Synthesis method and application of phenolic hydroxyl-containing alkenyl oxime ether

Abstract

The invention discloses a synthesis method and application of a pesticide and medical intermediate phenolic hydroxyl group-containing alkenyl oxime ether compound, and the synthesis method of the phenolic hydroxyl group-containing alkenyl oxime ether compound comprises the following steps: carrying out aldol condensation on p-hydroxy benzaldehyde and acetone under the action of alkali to obtain a phenolic hydroxyl group-containing alkenyl ketone compound 1; reacting the compound 1 with dimethyl tert-butyl chlorosilane (TBSCl) under the action of imidazole, so as to obtain a phenolic hydroxyl alkenyl ketone compound 2 protected by a silicon group; reacting the compound 2 with hydroxylamine hydrochloride under the action of alkali to obtain a silicon group protected alkenyl ketoxime compound 3; and carrying out nucleophilic substitution reaction on the compound 3 and a substituted benzyl bromide compound 4 under the action of alkali to prepare a phenolic hydroxyl group-containing alkenyl oxime ether compound 5. The phenolic hydroxyl-containing alkenyl oxime ether compound 5 or the preparation thereof can be used for preventing and treating diseases caused by common plant pathogenic fungi such as oomycetes, phycomycetes and ascomycetes on various crops.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of pharmaceutical and pesticide intermediates, and in particular relates to a synthesis method and application of phenolic hydroxyl alkenyl oxime ether. Background Art

[0002] The statements herein merely provide background information related to the present invention and do not necessarily constitute prior art.

[0003] Enoxastrobin is a strobilurin fungicide (CN1191670A) developed by Shenyang Institute of Chemical Industry. It has good control effects on common plant fungi such as cucumber downy mildew and wheat powdery mildew. Enoxastrobin is a fungal mitochondrial respiration inhibitor. It binds to the fungal cytochrome bc1 complex, inhibits the mitochondrial electron transfer process, destroys the energy synthesis of the pathogen, and plays a fungal inhibitory role. Enoxastrobin is also the first strobilurin fungicide developed in my country. It has the advantages of a broad fungicidal spectrum, low toxicity, high activity, and good environmental compatibility.

[0004] In the molecular structure of enoxamyl and the reported unsaturated oxime ether fungicides, the substituents on the benzene ring connected to the alkenyl group are halogen atoms, alkyl groups, alkoxy groups, nitro groups and haloalkyl groups (CN1042900A, CN1309897A, CN106278942A), while there are no literature reports on the synthesis and application of unsaturated oxime ether compounds substituted with phenolic hydroxyl groups. The introduction of phenolic hydroxyl groups into pharmaceutical and pesticide molecules can enhance the acidity of the molecules, thereby enhancing the affinity of the pesticide molecules with the plant surface, which helps them to adsorb and fix on the plants; at the same time, the presence of phenolic hydroxyl groups may change the lipid-water partition coefficient (LogP) of the molecules, thereby affecting their distribution and transmission in the plant body; phenolic hydroxyl groups can also adjust the ionization balance of the molecules, increase the polarity of the molecules, and improve the lipid solubility of the molecules. As a result, the permeability of the pesticide molecules containing phenolic hydroxyl groups on the plant surface may be improved, which helps them to enter the plant body. In view of the important influence of phenolic hydroxyl group on the activity of pesticide molecules, we introduced phenolic hydroxyl group into alkenyl oxime ether molecules and developed alkenyl oxime ether fungicides with different activities. Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing a phenolic hydroxyl alkenyl oxime ether compound which is an intermediate of pesticides and medicines. The synthesized compound has excellent inhibitory activity against some common plant fungi.

[0006] In order to achieve the above object, the present invention is implemented through the following technical solutions: A method for synthesizing a pesticide and pharmaceutical intermediate containing phenolic hydroxyl alkenyl oxime ether and its application. The chemical formula of the phenolic hydroxyl alkenyl oxime ether is compound 5. The synthesis process comprises the following steps:

[0007] Under the action of base, p-hydroxybenzaldehyde and acetone undergo aldol condensation to obtain phenolic hydroxyl alkenyl ketone compound 1; Compound 1 reacts with dimethyl tert-butyl chlorosilane (TBSCl) under the action of imidazole to obtain a silicon-protected phenolic hydroxyl enyl ketone compound 2; Compound 2 reacts with hydroxylamine hydrochloride under the action of a base to obtain a silicon-protected alkenyl ketoxime compound 3; Compound 3 undergoes a nucleophilic substitution reaction with substituted benzyl bromide compound 4 under the action of a base to obtain phenolic hydroxyl-containing alkenyl oxime ether compound 5.

