CN113121426A - Synthesis method of myrtenal aldehyde group dihydrazide compounds with fungal inhibition activity - Google Patents

Synthesis method of myrtenal aldehyde group dihydrazide compounds with fungal inhibition activity Download PDF

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CN113121426A
CN113121426A CN202110267880.9A CN202110267880A CN113121426A CN 113121426 A CN113121426 A CN 113121426A CN 202110267880 A CN202110267880 A CN 202110267880A CN 113121426 A CN113121426 A CN 113121426A
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段文贵
王晓宇
李宝谕
岑波
林桂汕
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Guangxi University
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Abstract

A synthetic method of a myrtenal aldehyde group bishydrazide compound with fungal inhibition activity comprises the following steps: the alpha-pinene is selectively oxidized into myrtenal, further oxidized into myrtenal, then reacted with thionyl chloride to obtain myrtenal acid chloride, and finally subjected to hydrazinolysis reaction with a series of substituted benzoyl hydrazide or 2-pyridine formhydrazide under anhydrous condition to synthesize the myrtenal aldehyde group bishydrazide compound. Antibacterial activity tests show that the myrtenal-aldehyde bishydrazide compound has excellent broad-spectrum inhibitory activity on various plant pathogenic fungi, and can be used as a lead compound of a novel agricultural bactericide.

Description

Synthesis method of myrtenal aldehyde group dihydrazide compounds with fungal inhibition activity
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a novel bioactive compound, namely a myrtenal aldehyde bishydrazide compound, based on alpha-pinene and bishydrazide.
Background
The pesticide is an effective means for preventing and treating plant diseases and insect pests and ensuring the stable increase of the yield and the quality of grains, but the traditional chemical pesticide has some non-negligible defects, such as low activity, high toxicity, more residues, environmental pollution, drug resistance generation and the like. Therefore, finding and developing novel pesticides with high efficiency, low toxicity and green color becomes one of the research hotspots in the current pesticide chemistry field. Natural product development and modification provide an effective way for this research.
Turpentine is a characteristic forest resource with rich content in China, and the main component is alpha-pinene. The alpha-pinene and the derivative thereof have various biological activities, such as weeding, bacteriostasis, tumor resistance, repelling and the like. Moreover, the alpha-pinene also has a unique molecular framework, and is a natural bicyclic monoterpene compound containing structural units such as carbon-carbon double bonds, small rings and the like. Therefore, research on chemical modification of α -pinene to prepare novel compounds having biological activity is receiving much attention from researchers in organic synthesis and forestry chemistry.
Myrtenal, also known as myrtenonal, is present in various medicinal plant essential oils, but has a low content, is biologically converted from alpha-pinene in plants, and is one of secondary metabolites of alpha-pinene. The myrtenal can be obtained by allylic catalytic oxidation of alpha-pinene, the molecular skeleton of the myrtenal reserves the mother ring of the alpha-pinene, and the myrtenal also has various biological activities of weeding, cancer resistance, bacteriostasis, disinsection, oxidation resistance, inflammation diminishing and the like, can be used as a spice and an organic synthesis intermediate, and is an alpha-pinene derivative with high added value. Therefore, the method has very important significance for the research of the myrtenal.
On the other hand, the bishydrazide group is not only an important organic synthesis structural unit, but also an important pharmacophore for developing novel drugs and agrochemicals, and a large number of documents report the biological activity research of bishydrazide derivatives, including antiviral, antitumor, antimalarial, insecticidal, bactericidal, herbicidal, and the like. However, the synthesis method and the anti-plant fungal activity of the myrtenal-aldehyde bishydrazide compound are not reported at home and abroad so far.
Disclosure of Invention
The invention aims to provide a synthesis method of a myrtenal bishydrazide compound, which introduces a bishydrazide group into a mother ring of a natural product alpha-pinene for the first time to synthesize the myrtenal bishydrazide compound with a novel structure. Antibacterial activity tests show that the compounds have excellent activity of inhibiting plant pathogenic fungi in a broad spectrum and can be used as lead compounds for developing novel agricultural fungicides. And the preparation method is simple and low in cost.
