.43 (d, 4H), 4.11 (s, 2H), 2.51 (s, 3H). ¹³CNMR (126 MHz, CDCl3) δ 184.19, 178.62, 149.73, 146.09, 141.12, 139.66, 134.47, 134.32, 133.55, 133.11, 131.71, 130.70, 129.90, 129.54, 129.12 (d,J = 33.5 Hz), 128.68, 128.62, 127.01, 126.82, 125.56 (d,J = 3.53 Hz), 125.50 (d,J = 3.8 Hz), 125.22 (d,J = 271.49 Hz), 30.54, 21.85. HRMS (ESI): calcd for C₂₅H₁₆F₃O₅S, ([M-H]⁺), 485.0680, found, 485.0676.

15. ¹HNMR (500 MHz, CDCl₃) δ 9.27 (d,1H), 8.94 (q,1H), 8.41 (m, 1H), 8.08 (m, 2H), 7.75 (m, 2H), 7.58 (q, 1H), 6.89 (s, 1H), 6.46 (s, 1H), 4.03 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.74 (s, 3H). ¹³CNMR (126 MHz, CDCl3)δ 183.83, 178.60, 154.62, 151.58, 149.10,149.03, 148.61, 142.90, 141.56, 136.17, 134.46, 134.08, 133.92, 131.94, 130.48, 127.02, 126.67, 123.62, 116.41, 114.85, 97.68, 56.73, 56.47, 56.10, 25.41. HRMS (ESI): calcd for C₂₅H₂₁NO₈SNa, ([M+Na]⁺), 518.0878, found, 518.0880。

EXAMPLE 2 acaricidal Activity assay

2.5 mg of the compound is weighed and dissolved in 0.5 mL of acetone, water is added to 50 mL to prepare liquid medicine with the concentration of 50 mg/L, and then liquid medicine with the concentrations of 25.00, 12.50, 6.25, 3.13, 1.56 and 0.78 mg/L is prepared by a double dilution method. Cutting the double-sided adhesive tape into 3cm long, sticking the double-sided adhesive tape to one end of a glass slide, removing paper sheets on the adhesive tape by using tweezers, and selecting healthy, active and tidy female tetranychus cinnabarinus adult mites by using a zero-number brush pen. The back of the piece was adhered to a double-sided tape, 3 lines each, and 10 or so lines each. 26 ℃, 70% humidity, illumination conditions L: d = 14: after standing for 4h under 10 conditions, the individuals who died or were inactive were removed by binocular observation, and the number of live mites was recorded as the number of subjects to be tested. And (3) uniformly wetting the glass slide with the live mites in the prepared liquid medicine, and then taking out the glass slide. Standing for 48 h under the above conditions, checking the result every 12 h for 1 time, and setting a solvent control with the brush pen touching the mite body and the mite with immobile limbs as death. And (4) calculating the acaricidal rate according to the survival rates of the mites of the control group and the treated group, and then regressing a toxicity equation by using software according to the acaricidal rate and the acaricidal concentration.

Table 1 acaricidal activity (% of the target compound)

a: a confidence interval.

Example 3 measurement of bacteriostatic Activity

Weighing 20 mg of compound, dissolving in 1 mL of acetone to prepare liquid medicine with concentration of 20 mg/mL, adding 0.05 mL of liquid medicine with different concentrations into 10 mL of molten potato agar culture medium, pouring into a culture dish while the liquid medicine is hot, cooling to form a toxic plate culture medium, inoculating test germs, using the same amount of acetone for comparison, and repeating three times for each treatment. Culturing at 25 deg.C, measuring colony diameter by cross method, calculating average value, and calculating inhibition rate.

TABLE 2 Primary screening for bacteriostatic Activity of target Compounds (100 mg/L, inhibition (%))

。

EXAMPLE 4 in vivo experiments on bacteriostatic Activity

Taking Botrytis cinerea as an example, the treatment and protection effects of the Botrytis cinerea on living tomato leaves are tested. 2.5 mg of each drug was weighed out and dissolved in 1 mL of acetone, and diluted to 50 mL with distilled water to prepare 50 mg/L drug solution. Prevention effect: uniformly spraying the liquid medicine on the back of the tomato leaf blades, airing for 24 h, inoculating bacteria, and observing the size of bacterial plaque after 72 h. The treatment effect is as follows: the bacterial cake is connected to the back of the leaf, the medicine is uniformly sprayed on the back of the leaf after being cultured for 24 h, and the size of the bacterial plaque is observed after 72 h. Blank controls were set up, with three replicates per treatment. Culturing at 25 deg.C, measuring the diameter of bacterial plaque by cross method, calculating average value, and calculating the preventing and treating effect.

TABLE 3 inhibition ratio (%) of target compound to Botrytis cinerea in vivo test