[0008] The fungicidal activity of the synthesized phenolic hydroxyl alkenyl oxime ether compound 5 was tested against common plant fungi. The results showed that the phenolic hydroxyl alkenyl oxime ether compound 5 exhibited good to excellent inhibitory effects on the test fungi.

[0009] The beneficial effects achieved by one or more embodiments of the present invention are as follows: Using p-hydroxybenzaldehyde as the starting material, the four-step reaction of aldol condensation of aldehyde and acetone, protection of phenolic hydroxyl group, condensation of enone and hydroxylamine, nucleophilic substitution of oxime and benzyl bromide and deprotection was used to synthesize phenolic hydroxyl alkenyl oxime ether compounds. The synthesized phenolic hydroxyl alkenyl oxime ether compounds can be used to control common plant pathogenic fungi such as Oomycetes, Phycomycetes and Ascomycetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0011] Figure 1 is the H NMR spectrum of the phenolic hydroxyl alkenyl oxime ether compound prepared in Example 1 of the present invention; Figure 2 This is the carbon NMR spectrum of the phenolic hydroxyl alkenyl oxime ether compound prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0012] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0013] A method for synthesizing a phenolic hydroxyl alkenyl oxime ether compound as a pesticide and pharmaceutical intermediate and its application, comprising the following steps: Under the action of sodium hydroxide, p-hydroxybenzaldehyde and acetone undergo aldol condensation to obtain phenolic hydroxyl alkenyl ketone compound 1; Compound 1 reacts with dimethyl tert-butyl chlorosilane (TBSCl) under the action of imidazole to obtain a silicon-protected phenolic hydroxyl enyl ketone compound 2; Compound 2 reacts with hydroxylamine hydrochloride in the presence of pyridine as a base to obtain a silicon-protected enyl ketoxime compound 3; Compound 3 undergoes nucleophilic substitution reaction with substituted benzyl bromide compound 4 under the action of potassium carbonate as a base to prepare phenolic hydroxyl-containing alkenyl oxime ether compound 5.

[0014] The fungicidal activity of the synthesized phenolic hydroxyl alkenyl oxime ether compound 5 was tested for common plant fungi. The results showed that the phenolic hydroxyl alkenyl oxime ether compound 5 exhibited good to excellent inhibitory effects on the test fungi, including: cucumber wilt, peanut brown spot, apple ring pattern, tomato early blight, wheat fusarium, rice seedling blight, rape sclerotium, pepper phytophthora, wheat sheath blight, corn spot, watermelon anthrax, potato late blight, rice sheath blight and cucumber gray mold. The present invention is further described below in conjunction with the embodiments. Embodiment 1:

[0015] The synthetic route of the phenolic hydroxyl alkenyl oxime ether compound is as follows:

[0016] The synthesis method of phenolic hydroxyl alkenyl oxime ether is as follows: A: At 25°C, to a 50 mL acetone solvent of p-hydroxybenzaldehyde (12.2 g, 100 mmol), add an aqueous NaOH solution (20% aqueous solution, 44 g, 220 mmmol), stir for 12 hours, remove most of the acetone solvent under reduced pressure, dilute with 100 mL of water, adjust the pH to 5 with a 1M aqueous hydrochloric acid solution at 0°C, extract and separate with 150 mL of dichloromethane, and after drying, remove the organic solvent by distillation under reduced pressure to obtain a crude product of phenolic hydroxyl alkenyl ketone compound 1 (15.1 g, 93.2 mmol) with a yield of 93%.

[0017] B: Compound 1 (15.1 g, 93.2 mmol) prepared in step A was dissolved in 150 mL DCM, triethylamine (14.1 g, 139.8 mmol) was added, and dimethyl tert-butyl chlorosilane (TBSCl, 16.9 g, 111.8 mmol) was added in batches at 0°C. After stirring for 30 minutes, the temperature was raised to room temperature and stirred for 6 hours. 150 mL of deionized water was added for extraction and separation. After drying, the solvent was removed by vacuum distillation to obtain a crude compound 2 (24.5 g, 88.6 mmol) with a yield of 95%.

