A dicaffeoylquinic acid compound, its synthesis method and application

Abstract

The present invention discloses a bicycloalkane compound, a synthesis method and an application thereof. Using aryl dicyanoethylene and allyl carbonate as reaction raw materials, a bicycloalkane compound is obtained under the action of an organophosphorus catalyst. The advantages of the present invention include: high reaction efficiency and high yield; the organophosphorus catalyst is cheap, easily available, stable and has no pungent odor; no strong acid or strong base, as well as additional oxidizing or reducing agents need to be added during the reaction, and the conditions are relatively mild; no transition metal is used as a catalyst during the reaction, which is economical and environmentally friendly; the reaction substrates are easy to prepare. The compound represented by formula (III) of the present invention has good inhibitory activities against Penicillium digitaum and Rhizoctonia solani, and among them, the effect of compound 11 is the best, reaching 91% and 83% respectively.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound process applications, and particularly relates to diquilarane compounds, an efficient and simple synthesis method thereof, and an application in drugs against Penicillium digitatum and / or Rhizoctonia solani Kuhn. Background Art

[0002] Diquilarane is a series of natural products with a distinct structural unit widely present in carbocyclic frameworks, such as alkaloids and terpenoids. These molecules containing diquilarane not only exhibit a special penta-fused five-carbon ring structure but also show a wide range of biological activities, attracting extensive attention from the worldwide organic synthesis field. In addition, a variety of natural compounds containing benzoquinilarane have been found to have significant biological and pharmacological activities. Another natural product Canataxapropellane, which also contains a penta-fused five-carbon ring, belongs to the important medicinal taxane diterpenoids. The most prominent paclitaxel is one of the most commonly used anti-cancer drugs in current clinical practice, as shown below:

[0003]

[0004] Developing a simple synthetic strategy for this class has always been a topic of great concern in the organic synthesis community. However, there are few reported catalytic methods for synthesizing this class, and synthesizing this class still poses a high challenge. The goal of the present invention is to design a simple and practical catalytic method to construct this class. As we know, organophosphorus catalysis is an excellent catalyst in cyclization reactions and is often used as an efficient catalyst for cycloaddition reactions. Therefore, the present invention splits this core structure into starting materials aryl dicyanoolefins and allyl carbonates, and constructs this core structure through the action of organophosphorus catalysis. Summary of the Invention

[0005] The present invention innovatively realizes a method for efficiently constructing diquilarane compounds. The inventors of the present invention have found through research that aryl dicyanoolefins are a class of very active aryl compounds containing electron-withdrawing groups, which have the characteristics of stability and easy preparation. In view of this, the present invention designs a reaction method for preparing diquilarane compounds by reacting aryl dicyanoolefins with allyl carbonates.

[0006] A synthesis method of diquilarane compounds proposed by the present invention, under the catalysis of an organophosphorus catalyst, uses aryl dicyanoolefins and allyl carbonates as reaction raw materials, reacts in a reaction solvent, effectively realizes the corresponding transformation, and prepares the diquilarane compounds shown in Figure (III). Among them, the reaction process is as shown in the following reaction formula a:

[0007]

[0008] Wherein, R 1is any one of 2-nitro, 4-nitro, 5-fluoro-2-nitro, 5-chloro-2-nitro, 5-bromo-2-nitro, 4-fluoro-2-nitro, 4-chloro-2-nitro, 4-bromo-2-nitro, and 4-methoxycarbonyl. R 2 is any one of ethyl, isopropyl, n-butyl, tert-butyl, benzyl, and cyclohexyl.

[0009] As shown in the above reaction formula a, the present invention uses the aryl dicyanoethylene shown in (I) and allyl carbonate as reaction raw materials, and reacts in a reaction solvent under the action of an organic phosphine catalyst to obtain the diquinuclidine compound shown in Figure (III).

[0010] In the present invention, the dosage ratio of the starting material, the aryl dicyanoethylene shown in (I), and the raw material, the allyl carbonate shown in (II), is 1:2-3.

