CN110367265B - Application of stilbene analogue containing phenylthiazole structure as bactericide - Google Patents
Application of stilbene analogue containing phenylthiazole structure as bactericide Download PDFInfo
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
Abstract
The invention discloses an application of a toluylene compound containing a phenylthiazole structure as a bactericide, wherein the toluylene compound containing the phenylthiazole structure has a structure shown in a formula (I):
Description
Technical Field
The invention relates to application of a stilbene analogue containing a phenylthiazole structure as a bactericide.
Background
According to the report of the literature, the stilbene compounds exist in a plurality of plants such as lindera reflexa Hemsl (Chinese medicine science report, 2015,30(07): 1010-. Stilbene compounds have various biological activities, and in the field of medicine, have activities such as anti-tumor (J.Agric.food Chem.,2019,67(17): 4709-) 4717, the fourth university of military medicine, 2008,29(23): 2141-; as for the research on the pesticide activity, the pesticide has relatively few studies, and the pesticide has activities such as insecticidal activity (J.Pest.Sci.,2018,91(2): 897-. Previous studies by the applicant have shown that stilbene compounds also have mosquito-killing (chem. biological 2016,13,1165-1177) activity.
Thiazole compounds have good biological activity and pharmacological activity because of having unique aromatic heterocyclic structures, such as anti-cancer (Eur.J.Med.chem.,2015,92(6): 866-brick-and-for-medicine, 2016,82: 555-brick-and-for-medicine 560), anti-bacteria (bioorg.Med.chem.Let., 2012,22(24):7719-7725, J.anti.,2014,68(4):259-66, Drug Metab Pharmack, 2017,1(32): S96), anti-inflammation (Comut.biol.chem., 2016,61:86-96), anti-oxidation (chemistry select,2019,4(19): 5570-brick-and-for-medicine 5576), and the like; and pesticidal activities such as insecticidal (J.Agric.food Chem,2011,59(9): 2932-. At present, many pesticides containing thiazole structure have been commercialized successfully, such as the bactericides imazethapyr, oryzalin; the herbicides thiazopyr and benazolin; insecticide moth-worm nitrile, clothianidin, etc. In earlier work, the applicant designs and synthesizes a class of fluorine-containing phenylthiazole acrylonitrile compounds (organic chemistry, 2009,29(12): 2000-containing 2004; agricultural and pharmaceutical science, 2010,12(4): 463-containing 467), and experiments prove that the compounds have better insecticidal and bactericidal activities.
The styrene compound and the thiazole heterocyclic compound both have good pesticide activity, but the prior art does not disclose the chemical structure of the stilbene analogue containing the phenylthiazole structure, and the biological activity of the stilbene analogue containing the phenylthiazole structure is not reported.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention aims to provide an application of a stilbene compound containing a phenylthiazole structure as a bactericide, wherein the stilbene compound containing the phenylthiazole structure is (E) -4- (4-fluorophenyl) -2-substituted styryl thiazole compound.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the structure of the stilbene compound containing the phenylthiazole structure is shown as a formula (I):
in the formula (I), H on a benzene ring is mono-substituted or multi-substituted by a substituent R; n is an integer of 1 to 5, preferably an integer of 1 to 2, and n represents the number of substituents R on the benzene ring; when n is 1, it represents that H on the benzene ring is monosubstituted with a substituent R; when n is 2-5, the H on the benzene ring is substituted by substituent R in multiple times, and the substituent R on different substituted positions is the same or different; the substituent R is C1-C8 alkyl, C1-C8 halogenated alkyl, C1-C3 alkoxy, halogen, nitro or cyano.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the substituent R is C1-C5 alkyl, C1-C5 haloalkyl, methoxy or halogen, preferably methyl, tert-butyl, trifluoromethyl, methoxy, F, Cl or Br.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that in the formula (I), R (n) is one of o-methyl, m-methyl, p-methyl, o-methoxy, m-methoxy, p-tert-butyl, p-trifluoromethyl, p-fluorine, o-chlorine, p-chlorine, o-bromine, m-bromine and 2, 4-dichloro.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the stilbene compound containing the phenylthiazole structure is used for preparing the bactericide for inhibiting corn small leaf spot pathogen, cucumber anthracnose pathogen, rice sheath blight pathogen or cucumber downy mildew pathogen.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the synthesis method of the stilbene compound containing the phenylthiazole structure comprises the following steps:
