Cyclohexadiene derivative as well as preparation method and application thereof
The synthesis of chiral 1-cyano-3-chloro-5-nitro-6-amino-1,5-cyclohexadiene derivatives via allylic Macaddition-cyclization reaction solves the synthesis challenge of multifunctional six-membered carbon ring compounds, enabling efficient, green, and environmentally friendly industrial production, and demonstrating significant antibacterial activity.
Patent Information
- Application Number
- CN202410645994.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-05-22
- Publication Date
- 2025-11-25
AI Technical Summary
Existing technologies are difficult to synthesize efficiently from six-membered carbon ring compounds with multiple functional groups, especially cyclohexadiene derivatives, and lack applications in antibacterial activity.
A chiral 1-acrylonitrile-3-chloro-5-nitro-6-amino-1,5-cyclohexadiene derivative was synthesized in toluene solvent via an allyl Mac addition-cyclization reaction using 2-(2-chloro-1-phenyleneethyl)malonitrile and nitrostyrene under the catalysis of chiral catalyst VIII.
The synthesis of cyclohexadiene derivatives with high purity (over 97%) and high yield was achieved, making it suitable for industrial production. The products also showed significant inhibitory effects on Bacillus subtilis.
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Figure CN121005637A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic chemistry, and particularly relates to a cyclohexadiene derivative and a preparation method and application thereof. BACKGROUND
[0002] Six-membered carbocyclic rings are widely present in natural products and drugs, such as prostaglandin synthesis inhibitor Sulindac (trade name Clinoril) [1. Felts A S, Siegel B S, Young S M, et al.. Journal of Medicinal Chemistry, 2008, 51(16): 4911. 2. Walters M J, Blobaum A L, Kingsley P J, et al.. Bioorganic & Medicinal Chemistry Letters, 2009, 19(12): 3271.] and natural product resveratrol dimerization with anticancer and hypotensive activity [3. Walters M J, Blobaum A L, Kingsley P J, et al. Bioorganic & Medicinal Chemistry Letters, 2009, 19(12): 3271. 4. Jeffrey JL, Sarpong R.. Tetrahedron Letters, 2009, 50(17): 1969. 5. Muthusamy S, Sivaguru M.. Organic Letters, 2014, 16(16): 4248.], and the like, which are compounds with indene as a skeleton and contain six-membered carbocyclic ring skeletons. For example, the mononuclear small molecules piperitol, camphor and borneol, which are widely present in plants and are converted from isoprene terpenoids, also have six-membered carbocyclic ring skeletons, as shown below:
[0003]
[0004] Therefore, it has been a research focus for organic chemists and pharmacologists to synthesize six-membered carbocyclic compounds, especially six-membered carbocyclic compounds with multiple functional groups, such as cyclohexadiene derivatives. SUMMARY
[0005] In view of this, the application provides a cyclohexadiene derivative and a preparation method and application thereof, and the main purpose is to synthesize a cyclohexadiene derivative by a new method and to study the application thereof in antibacterial activity.
[0006] In one aspect, the present application provides a cyclohexadiene derivative, which is a chiral 1-nitrile-3-chloro-5-nitro-6-amino-1, 5-cyclohexadiene derivative, and its chemical structural formula is as follows:
[0007]
[0008] wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl or methoxy; and / or, R 2 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl or methoxy.
[0009] In a second aspect, the present application provides a preparation method of the above-mentioned cyclohexadiene derivative, comprising the following steps:
[0010] The starting material containing a 2-(2-chloro-1-phenylethylene) malononitrile derivative and a nitrostyrene derivative is subjected to an allylic Michael addition-cyclization reaction under the condition of an organic solvent and a chiral catalyst to obtain the cyclohexadiene derivative.
[0011] The reaction formula is as follows:
[0012]
[0013] The advantages of the synthesis method of the present application mainly lie in that: starting from a simple and readily available 2-(2-chloro-1-phenylethylene) malononitrile derivative (I), a chiral 1-nitrile-3-chloro-5-nitro-6-amino-1, 5-cyclohexadiene derivative (III) is prepared through an allylic Michael addition-cyclization reaction under the catalysis of a chiral catalyst VIII and by selecting toluene as a reaction solvent, and the purity of the product is more than 97%. The synthesis method of the present application has the advantages of simple operation steps, preparation by one-pot method, cheap and readily available raw materials, green and mild reaction conditions, simple post-treatment and high yield, etc. The reaction conditions of the present application can also be applied to mass production, and are suitable for industrialized production of the chiral 1-nitrile-3-chloro-5-nitro-6-amino-1, 5-cyclohexadiene derivative (III), thus having high implementation value and potential social and economic benefits.