[0011] In the present invention, the solvent is any one of dichloromethane, dichloroethane, chloroform, toluene, acetonitrile, and acetone. From the perspective of the reaction effect of the product, acetone is selected as the solvent.

[0012] The synthesis reaction of the present invention includes the following steps:

[0013] The reaction described in Equation a includes the following steps: Add aryl dicyanoethylene, allyl carbonate, and acetone to a reaction vessel, and stir and react at room temperature (room temperature is generally about 25°C) to obtain the diquinuclidine compound shown in Figure (III).

[0014] In a specific example, as shown in Equation a, the synthesis reaction of the present invention is carried out in reaction flask A by adding aryl dicyanoethylene (X mmol), allyl carbonate (Y mmol), and solvent (V mL), and the reaction system is stirred at 25°C for 12 hours. After the reaction is completed, the reaction system is concentrated and separated by column chromatography to obtain the target product.

[0015] The present invention also provides a diquinuclidine compound shown in Figure (III) prepared by the above synthesis method of the present invention.

[0016]

[0017] Among them, R 1 is substituted by a halogen atom; R 2 is an alkyl or an aryl.

[0018] The present invention also provides an application method of the above diquinuclidine compound shown in (III) in the synthesis of potential drugs containing diquinuclidine-related substances.

[0019] The present invention has the following advantages: 1. High reaction efficiency and high yield; 2. The organophosphorus catalyst is cheap, readily available, stable, and has no pungent odor; 3. No strong acid or strong base, as well as additional oxidizing or reducing agents need to be added during the reaction, and the conditions are relatively mild; 4. No transition metal needs to be used as a catalyst during the reaction, which is economical and environmentally friendly; 5. The reaction substrates are easy to prepare; 6. The reaction efficiency is high after the reaction is scaled up, and it has practical value.

[0020] The present invention uses easily prepared aryl dicyanoethylene compounds and allyl carbonate compounds as reaction raw materials, and under the action of an organophosphorus catalyst, a diquaiane compound is obtained by reaction. The reaction operation is simple and the conditions are mild, which is suitable for large-scale industrial production. Specific Embodiments

[0021] Combined with the following specific embodiments, the present invention will be further described in detail. The protection scope of the present invention is not limited to the following embodiments. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be conceived by those skilled in the art are included in the present invention, and the appended claims are used as the protection scope. The processes, conditions, reagents, experimental methods, etc. for implementing the present invention, except for the specifically mentioned content below, are all common knowledge and well-known general knowledge in the art, and the present invention has no special restrictions. The data given in the following embodiments include specific operations, reaction conditions, and products. The product purity is identified by nuclear magnetic resonance.

[0022] The synthesis reaction of the aryl alkyl sulfide compound of the present invention includes the following steps:

[0023] As shown in Equation a: o-Nitrophenyl dicyanoethylene, allyl carbonate, and acetone are added to a reaction vessel, and the reaction is stirred at room temperature to obtain the diquaiane compound shown in (III). Then, it is concentrated and separated by column chromatography to obtain the target product.

[0024] The diquaiane compounds shown in Table 1 are all products synthesized by the method of the present invention, and there are no published literatures revealing these compounds.

[0025] Table 1 New diquaiane compounds of the present invention

[0026]

[0027] Example 1

[0028]

