Polysubstituted pentene diacid ester as well as synthesis method and application thereof

Abstract

The invention discloses polysubstituted pentene diacid ester as well as a synthesis method and application thereof, and belongs to the technical field of medicine synthesis. The structure of the polysubstituted pentene diacid ester is # imgabs0 #. According to the method, the polysubstituted pentene diacid ester is synthesized from diazo-2-methyl fluorophenylacetate and bicyclo [1.1. 0] butane-1-benzyl formate, the reaction conditions are mild, the used reagents and raw materials are cheap and easy to obtain, and the catalytic efficiency is high. The polysubstituted pentene diacid ester synthesized by the invention shows excellent bacteriostatic activity on tomato early blight, wheat gibberella, phytophthora capsici and cucumber gray mold, and can be used as a plant bacteriostatic agent.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a polysubstituted glutaconate ester and a synthesis method and application thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] 1,4-Pentadien-3-one exhibits a variety of important biological activities. Lipoxazolidinone A produced by marine actinomycete strains shows good broad-spectrum antibacterial activity. 1,4-Pentadien-3-one compounds containing coumarin and benzimidazole structures show good anti-tumor activity and broad-spectrum antifungal and bacterial activity. In addition, 1,5-disubstituted pyrazol-1,4-pentadien-3-one compounds and phosphite-1,4-pentadien-3-one compounds all show extremely excellent antibacterial activity.

[0004]

[0005] The synthesis methods of 1,4-pentadien-3-one compounds include: cycloaddition reaction between epoxyaziridine and ketoene, α-amino acid or anhydride, photoelectrochemical reaction involving α-ketoamide, domino reaction between enol ether and α-bromoamide alcohol, condensation reaction between carbonyl compound and α-hydroxyamide, and cycloaddition reaction of halogenated amide and aldehyde ketone developed in recent years. These synthesis methods have problems such as complex operation, harsh reaction conditions, expensive reagents and raw materials, and complex products that are difficult to purify. Summary of the invention

[0006] In order to solve the shortcomings of the prior art, the purpose of the present invention is to provide a polysubstituted glutaconate and a synthesis method and application thereof. The synthesis method provided by the present invention has the advantages of simple and efficient steps, cheap reagents and raw materials, mild reaction conditions, etc., and is more suitable for large-scale production. The polysubstituted glutaconate provided by the present invention exhibits good antibacterial activity against tomato early blight, wheat gibberella, pepper phytophthora and cucumber gray mold.

[0007] In order to achieve the above object, the technical solution of the present invention is: The first aspect of the present invention provides a multi-substituted glutaconate, the structure of which is as follows: .

[0008] The second aspect of the present invention provides a method for synthesizing the above-mentioned polysubstituted glutaconate, comprising: In the presence of a catalyst, methyl diazo-2-fluorophenylacetate and benzyl bicyclo[1.1.0]butane-1-carboxylate react to obtain a polysubstituted glutaconate.

[0009] In some embodiments of the present invention, the catalyst is a metal catalyst.

[0010] In some embodiments of the present invention, the catalyst is selected from ferric chloride, tetraacetonitrile copper (I) hexafluorophosphate ([(CH3CN)4Cu]PF6), Ir[dF(CF3)ppy]2(dtbbpy)PF6, dimerized rhodium acetate (Rh2(OAc)4) and Rh2( s -PTTL)4.

[0011] In some embodiments of the present invention, the molar ratio of benzyl bicyclo[1.1.0]butane-1-carboxylate, methyl diazo-2-fluorophenylacetate and the catalyst is 1:(1-1.5):(0.0001-0.2).

[0012] In some embodiments of the present invention, the synthesis method comprises: adding benzyl bicyclo[1.1.0]butane-1-carboxylate and a catalyst to an organic solvent, heating to reflux, adding methyl diazo-2-fluorophenylacetate under stirring conditions, and reacting under reflux stirring to obtain a polysubstituted glutaconate.

[0013] In some embodiments of the present invention, the organic solvent is one of dichloromethane and chloroform.

[0014] In some embodiments of the present invention, the synthesis method further comprises the steps of removing the organic solvent after the reaction is completed and isolating the polysubstituted glutaconate; Wherein, the separation is separation by column chromatography.

[0015] The third aspect of the present invention provides a use of the above-mentioned polysubstituted glutaconate or the polysubstituted glutaconate synthesized by the above-mentioned synthesis method in the preparation of a plant antibacterial agent.

[0016] In some embodiments of the present invention, the fungus includes at least one of tomato early blight, wheat fusarium, pepper phytophthora and cucumber gray mold.