The invention adopts the following technical scheme to achieve the aim: a myrtenal aldehyde group dihydrazide compound has the following structural general formula:
Figure BDA0002972714430000021
wherein X represents carbon or nitrogen, R is any one of hydrogen, methyl, chlorine, bromine and nitro;
the synthesis method of the myrtenal aldehyde group dihydrazide compound comprises the following specific compound structure:
Figure BDA0002972714430000022
Figure BDA0002972714430000031
the preparation method of the compound 1 comprises the following steps:
(1) to a 250mL reaction flask were added 100mL of absolute ethanol and 40g of SeO2Refluxing for half an hour, then distilling off ethanol to obtain white liquid which is a selenious acid monoester oxidant, adding 30mL of 1, 4-dioxane to prepare a selenious acid monoester 1, 4-dioxane solution, adding 54.03g of alpha-pinene, 60mL of 1, 4-dioxane and 1.0g of hydroquinone into a 250mL three-neck flask, raising the temperature of an oil bath to 65 ℃, slowly dropwise adding the selenious acid monoester 1, 4-dioxane solution into the three-neck flask, continuously raising the temperature while controlling the dropwise adding speed to be slightly higher than the distillation speed, maintaining the temperature at 100 ℃ after dropwise adding until no distillate is produced, recovering elemental selenium by suction filtration, decompressing and steaming the 1, 4-dioxane, adding 0.90g of hydroquinone and 1.75g of sodium sulfite to carry out steam distillation to obtain clear distillate, adding sodium chloride saturated distillate into the oil bath, extracting the water phase with anhydrous ether for 3 times, each time 30mL, combining the organic layers, drying with anhydrous magnesium sulfate, distilling to remove ether, distilling under reduced pressure to collect 65-66 deg.C/5 mmHg fraction to obtain light yellow transparent liquid;
(2) dissolving 15.5g of myrtenal in 100mL of acetonitrile, and sequentially adding 5.3g of PEG-400 and 40mL of NaH with the mass fraction of 7.4%2PO4Aqueous solution, 9.7mL of 30% by mass H2O2Stirring the aqueous solution in ice bath for 10min to cool the aqueous solution to below 10 ℃, continuing stirring and slowly dropwise adding 100mL of 17% NaClO by mass fraction2Stirring the aqueous solution at room temperature for 7h after the completion of the dropping, adding 1.0g of sodium sulfite after the reaction is completed, adjusting the pH of the reaction solution to 3.0 with an appropriate amount of dilute HCl, extracting with anhydrous ether for 3 times (50 mL each time), combining the organic phases, and sequentially adding saturated NaHSO3Washing with saturated saline water, drying the obtained organic phase with anhydrous sodium sulfate, distilling the residue under reduced pressure after ether is removed by evaporation, collecting 105-106 ℃/6mmHg fractions to obtain colorless viscous liquid, and standing for a period of time to obtain waxy solid;
(3) under the absolute water condition, dissolving 20.0g of myrtenoic acid in 50mL of benzene, adding a few drops of N, N-dimethylformamide, slowly dropwise adding a solution prepared from 17.3g of thionyl chloride and 20mL of benzene while stirring, heating and refluxing for 6-8 hours after the dropping is finished, distilling at normal pressure to remove benzene and unreacted thionyl chloride after the reaction is finished, and distilling under reduced pressure to collect 70-71 ℃/5mmHg fractions to obtain light yellow liquid;
(4) under the absolute water condition, sequentially adding 10mmol of 2-pyridine formylhydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath while stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 4 hours at room temperature, simultaneously monitoring the reaction process by TLC (thin layer chromatography), adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, performing extraction for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 1;
the preparation method of the compound 2 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of benzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride under the condition of ice-water bath while stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC (thin layer chromatography), adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, performing three-time extraction by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 2;
the preparation method of the compound 3 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 3-methylbenzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then performing extraction for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 3;
the preparation method of the compound 4 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 4-methylbenzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 4;
the preparation method of the compound 5 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 4-chlorobenzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 5;
the preparation method of the compound 6 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 3-bromobenzoyl hydrazide compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 6;
the preparation method of the compound 7 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 2-nitrobenzoyl hydrazide compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then performing extraction for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 7;
the preparation method of the compound 8 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of benzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride under the condition of ice-water bath while stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC (thin layer chromatography), adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, performing three-time extraction by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 8;
the preparation method of the compound 9 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 4-chloro-2-pyridine formylhydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath while stirring, removing the ice-water bath after the dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 9;
the preparation method of the compound 10 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 5-chloro-2-pyridine formylhydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath while stirring, removing the ice-water bath after the dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 10;
the synthesis method of the myrtenal aldehyde group dihydrazide compound comprises the following reaction steps:
Figure BDA0002972714430000071
wherein X represents carbon or nitrogen, and R is any one of hydrogen, methyl, chlorine, bromine and nitro.
The synthesis method of the myrtenal aldehyde group dihydrazide compound comprises the following steps:
(1) preparation of intermediate myrtenal
To a 250mL reaction flask were added 100mL of absolute ethanol and 40g of SeO2Refluxing for half an hour, evaporating ethanol to obtain white liquid which is selenious acid monoester oxidant, adding 30mL of 1, 4-dioxane to prepare 1, 4-dioxane solution of selenious acid monoester, adding 54.03g of alpha-pinene, 60mL of 1, 4-dioxane and 1.0g of hydroquinone into a 250mL three-neck flask, raising the temperature of an oil bath to 65 ℃, and then adding selenious acid into the three-neck flaskSlowly dripping a 1, 4-dioxane solution of acid monoester into a three-mouth bottle, continuously heating while controlling the dripping speed to enable the dripping speed to be slightly higher than the distillation speed, maintaining the oil bath temperature at 100 ℃ after dripping is finished until no distillate is generated, performing suction filtration to recover elemental selenium, performing reduced pressure distillation on the 1, 4-dioxane, adding 0.90g of hydroquinone and 1.75g of sodium sulfite to perform steam distillation to obtain clear distillate, adding sodium chloride saturated distillate, extracting a water phase for 3 times by using anhydrous ether, extracting 30mL each time, combining organic layers, drying by using magnesium sulfate, distilling to remove ether, and finally performing reduced pressure distillation to collect a fraction with the temperature of 65-66 ℃/5mmHg to obtain a light yellow transparent liquid;
(2) preparation of intermediate myrtenoic acid
Dissolving 15.5g of myrtenal in 100mL of acetonitrile, and sequentially adding 5.3g of PEG-400 and 40mL of NaH with the mass fraction of 7.4%2PO4Aqueous solution, 9.7mL of 30% by mass H2O2Stirring the aqueous solution in ice bath for 10min to cool the aqueous solution to below 10 ℃, continuing stirring and slowly dropwise adding 100mL of 17% NaClO by mass fraction2Stirring the aqueous solution at room temperature for 7h after the completion of the dropping, adding 1.0g of sodium sulfite after the reaction is completed, adjusting the pH of the reaction solution to 3.0 with an appropriate amount of dilute HCl, extracting with anhydrous ether for 3 times (50 mL each time), combining the organic phases, and sequentially adding saturated NaHSO3Washing with saturated saline water, drying the obtained organic phase with anhydrous sodium sulfate, distilling the residue under reduced pressure after ether is removed by evaporation, collecting 105-106 ℃/6mmHg fractions to obtain colorless viscous liquid, and standing for a period of time to obtain waxy solid;
(3) preparation of intermediate myrtenoic acid acyl chloride
Under the absolute water condition, 20.0g of myrtenoic acid is dissolved in 50mL of benzene, a few drops of N, N-dimethylformamide are added, a solution prepared from 17.3g of thionyl chloride and 20mL of benzene is slowly dropped while stirring, the temperature is raised and the reflux is carried out for 6-8 hours after the dropping is finished, benzene and unreacted thionyl chloride are removed by normal pressure distillation after the reaction is finished, and fractions at 70-71 ℃/5mmHg are collected by reduced pressure distillation to obtain light yellow liquid.