[0029] After adding o-nitro-substituted dicyanophenyl ethylene (19.9 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphine catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 1 was obtained by column chromatography (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 93%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.4, 1.2 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.77–7.73 (m, 1H), 7.59–7.55 (m, 1H), 6.69 (dd, J = 4.0, 2.0 Hz, 1H), 4.59 (d, J = 6.4 Hz, 1H), 4.36 (d, J = 6.4 Hz, 1H), 4.29 (t, J = 6.8 Hz, 2H), 4.07–4.01 (m, 1H), 3.90–3.84 (m, 1H), 3.49 (d, J = 13.6 Hz, 1H), 3.06 (dt, J = 19.6, 1.6 Hz, 1H), 2.92 (dt, J = 19.6, 2.8 Hz, 1H), 2.58 (d, J = 13.6 Hz, 1H), 1.75–1.71 (m, 2H), 1.47–1.40 (m, 2H), 1.36–1.32 (m, 2H), 1.20–1.14 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.6, 163.1, 149.8, 140.3, 137.2, 133.4, 131.2, 129.8, 129.6, 125.2, 114.2, 113.5, 66.6, 64.8, 59.5, 58.8, 53.5, 47.2, 44.4, 41.8, 30.4, 30.2, 19.2, 18.9, 13.7, 13.6. HRMS (ESI) m / z: calcd. for C 26 H 29 N3O6H + (M + H) + 514.1973, found 514.1978.

[0030] Example 2

[0031]

[0032] After adding m-nitro-substituted dicyanophenyl ethylene (19.9 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into a reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphine catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 2 was obtained after column chromatography separation (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 51%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.36 (t, J = 2.0 Hz, 1H), 8.29 (dd, J = 8.4, 1.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 6.72 (dd, J = 4.0, 2.0 Hz, 1H), 4.52 (dd, J = 7.2, 1.6 Hz, 1H), 4.33–4.26 (m, 2H), 4.00–3.94 (m, 1H), 3.91–3.85 (m, 1H), 3.74 (d, J = 7.2 Hz, 1H), 3.57 (d, J = 13.6, 1H), 3.01 (dt, J = 19.6, 2.0 Hz, 1H), 2.86 (dt, J = 19.6, 2.8 Hz, 1H), 2.46 (d, J = 13.6 Hz, 1H), 1.78–1.71 (m, 2H), 1.47–1.41 (m, 2H), 1.34–1.29 (m, 2H), 1.20–1.14 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.3, 163.1, 148.4, 140.5, 137.6, 137.1, 134.4, 130.0, 124.0, 123.5, 114.4, 112.8, 66.7, 64.8, 61.0, 59.0, 57.0, 46.6, 44.4, 42.6, 30.4, 30.3, 19.2, 19.0, 13.7, 13.6. HRMS (ESI) m / z: calcd. for C 26 H 29 N3O6H + (M + H) + 514.1973, found 514.1978.

[0033] Example 3

[0034]

[0035] After adding p-nitro-substituted dicyanophenyl ethylene (19.9 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphorus catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 3 was obtained by column chromatography (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 59%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 6.70 (dd, J = 4.0, 2.0 Hz, 1H), 4.53 (dd, J = 7.6, 1.6 Hz, 1H), 4.31–4.25 (m, 2H), 4.00–3.85 (m, 2H), 3.71 (d, J = 7.6 Hz, 1H), 3.57 (d, J = 13.6 Hz, 1H), 2.98 (dt, J = 19.6, 2.4 Hz, 1H), 2.85 (dt, J = 19.6, 2.8 Hz, 1H), 2.45 (d, J = 13.6 Hz, 1H), 1.76–1.70 (m, 2H), 1.47–1.41 (m, 2H), 1.34–1.28 (m, 2H), 1.22–1.15 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.3, 163.1, 148.2, 142.5, 140.2, 137.2, 129.5, 124.1, 114.3, 112.8, 66.7, 64.9, 61.1, 59.1, 56.8, 46.7, 44.4, 42.6, 30.4, 30.3, 19.2, 19.0, 13.7, 13.6. HRMS (ESI) m / z: calcd. for C 26 H 29 N3O6Na + (M+Na) + 502.1949, found 502.1960.