[0018] C: The silicon-protected phenolic hydroxyl alkenyl ketone compound 2 (24.5 g, 88.6 mmol) prepared in step B was dissolved in 80 mL of ethanol, and pyridine (9.1 g, 115.2 mmol) and hydroxylamine hydrochloride (8 g, 115.2 mmol) were added respectively under stirring at 0°C, and stirred at room temperature for 12 hours. The ethanol was removed by distillation under reduced pressure, and the mixture was diluted with dichloromethane and deionized water was added. The mixture was separated by extraction, and the solvent was removed by distillation under reduced pressure after drying to obtain silicon-protected alkenyl ketone oxime compound 3 (23 g, 78.9 mmol) with a yield of 89%.

[0019] D: In 50 mL DMF solution, the synthesized silicon-protected alkenyl ketoxime compound 3 (23 g, 78.9 mmol), potassium carbonate (16.3 g, 118.4 mmol), and substituted benzyl bromide compound 4 (24.7 g, 86.8 mmol) were added respectively, heated to 65°C and stirred for 10 hours, then cooled to 0°C, 1M hydrochloric acid aqueous solution was slowly added dropwise to adjust the pH to 5-6, stirred at room temperature for 2 hours, 200 mL of dichloromethane and 200 mL of deionized water were added, extracted and separated, the organic phase was dried, and the solvent was removed by vacuum distillation, and the phenolic hydroxyl alkenyl oxime ether compound 5 (25.9 g, 67.9 mmol) was separated by column chromatography with a yield of 86%.

[0020] 1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.66 (s, 1H), 7.55 – 7.40 (m,3H), 7.35 – 7.27 (m, 2H), 7.15 – 7.08 (m, 1H), 6.95 – 6.79 (m, 3H), 6.74 –6.65 (m, 1H), 4.92 (s, 2H), 3.83 (s, 3H), 3.62 (s, 3H), 1.96 (s, 3H). 13C NMR (125 MHz, DMSO) δ 167.4, 161.2, 158.7, 154.8, 136.2, 132.4, 131.6, 131.4,129.7, 128.4, 128.0, 127.9, 127.8, 125.0, 115.3, 109.1, 67.8, 62.3, 51.7,9.9. The inhibitory activity results of phenolic hydroxyl alkenyl oxime ether compound 5 against common plant fungi are shown in Table 1.

[0021]

[0022] The in vitro antibacterial activity of compound 5 containing phenolic hydroxyl alkenyl oxime ether at a concentration of 50 mg / L against common plant fungi such as cucumber wilt, peanut brown spot, apple ring pattern, tomato early blight, wheat fusarium, rice seedling rot, rape sclerotium, pepper phytophthora, wheat sheath blight, corn leaf spot, watermelon anthrax, potato late blight, rice sheath blight and cucumber gray mold is shown in Table 1. Compound 5 containing phenolic hydroxyl alkenyl oxime ether exhibits good to excellent antibacterial activity. In particular, it shows comparable or better inhibitory activity to carbendazim and thiophanate-methyl against peanut brown spot, apple ring pattern, wheat sheath blight and cucumber gray mold. Embodiment 2:

[0023] The synthetic route of the phenolic hydroxyl alkenyl oxime ether compound is as follows:

[0024] The synthesis method of phenolic hydroxyl alkenyl oxime ether is as follows: A: At 25°C, to a 50 mL acetone solvent of p-hydroxybenzaldehyde (12.2 g, 100 mmol), add an aqueous NaOH solution (20% aqueous solution, 44 g, 220 mmmol), stir for 12 hours, remove most of the acetone solvent under reduced pressure, dilute with 100 mL of water, adjust the pH to 5 with a 1M aqueous hydrochloric acid solution at 0°C, extract and separate with 150 mL of dichloromethane, and after drying, remove the organic solvent by distillation under reduced pressure to obtain a crude product of phenolic hydroxyl alkenyl ketone compound 1 (15.1 g, 93.2 mmol) with a yield of 93%.

[0025] B: Compound 1 (15.1 g, 93.2 mmol) prepared in step A was dissolved in 50 mL DMF, triethylamine (14.1 g, 139.8 mmol) was added, and dimethyl tert-butyl chlorosilane (TBSCl, 16.9 g, 111.8 mmol) was added in batches at 0°C. After stirring for 30 minutes, the temperature was raised to room temperature and stirred for 6 hours. The mixture was extracted and separated with 100 mL of n-hexane, and the silicon-protected phenolic hydroxyl enyl ketone compound 2 entered n-hexane. The n-hexane was removed by vacuum distillation to obtain a crude compound 2 (23.2 g, 83.9 mmol) with a yield of 90%.