The myrtenal aldehyde group dihydrazide compound is applied to the preparation of agricultural bactericides.
The invention also provides the inhibitory activity of the myrtenal diacylhydrazine compound on plant pathogenic fungi, which comprises physalospora malorum P.piricola, fusarium oxysporum F.sp.Cucumerinum, fusarium graminearum G.Zeae, alternaria arachidicola C.Arachidacea, rhizoctonia solani R.Solani, alternaria solani A.Solani, alternaria zeae B.Maydis, colletotrichum C.lagenarium and cercospora cucumerinum C.casicola.
The invention has the beneficial effects that:
according to the invention, based on the splicing principle of an active substructure, abundant natural product alpha-pinene is used as an initial raw material, and bishydrazide groups are introduced into an alpha-pinene mother ring through multi-step reactions to synthesize 27 myrtenal aldehyde group bishydrazide compounds. The synthesis method is simple, efficient, easy to operate and low in cost. Antibacterial activity tests show that some target compounds have excellent broad-spectrum inhibition effect on plant pathogenic fungi, can be used as lead compounds for developing novel agricultural fungicides, and provide experimental basis for high-value utilization of the characteristic dominant forest resource alpha-pinene in China.
Detailed Description
The technical solution of the present invention is further illustrated by the following specific examples.
Example 1
Preparation of myrtenal aldehyde group 2' -pyridine formhydrazide compound 1
Figure BDA0002972714430000081
Under the absolute condition, 10mmol of 2-pyridine formhydrazide, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride is slowly dropped while stirring under the condition of ice-water bath. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, 5mL of water is added to quench the reaction, rotary evaporation is carried out, 25mL of water is added to wash the residue, 75mL of ethyl acetate is used for extraction for three times, the organic phases are combined, and the mixture is addedDrying the mixture with anhydrous sodium sulfate, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent to finally obtain a target compound, namely the myrtenal aldehyde 2' -pyridine formhydrazide which is a white solid, wherein the yield is 78.7%, and the HPLC purity is as follows: 98.63 percent. m.p.149.6-150.2 deg.C, UV-Vis (EtOH) lambdamax/nm:259.05,219.31；IR(KBr)ν/cm-1:3202(N-H),3056(＝C-H),2988,2913(C-H),1689,1645(C＝O),1619,1586,1514,1462(C＝C,Ar-C＝N),1243,1099(C-N)；1H NMR(600MHz,CDCl3):δ＝10.45(s,1H,N-H),9.12(d,J＝34.4Hz,1H,N-H),8.61～8.55(m,1H,H-13),8.13(ddd,J＝7.8,1.7,0.9Hz,1H,H-16),7.85(tdd,J＝7.7,2.7,1.8Hz,1H,H-15),7.48～7.43(m,1H,H-14),6.65(s,1H,H-3),2.73(td,J＝5.6,1.5Hz,1H,H-1),2.48(td,J＝10.4,5.4Hz,1H,Hb-4),2.46～2.36(m,2H,H-7),2.14(d,J＝2.7Hz,1H,H-5),1.33(d,J＝4.1Hz,3H,H-9),1.18(dd,J＝9.1,4.3Hz,1H,Ha-4),0.84(d,J＝3.1Hz,3H,H-8)；13C NMR(151MHz,CDCl3):δ＝163.59(C-10),160.35(C-11),148.60(C-12),148.27(C-13),140.98(C-2),137.31(C-15),132.15(C-3),126.72(C-14),122.30(C-16),41.63(C-1),40.38(C-5),37.85(C-6),32.00(C-7),31.39(C-4),25.87(C-8),20.94(C-9)；ESI-MS m/z:286.15[M+H]+。
Example 2
Preparation of myrtenal benzoyl hydrazine compound 2
Figure BDA0002972714430000091
Under absolute water conditions, 10mmol of benzoyl hydrazine, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride is slowly added dropwise while stirring under the condition of ice-water bath. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue with 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate, drying, and mixing the organic phases in a volume ratio of 3:1 as eluent, and performing column chromatography for further separation and purification to finally obtain the target compound myrtenal benzoyl hydrazine, white solid, wherein the yield is 76.1%, and the HPLC purity is as follows: 97.59 percent. m.p.183.2-184.1 ℃. UV-Vis (EtOH) lambdamax/nm:228.14；IR(KBr)ν/cm-1:3222(N-H),3056(＝C-H),2971,2916(C-H),1671,1639(C＝O),1538,1490,1424(C＝C,Ar-C＝C),1221,1029(C-N)；1H NMR(600MHz,CDCl3):δ＝9.99(s,1H,N-H),9.39(s,1H,N-H),7.88～7.82(m,2H,H-13,H-17),7.49(dd,J＝10.6,4.2Hz,1H,H-15),7.39(t,J＝7.7Hz,2H,H-14,H-16),6.62(s,1H,H-3),2.68(td,J＝5.6,1.3Hz,1H,H-1),2.48～2.35(m,3H,Hb-4,H-7),2.12(s,1H,H-5),1.31(s,3H,H-9),1.11(d,J＝9.1Hz,1H,Ha-4),0.80(s,3H,H-8)；13C NMR(151MHz,CDCl3)δ＝164.44(C-10),164.32(C-11),140.82(C-2),132.47(C-12),132.18(C-15),131.49(C-3),128.60(C-14,C-16),127.38(C-13,C-17),41.60(C-1),40.34(C-5),37.82(C-6),32.01(C-7),31.35(C-4),25.86(C-8),20.91(C-9)；ESI-MS m/z:285.16[M+H]+。
