A pyrazole benzophenone compound and its preparation method and application

Abstract

The present invention belongs to the technical field of chemical synthesis and blue algae growth inhibition, and specifically relates to a pyrazole benzophenone compound and its preparation method and application. The structure of the pyrazole benzophenone compound is shown in Formula I; wherein R 1 is selected from one of hydrogen, halogen and C1-C4 alkyl; R 2 The pyrazole benzophenone compound proposed in the present invention is a new compound, which has a good inhibitory effect on the growth of cyanobacteria. 50 The concentration is 0.61μM~2.01μM, which can provide a new method for the treatment of cyanobacteria. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and blue algae growth inhibition, and specifically relates to a pyrazole benzophenone compound and a preparation method and application thereof. Background Art

[0002] Blue algae bloom refers to the phenomenon that phytoplankton represented by blue algae rapidly proliferates in a short period of time due to eutrophication and ecological imbalance caused by the discharge of industrial, agricultural and domestic sewage. The rapid proliferation of blue algae not only squeezes out the growth needs of other organisms, but also produces and releases a variety of algae toxins (algae toxins are strong carcinogens that can cause liver cancer, are very toxic and pose a great threat), which poses a severe challenge to drinking water safety and causes great damage to the ecological environment and the development of the aquaculture industry.

[0003] Therefore, how to control cyanobacteria has become an urgent problem to be solved. Microcystis aeruginosa FACHB905 is a representative one among cyanobacteria. Summary of the invention

[0004] The purpose of the present invention is to solve the deficiencies of the prior art and provide a pyrazole benzophenone compound and a preparation method and application thereof, specifically adopting the following technical scheme:

[0005] A pyrazole benzophenone compound, characterized in that its structure is as shown in Formula I:

[0006]

[0007] Among them, R 1 is selected from one of hydrogen, halogen and C1-C4 alkyl; R 2 Selected from fluorine or bromine.

[0008] Preferably, the pyrazole benzophenone compound is one of the following compounds:

[0009]

[0010] The present invention also provides a method for preparing the above-mentioned pyrazole benzophenone compounds, and the synthetic route thereof is as follows:

[0011]

[0012] Preferably, the specific process of the above preparation method is: mixing the compound represented by formula II with potassium carbonate in acetonitrile, heating to reflux, and monitoring by TLC until the reaction is completed. Further preferably, after the reaction is completed, standing for 10h-14h (preferably 12h or overnight), vacuum rotary evaporation, adding ethyl acetate to shake, suction filtration, washing with ethyl acetate, vacuum rotary evaporation of the filtrate, and column chromatography (preferably using PE / EtOAc) to separate the pyrazole benzophenone compound.

[0013] The present invention also provides a blue algae growth inhibitor, the components of which include the above-mentioned pyrazolylbenzophenone compounds.

[0014] The beneficial effects of the present invention are as follows: the pyrazole benzophenone compound proposed in the present invention is a new compound, which has a good inhibitory effect on the growth of cyanobacteria including Microcystis aeruginosa FACHB905, EC 50 It is 0.61μM~2.01μM, which can provide a new means for the control of cyanobacteria. DETAILED DESCRIPTION

[0015] The following will provide a clear and complete description of the concept and technical effects of the present invention in conjunction with the embodiments, so as to fully understand the purpose, scheme and effects of the present invention.

[0016] The present invention provides a series of pyrazole benzophenone compounds, the general structural formula of which is shown in Formula I:

[0017]

[0018] Among them, R 1 is selected from one of hydrogen, halogen and C1-C4 alkyl; R 2 Selected from fluorine or bromine.

[0019] It can be obtained by using N'-chromone hydrazone compounds as raw materials, acetonitrile as solvent, and potassium carbonate as catalyst to undergo a ring-opening reaction. The synthesis route is as follows:

[0020]

[0021] A series of pyrazole benzophenone compounds are shown in Table 1. The synthesis of N'-chromone hydrazone compounds corresponding to the compounds in Table 1 is shown in Table 2.