[0014] Alternatively, the synthesis method of the present application uses a 2-(2-chloro-1-phenylethylene) malononitrile derivative (I) and a nitrostyrene (II) as starting materials, and a chiral catalyst is used for reaction in an organic solvent for 5 days to obtain a chiral 1-nitrile-3-chloro-5-nitro-6-amino-1, 5-cyclohexadiene derivative (III) with antibacterial activity through an allylic Michael addition-cyclization reaction.
[0015] Optionally, the molar ratio of the 2-(2-chloro-1-phenylethylene) propanedinitrile derivative and the nitrostyrene derivative is 1:(1-2); preferably the molar ratio of the two is 1:(1.2-1.8); further preferably the molar ratio of the two is 1:(1.3-1.7); further preferably the molar ratio of the two is 1:(1.4-1.6); further preferably the molar ratio of the two is 1:1.5.
[0016] Optionally, the temperature of the reaction is -55℃ to -65℃, and the reaction time is 4-6 days. Preferably, the reaction temperature is -58℃ to -62℃, and preferably the reaction temperature is -60℃; and the reaction time is preferably 5 days.
[0017] Optionally, the chemical structure of the 2-(2-chloro-1-phenylethylene) propanedinitrile derivative is:
[0018]
[0019] wherein R is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl or methoxy. 1
[0020] Optionally, the chemical structure of the nitrostyrene derivative is:
[0021]
[0022] wherein R is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl or methoxy. 2
[0023] Optionally, the chiral catalyst is selected from chiral thiourea VIII, which has the chemical structure:
[0024]
[0025] Preferably, the organic solvent is selected from toluene.
[0026] Optionally, the preparation method further comprises a process of separating and purifying the reaction product; the process of separating and purifying comprises: using a mixed solution of petroleum ether and ethyl acetate to perform column chromatography on the reaction product; and the volume ratio of the petroleum ether to the ethyl acetate is 8-4:1.
[0027] In a third aspect, the present application provides an application of the cyclohexadiene derivative or the cyclohexadiene derivative prepared by the above method in an antibacterial agent.
[0028] In a fourth aspect, the present application provides an antibacterial agent, which comprises the above cyclohexadiene derivative or the cyclohexadiene derivative prepared by the above method.
[0029] Optionally, the cyclohexadiene derivative has an inhibitory effect on Bacillus subtilis.
[0030] Compared with the prior art, the present application has the following beneficial effects:
[0031] (1) The synthetic method of the present application has simple operation steps, i.e. prepared by one-pot method, raw materials are cheap and easy to obtain, reaction conditions are green and mild, post-treatment is simple and the yield is high, and the purity of the product reaches more than 97%. The reaction conditions of the present application can also be applied to mass production, and are suitable for industrialized production of chiral 1-nitrile-3-chloro-5-nitro-6-amino-1, 5-cyclohexadiene derivatives, thus having high implementation value and potential social and economic benefits.
[0032] (2) The chiral 1-nitrile-3-chloro-5-nitro-6-amino-1, 5-cyclohexadiene derivative prepared by the present application has antibacterial effect, especially good inhibitory effect on Bacillus subtilis. BRIEF DESCRIPTION OF DRAWINGS
[0033] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of compound 4aa synthesized in Example 1 of the present application;
[0034] Figure 2 is the nuclear magnetic resonance carbon spectrum of compound 4aa synthesized in Example 1 of the present application;
[0035] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of compound 4ab synthesized in Example 2 of the present application;
[0036] Figure 4 is the nuclear magnetic resonance carbon spectrum of compound 4ab synthesized in Example 2 of the present application;
[0037] Figure 5 is the nuclear magnetic resonance hydrogen spectrum of compound 4ac synthesized in Example 3 of the present application;
[0038] Figure 6 is the nuclear magnetic resonance carbon spectrum of compound 4ac synthesized in Example 3 of the present application. DETAILED DESCRIPTION
[0039] The present application will be further described below in combination with specific examples. The following description is only a few examples of the present application, and does not limit the present application in any form. Although the present application is disclosed as follows with preferred examples, it is not intended to limit the present application, and any skilled person in the art can make some changes or modifications to the disclosed technical content without departing from the scope of the technical solution of the present application, which are equivalent to equivalent examples, and are within the scope of the technical solution.