Example 3
Preparation of myrtenal aldehyde group 3' -methylbenzoyl hydrazine compound 3
Figure BDA0002972714430000101
Under the absolute condition, 10mmol of 3-methylbenzoyl hydrazine, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride is slowly added dropwise under the condition of ice-water bath while stirring. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue with 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent for further separation and purification to finally obtain a target compound, namely the myrtenal 3' -methyl aldehydeBenzoyl hydrazine, white solid, yield 79.3%, HPLC purity: 97.35 percent. m.p.159.6-160.1 ℃. UV-Vis (EtOH) lambdamax/nm:232.87；IR(KBr)ν/cm-1:3222(N-H),3016(＝C-H),2951,2915(C-H),1670,1641(C＝O),1532,1485,1421(C＝C,Ar-C＝C),1275,1061(C-N)；1H NMR(600MHz,CDCl3)δ＝9.87(d,J＝5.4Hz,1H,N-H),9.38(d,J＝5.2Hz,1H,N-H),7.66～7.61(m,2H,H-13,H-17),7.33～7.23(m,2H,H-15,H-16),6.72～6.57(m,1H,H-3),2.68(td,J＝5.6,1.5Hz,1H,H-1),2.47～2.36(m,3H,H-18),2.35(s,3H,Hb-4,H-7),2.15–2.09(m,1H,H-5),1.31(s,3H,H-9),1.11(d,J＝9.1Hz,1H,Ha-4),0.80(s,3H,H-8)；13C NMR(151MHz,CDCl3)δ＝164.52(C-10),164.19(C-11),140.82(C-2),138.46(C-14),132.93(C-12),132.38(C-15),131.44(C-3),128.50(C-16),128.00(C-13),124.37(C-17),41.59(C-1),40.35(C-5),37.82(C-6),32.00(C-7),31.35(C-4),25.86(C-8),21.29(C-18),20.91(C-9)；ESI-MS m/z:299.15[M+H]+。
Example 4
Preparation of myrtenal aldehyde 4' -methylbenzoyl hydrazine compound 4
Figure BDA0002972714430000111
Under the absolute condition, 10mmol of 4-methylbenzoyl hydrazine, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride is slowly added dropwise under the condition of ice-water bath while stirring. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue with 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent for further separation and purification to finally obtain a target compound, namely the myrtenal aldehyde 4' -methylbenzoyl hydrazine, a white solid, wherein the yield is 78.8%, and the HPLC purity is as follows: 98.35 percent. m.p.179.1-180.1 ℃.UV-Vis(EtOH)λmax/nm:237.59；IR(KBr)ν/cm-1:3232(N-H),3062(＝C-H),2980,2955(C-H),1667,1638(C＝O),1534,1503,1421(C＝C,Ar-C＝C),1269,1096(C-N)；1H NMR(600MHz,CDCl3)δ＝9.84(s,1H,N-H),9.36(d,J＝12.1Hz,1H,N-H),7.75(d,J＝8.2Hz,2H,H-13,H-17),7.22～7.16(m,2H,H-14,H-16),6.61(s,1H,H-3),2.68(td,J＝5.6,1.3Hz,1H,H-1),2.47～2.33(m,6H,H-18,Hb-4,H-7),2.12(s,1H,H-5),1.31(s,3H,H-9),1.11(dd,J＝9.1,3.0Hz,1H,Ha-4),0.80(d,J＝1.5Hz,3H,H-8)；13C NMR(151MHz,CDCl3)δ＝164.36(C-10),164.15(C-11),142.73(C-15),140.83(C-2),132.33(C-3),129.28(C-12),128.68(C-14,C-16),127.35(C-13,C-17),41.60(C-1),40.35(C-5),37.81(C-6),31.99(C-7),31.35(C-4),25.86(C-8),21.52(C-18),20.90(C-9)；ESI-MS m/z:299.17[M+H]+。
Example 5
Preparation of myrtenal aldehyde group 4' -chlorobenzoyl hydrazine compound 5
Figure BDA0002972714430000112
Under the absolute condition, 10mmol of 4-chlorobenzoyl hydrazine, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride is slowly dropped while stirring under the condition of ice water bath. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue with 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent for further separation and purification to finally obtain a target compound, namely the myrtenal aldehyde 4' -chlorobenzoyl hydrazine, a white solid with a yield of 78.1%, and the HPLC purity: 97.59 percent. m.p.168.2-169.2 ℃. UV-Vis (EtOH) lambdamax/nm:238.22；IR(KBr)ν/cm-1:3230(N-H),3058(＝C-H),2969,2934(C-H),1674,1638(C＝O),1612,1571,1532,1490,1421(C＝C,Ar-C＝C),1146,1098(C-N)；1H NMR(600MHz,CDCl3)δ＝10.31(s,1H,N-H),9.29(s,1H,N-H),7.86～7.68(m,2H,H-13,H-17),7.43～7.29(m,2H,H-14,H-16),6.60(d,J＝1.2Hz,1H,H-3),2.65(td,J＝5.6,1.3Hz,1H,H-1),2.47～2.34(m,3H,Hb-4,H-7),2.13(s,1H,H-5),1.31(s,3H,H-9),1.09(d,J＝9.1Hz,1H,Ha-4),0.78(s,3H,H-8)；13C NMR(151MHz,CDCl3)δ＝164.88(C-10),163.79(C-11),140.80(C-2),138.50(C-15),132.72(C-3),129.76(C-12),128.89(C-14,C-16),128.79(C-13,C-17),41.62(C-1),40.30(C-5),37.80(C-6),32.03(C-7),31.33(C-4),25.84(C-8),20.88(C-9)；ESI-MS m/z:319.12[M+H]+。
Example 6
Preparation of myrtenal aldehyde group 3' -bromobenzoyl hydrazine compound 6
Figure BDA0002972714430000121