[0022] Table 1

[0023]

[0024]

[0025] Table 2

[0026] No Ⅱ-1 Ⅱ-2 Ⅱ-3 Ⅱ-4 Ⅱ-5 Ⅱ-6 Ⅱ-7 <![CDATA[R 1 ]]> H Me Et i-Pr i-Pr t-Bu t-Bu <![CDATA[R 2 ]]> 3-Br 3-Br 3-Br 4-F 4-Br 4-F 4-Br No Ⅱ-8 Ⅱ-9 Ⅱ-10 Ⅱ-11 Ⅱ-12 Ⅱ-13 Ⅱ-14 <![CDATA[R 1 ]]> t-Bu F F Cl Cl Cl Br <![CDATA[R 2 ]]> 3-Br 4-F 4-Br 4-F 4-Br 3-Br 4-F

[0027] Embodiment 1:

[0028] (1) Preparation of compound I-1 ((1-(3-bromophenyl)-1H-pyrazole-4-)(2-hydroxyphenyl)methanone), the structure of which is shown below:

[0029]

[0030] The specific preparation process is as follows:

[0031] Dissolve 0.1212g (0.35mmol) of compound II-1 and 0.0979g (0.7mmol) of potassium carbonate in acetonitrile and heat under reflux for 10h. Monitor by TLC until the reaction is complete, let stand overnight, evaporate under reduced pressure, add EtOAc to shake, filter, and wash the filter cake with ethyl acetate several times. Take the filtrate, evaporate under reduced pressure, and separate the target product by PE / EtOAc column chromatography.

[0032] The obtained pure product is a reddish brown solid with a yield of 54% and a melting point of 132-137°C. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ11.97(s,1H),8.46(s,1H),8.18(s,1H),7.89(d,J=8.0Hz,1H ), 7.64 (s, 4H), 7.53 (t, J = 7.8Hz, 1H), 7.07 (d, J = 8.4Hz, 1H), 6.98 (t, J = 7.6Hz, 1H). MS(EI)m / z:343.00(M+H) + .Anal.calcd for C 16 H 11 BrN2O2:C,56.00;H,3.23;N,8.16. Found C,56.05;H,3.17;N,8.11.

[0033] Compounds I-2 to I-14 were prepared by a method similar to that of compound I-1, and their specific characterization data and structures are as follows:

[0034] (2) The structure of compound I-2 ((1-(3-bromophenyl)-1H-pyrazole-4-)(2-hydroxy-5-methylphenyl)methanone) is shown below:

[0035]

[0036] The obtained pure product is a brown solid with a yield of 20% and a melting point of 128-133°C. The test results are as follows: 1 H NMR(400MHz,DMSO)δ11.76(s,1H),8.46(s,1H),8.17(s,1H),7.98(s,1H),7.72-7.64(m,2H ), 7.53 (d, J = 8.1Hz, 1H), 7.38 (dd, J = 18.2, 8.9Hz, 2H), 6.98 (d, J = 8.5Hz, 1H), 2.35 (s, 3H). MS(EI)m / z:357.02(M+H) +.Anal.calcd for C 17 H 13 BrN2O2:C,57.16;H,3.67;N,7.84. Found C,57.09;H,3.61;N,7.90.

[0037] (3) The structure of compound I-3 ((1-(3-bromophenyl)-1H-pyrazole-4-)(2-hydroxy-5-ethylphenyl)methanone) is shown below:

[0038]

[0039] The obtained pure product is a yellow powder with a yield of 20% and a melting point of 127-132°C. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ11.76(s,1H),8.47(s,1H),8.17(s,1H),7.98(s,1H),7.68(s,2H),7. 53(d,J=7.0Hz,1H),7.39(s,2H),7.01(d,J=8.3Hz,1H),2.65(d,J=7.2Hz,2H),1.67(s,3H). MS(EI)m / z:371.03(M+H) + .Anal.calcd for C 18 H 15 BrN2O2:C,58.24;H,4.07;N,7.55. Found C,58.29;H,4.16;N,7.50.

[0040] (4) The structure of compound I-4 ((1-(4-fluorophenyl)-1H-pyrazole-4-)(2-hydroxy-5-isopropylphenyl)methanone) is shown below:

[0041]

[0042] The obtained pure product is a yellow-brown powder with a yield of 45% and a melting point of 124-129°C. The test results are as follows: 1 H NMR (400MHz, DMSO) δ8.52(s,1H),8.16(s,1H),7.77(dd,J=8.1,4.1Hz,2H),7.60(d,J=8.7Hz ,1H),7.47(d,J=8.6Hz,1H),7.23(t,J=8.4Hz,3H),3.12-2.99(m,1H),1.32(d,J=6.8Hz,6H). MS(EI)m / z:325.13(M+H) + .Anal.calcd for C19 H 17 FN2O2:C,70.36;H,5.28;N,8.64. Found C,70.40;H,5.31;N,8.67.