[0040] Unless otherwise specified, the raw materials in the examples of the present application are purchased through commercial channels and directly used without any special treatment.
[0041] The detection instrument used in the embodiments of the present application is as follows:
[0042] Nuclear magnetic detection instrument: Bruker Avance 400 or 600 type nuclear magnetic resonance spectrometer (DMSO or CDCl3 as solvent, TMS as reference substance).
[0043] Mass spectrometer: German Bruker high-resolution mass spectrometer (BioTOF III Q).
[0044] Example 1
[0045] 2-(2-chloro-1-phenylethylene) malononitrile (0.20 mmol), nitrostyrene (0.30 mmol) and chiral thiourea VIII (0.04 mmol) were dissolved in toluene (1.0 mL), stirred at -60 for 5 days, TLC tracking to complete reaction of raw materials, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which is shown in formula 4aa.
[0046]
[0047] The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain pure product 4aa; the yield was 67%. The structure of the product was identified by nuclear magnetic resonance and high-resolution mass spectrometry, 1 H NMR (400 MHz, CDCl3) δ 9.65 (s, 1H), 7.54-7.47 (m, 2H), 7.47-7.41 (m, 3H), 7.41-7.29 (m, 6H), 7.24-7.18 (m, 2H), 6.23 (s, 1H), 5.05 (d, J = 1.7 Hz, 1H), 4.99 (d, J = 1.9 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 160.6, 144.1, 135.9, 134.4, 132.3, 129.6 (s), 129.4, 128.7, 127.8, 127.2, 117.2, 114.1, 106.9, 59.8, 47.4. ESI-HRMS: calcd. For C 19 H 14 ClN3O2+H 352.0847found 352.0851,[α] 20 D = -53 (c 0.6, CH2Cl2), ee = 85%, dr > 99:1; the enantiomeric excess was determined by high performance liquid chromatography, the column was chiral AD column, the mobile phase was 15 isopropanol / n-hexane, the flow rate was 1 milliliter / minute, t major = 16.466 min, t minor= 11.352 min. indicating that the chiral 1-nitrile-3-chloro-5-nitro-6-amino-1,5- cyclohexadiene derivative obtained has the structure shown in formula 4aa.
[0048] Example 2
[0049] The 2-(2-chloro-1-phenylethylene)propanedinitrile (0.20 mmol), 4-methyl nitrostyrene (0.30 mmol) and chiral thiourea VIII (0.04 mmol) were dissolved in toluene (1.0 mL) and stirred at -60 for 5 days, TLC tracking until the starting material was completely consumed, the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, which has the structure shown in formula 4ab.
[0050]
[0051] The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain the pure product 4ab, with a yield of 65%, the structure of the product was identified by nuclear magnetic resonance and high resolution mass spectrometry, 1 H NMR (600 MHz, CDC13) δ 9.64 (s, 1H), 7.50 (dd, J = 4.9, 3.7 Hz, 1H), 7.44 (dd, J = 10.5, 4.9 Hz, 2H), 7.39 (dd, J = 5.3, 3.5 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 6.22 (s, 1H), 5.01 (d, J = 1.6 Hz, 1H), 4.97 (d, J = 1.9 Hz, 1H), 2.31 (s, 3H). 13 C NMR (151 MHz, CDC13) δ 160.6, 144.1, 138.5, 134.5, 132.7, 132.2, 130.2, 129.4, 127.8, 127.1, 117.4, 114.2, 106.9, 59.9, 47.1, 21.2. ESI-HRMS: calcd. For C 20 H 16 ClN3O2+H 366.1004 found 366.1009, [a] 20 D = -110 (c 0.8, CH2CI2), ee = 90%, dr > 99: 1; enantiomeric excess was determined by high performance liquid chromatography, column Chiral AD, mobile phase 15 isopropanol / n-hexane, flow rate 1 ml / min, t major = 17.670 min, t minor= 10.050 min. indicating that the chiral 1-nitrile-3-chloro-5-nitro-6-amino-1,5- cyclohexadiene derivative obtained has the structure shown in formula 4ab.