Under the absolute condition, 10mmol of 3-bromobenzoyl hydrazine, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride is slowly added dropwise under the condition of ice-water bath while stirring. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue by using 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent for further separation and purification to finally obtain a target compound, namely the myrtenal aldehyde 3' -bromobenzoyl hydrazine, a white solid, wherein the yield is 76.4%, and the HPLC purity is as follows: 97.36 percent. m.p.173.4-174.2 ℃. UV-Vis (EtOH) lambdamax/nm:203.55；IR(KBr)ν/cm-1:3219(N-H),3025(＝C-H),2973,2936(C-H),1743,1680,1641(C＝O),1615,1567,1536,1471,1421(C＝C,Ar-C＝C),1143,1072(C-N)；1H NMR(600MHz,CDCl3)δ＝10.18(d,J＝4.6Hz,1H,N-H),9.21(d,J＝4.1Hz,1H,N-H),7.99(t,J＝1.7Hz,1H,H-13),7.76(d,J＝7.9Hz,1H,H-17),7.62(ddd,J＝8.0,1.9,0.9Hz,1H,H-15),7.30～7.25(m,1H,H-16),6.62(s,1H,H-3),2.66(td,J＝5.6,1.4Hz,1H,H-1),2.50～2.35(m,3H,Hb-4,H-7),2.14(s,1H,H-5),1.32(s,3H,H-9),1.12(d,J＝9.1Hz,1H,Ha-4),0.80(s,3H,H-8)；13C NMR(151MHz,CDCl3)δ＝164.49(C-10),163.01(C-11),140.72(C-2),135.13(C-12),133.31(C-15),132.80(C-3),130.77(C-16),130.11(C-13),125.75(C-17),122.82(C-14),41.62(C-1),40.33(C-5),37.84(C-6),32.04(C-7),31.36(C-4),25.85(C-8),20.92(C-9)；ESI-MS m/z:363.05[M+H]+。
Example 7
Preparation of myrtenal aldehyde group 2' -nitrobenzyl hydrazide compound 7
Figure BDA0002972714430000131
Under absolute water conditions, 10mmol of 2-nitrobenzoyl hydrazide, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride is slowly added dropwise under the condition of ice-water bath and stirring. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue by using 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent for further separation and purification to finally obtain a target compound, namely the myrtenal aldehyde 2' -nitrobenzohydrazide, wherein the yield is 75.2%, and the HPLC purity is as follows: 98.34 percent. m.p.215.8-216.7 ℃. UV-Vis (EtOH) lambdamax/nm:200.57；IR(KBr)ν/cm-1:3223(N-H),3089,3024(＝C-H),2978,2923(C-H),1689,1638(C＝O),1609,1538,1506(C＝C,Ar-C＝C),1147,1075(C-N)；1H NMR(600MHz,DMSO)δ＝10.42(s,1H,N-H),10.07(s,1H,N-H),8.07(dd,J＝8.1,0.9Hz,1H,H-14),7.85(td,J＝7.5,1.1Hz,1H,H-17),7.75(ddd,J＝7.7,6.5,1.4Hz,1H,H-16),7.71(d,J＝7.4Hz,1H,H-15),6.58(s,1H,H-3),2.73(t,J＝5.4Hz,1H,H-1),2.51～2.36(m,3H,Hb-4,H-7),2.11(d,J＝4.6Hz,1H,H-5),1.31(s,3H,H-9),1.06(d,J＝8.8Hz,1H,Ha-4),0.79(s,3H,H-8)；13C NMR(151MHz,DMSO)δ＝165.89(C-10),165.14(C-11),147.84(C-13),141.53(C-2),134.04(C-16),131.91(C-3),130.89(C-15),130.79(C-12),130.01(C-17),124.73(C-14),41.34(C-1),40.41(C-5),37.66(C-6),31.91(C-7),31.36(C-4),26.24(C-8),21.32(C-9)；ESI-MS m/z:330.12[M+H]+。
Example 8
Preparation of myrtenal 6 '-chloro-2' -pyridine formhydrazide compound 8
Figure BDA0002972714430000141
Under the absolute condition, 10mmol of 6-chloro-2-pyridine formhydrazide, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride is slowly dropped while stirring under the condition of ice water bath. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue with 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent for further separation and purification to finally obtain a target compound, namely the myrtenal 6 '-chloro-2' -pyridine formhydrazide which is a white solid and has a yield of 78.2%, and the HPLC purity: 97.49 percent. m.p.175.4-175.6 ℃. UV-Vis (EtOH) lambdamax/nm:223.00,275.50；IR(KBr)ν/cm-1:3392.02,3274.55(N-H),3075.51(＝C-H,Ar-H),2981.63,2920.41(C-H),1692.89,1669.35(C＝O),1620.41(C＝C),1559.63,1506.99,1438.78(Ar-C＝C,Ar-C＝N),1241.03,1173.47,1140.82(C-N)；1H NMR(600MHz,CDCl3)δ＝10.21(d,J＝4.9Hz,1H,N-H),8.98(d,J＝3.0Hz,1H,N-H),8.07(dd,J＝7.2,0.6Hz,1H,H-13),7.84(t,J＝7.8Hz,1H,H-14),7.50(dd,J＝7.8,0.6Hz,1H,H-15),6.66(dt,J＝3.2,1.7Hz,1H,H-3),2.74(td,J＝5.6,1.4Hz,1H,H-1),2.53～2.41(m,3H,H-7,Hb-4),2.18～2.14(m,1H,H-5),1.35(s,3H,H-9),1.19(d,J＝9.1Hz,1H,Ha-4),0.85(s,3H,H-8)；13C NMR(151MHz,CDCl3)δ＝163.82(C-10),159.19(C-11),150.54(C-16),148.62(C-12),140.92(C-2),139.94(C-3),132.38(C-14),127.70(C-15),121.05(C-13),41.62(C-5),40.35(C-1),37.85(C-6),32.03(C-7),31.37(C-4),25.87(C-9),20.94(C-8)；ESI-MS m/z:320.13[M+H]+。
Example 9
Preparation of myrtenal 4 '-chloro-2' -pyridine formhydrazide compound 9
Figure BDA0002972714430000142