[0043] (5) The structure of compound I-5 ((1-(4-bromophenyl)-1H-pyrazole-4-)(2-hydroxy-5-isopropylphenyl)methanone) is shown below:

[0044]

[0045] The obtained pure product is a yellow powder with a yield of 19% and a melting point of 122-132°C. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ11.76(s,1H),8.47(s,1H),8.15(s,1H),7.72(d,J=1.9Hz,1H),7.65(s,4H),7. 42(dd,J=8.5,2.0Hz,1H),7.01(d,J=8.6Hz,1H),2.91(dt,J=14.0,7.1Hz,1H),1.26(d,J=6.9Hz,6H). MS(EI)m / z:385.05(M+H) + .Anal.calcd forC 19 H 17 BrN2O2:C,59.23;H,4.45;N,7.27. Found C,59.21;H,4.49;N,7.30.

[0046] (6) The structure of compound I-6 ((1-(4-fluorophenyl)-1H-pyrazole-4-)(2-hydroxy-5-tert-butylphenyl)methanone) is shown below:

[0047]

[0048] The obtained pure product is a yellow solid with a yield of 43% and a melting point of 126-130°C. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ11.79(s,1H),8.45(s,1H),8.15(s,1H),7.90(d,J=2.4Hz,1H),7.73(dd,J=9.0 ,4.6Hz,2H),7.60(dd,J=8.7,2.4Hz,1H),7.22(t,J=8.5Hz,2H),7.02(d,J=8.8Hz,1H),1.34(s,9H). MS(EI)m / z:339.14(M+H) +.Anal.calcd for C 20 H 19 FN2O2:C,70.99;H,5.66;N,8.28. Found C,70.91;H,5.60;N,8.36.

[0049] (7) The structure of compound I-7 ((1-(4-bromophenyl)-1H-pyrazole-4-)(2-hydroxy-5-tert-butylphenyl)methanone) is shown below:

[0050]

[0051] The obtained pure product is a yellow-brown solid with a yield of 34% and a melting point of 124-127°C. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ11.75(s,1H),8.49(s,1H),8.16(s,1H),7.99(t,J=1.9Hz,1H),7.88(d,J=2.4Hz,1H),7.70-7.66 (m,1H),7.60(dd,J=8.8,2.4Hz,1H),7.53(d,J=8.0Hz,1H),7.39(t,J=8.1Hz,1H),7.02(d,J=8.8Hz,1H),1.35(s,9H). MS(EI)m / z:399.06(M+H) + .Anal.calcdfor C 20 H 19 BrN2O2:C,60.16;H,4.80;N,7.02. Found C,60.14;H,4.71;N,7.09.

[0052] (8) The structure of compound I-8 ((1-(3-bromophenyl)-1H-pyrazole-4-)(2-hydroxy-5-tert-butylphenyl)methanone) is shown below:

[0053]

[0054] The obtained pure product is a reddish brown solid with a yield of 38% and a melting point of 128-133°C. The test results are as follows: 1H NMR (400MHz, DMSO) δ10.60(s,1H),9.17(s,1H),8.22(s,1H),8.17(s,1H),8.00(d,J=8.3Hz, 1H), 7.59 (d, J = 8.0Hz, 1H), 7.52 (dd, J = 13.5, 7.6Hz, 3H), 6.96 (d, J = 9.3Hz, 1H), 1.28 (s, 9H). MS(EI)m / z:399.06(M+H) + .Anal.calcd for C 20 H 19 BrN2O2:C,60.16;H,4.80;N,7.02. Found C,60.11;H,4.89;N,7.00.

[0055] (9) The structure of compound I-9 ((1-(4-fluorophenyl)-1H-pyrazole-4-)(2-hydroxy-5-fluorophenyl)methanone) is shown below:

[0056]

[0057] The obtained pure product is a reddish brown solid with a yield of 22% and a melting point of 123-130°C. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ11.70(s,1H),8.44(s,1H),8.18(s,1H),7.74(dd,J=9.0,4.5Hz,2H),7.58(dd ,J=8.8,3.0Hz,1H),7.29(dd,J=8.7,2.5Hz,1H),7.22(t,J=8.5Hz,2H),7.05(dd,J=9.2,4.5Hz,1H). MS(EI)m / z:301.07(M+H) + .Anal.calcd for C 16 H 10 F2N2O2: C, 64.00; H, 3.36; N, 3.36. Found C, 64.15; H, 3.31; N, 3.30.