1) reacting 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole shown as a formula (II) with triethyl phosphite shown as a formula (III) in a reflux state, and concentrating and removing redundant triethyl phosphite after TLC monitoring is carried out until the reaction is finished to obtain a concentrated solution;
2) adding a solvent DMF, sodium hydroxide and substituted benzaldehyde shown as a formula (IV) into the concentrated solution obtained in the step 1), reacting at room temperature, monitoring by TLC until the reaction is finished, and finally carrying out post-treatment to obtain a toluylene compound shown as a formula (I) and containing a phenylthiazole structure;
in the formula (IV), H on a benzene ring is mono-substituted or multi-substituted by a substituent R; n is an integer of 1 to 5, preferably an integer of 1 to 2, and n represents the number of substituents R on the benzene ring; when n is 1, it represents that H on the benzene ring is monosubstituted with a substituent R; when n is 2-5, the H on the benzene ring is substituted by substituent R in multiple times, and the substituent R on different substituted positions is the same or different; the substituent R in the formula (IV) is C1-C8 alkyl, C1-C8 haloalkyl, C1-C3 alkoxy, halogen, nitro or cyano.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the amount ratio of the 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole shown as the formula (II), the triethyl phosphite shown as the formula (III), the substituted benzaldehyde shown as the formula (IV) and the sodium hydroxide is 1: 10.0-30.0: 1.0-8.0: 1.0-20.0, and preferably 1: 15.0-20.0: 1.0-3.0: 1.0-5.0.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the mass ratio of the 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole shown as the formula (II) to the DMF solvent is 1: 2.0-20, and preferably 1: 4.0-10.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the reaction time of the step 1) is 1-3 hours, and the reaction time of the step 2) is 1-4 hours.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the post-treatment process in the step 2) is as follows: after the reaction is finished, adding a large amount of ice water into the reaction liquid, stirring, separating out solids, filtering, and recrystallizing and purifying a filter cake by using an organic solvent to obtain a toluylene compound containing a phenylthiazole structure shown in the formula (I); if no solid is separated out, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography to obtain a stilbene compound containing a phenylthiazole structure shown in the formula (I); wherein the mass ratio of the added mass of the ice water to the 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole added in the step 1) is 50-150: 1.
The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that an organic solvent used for recrystallization is ethanol, ethyl acetate or n-hexane; the eluent used for column chromatography is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 3-5.
In the process of preparing the toluylene compound containing the thiazole ring structure, the amount of triethyl phosphite and the reaction temperature must be controlled within a certain range, because triethyl phosphite has certain reducibility, and if the amount of triethyl phosphite is large and the reaction temperature is high (reflux temperature), the toluylene compound containing the benzothiazole structure and having the structure shown in the formula (I) can be prepared.
Compared with the prior art, the invention has the beneficial effects that:
1) the invention designs and synthesizes a novel stilbene compound containing a phenylthiazole structure by replacing a benzene ring in a stilbene skeleton with fluorine-containing phenylthiazole by utilizing active substructure splicing and biological isostere substitution methods, and aims to find out the novel pesticide activity of the stilbene compound.