[0052] Example 3
[0053] The 2-(2-chloro-1-phenylethylene)propanedinitrile (0.20 mmol), 4-chloronitrostyrene (0.30 mmol) and chiral thiourea VIII (0.04 mmol) were dissolved in toluene (1.0 mL) and stirred at -60 °C for 5 days, TLC tracking until the starting material was completely consumed, the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product, which has the structure shown in formula 4ac.
[0054]
[0055] The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain the pure product 4ac, with a yield of 62%, the structure of the product was identified by nuclear magnetic resonance and high resolution mass spectrometry, 1 H NMR (600 MHz, CDC13) δ 9.64 (s, 1H), 7.56-7.51 (m, 1H), 7.46 (dd, J = 10.5, 4.9 Hz, 2H), 7.43-7.39 (m, 2H), 7.35-7.30 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.26 (s, 1H), 5.01 (d, J = 1.7 Hz, 1H), 4.94 (d, J = 1.9 Hz, 1H). 13 C NMR (151 MHz, CDC13) δ 160.4, 144.1, 134.7, 134.5, 134.2, 132.5, 129.8, 129.5, 128.6, 127.8, 116.8, 114.0, 106.8, 59.5, 46.9. ESI-HRMS: calcd. For C 19 H 13 Cl2N3O2+H 386.0458 found 386.0467, [a] 20 D = -76 (c 0.8, CH2CI2), ee = 86%, dr > 99: 1; enantiomeric excess was determined by high performance liquid chromatography, column chiral AD, mobile phase 15 isopropanol / n-hexane, flow rate 1 ml / min, t major = 18.316 min, t minor = 12.229 min. indicating that the chiral 1-nitrile-3-chloro-5-nitro-6-amino-1,5- cyclohexadiene derivative obtained has the structure shown in formula 4ac.
[0056] Example 4
[0057] To a solution of 2-(2-chloro-l-(4-methoxyphenylethylidene)) propanedinitrile (0.20 mmol), nitrostyrene (0.30 mmol) and chiral thiourea VIII (0.04 mmol) in toluene (1.0 mL) was stirred at room temperature (-60) for 5 days, TLC tracking until the starting material was consumed, the solvent was removed by rotary evaporation under reduced pressure to give the crude product, which was shown to have the structure of formula 4ad.
[0058]
[0059] The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 8: 1) to give the pure product 4ad in 40% yield. The structure of the product was identified by NMR and high resolution mass spectrometry, 1 H NMR (600 MHz, CDC13) δ 9.71 (s, 1H), 7.51-7.47 (m, 2H), 7.34-7.27 (m, 3H), 7.19 (d, J = 7.2 Hz, 2H), 6.96-6.92 (m, 2H), 6.23 (s, 1H), 5.03 (d, J = 1.8 Hz, 1H), 5.01 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H). 13 C NMR (151 MHz, CDC13) δ 163.1, 159.8, 144.8, 135.9, 129.9, 129.4, 128.5, 127.1, 126.3, 116.8, 114.8, 77.0, 59.6, 55.6, 47.3. ESI-HRMS: calcd. For C 19 H 14 ClN3O2+H 382.0953found 382.0962, [a] 20 D = -94 (c 0.8, CH2CI2), ee = 68%, dr > 99: 1; enantiomeric excess was determined by high performance liquid chromatography, column Chiral AD, mobile phase 15 isopropanol / n-hexane, flow rate 1 ml / min, t major = 29.631 min, t minor = 17.392 min. The chiral l-nitrile-3-chloro-5-nitro-6-amino-l,5-cyclohexadiene derivative obtained was shown to have the structure of formula 4ad.
[0060] Example 5
[0061] To a solution of 2-(2-chloro-l-(3-chlorophenylethylidene))propanedinitrile (0.20 mmol), nitrostyrene (0.30 mmol) and chiral thiourea VIII (0.04 mmol) in toluene (1.0 mL) was stirred at room temperature (-60) for 5 days, TLC tracking until the starting material was consumed, the solvent was removed by rotary evaporation under reduced pressure to give the crude product, which was identified as structure 4ae.