[0058] (10) The structure of compound I-10 ((1-(4-bromophenyl)-1H-pyrazole-4-)(2-hydroxy-5-fluorophenyl)methanone) is shown below:

[0059]

[0060] The obtained pure product is a yellow powder with a yield of 37% and a melting point of 141-144°C. The test results are as follows: 1H NMR (400MHz, CDCl3) δ11.69(s,1H),8.47(s,1H),8.18(s,1H),7.65(s,4H),7.57(dd,J=8.8,3.0Hz,1H),7.34-7.26(m,1H),7.04(dd,J=9.1,4.6Hz,1H). MS(EI)m / z:360.99(M+H) + .Anal.calcd for C 16 H 10 BrFN2O2: C, 53.21; H, 2.79; N, 7.76. Found C, 53.30; H, 2.84; N, 7.73.

[0061] (11) The structure of compound I-11 ((1-(4-fluorophenyl)-1H-pyrazole-4-)(2-hydroxy-5-chlorophenyl)methanone) is shown below:

[0062]

[0063] The obtained pure product is a yellow powder with a yield of 25% and a melting point of 136-139°C. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ11.93(s,1H),8.08(s,1H),7.86(s,1H),7.80-7.74(m,2H),7.60(s,1H),7. 23(d,J=8.8Hz,1H),7.18(dd,J=8.7,2.6Hz,1H),6.99(d,J=3.0Hz,2H).MS(EI)m / z:317.04(M+H) + .Anal.calcd for C 16 H 10 ClFN2O2: C, 60.68; H, 3.18; N, 8.85. Found C, 60.71; H, 3.14; N, 8.80.

[0064] (12) The structure of compound I-12 ((1-(4-bromophenyl)-1H-pyrazole-4-)(2-hydroxy-5-chlorophenyl)methanone) is shown below:

[0065]

[0066] The obtained pure product is a yellow-brown solid with a yield of 35% and a melting point of 137-140°C. The test results are as follows: 1H NMR (400MHz, CDCl3) δ 11.85 (s, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 7.85 (d, J = 2.6Hz, 1H), 7.66 (s, 4H), 7.48 (dd, J = 8.9, 2.5Hz, 1H), 7.04 (d, J = 8.9Hz, 1H). MS(EI)m / z:378.96(M+H) + .Anal.calcdfor C 16 H 10 BrClN2O2: C, 50.89; H, 2.67; N, 9.39. Found C, 50.93; H, 2.61; N, 9.47.

[0067] (13) The structure of compound I-13 ((1-(3-bromophenyl)-1H-pyrazole-4-)(2-hydroxy-5-chlorophenyl)methanone) is shown below:

[0068]

[0069] The obtained pure product is a yellow-brown powder with a yield of 25% and a melting point of 139-142°C. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ11.85(s,1H),8.47(s,1H),8.19(s,1H),7.98(t,J=1.9Hz,1H),7.85(d,J=2.5Hz,1H),7.70( d, J=7.3Hz, 1H), 7.54 (d, J=7.9Hz, 1H), 7.48 (dd, J=8.9, 2.5Hz, 1H), 7.40 (t, J=8.1Hz, 1H), 7.04 (d, J=8.9Hz, 1H). MS(EI)m / z:378.96(M+H) + .Anal.calcd for C 16 H 10 BrClN2O2: C, 50.89; H, 2.67; N, 7.42. Found C, 50.92; H, 2.79; N, 7.44.

[0070] (14) The structure of compound I-14 ((1-(4-fluorophenyl)-1H-pyrazole-4-)(2-hydroxy-5-bromophenyl)methanone) is shown below:

[0071]

[0072] The obtained pure product is a yellow powder with a yield of 27% and a melting point of 156-159°C. The test results are as follows: 1H NMR (400MHz, CDCl3) δ11.89 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 8.00 (d, J = 2.4Hz, 1H), 7. 79-7.70(m,2H),7.60(dd,J=8.9,2.4Hz,1H),7.26-7.17(m,2H),6.98(d,J=8.9Hz,1H). MS(EI)m / z:360.99(M+H) + .Anal.calcd for C 16 H 10 BrFN2O2:C,53.21;H,2.79;N,7.76.FoundC,53.18;H,2.72;N,7.75.