[0017] The beneficial effects of the present invention are: The present invention provides a method for synthesizing a polysubstituted glutaconate, comprising: methyl diazo-2-fluorophenylacetate and benzyl bicyclo[1.1.0]butane-1-carboxylate to directly obtain a polysubstituted glutaconate product. The method for synthesizing a polysubstituted glutaconate provided by the present invention has mild reaction conditions, the reagents and raw materials used are cheap and readily available, and the catalytic efficiency is high. The polysubstituted glutaconate exhibits certain antibacterial activity against tomato early blight, wheat fusarium, pepper phytophthora and cucumber gray mold. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] 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.

[0019] Figure 1 This is the H-NMR spectrum of the multi-substituted glutaconate prepared in Example 1 of the present invention; Figure 2 This is the NMR carbon spectrum of the multi-substituted glutaconate prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0020] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] A first typical embodiment of the present invention provides a multi-substituted glutaconate ester, the structure of which is as follows: .

[0022] The polysubstituted glutaconate provided by the present invention exhibits good antibacterial activity against tomato early blight, wheat gibberella, pepper phytophthora and cucumber gray mold, and can be used as a plant antibacterial agent.

[0023] A second typical embodiment of the present invention provides a method for synthesizing the above-mentioned polysubstituted glutaconate, comprising: In the presence of a catalyst, methyl diazo-2-fluorophenylacetate and benzyl bicyclo[1.1.0]butane-1-carboxylate react to obtain a polysubstituted glutaconate.

[0024] The process route of the above-mentioned synthesis method is shown as follows:

[0025] The invention uses methyl diazo-2-fluorophenylacetate and benzyl bicyclo[1.1.0]butane-1-carboxylate as raw materials and uses a catalyst to synthesize polysubstituted glutaconate. The synthesis steps are simple and efficient, the reagents and raw materials used are cheap, the reaction conditions are mild, and the product is suitable for large-scale production.

[0026] It should be noted that the methyl diazo-2-fluorophenylacetate is an existing product and can be purchased or prepared. The structure of the methyl diazo-2-fluorophenylacetate is as follows: .

[0027] The bicyclo[1.1.0]butane-1-carboxylic acid benzyl ester is also an existing product and can be purchased or prepared. The structure of the bicyclo[1.1.0]butane-1-carboxylic acid benzyl ester is as follows: .

[0028] In some examples of this embodiment, the catalyst is a metal catalyst.

[0029] In some examples of this embodiment, the catalyst is selected from FeCl3, [(CH3CN)4Cu]PF6, Ir[dF(CF3)ppy]2(dtbbpy)PF6, Rh2(OAc)4 and Rh2( s -PTTL)4.

[0030] It should be noted that the above catalysts all have catalytic activity and can catalyze the reaction of methyl 2-fluorophenylacetate and benzyl bicyclo[1.1.0]butane-1-carboxylate to synthesize polysubstituted glutaconate. s -PTTL)4 has the best catalytic activity and the highest catalytic efficiency.

[0031] In some examples of this embodiment, the molar ratio of benzyl bicyclo[1.1.0]butane-1-carboxylate, methyl diazo-2-fluorophenylacetate and the catalyst is 1:(1-1.5):(0.0001-0.2).

[0032] It should be noted that the yield of the polysubstituted glutaconate obtained at the above molar ratio is high. At a raw material ratio other than this molar ratio, the reaction can also proceed, but the reaction rate or product yield is low. For example, the amount of the catalyst can be as low as one hundred thousandth of the amount of the bicyclo[1.1.0]butane-1-carboxylic acid benzyl ester.

[0033] In some examples of this embodiment, the synthesis method includes: adding benzyl bicyclo[1.1.0]butane-1-carboxylate and a catalyst to an organic solvent, heating to reflux, adding methyl diazo-2-fluorophenylacetate under stirring conditions, and reacting under reflux and stirring to obtain a polysubstituted glutaconate.

[0034] In some examples of this embodiment, the organic solvent is one of dichloromethane and chloroform.

[0035] It should be noted that when a solvent other than dichloromethane and chloroform is used for the reaction, the reaction can also proceed, but the yield of the target product is lower. In order to increase the yield of the target product, dichloromethane or chloroform is preferably used as the organic solvent.

[0036] The boiling point of dichloromethane is 39.8°C, so when dichloromethane is used as an organic solvent, the reaction system can be refluxed by heating it to 40°C. The boiling point of chloroform is 61.2°C, so when chloroform is used as a solvent, the reaction system needs to be heated to ~60°C to achieve reflux.

[0037] In some examples of this embodiment, methyl diazo-2-fluorophenylacetate may be added to the reaction system by injection or dropwise addition using a constant flow injection pump or a syringe.