2) The invention provides application of a novel stilbene compound containing a phenylthiazole structure as a pesticide, which is particularly suitable for fungi such as wheat scab, corn small leaf spot pathogen, cucumber anthracnose pathogen, rice sheath blight pathogen, cucumber downy mildew pathogen and the like, and the results of antibacterial activity tests of embodiments show that the stilbene compound containing the phenylthiazole structure shows certain inhibition activity on test targets under the concentration of 200mg/L, wherein the inhibition rates of compounds Ia, Ic, If and Ii on the wheat scab pathogen are all more than 50%, the inhibition rate of compound Ik on the cucumber anthracnose pathogen is all more than 50%, and the inhibition rate of compound Ih on the cucumber downy mildew pathogen is more than 50%, so that the stilbene compound shows medium inhibition activity. Wherein, the compound Ia has 95 percent of inhibition rate on wheat scab germs and shows better inhibition activity.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1 synthesis of compound Ia (r (n) ═ o-methyl):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (24.9g,150.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 1.0h of reaction, concentrating to remove redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (11.6g), o-methylbenzaldehyde (1.2g,10mmol) and sodium hydroxide (0.4g,10mmol) to react at room temperature. And (3) detecting the reaction progress by TLC (thin layer chromatography), finishing the reaction within about 1.0 hour, pouring the reaction liquid into ice water (145g), stirring, separating out a solid, filtering, and recrystallizing a filter cake by using n-hexane to obtain 1.4g of a yellow solid, namely (E) -4- (4-fluorophenyl) -2-o-methylstyrene thiazole (which is marked as a compound Ia), wherein the yield is 57.4%. m.p. 71-75 ℃;
1H NMR(500MHz,CDCl3)δ7.94(dd,J＝8.5,5.5Hz,2H),7.76(d,J＝16.0Hz,1H),7.69–7.62(m,1H),7.33(s,1H),7.31–7.21(m,4H),7.16(t,J＝9.0Hz,2H),2.51(s,3H).HRMS(ESI)calcd C18H13BrFNS[M+H]+296.0904,found 296.0888。
example 2 synthesis of compound Ib (r (n) ═ m methyl):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (3.5g,10mmol) into triethyl phosphite (24.9g,150.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 1.0h of reaction, concentrating to remove redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (11.6g), m-tolualdehyde (1.2g,10mmol) and sodium hydroxide (0.4g,10mmol) to react at room temperature. TLC detects the reaction progress, the reaction is finished within about 1.0 hour, the reaction liquid is poured into ice water (145g), solid is separated out by stirring, the filtration is carried out, and the filter cake is recrystallized by normal hexane to obtain 1.3g of yellow solid, namely (E) -4- (4-fluorophenyl) -2-m-methylstyrene thiazole (which is marked as a compound Ib), and the yield is 44.5%. m.p. 148-149 ℃;
1H NMR(500MHz,CDCl3)δ7.93(dd,J＝8.5,5.5Hz,2H),7.46(d,J＝16.0Hz,1H),7.39(d,J＝8.5Hz,2H),7.35(d,J＝16.0Hz,1H),7.33(s,1H),7.31(t,J＝7.5Hz,1H),7.21–7.09(m,3H),2.41(s,3H).HRMS(ESI)calcd C18H14FNS[M+H]+296.0904,found 296.0883。
example 3 synthesis of compound Ic (r (n) ═ p-methyl):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (24.9g,150.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 1.0h of reaction, concentrating to remove redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (14.5g), p-tolualdehyde (1.4g,12mmol) and sodium hydroxide (0.4g,10mmol) to react at room temperature. The reaction progress was checked by TLC, and after about 1.0 hour, the reaction solution was poured into ice water (145g), stirred, and a solid precipitated, filtered, and the filter cake was recrystallized from n-hexane to give 1.4g of a yellow solid, i.e., (E) -4- (4-fluorophenyl) -2-p-methylstyrene thiazole (labeled as compound Ic), in 57.3% yield. m.p. 164-167 ℃;
1H NMR(500MHz,CDCl3)δ7.92(t,J＝6.0Hz,2H),7.53–7.39(m,3H),7.32(t,J＝6.0Hz,2H),7.22(d,J＝7.5Hz,2H),7.14(t,J＝8.5Hz,2H),2.40(s,3H).HRMS(ESI)calcd C18H14FNS[M+H]+296.0904,found 296.0890。