[0036] Example 4

[0037]

[0038] 5-Fluoro-2-nitro-substituted dicyanophenyl ethylene (21.7 mg, 0.1 mmol, 1.0 equiv.) and the solvent acetone (1.0 mL) were added to a reaction tube. Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the phosphine catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the solvent was removed under reduced pressure from the reaction solution, and the product 4 was obtained after column chromatography separation (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 61%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 9.2, 5.2 Hz, 1H), 7.58 (dd, J = 9.2, 2.4 Hz, 1H), 7.26–7.22 (m, 1H), 6.69 (d, J = 2.0 Hz, 1H), 4.71 (d, J = 6.4 Hz, 1H), 4.30 (t, J = 6.8 Hz, 3H), 4.08–4.01 (m, 1H), 3.95–3.89 (m, 1H), 3.47 (d, J = 14.0 Hz, 1H), 3.11 (d, J = 19.6 Hz, 1H), 2.93 (dt, J = 20.0, 2.4 Hz, 1H), 2.61 (d, J = 14.0 Hz, 1H), 1.78–1.71 (m, 2H), 1.46–1.39 (m, 4H), 1.24–1.19 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.4, 163.1 (d, J = 23.4 Hz), 140.5, 136.9, 135.1 (d, J = 8.7 Hz), 128.3 (d, J = 9.8 Hz), 117.4 (d, J = 24.8 Hz), 116.8 (d, J = 22.8 Hz), 114.1, 113.3, 66.8, 59.6, 58.8, 53.4, 47.3, 44.3, 41.7, 30.4, 30.3, 19.2, 19.0, 13.6, 13.6. HRMS (ESI) m / z: calcd. for C 26 H 28 FN3O6H + (M + H) + 498.2040, found 498.2043.

[0039] Example 5

[0040]

[0041] After adding 5-chloro-2-nitro-substituted dicyanophenyl ethylene (23.3 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into a reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added. Then, the organophosphorus catalyst PPh3 (7.9 mg, 30 mol%) was added, and the mixture was stirred at 25 °C for 12 hours. Then, the solvent of the reaction solution was removed under reduced pressure, and the product 5 was obtained after column chromatography separation (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 63%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H), 6.69 (dd, J = 4.0, 2.0 Hz, 1H), 4.65 (d, J = 6.4 Hz, 1H), 4.34–4.27 (m, 3H), 4.28–4.02 (m, 1H), 3.94–3.88 (m, 1H), 3.48 (d, J = 14.0 Hz, 1H), 3.11 (dt, J = 19.6, 1.6 Hz, 1H), 2.93 (dt, J = 19.6, 2.8 Hz, 1H), 2.59 (d, J = 13.6 Hz, 1H), 1.79–1.72 (m, 2H), 1.47–1.39 (m, 4H), 1.23–1.19 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H), 0.86 (t, J = 7.6 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.4, 163.1, 147.9, 140.1, 136.9, 133.4, 130.1, 129.8, 126.8, 114.1, 113.3, 66.8, 64.9, 59.5, 58.8, 53.3, 47.3, 44.4, 41.7, 30.4, 30.3, 19.2, 19.0, 13.7, 13.6. HRMS (ESI) m / z: calcd. for C 26 H 28 ClN3O6H + (M + H) + 514.1740, found 514.1748.

[0042] Example 6

[0043]

[0044] After adding 5-bromo-2-nitro-substituted dicyanophenyl ethylene (27.8 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into a reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphorus catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 6 was obtained by column chromatography (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 64%, >20:1 d.r.; 1 H NMR(400MHz,CDCl3)δ7.98(d,J=1.6Hz,1H),7.92(d,J=8.8Hz,1H),7.70(dd,J=8.8,2.0Hz,1H),6.69(d,J=2.0Hz,1H),4.62(d,J=6.4Hz,1H),4.35–4.28(m,3H),4.08–4.02(m,1H),3.94–3.88(m,1H),3.48(d,J=14.0Hz,1H),3.11(d,J=19.6Hz,1H),2.93(dt,J=19.6,2.4Hz,1H),2.59(d,J=14.0Hz,1H),1.80–1.72(m,2H),1.42–1.39(m,2H),1.28–1.21(m,4H),0.98(t,J=7.2Hz,3H),0.86(t,J=7.2Hz,3H). 13 C NMR(100MHz,CDCl3)δ173.4,163.1,140.6,136.9,133.4,133.1,132.8,128.4,126.7,114.1,113.3,66.8,64.9,59.5,58.8,53.2,47.3,44.4,41.7,30.5,30.4,19.2,19.0,13.7,13.6.HRMS(ESI)m / z:calcd.for C 26 H 28 BrN3O6H + (M+H) + 558.1235,found 558.1246.