[0038] In some examples of this embodiment, the synthesis method further comprises the steps of removing the organic solvent after the reaction is completed and separating the polysubstituted glutaconate; Wherein, the separation is separation by column chromatography.

[0039] A third typical embodiment of the present invention provides a use of the above-mentioned polysubstituted glutaconate or the polysubstituted glutaconate synthesized by the above-mentioned synthesis method in the preparation of a plant antibacterial agent.

[0040] In some embodiments of the present invention, the fungus includes at least one of tomato early blight, wheat fusarium, pepper phytophthora and cucumber gray mold.

[0041] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0042] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased on the market.

[0043] Example 1 A method for synthesizing a polysubstituted glutaconate ester comprises the following steps: To 40 mL of dichloromethane solution, add benzyl bicyclo[1.1.0]butane-1-carboxylate (0.94 g, 5.0 mmol) and Rh2(s-PTTL)4 (14 mg, 0.01 mmol), heat to 40°C, add methyl diazo-2-fluorophenylacetate (1.05 g, 6.0 mmol) to the reaction system with stirring using a constant flow injection pump or syringe, and stir at 600 rpm for 3 hours. Monitor the reaction progress by thin layer chromatography. After the reaction is complete, remove the organic solvent by rotary evaporation and separate by column chromatography to obtain 1.3 g of polysubstituted glutaconate with a yield of 77%.

[0044] 1H NMR (600 MHz, Chloroform-d) δ 7.38 – 7.30 (m, 6H), 7.21 (t, J =7.5 Hz, 1H), 7.15 – 7.11 (m, 2H), 7.08 (t, J = 9.0 Hz, 1H), 6.27 (s, 1H),5.57 (s, 1H), 5.18 (s, 2H), 3.74 (s, 3H), 3.09 (d, J = 7.5 Hz, 2H). 13 C NMR (151 MHz, CDCl3) δ 166.5, 166.1, 160.8, 159.2, 142.9, 137.2,135.7, 131.4, 130.0, 129.9, 129.5, 128.6, 128.3, 128.1, 127.0, 123.9, 123.8,122.5, 122.4, 115.6, 115.5, 66.7, 52.3, 31.9. Example 2 A method for synthesizing a polysubstituted glutaconate ester comprises the following steps: To 40 mL of chloroform, add benzyl bicyclo[1.1.0]butane-1-carboxylate (0.94 g, 5.0 mmol) and Rh2(s-PTTL)4 (14 mg, 0.01 mmol), heat to 60°C, add methyl diazo-2-fluorophenylacetate (1.05 g, 6.0 mmol) to the reaction system with stirring using a constant flow injection pump or syringe, and stir at 600 rpm for 3 hours. Monitor the reaction progress by thin layer chromatography. After the reaction is complete, remove the organic solvent by rotary evaporation and separate by column chromatography to obtain 1.1 g of polysubstituted glutaconate with a yield of 65%.

[0045] The NMR-MS-C spectrum of the polysubstituted glutaconate obtained in Example 2 is consistent with that in Example 1.

[0046] Example 3 A method for synthesizing a polysubstituted glutaconate ester comprises the following steps: Add benzyl bicyclo[1.1.0]butane-1-carboxylate (38 mg, 1 eq) and Rh2(s-PTTL)4 (0.3 mg, 0.01 mol%) to 40 mL of dichloromethane solution, heat to 40°C, add methyl diazo-2-fluorophenylacetate (38 mg, 1 eq) to the reaction system with a constant flow injection pump or syringe under stirring conditions, and stir at 600 rpm for 3 hours. Monitor the reaction progress by thin layer chromatography. After the reaction is complete, remove the organic solvent by rotary evaporation and separate by column chromatography to obtain 53 mg of polysubstituted glutaconate with a yield of 75%.

[0047] The NMR-MS-C spectrum of the polysubstituted glutaconate obtained in Example 3 is consistent with that in Example 1.

[0048] Example 4 A method for synthesizing a polysubstituted glutaconate ester comprises the following steps: Add benzyl bicyclo[1.1.0]butane-1-carboxylate (38 mg, 1 eq) and Rh2(s-PTTL)4 (56 mg, 20 mol%) to 40 mL of dichloromethane solution, heat to 40°C, add methyl diazo-2-fluorophenylacetate (57 mg, 1.5 eq) to the reaction system with a constant flow injection pump or syringe under stirring conditions, and stir at 600 rpm for 3 hours. Monitor the reaction progress by thin layer chromatography. After the reaction is complete, remove the organic solvent by rotary evaporation and separate by column chromatography to obtain 50 mg of polysubstituted glutaconate with a yield of 70%.