example 4 synthesis of compound Id (r (n) ═ o-methoxy):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (27.4g,165.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 1.5h, finishing the reaction, concentrating to remove redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (14.5g), o-methoxybenzaldehyde (2.0g,15mmol) and sodium hydroxide (0.6g,15mmol) and reacted at room temperature. The reaction progress was checked by TLC for about 1.5 hours, the reaction solution was poured into ice water (145g), stirred, extracted with ethyl acetate, and after desolventizing, the desolventized residue was separated by column chromatography (eluent used was a mixture of ethyl acetate and petroleum ether, V ethyl acetate: V petroleum ether ═ 1:3) to obtain 1.3g of a yellow solid, i.e., (E) -4- (4-fluorophenyl) -2-o-methoxystyrylthiazole (this was labeled as compound Id), with a yield of 50.9%. m.p. 73-76 ℃;
1H NMR(500MHz,CDCl3)δ7.93(dd,J＝9.0,5.5Hz,2H),7.80(d,J＝16.0Hz,1H),7.61(dd,J＝8.0,1.5Hz,1H),7.47(d,J＝16.0Hz,1H),7.36–7.29(m,2H),7.14(t,J＝8.5Hz,2H),7.01(t,J＝7.5Hz,1H),6.94(d,J＝8.5Hz,1H),3.93(s,3H).HRMS(ESI)calcd C18H14FNOS[M+H]+312.0853,found 312.0830。
example 5 synthesis of compound Ie (r (n) ═ m-methoxy):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (3.5g,10mmol) into triethyl phosphite (27.4g,165.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 1.5h, finishing the reaction, concentrating to remove redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (17.4g), m-methoxybenzaldehyde (2.0g,15mmol) and sodium hydroxide (0.6g,15mmol) and reacted at room temperature. The reaction progress was checked by TLC for about 1.5 hours, the reaction solution was poured into ice water (145g), stirred, extracted with ethyl acetate, and after desolventizing, the desolventized residue was separated by column chromatography (eluent used was a mixture of ethyl acetate and petroleum ether, V ethyl acetate: V petroleum ether is 1:5) to obtain 1.4g of a yellow solid, which was (E) -4- (4-fluorophenyl) -2-m-methoxybenzylthiazole (labeled as compound Ie), with a yield of 52.6%. m.p. 115-116 ℃;
1H NMR(500MHz,CDCl3)δ7.92(dd,J＝9.0,5.5Hz,2H),7.44(d,J＝16.0Hz,1H),7.37–7.28(m,3H),7.19–7.08(m,4H),6.96–6.86(m,1H),3.85(s,3H).HRMS(ESI)calcd C18H14FNOS[M+H]+312.0853,found 312.0836。
example 6 synthesis of compound If (r (n) ═ p-methoxy):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (27.4g,165.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 1.5h, finishing the reaction, concentrating to remove redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (17.4g), p-methoxybenzaldehyde (2.0g,15mmol) and sodium hydroxide (0.6g,15mmol) and reacted at room temperature. And (3) detecting the reaction progress by TLC (thin layer chromatography), finishing the reaction within about 1.5 hours, pouring the reaction liquid into ice water (145g), stirring, separating out a solid, filtering, recrystallizing a filter cake by using ethyl acetate to obtain 1.6g of a yellow solid, namely (E) -4- (4-fluorophenyl) -2-p-methoxystyrylthiazole (which is marked as a compound If), and calculating the yield to be 59.9%. m.p. 124-129 ℃;
1H NMR(500MHz,CDCl3)δ7.92(dd,J＝8.5,5.5Hz,2H),7.52(d,J＝9.0Hz,2H),7.43(d,J＝16.0Hz,1H),7.31(s,1H),7.23(d,J＝16.0Hz,1H),7.14(t,J＝9.0Hz,2H),6.94(d,J＝8.5Hz,2H),3.86(s,1H).HRMS(ESI)calcd C18H14FNOS[M+H]+312.0853,found 312.0835。
example 7 synthesis of the compound Ig (r (n) ═ p-tert-butyl):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (29.1g,175.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 2.0h, finishing the reaction, concentrating to remove redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (20.3g), p-tert-butylbenzaldehyde (2.4g,15mmol) and sodium hydroxide (0.8g,20mmol) to react at room temperature. The reaction progress was checked by TLC for about 2.0 hours, the reaction was terminated, the reaction solution was poured into ice water (232g), stirred, and a solid precipitated, filtered, and the filter cake was recrystallized from ethyl acetate to obtain 1.6g of a yellow solid, i.e., (E) -4- (4-fluorophenyl) -2-p-tert-butylstyrylthiazole (which was labeled as compound Ig), with a yield of 56.6%. m.p. 146-148 ℃;
1H NMR(500MHz,CDCl3)δ7.93(dd,J＝8.5,5.5Hz,2H),7.53(d,J＝8.5Hz,2H),7.44(m,3H),7.34(d,J＝15.0Hz,2H),7.14(t,J＝8.5Hz,2H),1.37(s,9H).HRMS(ESI)calcd C21H20FNS[M+H]+338.1373,found 338.1381。
example 8 synthesis of compound Ih (r (n) ═ p-trifluoromethyl):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (30.2g,185.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, concentrating after the reaction is finished after about 2 hours, and removing redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (20.3g), p-trifluoromethylbenzaldehyde (3.5g,20mmol) and sodium hydroxide (1.0g,25mmol) and reacted at room temperature. The reaction progress was checked by TLC for about 2.5 hours, the reaction solution was poured into ice water (232g), stirred, extracted with ethyl acetate, and after desolventizing, the desolventized residue was separated by column chromatography (eluent used was a mixture of ethyl acetate and petroleum ether, V ethyl acetate: V petroleum ether is 1:5) to obtain 1.8g of a yellow solid, which was (E) -4- (4-fluorophenyl) -2-p-trifluoromethylstyrylthiazole (this was labeled as compound Ih) with a yield of 61.4%. m.p. 111-115 ℃;