[0026] C: The silicon-protected phenolic hydroxyl alkenyl ketone compound 2 (23.2 g, 83.9 mmol) prepared in step B was dissolved in 80 mL of ethanol, and triethylamine (11 g, 109.1 mmol) and hydroxylamine hydrochloride (7.6 g, 109.1 mmol) were added respectively under stirring at 0°C, and stirred at room temperature for 12 hours. The ethanol was removed by distillation under reduced pressure, and the mixture was diluted with dichloromethane and deionized water was added. The mixture was separated by extraction, and the solvent was removed by distillation under reduced pressure after drying to obtain silicon-protected alkenyl ketone oxime compound 3 (20.3 g, 69.6 mmol) with a yield of 83%.

[0027] D: In 50 mL of acetonitrile solution, the synthesized silicon-protected alkenyl ketoxime compound 3 (20.3 g, 69.6 mmol), potassium carbonate (14.4 g, 104.4 mmol), and substituted benzyl bromide compound 4 (21.8 g, 76.6 mmol) were added respectively, heated to 65°C and stirred for 10 hours, then cooled to 0°C, 1M hydrochloric acid aqueous solution was slowly added dropwise to adjust the pH to 5-6, stirred at room temperature for 2 hours, 200 mL of dichloromethane and 200 mL of deionized water were added, extracted and separated, the organic phase was dried, and the solvent was removed by vacuum distillation, and the phenolic hydroxyl alkenyl oxime ether compound 5 (21.8 g, 57.1 mmol) was separated by column chromatography in a yield of 82%.

[0028] 1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.66 (s, 1H), 7.55 – 7.40 (m,3H), 7.35 – 7.27 (m, 2H), 7.15 – 7.08 (m, 1H), 6.95 – 6.79 (m, 3H), 6.74 –6.65 (m, 1H), 4.92 (s, 2H), 3.83 (s, 3H), 3.62 (s, 3H), 1.96 (s, 3H). 13C NMR (125 MHz, DMSO) δ 167.4, 161.2, 158.7, 154.8, 136.2, 132.4, 131.6, 131.4,129.7, 128.4, 128.0, 127.9, 127.8, 125.0, 115.3, 109.1, 67.8, 62.3, 51.7,9.9. Embodiment 3:

[0029] The synthetic route of the phenolic hydroxyl alkenyl oxime ether compound is as follows:

[0030] The synthesis method of phenolic hydroxyl alkenyl oxime ether is as follows: A: At 25°C, to a solution of p-hydroxybenzaldehyde (12.2 g, 100 mmol) in 50 mL of acetone solvent, add an aqueous NaOH solution (20% aqueous solution, 44 g, 200 mmmol), stir for 12 hours, remove most of the acetone solvent under reduced pressure, dilute with 100 mL of water, adjust the pH to 5 with a 1M aqueous hydrochloric acid solution at 0°C, extract and separate with 150 mL of dichloromethane, and after drying, remove the organic solvent by distillation under reduced pressure to obtain a crude product of phenolic hydroxyl alkenyl ketone compound 1 (14.8 g, 91 mmol) with a yield of 91%.

[0031] B: Compound 1 (14.8 g, 91 mmol) prepared in step A was dissolved in 150 mL DCM, triethylamine (11 g, 109.2 mmol) was added, and dimethyl tert-butyl chlorosilane (TBSCl, 16.5 g, 109.2 mmol) was added in batches at 0°C. After stirring for 30 minutes, the temperature was raised to room temperature and stirred for 6 hours. 150 mL of deionized water was added for extraction and separation. After drying, the solvent was removed by vacuum distillation to obtain a crude compound 2 (23.4 g, 84.6 mmol) with a yield of 93%.

[0032] C: The silicon-protected phenolic hydroxyl alkenyl ketone compound 2 (23.4 g, 84.6 mmol) prepared in step B was dissolved in 80 mL of methanol, and pyridine (8.7 g, 110 mmol) and hydroxylamine hydrochloride (7.6 g, 110 mmol) were added respectively under stirring at 0°C, and the mixture was stirred at room temperature for 12 hours. Methanol was removed by distillation under reduced pressure, and deionized water was added after dilution with dichloromethane, and the mixture was separated by extraction. After drying, the solvent was removed by distillation under reduced pressure to obtain silicon-protected alkenyl ketone oxime compound 3 (21.7 g, 74.4 mmol) with a yield of 88%.