[0062]
[0063] The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 8: 1) to give the pure product 4ae in 53% yield. The structure of the product was identified by NMR and high resolution mass spectrometry, 1 H NMR (600 MHz, CDC13) δ 9.60 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.41-7.34 (m, 3H), 7.34-7.30 (m, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.2 Hz, 2H), 6.18 (s, 1H), 5.05 (s, 1H), 4.92 (d, J = 1.4 Hz, 1H). 13 C NMR (151 MHz, CDC13) δ 158.62, 143.32, 135.92, 135.43, 132.02, 130.61, 129.55, 128.75, 127.45, 127.00, 125.81, 117.21, 113.48, 107.90, 59.53, 47.22. ESI-HRMS: calcd. For C 19 H 13 Cl2N3O2+H 386.0458 found 386.0463, [a] 20 D = -126 (c 0.7, CH2CI2), ee = 76%, dr > 99: 1; enantiomeric excess was determined by high performance liquid chromatography, column Chiral AD, mobile phase 15 isopropanol / n-hexane, flow rate 1 ml / min, t major = 21.374 min, t minor = 16.798 min. The chiral 1-nitrile-3-chloro-5-nitro-6-amino-1,5-cyclohexadiene derivative obtained was identified as structure 4ae.
[0064] Example 6
[0065] To a solution of 2-(2-chloro-l-(4-fluorophenylethylidene))propanedinitrile (0.20 mmol), nitrostyrene (0.30 mmol) and chiral thiourea VIII (0.04 mmol) in toluene (1.0 mL) was stirred at room temperature (-60) for 5 days, TLC tracking until the raw material was completely reacted, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, which had a structure as shown in formula 4af.
[0066]
[0067] The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain pure product 4af with a yield of 57%. The structure of the product was identified by nuclear magnetic resonance and high resolution mass spectrometry 1 H NMR (600 MHz, CDC13) δ 9.63 (s, 1H), 7.41 (dt, J = 16.2, 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.33-7.28 (m, 1H), 7.19 (d, J = 7.2 Hz, 2H), 7.14 (t, J = 8.5 Hz, 2H), 6.18 (s, 1H), 5.04 (s, 1H), 4.94 (d, J = 1.7 Hz, 1H). 13 C NMR (151 MHz, CDC13) δ 165.7, 164.1, 159.3, 143.9, 135.7, 130.5, 130.2 (d, J = 9.1 Hz), 129.6, 128.8, 127.2, 117.2, 116.9, 116.8, 114.1, 106.9, 59.9, 47.4. ESI-HRMS: calcd. For C 19 H 13 ClFN302+H 370.0753 found 370.0758, [a] 20 D = -31 (c 0.4, CH2Cl2), ee = 87%, dr > 99: 1; enantiomeric excess was determined by high performance liquid chromatography, column chiral AD, mobile phase 15 isopropanol / n-hexane, flow rate 1 ml / min, t major = 19.712 min, t minor = 10.751 min. The chiral 1-nitrile-3-chloro-5-nitro-6-amino-1,5-cyclohexadiene derivative obtained had a structure as shown in formula 4af.
[0068] Example 7 Bacteriostatic test
[0069] 1. Experimental strain: The bacteriostatic circle method was used to determine the antibacterial activity of the compound, and filter paper method was used to test Bacillus subtilis (ATCC 6633).
[0070] 2. Bacterial solution preparation: the bacterial strain was cultured in a liquid broth medium (10 g of proteose peptone, 3 g of beef extract, 5 g of sodium chloride, 1 L of distilled water, pH 7.2-7.4) at 37, 180 r / min for 12 h, and then 200 μL of bacterial suspension (1 x 108cfu / mL) was taken by a sterile pipette and spread on a solid broth medium (10 g of proteose peptone, 3 g of beef extract, 5 g of sodium chloride, 1 L of distilled water, 15 g of agar powder, pH 7.2-7.4), and left still for 5 min. 2 μL of the tested compound was taken and pressed on a filter paper sheet, which was then placed on a plate and left in a constant temperature incubator at 37 for 15 h.
[0071] 3. Preparation of a drug solution: the tested compound was dissolved in imported DMSO to prepare a solution with a concentration of 50 μg / μL.