[0049] The NMR-MS-C spectrum of the polysubstituted glutaconate obtained in Example 4 is consistent with that in Example 1.

[0050] Performance Verification The present invention has carried out relevant in vitro antibacterial activity evaluation on the polysubstituted glutaconate synthesized in Example 1, and carried out relevant in vitro fungicidal activity test on 14 plant pathogens, which are tomato early blight ( Alternaria solani )、Triticum gibberella( Fusarium gramineae ), Rice Blast ( Firefly orya )、Phytophthora capsici( Phytophthora capsicum )、Brassica napus sclerotia( Sclerotinia sclerotiorum )、Cucumber gray mold ( Botrytis cinerea )、Rice sheath blight( Cucumber beetle ), cucumber wilt( Fusarium oxysporum )、Peanut brown spots( Cercospora arachidicola )、Apple ring pattern( Physalospora piricola )、Wheat stripe blight( Geratobasidium hornigeru ), Corn Spot( Bipolaris maydis )、Watermelon Anthrax( Colletorichum lagenerium ), bad rice seedlings ( Fusarium moniliforme ). The specific test method and bactericidal activity results are as follows.

[0051] Test method: Plate method - bacterial growth rate determination method Dissolve 10 mg of the polysubstituted glutaconate synthesized in Example 1 in an appropriate amount of acetone, then dilute with an aqueous solution containing 200 μg / mL of an emulsifier to a target compound concentration of 500 μg / mL, then draw 1 mL of the drug solution and 9 mL of the culture medium into a culture dish, shake well to obtain a 50 μg / mL drug-containing plate, and add 1 mL of sterilized water to the blank group as a blank control. Use a 4 mm diameter puncher to cut the bacterial disc along the edge of the hyphae where the growth is better, and move it to the drug-containing plate. Each treatment was repeated three times, and the culture dish was placed in a constant temperature incubator at 24±1°C for culture. After 48 h, the expansion diameter of each bacterial disc was measured, the average value was calculated, and compared with the blank control to calculate the relative inhibition rate.

[0052] Relative inhibition rate (%) = (control group bacterial disk diameter - treatment group bacterial disk diameter) / control group bacterial disk diameter × 100% The biological activities are shown in the table below.

[0053] Table 1 Statistics of biological activities of polysubstituted glutaconate esters

[0054] At 50 μg / mL, the polysubstituted glutaconate esters prepared in the examples of the present invention showed excellent fungicidal activity against tomato early blight, wheat fusarium, pepper phytophthora and cucumber gray mold, among which the activity against pepper phytophthora was better than the positive control drug thiophanate-methyl.

[0055] 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 polysubstituted glutaconate, characterized in that: Its structure is as follows: 。 2. A method for synthesizing a polysubstituted glutaconate according to claim 1, characterized in that: include: In the presence of a catalyst, methyl diazo-2-fluorophenylacetate and benzyl bicyclo[1.1.0]butane-1-carboxylate react to obtain a polysubstituted glutaconate.

3. The synthesis method according to claim 2, characterized in that The catalyst is a metal catalyst.

4. The synthesis method according to claim 2, characterized in that The catalyst is selected from ferric chloride, copper tetraacetonitrile hexafluorophosphate, Ir[dF(CF3)ppy]2(dtbbpy)PF6, dimerized rhodium acetate and Rh2( s -PTTL)4.

5. The synthesis method according to claim 2, characterized in that The molar ratio of benzyl bicyclo[1.1.0]butane-1-carboxylate, methyl diazo-2-fluorophenylacetate and the catalyst is 1:(1-1.5):(0.0001-0.2).

6. The synthesis method according to claim 2, characterized in that The synthesis method comprises: adding bicyclo[1.1.0]butane-1-carboxylic acid benzyl ester and a catalyst into an organic solvent, heating to reflux, adding diazo-2-fluorophenylacetic acid methyl ester under stirring conditions, and reacting under reflux stirring to obtain a polysubstituted glutaconate.

7. The synthesis method according to claim 6, characterized in that The organic solvent is one of dichloromethane and chloroform.

8. The synthesis method according to claim 6, characterized in that The synthesis method further comprises the steps of removing the organic solvent after the reaction is completed and separating to obtain the multi-substituted glutaconate; Wherein, the separation is separation by column chromatography.

9. Use of the polysubstituted glutaconate according to claim 1 or the polysubstituted glutaconate synthesized by the synthesis method according to any one of claims 2 to 8 in the preparation of a plant antibacterial agent.

10. The use according to claim 9, characterized in that The fungus comprises at least one of tomato early blight, wheat fusarium, pepper phytophthora and cucumber gray mold.

Images