[0045] Example 7

[0046]

[0047] After adding 4-fluoro-2-nitro-substituted dicyanophenyl ethylene (21.7 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphine catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 7 was obtained by column chromatography (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 63%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 8.8, 5.2 Hz, 1H), 7.75 (dd, J = 8.0, 2.4 Hz, 1H), 7.49–7.45 (m, 1H), 6.66 (d, J = 1.6 Hz, 1H), 4.58 (d, J = 6.8 Hz, 1H), 4.28 (t, J = 6.8 Hz, 1H), 4.08–4.02 (m, 1H), 3.93–3.87 (m, 1H), 3.49 (d, J = 14.0 Hz, 1H), 3.03 (d, J = 19.6 Hz, 1H), 2.89 (d, J = 19.6 Hz, 1H), 2.56 (d, J = 13.6 Hz, 1H), 1.76–1.69 (m, 2H), 1.46–1.37 (m, 4H), 1.24–1.19 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 173.5, 163.2 (d, J = 13.3 Hz), 160.5, 150.4, 140.1, 137.1, 131.9 (d, J = 8.2 Hz), 127.3 (d, J = 4.1 Hz), 120.9 (d, J = 21.1 Hz), 114.0 (d, J = 53.3 Hz), 113.1 (d, J = 26.4 Hz), 66.7, 64.9, 59.5, 58.8, 53.1, 47.2, 44.3, 41.8, 30.4, 30.3, 19.2, 19.0, 13.7, 13.6. HRMS (ESI) m / z: calcd. for C 26 H 28 FN3O6H + (M + H) + 498.2040, found 498.2046.

[0048] Example 8

[0049]

[0050] After adding 4-chloro-2-nitro-substituted dicyanophenyl ethylene (23.3 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into a reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphorus catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 8 was obtained by column chromatography (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 64%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 8.4, 2.0 Hz, 1H), 6.66 (dd, J = 4.0, 2.0 Hz, 1H), 4.55 (d, J = 6.8 Hz, 1H), 4.28 (t, J = 6.8 Hz, 3H), 4.09–4.03 (m, 1H), 3.93–3.87 (m, 1H), 3.50 (d, J = 13.6 Hz, 1H), 3.02 (dt, J = 19.6, 2.0 Hz, 2H), 2.89 (dt, J = 19.6, 2.4 Hz, 1H), 2.56 (d, J = 13.6 Hz, 1H), 1.76–1.69 (m, 2H), 1.46–1.37 (m, 4H), 1.24–1.18 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.5, 163.1, 150.1, 140.0, 137.1, 135.6, 133.5, 131.2, 129.6, 125.3, 113.9, 113.4, 66.7, 64.9, 59.3, 58.8, 53.1, 47.3, 44.2, 41.7, 30.4, 30.3, 19.2, 19.0, 13.7, 13.6. HRMS (ESI) m / z: calcd. for C 26 H 28 ClN3O6Na + (M + Na) + 536.1560, found 536.1559.

[0051] Example 9

[0052]