Under the absolute condition, 10mmol of 4-chloro-2-pyridine formhydrazide, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride is slowly dropped while stirring under the condition of ice water bath. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue by using 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent for further separation and purification to finally obtain a target compound, namely the myrtenal 4 '-chloro-2' -pyridine formhydrazide which is a white solid and has a yield of 74.3 percent and an HPLC purity: 97.18 percent. m.p.143.9-144.4 ℃. IR (KBr) v/cm-1:3246.94(N-H),3061.22(＝C-H,Ar-H),2993.88,2972.59,2916.33(C-H),1697.00,1647.47(C＝O),1620.75(C＝C),1579.59,1559.18,1514.20,1460.30(Ar-C＝C,Ar-C＝N),1263.27(C-N)；1H NMR(600MHz,CDCl3)δ＝10.43(s,1H,N-H),9.01(s,1H,N-H),8.50(d,J＝5.2Hz,1H,H-16),8.14(s,1H,H-13),7.48(dd,J＝5.2,2.0Hz,1H,H-15),6.67(s,1H,H-3),2.74(t,J＝5.5Hz,1H,H-1),2.59～2.37(m,3H,H-7,Hb-4),2.17(s,1H,H-5),1.36(s,3H,H-9),1.20(d,J＝9.1Hz,1H,Ha-4),0.85(s,3H,H-8)；13C NMR(151MHz,CDCl3)δ＝163.47(C-10),159.03(C-11),149.62(C-2),149.52(C-3),145.87(C-14),140.85(C-12),132.44(C-16),126.87(C-15),122.92(C-13),41.61(C-5),40.36(C-1),37.87(C-6),32.02(C-7),31.39(C-4),25.87(C-9),20.95(C-8)；ESI-MS m/z:320.12[M+H]+。
Example 10
Preparation of myrtenal 5 '-chloro-2' -pyridine formhydrazide compound 10
Figure BDA0002972714430000151
Under the absolute condition, 10mmol of 5-chloro-2-pyridine formhydrazide, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, and 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride is slowly dropped while stirring under the condition of ice water bath. After the addition, the ice-water bath was removed and the reaction was continued at room temperature for 3-4 hours while monitoring the progress of the reaction by TLC. After the reaction is completed, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, extracting the residue with 75mL of ethyl acetate for three times, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 3:1 as an eluent for further separation and purification to finally obtain a target compound, namely the myrtenal aldehyde 5 '-chloro-2' -pyridine formhydrazide which is a white solid and has a yield of 79.8 percent and an HPLC purity: 94.02 percent. m.p.124.4-124.8 ℃. UV-Vis (EtOH) lambdamax/nm:232.50,273.00；IR(KBr)ν/cm-1:3220.41(N-H),3075.51,3046.94(＝C-H,Ar-H),2991.84,2934.69(C-H),1687.76,1646.94(C＝O),1618.37(C＝C),1577.55,1508.16,1463.27(Ar-C＝C,Ar-C＝N),1234.69,1110.20,1014.29(C-N)；1H NMR(600MHz,CDCl3)δ＝10.33(s,1H,N-H),8.95(s,1H,N-H),8.55(s,1H,H-16),8.10(d,J＝8.4Hz,1H,H-13),7.91～7.77(m,1H,H-14),6.66(s,1H,H-3),2.73(t,J＝5.5Hz,1H,H-1),2.55～2.37(m,3H,H-7,Hb-4),2.17(s,1H,H-5),1.35(s,3H,H-9),1.19(d,J＝9.1Hz,1H,Ha-4),0.85(s,3H,H-8)；13C NMR(151MHz,CDCl3)δ＝163.51(C-10),159.39(C-11),147.69(C-3),146.26(C-2),140.88(C-12),137.10(C-16),135.59(C-15),132.37(C-14),123.30(C-13),41.62(C-5),40.36(C-1),37.87(C-6),32.02(C-7),31.39(C-4),25.87(C-9),20.95(C-8)；ESI-MS m/z:320.13[M+H]+。
Example 11
The myrtenal bishydrazide compounds prepared in examples 1 to 10 were tested for antibacterial activity, and the test methods and results were as follows.
The test was performed by the agar dilution method. The tested plant pathogenic fungi comprise 8 types in total, including cucumber fusarium wilt, peanut brown spot, apple ring spot, tomato early blight, wheat gibberellic disease, rice sheath blight, corn small spot and watermelon anthracnose, and commercial fungicide chlorothalonil is used as a positive control drug. Firstly, a sample to be detected is dissolved in acetone, and then the solution is diluted into a drug-containing solution with the concentration of 500 mu g/mL by using Sorporl-144 emulsifier with the concentration of 200 mu g/mL. 1mL of the drug-containing solution was poured into a petri dish, and then 9mL of potato sucrose agar medium was added to prepare a drug-containing plate having a final concentration of 50. mu.g/mL, which was the treatment group. The cultured test bacteria are punched by a puncher to obtain a bacterial cake with the diameter of 4mm, and the bacterial cake is placed in a drug-containing flat plate, wherein three plates are placed in an equilateral triangle. Using a blank solution without a sample to be detected as a control group, culturing each treatment group and the control group in an incubator at 24 +/-1 ℃ for 48 hours, measuring the hypha expansion diameter of each group, calculating the relative bacteriostasis rate according to the following formula and evaluating the activity level: relative inhibition (%) - (control colony diameter-treatment colony diameter)/control colony diameter × 100%; activity level: the grade A is more than or equal to 90 percent; grade B70% -90%; grade C50% -70%; grade D < 50%.