[0072] 4. Detection: the diameter of the inhibition circle was measured by a vernier caliper, and compared with the negative and positive control groups. Each sample was tested in triplicate, and the average value was taken.
[0073] 5. Results: the experimental results proved that the chiral 1-nitrile-3-chloro-5-nitro-6-amino-1, 5-cyclohexadiene derivative had certain inhibitory effect on Bacillus subtilis. The antibacterial performance of the compound against Bacillus subtilis is shown in Table 1:
[0074] Table 1: antibacterial activity of cyclohexadiene derivatives against Bacillus subtilis
[0075]
[0076] As shown in Table 1, all the tested cyclohexadiene compounds prepared in Examples 1-6 of the present application had activity against Bacillus subtilis; among them, 4af, 4ac and 4ae had relatively strong activity.
[0077] The above is only a few embodiments of the present application, and does not limit the present application in any form. Although the present application is disclosed with preferred embodiments, it is not intended to limit the present application. Any skilled person in the art can make some changes or modifications to the above disclosed technical content without departing from the scope of the technical solution of the present application, and such changes or modifications are equivalent to equivalent embodiments, and are within the scope of the technical solution.
Claims
1. A cyclohexadiene derivative, characterized by, The cyclohexadiene derivative is a chiral 1-nitrile-3-chloro-5-nitro-6-amino-1,5-cyclohexadiene derivative, and its chemical structural formula is: wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl or methoxy; and / or, R 2 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl or methoxy.
2. The method for preparing a cyclohexadiene derivative according to claim 1, characterized in that, The preparation method comprises the following steps: The raw material containing the 2-(2-chloro-1-phenylethylene) propanedinitrile derivative and the nitrostyrene derivative is subjected to allylic Michael addition-cyclization reaction in the presence of an organic solvent and a chiral catalyst to obtain the cyclohexadiene derivative.
3. The method for preparing a cyclohexadiene derivative according to claim 2, characterized in that, The molar ratio of the 2-(2-chloro-1-phenylethylene) propanedinitrile derivative to the nitrostyrene derivative is 1:(1-2); Preferably, the molar ratio of the 2-(2-chloro-1-phenylethylene) propanedinitrile derivative to the nitrostyrene derivative is 1:(1.4-1.6); Preferably, the molar ratio of the 2-(2-chloro-1-phenylethylene) propanedinitrile derivative to the nitrostyrene derivative is 1:1.
5.
4. The method for preparing a cyclohexadiene derivative according to claim 2, characterized in that, The reaction temperature is -55 to -65 DEG C, and the reaction time is 4 to 6 days; Preferably, the reaction temperature is -58 to -62 DEG C, and the reaction time is 4 to 5 days; Preferably, the reaction temperature is -60 DEG C, and the reaction time is 5 days.
5. The method for preparing a cyclohexadiene derivative according to claim 2, characterized in that, The chemical structural formula of the 2-(2-chloro-1-phenylethylene) propanedinitrile derivative is: wherein R 1 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl or methoxy.
6. The method for preparing a cyclohexadiene derivative according to claim 2, characterized in that, The chemical structural formula of the nitrostyrene derivative is: wherein R 2 is selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl or methoxy.
7. The method for preparing a cyclohexadiene derivative according to claim 2, characterized in that, The chiral catalyst is selected from a chiral thiourea VIII, and its chemical structural formula is: Preferably, the organic solvent is selected from toluene.
8. The method for preparing a cyclohexadiene derivative according to claim 2, characterized in that, The preparation method further comprises a process of separating and purifying the reaction product; The process of separating and purifying the reaction product comprises: subjecting the reaction product to column chromatography by using a mixed solution of petroleum ether and ethyl acetate; and the volume ratio of the petroleum ether to the ethyl acetate is 8-4:
1.
9. The cyclohexadiene derivative of claim 1 or the cyclohexadiene derivative prepared by the preparation method of any one of claims 2-8 is applied to a Bacillus subtilis antibacterial agent.
10. A Bacillus subtilis antibacterial agent, characterized in that, The antibacterial agent comprises the cyclohexadiene derivative of claim 1 or the cyclohexadiene derivative prepared by the preparation method of any one of claims 2-8.