[0053] After adding 4-bromo-2-nitro-substituted dicyanophenyl ethylene (27.8 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphorus catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the solvent of the reaction solution was removed under reduced pressure, and the product 9 was obtained after column chromatography separation (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 68%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.8, 2.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 6.66 (dd, J = 4.0, 2.0 Hz, 1H), 4.53 (d, J = 6.8 Hz, 1H), 4.28 (t, J = 6.8 Hz, 3H), 4.08–4.02 (m, 1H), 3.93–3.87 (m, 1H), 3.50 (d, J = 13.6 Hz, 1H), 3.02 (dt, J = 19.6, 2.0 Hz, 1H), 2.89 (dt, J = 19.6, 2.4 Hz, 1H), 2.55 (d, J = 13.6 Hz, 1H), 1.74–1.69 (m, 2H), 1.44–1.37 (m, 4H), 1.24–1.18 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.5, 163.1, 150.1, 140.0, 137.1, 136.5, 131.4, 130.1, 128.2, 123.1, 113.9, 113.4, 66.7, 65.0, 59.3, 58.8, 53.2, 47.3, 44.2, 41.6, 30.4, 30.3, 19.2, 19.0, 13.7, 13.6. HRMS (ESI) m / z: calcd. for C 26 H 28 BrN3O6H + (M + H) + 558.1235, found 558.1246.

[0054] Example 10

[0055]

[0056] After adding o-nitropiperonal-substituted dicyanophenyl ethylene (24.3 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added. Then, the organophosphine catalyst PPh3 (7.9 mg, 30 mol%) was added, and the mixture was stirred at 25 °C for 12 hours. Then, the solvent was removed under reduced pressure from the reaction solution, and the product 10 was obtained after column chromatography separation (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 73%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.23 (s, 1H), 6.69 (dd, J = 4.0, 2.4 Hz, 1H), 6.17 (s, 2H), 4.71 (d, J = 6.0 Hz, 1H), 4.28 (t, J = 6.8 Hz, 2H), 4.08–4.01 (m, 1H), 3.98–3.92 (m, 1H), 3.41 (d, J = 14.0 Hz, 1H), 3.12 (ddd, J = 19.6, 3.6, 1.2 Hz, 1H), 2.93 (dt, J = 19.6, 2.4 Hz, 1H), 2.60 (d, J = 13.6 Hz, 1H), 1.75–1.70 (m, 2H), 1.47–1.40 (m, 4H), 1.26–1.23 (m, 2H), 0.97 (t, J = 7.2 Hz, 4H), 0.86 (t, J = 7.2 Hz, 4H). 13 C NMR (100 MHz, CDCl3) δ 173.6, 163.2, 152.0, 148.0, 144.1, 140.5, 137.1, 127.8, 114.4, 113.7, 108.3, 106.2, 103.4, 66.7, 64.9, 59.5, 58.8, 53.8, 47.0, 44.3, 41.8, 30.4, 30.6, 27.4, 19.2, 19.0, 13.7. HRMS (ESI) m / z: calcd. for C 27 H 29 N3O8Na + (M + Na) + 546.1848, found 546.1847.

[0057] Example 11

[0058]

[0059] After adding methyl formate-substituted dicyanophenyl ethylene (21.2 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphine catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 11 was obtained after column chromatography separation (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 51%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 1.6 Hz, 1H), 4.53 (d, J = 6.0 Hz, 1H), 4.30–4.23 (m, 2H), 3.93 (s, 3H), 3.84–3.78 (m, 1H), 3.65 (d, J = 7.6 Hz, 1H), 3.55 (d, J = 13.6 Hz, 1H), 2.98 (dt, J = 19.6, 2.0 Hz, 1H), 2.83 (dt, J = 19.6, 2.8 Hz, 1H), 2.43 (d, J = 13.6 Hz, 1H), 1.74–1.69 (m, 2H), 1.47–1.41 (m, 2H), 1.23–1.19 (m, 2H), 1.14–1.09 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.5, 166.5, 163.2, 140.2, 137.5, 130.7, 130.2, 128.4, 114.7, 113.0, 85.2, 66.5, 64.7, 61.4, 59.0, 56.8, 52.2, 46.7, 44.6, 42.7, 30.4, 30.1, 27.4, 19.2, 18.9, 13.7, 13.5. HRMS (ESI) m / z: calcd. for C 28 H 32 N2O6Na + (M+Na) + 515.2153, found 515.2158.