[0033] D: In 50 mL DMF solution, the synthesized silicon-protected alkenyl ketoxime compound 3 (21.7 g, 74.4 mmol), potassium carbonate (12.3 g, 89.3 mmol), and substituted benzyl bromide compound 4 (23.3 g, 81.8 mmol) were added respectively, heated to 65°C and stirred for 10 hours, then cooled to 0°C, 1M hydrochloric acid aqueous solution was slowly added dropwise to adjust the pH to 5-6, stirred at room temperature for 2 hours, 200 mL of dichloromethane and 200 mL of deionized water were added, extracted and separated, the organic phase was dried, and the solvent was removed by vacuum distillation, and the phenolic hydroxyl alkenyl oxime ether compound 5 (23.3 g, 61 mmol) was separated by column chromatography with a yield of 82%.

[0034] 1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 7.66 (s, 1H), 7.55 – 7.40 (m,3H), 7.35 – 7.27 (m, 2H), 7.15 – 7.08 (m, 1H), 6.95 – 6.79 (m, 3H), 6.74 –6.65 (m, 1H), 4.92 (s, 2H), 3.83 (s, 3H), 3.62 (s, 3H), 1.96 (s, 3H). 13C NMR (125 MHz, DMSO) δ 167.4, 161.2, 158.7, 154.8, 136.2, 132.4, 131.6, 131.4,129.7, 128.4, 128.0, 127.9, 127.8, 125.0, 115.3, 109.1, 67.8, 62.3, 51.7,9.9. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing phenolic hydroxyl alkenyl oxime ethers as pesticide and pharmaceutical intermediates and its application, characterized in that: The structure of the phenolic hydroxyl alkenyl oxime ether is compound 5, and the synthesis steps of compound 5 include: A: p-Hydroxybenzaldehyde and acetone undergo aldol condensation under the action of a base to obtain a phenolic hydroxyl alkenyl ketone compound 1; B: Compound 1 reacts with dimethyl tert-butyl chlorosilane (TBSCl) under the action of imidazole to obtain silicon-protected phenolic hydroxyl enyl ketone compound 2; C: Compound 2 reacts with hydroxylamine hydrochloride under the action of a base to obtain a silicon-protected alkenyl ketoxime compound 3; D: Compound 3 reacts with substituted benzyl bromide compound 4 under the action of a base to undergo a nucleophilic substitution reaction to obtain phenolic hydroxyl alkenyl oxime ether compound 5; The fungicidal activity of the synthesized phenolic hydroxyl alkenyl oxime ether compound 5 was tested against common plant fungi. The results showed that the phenolic hydroxyl alkenyl oxime ether compound 5 exhibited good to excellent inhibitory effects on the test fungi.

2. According to claim 1, the structure of the phenolic hydroxyl alkenyl oxime ether is compound 5, and the para-substituent of the benzene ring is a hydroxyl group.

3. The method for synthesizing phenolic hydroxyl alkenyl oxime ether according to claim 1, characterized in that: In the step A, the base used for the aldol condensation is one of NaOH, KOH and LiOH; in the step A, the molar ratio of p-hydroxybenzaldehyde to the base is 1:2.0-3.

0.

4. The method for synthesizing phenolic hydroxyl alkenyl oxime ether according to claim 1, characterized in that: In the step B, the base used is one of triethylamine and pyridine; in the step B, the molar ratio of the phenolic hydroxyl alkenyl ketone compound 1, the base and dimethyl tert-butyl chlorosilane is 1:1.0~2.0:1.0~1.

5.

5. The method for synthesizing phenolic hydroxyl alkenyl oxime ether according to claim 1, characterized in that: In the step C, the base used is one of triethylamine, pyridine and sodium acetate; in the step C, the molar ratio of the silicon-protected phenolic hydroxyl alkenyl ketone compound 2, the base and the hydroxylamine is 1:1.0~2.0:1.0~2.

0.

6. The method for synthesizing phenolic hydroxyl alkenyl oxime ether according to claim 1, characterized in that: In the step D, the base used is one of potassium carbonate, sodium carbonate and sodium hydroxide; in the step D, the molar ratio of the silicon-protected alkenyl ketoxime compound 3, the base and the substituted benzyl bromide compound 4 is 1:1.0~2.0:1.0~1.

3.

7. The phenolic hydroxyl alkenyl oxime ether compound 5 or its preparation according to claim 1 can be used to prevent and control diseases on various crops caused by common plant pathogenic fungi such as Oomycetes, Phycomycetes and Ascomycetes.

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