And (3) testing results:
Figure BDA0002972714430000161
Figure BDA0002972714430000171
from the above results, it can be seen that at an administration concentration of 50 μ g/mL, two compounds exhibited relatively broad-spectrum and excellent antibacterial activity, namely compound 1(X ═ N, R ═ H) and compound 6(X ═ C, R ═ 3' -Br). The relative inhibition rates of compound 1(X ═ N, R ═ H) on physalospora parasitica, physalospora malorum and rhizoctonia solani are 93.8%, 96.0% and 93.1% respectively, while the relative inhibition rates of compound 6(X ═ C, R ═ 3' -Br) on physalospora parasitica, physalospora malorum, fusarium graminearum and rhizoctonia solani are 93.8%, 96.0%, 90.0% and 96.6% respectively, all of which are level A and superior to or equivalent to that of the positive control medicament chlorothalonil.

Claims (5)

1. A myrtenal aldehyde group dihydrazide compound is characterized in that the structural general formula of the compound is as follows:
Figure FDA0002972714420000011
wherein X represents carbon or nitrogen, and R is any one of hydrogen, methyl, chlorine, bromine and nitro.
2. A method for synthesizing a myrtenal bishydrazide compound according to claim 1, wherein the specific compound has the following structure:
Figure FDA0002972714420000012
Figure FDA0002972714420000021
the preparation method of the compound 1 comprises the following steps:
(1) to a 250mL reaction flask were added 100mL of absolute ethanol and 40g of SeO2Refluxing for half an hour, and removing ethanol to obtain white liquidAdding 30mL of 1, 4-dioxane into selenious acid monoester oxidant to prepare 1, 4-dioxane solution of selenious acid monoester, adding 54.03g of alpha-pinene, 60mL of 1, 4-dioxane and 1.0g of hydroquinone into a 250mL three-neck flask, raising the temperature of an oil bath to 65 ℃, slowly dropwise adding the 1, 4-dioxane solution of selenious acid monoester into the three-neck flask, continuously raising the temperature while controlling the dropwise adding speed to be slightly faster than the distilling speed, maintaining the temperature of the oil bath at 100 ℃ after the dropwise adding is finished until no distillate is produced, performing suction filtration to recover elemental selenium, performing reduced pressure distillation on the 1, 4-dioxane, adding 0.90g of hydroquinone and 1.75g of sodium sulfite to perform steam distillation to obtain a clear distillate, adding saturated sodium chloride distillate, extracting the water phase for 3 times by using anhydrous ether, 30mL each time, combining the organic layers, drying with anhydrous magnesium sulfate, distilling to remove ether, and distilling under reduced pressure to collect 65-66 deg.C/5 mmHg fraction to obtain light yellow transparent liquid;
(2) dissolving 15.5g of myrtenal in 100mL of acetonitrile, and sequentially adding 5.3g of PEG-400 and 40mL of NaH with the mass fraction of 7.4%2PO4Aqueous solution, 9.7mL of 30% by mass H2O2Stirring the aqueous solution in ice bath for 10min to cool the aqueous solution to below 10 ℃, continuing stirring and slowly dropwise adding 100mL of 17% NaClO by mass fraction2Stirring the aqueous solution at room temperature for 7h after the completion of the dropping, adding 1.0g of sodium sulfite after the reaction is completed, adjusting the pH of the reaction solution to 3.0 with an appropriate amount of dilute HCl, extracting with anhydrous ether for 3 times (50 mL each time), combining the organic phases, and sequentially adding saturated NaHSO3Washing with saturated saline water, drying the obtained organic phase with anhydrous sodium sulfate, distilling the residue under reduced pressure after ether is removed by evaporation, collecting 105-106 ℃/6mmHg fractions to obtain colorless viscous liquid, and standing for a period of time to obtain waxy solid;
(3) under the absolute water condition, dissolving 20.0g of myrtenoic acid in 50mL of benzene, adding a few drops of N, N-dimethylformamide, slowly dropwise adding a solution prepared from 17.3g of thionyl chloride and 20mL of benzene while stirring, heating and refluxing for 6-8 hours after the dropping is finished, distilling at normal pressure to remove benzene and unreacted thionyl chloride after the reaction is finished, and distilling under reduced pressure to collect 70-71 ℃/5mmHg fractions to obtain light yellow liquid;
(4) under the absolute water condition, sequentially adding 10mmol of 2-pyridine formylhydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath while stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 4 hours at room temperature, simultaneously monitoring the reaction process by TLC (thin layer chromatography), adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, performing extraction for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 1;
the preparation method of the compound 2 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of benzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride under the condition of ice-water bath while stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC (thin layer chromatography), adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, performing three-time extraction by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 2;
the preparation method of the compound 3 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 3-methylbenzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then performing extraction for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 3;
the preparation method of the compound 4 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 4-methylbenzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 4;
the preparation method of the compound 5 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 4-chlorobenzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 5;
the preparation method of the compound 6 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 3-bromobenzoyl hydrazide compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 6;
the preparation method of the compound 7 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 2-nitrobenzoyl hydrazide compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath under stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, after the reaction is finished, adding 5mL of water to quench the reaction, performing rotary evaporation, adding 25mL of water to wash the residue, then performing extraction for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 7;