[0060] Example 12

[0061]

[0062] After adding p-methoxy-substituted dicyanophenyl ethylene (18.4 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphorus catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the solvent of the reaction solution was removed under reduced pressure, and the product 12 was obtained after column chromatography separation (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 43%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 2.0 Hz, 1H), 4.45 (d, J = 7.6 Hz, 1H), 4.29–4.22 (m, 2H), 3.98–3.92 (m, 1H), 3.87–3.84 (m, 1H), 3.82 (s, 3H), 3.57 (d, J = 7.6 Hz, 1H), 3.51 (d, J = 13.6 Hz, 1H), 2.98 (dt, J = 19.2, 1.6 Hz, 1H), 2.81 (dt, J = 19.2, 2.4 Hz, 1H), 2.40 (d, J = 13.6 Hz, 1H), 1.73–1.68 (m, 2H), 1.46–1.40 (m, 2H), 1.29–1.25 (m, 2H), 1.17–1.11 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.8, 163.4, 160.0, 140.1, 137.9, 129.4, 127.3, 115.1, 114.2, 113.4, 66.4, 64.7, 61.1, 58.8, 57.1, 55.2, 46.4, 44.7, 43.1, 30.4, 30.2, 19.2, 19.0, 13.7, 13.6. HRMS (ESI) m / z: calcd. for C 27 H 32 N2O5H + (M + H) + 465.2389, found 465.2394.

[0063] Example 13

[0064]

[0065] After adding o-nitro-substituted dicyanophenyl alkene (19.9 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl tert-butyl carbonate (77.4 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphorus catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 hours. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 13 was obtained by column chromatography (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 63%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 8.0, 1.2 Hz, 1H), 7.88 (dd, J = 8.0, 0.8 Hz, 1H), 7.77–7.73 (m, 1H), 7.58–7.53 (m, 1H), 6.56 (dd, J = 4.4, 2.4 Hz, 1H), 4.58 (d, J = 6.4 Hz, 1H), 4.31 (d, J = 6.0 Hz, 1H), 3.43 (d, J = 13.2 Hz, 1H), 2.96 (ddd, J = 19.6, 4.0, 1.6 Hz, 1H), 2.84 (dt, J = 19.6, 2.8 Hz, 1H), 2.52 (d, J = 14.0 Hz, 1H), 1.56 (s, 9H), 1.24 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 172.6, 162.5, 149.8, 139.1, 139.0, 133.4, 131.4, 129.9, 129.5, 125.2, 114.4, 113.6, 83.3, 81.6, 59.7, 58.7, 53.7, 47.4, 44.6, 41.8, 27.9, 27.7. HRMS (ESI) m / z: calcd. for C 26 H 29 N3O6Na + (M+Na) + 502.1949, found 502.1950.

[0066] Example 14

[0067]

[0068] After adding o-nitro-substituted dicyanophenyl alkene (19.9 mg, 0.1 mmol, 1.0 equiv.) and the reaction solvent acetone (1.0 mL) into the reaction tube, Boc-protected allyl benzyl carbonate (87.6 mg, 0.3 mmol, 3.0 equiv.) was added, and then the organophosphorus catalyst PPh3 (7.9 mg, 30 mol%) was added. The mixture was stirred at 25 °C for 12 h. Then the reaction solution was concentrated under reduced pressure to remove the solvent, and the product 14 was obtained by column chromatography (eluent polarity: petroleum ether / dichloromethane / ethyl acetate = 60:40:1). Yield: 81%, >20:1 d.r.; 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.41 (s, 5H), 7.28 (d, J = 2.0 Hz, 2H), 7.11 (dd, J = 5.2, 1.6 Hz, 2H), 6.73 (d, J = 1.6 Hz, 1H), 5.29 (dd, J = 32.4, 12.0 Hz, 2H), 5.08 (d, J = 12.4 Hz, 1H), 4.87 (d, J = 12.4 Hz, 1H), 4.63 (d, J = 6.4 Hz, 1H), 4.35 (d, J = 5.6 Hz, 1H), 3.48 (d, J = 13.6 Hz, 1H), 3.06 (d, J = 19.2 Hz, 1H), 2.91 (dt, J = 19.6, 2.4 Hz, 1H), 2.57 (d, J = 13.6 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 173.2, 162.8, 149.6, 141.0, 136.9, 135.1, 134.7, 133.3, 131.0, 129.7, 129.5, 128.9, 128.9, 128.8, 128.5, 128.3, 128.2, 125.2, 114.2, 113.5, 68.5, 66.7, 59.5, 58.8, 53.5, 47.1, 44.3, 41.8. HRMS (ESI) m / z: calcd. for C 32 H 25 N3O6Na + (M + Na) + 570.1636, found 570.1629.