[0073] Embodiment 2:

[0074] The 14 compounds from I-1 to I-14 prepared in Example 1 were subjected to an algal growth inhibition test on Microcystis aeruginosa FACHB 905. Microcystis aeruginosa FACHB 905 was cultured in a BG-11 (+N) liquid culture medium containing different concentrations of the compounds in an artificial climate incubator. The incubator temperature was controlled at 28°C ± 1°C, humidity was 60%, light intensity was 6000lx, 12h (light): 12h (dark), vibration mode, and manual shaking was performed 3 times a day.

[0075] The specific operations are as follows:

[0076] 1. Pre-cultivate a batch of cyanobacteria, and measure OD after 4-7 days of growth to the logarithmic phase. 680 , inoculate and set aside;

[0077] 2. Dilute the above-mentioned logarithmic phase algae solution with fresh BG-11 (+N) medium to obtain inoculated algae solution, and control the algae cell concentration to about 1×10 6 Pieces / mL;

[0078] 3. Weigh the compound in advance, dissolve it with DMSO, and prepare different concentrations of the compound; add 200 μL of the diluted inoculated algae solution to each well of the 96-well plate, and then add 1 μL of a certain concentration of the compound; make 5 groups of parallel experiments for each concentration of the compound, and set up a blank control without the compound and a compound background control;

[0079] 4. After 7 days of cultivation in an artificial climate incubator, measure the OD with an enzyme marker 680 , calculate the inhibition rate of compounds at different concentrations;

[0080] Inhibition rate calculation formula:

[0081] Growth inhibition rate = [blank control group OD 680-(Experimental group OD 680 - Compound background control group OD 680 )]×100 / blank control group OD 680 ;

[0082] 5. Plot the concentration of the compound as the horizontal axis and the growth inhibition rate as the vertical axis. Use the logistic fitting formula in Origin to obtain the EC values ​​of the five most active compounds. 50 The results are listed in Table 3.

[0083] Table 3 EC values ​​of compounds for inhibition of Microcystis aeruginosa FACHB 905 50 value

[0084]

[0085] The meanings of the omitted symbols in the table are: Me methyl, Et ethyl, i-Pr isopropyl.

[0086] From the above table EC 50 It can be seen that 14 compounds with formula I as the general formula were selected for activity testing against Microcystis aeruginosa FACHB 905, and 5 compounds had EC 50 The values ​​were between 0.61 and 2.01 μM, showing strong inhibitory activity and could be used as a potential algaecide.

[0087] The above is only a preferred embodiment of the present invention. The present invention is not limited to the above implementation. As long as the technical effect of the present invention is achieved by the same means, it should belong to the protection scope of the present invention. Within the protection scope of the present invention, its technical scheme and / or implementation method can have various modifications and changes.

Claims

1. Application of a pyrazole benzophenone compound in inhibiting the growth of cyanobacteria, It is characterized in that The cyanobacteria is Microcystis aeruginosa FACHB905; The structure of the pyrazole benzophenone compound is shown in Formula I: Formula I; Among them, R 1 is selected from hydrogen, halogen and C 1 -C 4 One of the alkyl groups; R 2 Selected from fluorine or bromine.

2. The use according to claim 1, It is characterized in that The pyrazole benzophenone compound is one of the following compounds: 、 、 、 、 。 3. The use according to claim 1, It is characterized in that The synthetic route of the pyrazole benzophenone compound is as follows: Formula II Formula I 4. The use according to claim 3, It is characterized in that The specific process of the preparation method of the pyrazole benzophenone compound is: mixing the compound represented by formula II and potassium carbonate in acetonitrile, heating to reflux, and monitoring by TLC until the reaction is completed.

5. The use according to claim 4, It is characterized in that After the reaction is completed, the mixture is allowed to stand for 10 h to 14 h, and then subjected to rotary evaporation under reduced pressure. Ethyl acetate is added and shaken, and the mixture is filtered and washed with ethyl acetate. The filtrate is rotary evaporated under reduced pressure, and the pyrazole benzophenone compound is separated by column chromatography.

6. The use according to claim 5, It is characterized in that Column chromatography was performed using PE / EtOAc.

7. The use according to claim 5, It is characterized in that Let stand for 12 hours.

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