the preparation method of the compound 8 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of benzoyl hydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid chloride under the condition of ice-water bath while stirring, removing the ice-water bath after dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC (thin layer chromatography), adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, performing three-time extraction by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 8;
the preparation method of the compound 9 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute water condition, sequentially adding 10mmol of 4-chloro-2-pyridine formylhydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane into a 100mL round-bottom flask, slowly dropwise adding 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride under the condition of ice-water bath while stirring, removing the ice-water bath after the dropwise adding is finished, continuing to react for 3-4 hours at room temperature, simultaneously monitoring the reaction process by TLC, adding 5mL of water to quench the reaction after the reaction is finished, performing rotary evaporation, adding 25mL of water to wash the residue, extracting for three times by using 75mL of ethyl acetate, combining organic phases, adding anhydrous sodium sulfate for drying, and performing column chromatography for further separation and purification by using a petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 as an eluent to obtain a compound 9;
the preparation method of the compound 10 comprises the following steps:
(1) the steps are the same as the steps (1), (2) and (3) of the preparation method of the compound 1, so as to prepare myrtenoic acid acyl chloride;
(2) under the absolute condition, 10mmol of 5-chloro-2-pyridine formylhydrazine compound, 6 drops of anhydrous pyridine and 40mL of dichloromethane are sequentially added into a 100mL round-bottom flask, 15mL of dichloromethane solution containing 7.6mmol of myrtenoic acid acyl chloride is slowly dropped while stirring under the condition of ice-water bath, the ice-water bath is removed after the dropping is finished, the reaction is continued for 3 to 4 hours under the condition of room temperature, TLC is used for monitoring the reaction process, 5mL of water is added for quenching reaction after the reaction is finished, rotary evaporation is carried out, 25mL of water is added for washing the residue, 75mL of ethyl acetate is used for three times of extraction, organic phases are combined, anhydrous sodium sulfate is added for drying, and the petroleum ether/ethyl acetate mixed solvent with the volume ratio of 3:1 is used as eluent for further separation and purification, so that the compound 10 is obtained.
3. A method of synthesizing a myrtenal bishydrazide compound according to claim 2, wherein the reaction is performed according to the following formula:
Figure FDA0002972714420000061
wherein X represents carbon or nitrogen, and R is any one of hydrogen, methyl, chlorine, bromine and nitro.
4. A method of synthesizing a myrtenal bishydrazide compound according to claim 3, wherein the intermediate preparation method comprises the steps of:
(1) preparation of intermediate myrtenal
To a 250mL reaction flask were added 100mL of absolute ethanol and 40g of SeO2Refluxing for half an hour, then distilling off ethanol to obtain white liquid which is a selenious acid monoester oxidant, adding 30mL of 1, 4-dioxane to prepare a selenious acid monoester 1, 4-dioxane solution, adding 54.03g of alpha-pinene, 60mL of 1, 4-dioxane and 1.0g of hydroquinone into a 250mL three-neck bottle, raising the temperature of an oil bath to 65 ℃, slowly dropwise adding the selenious acid monoester 1, 4-dioxane solution into the three-neck bottle, continuously raising the temperature while controlling the dropwise adding speed to make the temperature slightly faster than the distillation speed, and maintaining the temperature at 100 ℃ after the dropwise adding is finished until no distillate is produced in the oil bathStopping, recovering elemental selenium by suction filtration, carrying out reduced pressure distillation on 1, 4-dioxane, adding 0.90g of hydroquinone and 1.75g of sodium sulfite to carry out steam distillation to obtain clear distillate, adding sodium chloride saturated distillate, extracting a water phase for 3 times by using anhydrous ether, wherein each time is 30mL, combining organic layers, drying by using anhydrous magnesium sulfate, distilling to remove ether, and finally carrying out reduced pressure distillation to collect 65-66 ℃/5mmHg fraction to obtain a product which is light yellow transparent liquid;
(2) preparation of intermediate myrtenoic acid
Dissolving 15.5g of myrtenal in 100mL of acetonitrile, and sequentially adding 5.3g of PEG-400 and 40mL of NaH with the mass fraction of 7.4%2PO4Aqueous solution, 9.7mL of 30% by mass H2O2Stirring the aqueous solution in ice bath for 10min to cool the aqueous solution to below 10 ℃, continuing stirring and slowly dropwise adding 100mL of 17% NaClO by mass fraction2Stirring the aqueous solution at room temperature for 7h after the completion of the dropping, adding 1.0g of sodium sulfite after the reaction is completed, adjusting the pH of the reaction solution to 3.0 with an appropriate amount of dilute HCl, extracting with anhydrous ether for 3 times (50 mL each time), combining the organic phases, and sequentially adding saturated NaHSO3Washing with saturated saline water, drying the obtained organic phase with anhydrous sodium sulfate, distilling the residue under reduced pressure after ether is removed by evaporation, collecting 105-106 ℃/6mmHg fractions to obtain colorless viscous liquid, and standing for a period of time to obtain waxy solid;
(3) preparation of intermediate myrtenoic acid acyl chloride
Under the absolute water condition, 20.0g of myrtenoic acid is dissolved in 50mL of benzene, a few drops of N, N-dimethylformamide are added, a solution prepared from 17.3g of thionyl chloride and 20mL of benzene is slowly dropped while stirring, the temperature is raised and the reflux is carried out for 6-8 hours after the dropping is finished, benzene and unreacted thionyl chloride are removed by normal pressure distillation after the reaction is finished, and fractions at 70-71 ℃/5mmHg are collected by reduced pressure distillation to obtain light yellow liquid.
5. The use of a myrtenal bishydrazide compound as defined in claim 1 for preparing an agricultural fungicide.
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