[0069] Example 15

[0070] Bactericidal activity test

[0071] The concentration of the compound is 100 ppm. Use a hole puncher (5 mm) to take agar slices of the strain, and inoculate them with the mycelium side facing down on the PDA medium containing the compound to be tested, placing them at the center of the circular medium. Three inoculations are made for each sample to be tested. The blank control group is a medium containing the same concentration of DMSO but no compound to be tested. After culturing in a biochemical incubator at 25 °C for 3 to 5 days, measure the diameter of the colonies on the medium. Observe the effect of the sample to be tested on the mycelial growth by comparing with the above blank control group, and calculate the inhibition rate of the sample to be tested on the colony growth at 100 mg / L. Inhibition rate (%) = [(blank control colony diameter - sample to be tested colony diameter) / (blank colony diameter - hole puncher diameter)] × 100%. The following table shows the measurement results of some compounds:

[0072]

[0073] It can be found from the above table that Compound 11 has the best effect, achieving antibacterial effects of 91% and 83% on Penicillium digitatum and Rhizoctonia solani, respectively. Other compounds also have significant antibacterial effects. In the above embodiments of the present application, Compound 2 and 3 are structurally similar to Compound 1; Compounds 5, 6, 7, 8, 9, and 10 are structurally similar to Compound 4; Compound 12 is structurally similar to Compound 11; Compound 13 is structurally similar to Compound 14. Therefore, those skilled in the art can also predict that compounds with similar structures have significant antibacterial effects on Penicillium digitatum and Rhizoctonia solani.

Claims

1. A method for synthesizing a bicycloalkane compound, characterized in that, Using aryl dicyanoethylene and allyl carbonate as reaction raw materials, under the action of an organophosphorus catalyst PPh3, a diquinuclidine compound shown in formula (III) is obtained in a reaction solvent; the reaction process is as shown in reaction formula a: ； Among them, aryl dicyanoethylene R 1 is selected from 2-nitro, 4-nitro, 5-fluoro-2-nitro, 5-chloro-2-nitro, 5-bromo-2-nitro, 4-fluoro-2-nitro, 4-chloro-2-nitro, 4-bromo-2-nitro, 4-methyl formate group; R 2 is selected from ethyl, isopropyl, n-butyl, tert-butyl, benzyl, cyclohexyl.

2. The synthesis method according to claim 1, wherein The reaction solvent is selected from any one of dichloromethane, dichloroethane, chloroform, toluene, acetonitrile, and acetone.

3. The synthesis method according to claim 1, wherein In the reaction, the molar ratio of the raw material aryl dicyanoethylene to allyl carbonate is 1:2 - 3.

4. A bicycloalkane compound prepared by the synthesis method according to claim 1, characterized in that, Its structure is as shown in (III): Among them, aryl dicyanoethylene R 1 is selected from 2-nitro, 4-nitro, 5-fluoro-2-nitro, 5-chloro-2-nitro, 5-bromo-2-nitro, 4-fluoro-2-nitro, 4-chloro-2-nitro, 4-bromo-2-nitro, 4-methoxycarbonyl; R 2 is selected from ethyl, isopropyl, n-butyl, tert-butyl, benzyl, cyclohexyl.

5. Use of the diquinuclidine compound according to claim 4 in the preparation of a medicament against Penicillium digitatum and / or Rhizoctonia solani.

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