1H NMR(500MHz,CDCl3)δ7.93(dd,J＝9.0,5.5Hz,2H),7.66(s,4H),7.51(d,J＝16.5Hz,2H),7.41(d,J＝16.5Hz,1H),7.15(t,J＝8.5Hz,2H).HRMS(ESI)calcd C18H11F4NS[M+H]+350.0621,found 350.0599。
example 9 synthesis of compound Ii (r (n) ═ p-fluoro):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (32.4g,195.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 2.5 hours of reaction, concentrating to remove excessive triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (23.2g), p-fluorobenzaldehyde (2.5g,20mmol) and sodium hydroxide (1.2g,30mmol) and reacted at room temperature. And (3) detecting the reaction progress by TLC (thin layer chromatography), finishing the reaction for about 3 hours, pouring the reaction liquid into ice water (232g), stirring, separating out a solid, filtering, and recrystallizing a filter cake by using n-hexane to obtain 1.2g of a yellow solid, namely (E) -4- (4-fluorophenyl) -2-p-fluorostyrylthiazole (which is marked as a compound Ii), wherein the yield is 49.0 percent. m.p. 146-149 ℃;
1H NMR(500MHz,CDCl3)δ7.92(dd,J＝8.5,5.5Hz,2H),7.54(dd,J＝8.5,5.5Hz,2H),7.44(d,J＝16.5Hz,1H),7.34(s,1H),7.26(d,J＝16.5Hz,1H),7.12(dt,J＝21.5,8.5Hz,4H).HRMS(ESI)calcd C17H11F2NS[M+H]+300.0642,found 300.0653。
example 10 synthesis of compound Ij (r (n) ═ o-chloro):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (32.4g,195.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 2.5 hours of reaction, concentrating to remove excessive triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (23.2g), o-chlorobenzaldehyde (2.8g,20mmol) and sodium hydroxide (1.6g,40mmol) to react at room temperature. And (3) detecting the reaction progress by TLC (thin layer chromatography), finishing the reaction within about 3.0 hours, pouring the reaction liquid into ice water (232g), stirring, separating out a solid, filtering, recrystallizing a filter cake by using ethanol to obtain 1.5g of a yellow solid, namely (E) -4- (4-fluorophenyl) -2-o-chlorostyrenyl thiazole (which is marked as a compound Ij), and calculating the yield to be 58.5%. m.p. 95-98 ℃;
1H NMR(500MHz,CDCl3)δ7.93(t,2H),7.87(d,J＝16.5Hz,1H),7.73(d,J＝7.5Hz,1H),7.44(d,J＝7.5Hz,1H),7.41–7.26(m,4H),7.15(t,J＝8.0Hz,2H).HRMS(ESI)calcd C17H11ClFNS[M+H]+316.0358,found 316.0357。
example 11 synthesis of compound Ik (r (n) ═ p-chloro):
5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) was added to triethyl phosphite (32.4g,195.0mmol), heated to reflux for reaction, the progress of the reaction was checked by TLC, and the reaction was complete after about 2.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (23.2g), p-chlorobenzaldehyde (2.8g,20mmol) and sodium hydroxide (1.6g,40mmol) to react at room temperature. And (3) detecting the reaction progress by TLC (thin layer chromatography), finishing the reaction within about 3.0 hours, pouring the reaction liquid into ice water (232g), stirring, separating out a solid, filtering, recrystallizing a filter cake by using n-hexane to obtain 1.3g of a yellow solid, namely (E) -4- (4-fluorophenyl) -2-p-chlorostyrenyl thiazole (which is marked as a compound Ik), and calculating the yield to be 48.3%. m.p. 171-175 ℃;
1H NMR(500MHz,CDCl3)δ7.92(dd,J＝9.0,5.5Hz,2H),7.50(d,J＝8.5Hz,2H),7.44(d,J＝16.5Hz,1H),7.40–7.35(m,3H),7.32(d,J＝16.5Hz,1H),7.14(t,J＝9.0Hz,2H).HRMS(ESI)calcd C17H11ClFNS[M+H]+316.0358,found 316.0359。
example 12 synthesis of compound Il (r (n) ═ o-bromine):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (32.4g,195.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 3.0h of reaction, concentrating to remove excessive triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (23.2g), o-bromobenzaldehyde (5.5g,30mmol) and sodium hydroxide (1.9g,47mmol) to react at room temperature. And (3) detecting the reaction progress by TLC (thin layer chromatography), finishing the reaction within about 3.5 hours, pouring the reaction liquid into ice water (319g), stirring, separating out a solid, filtering, and recrystallizing a filter cake by using ethyl acetate to obtain 1.3g of a yellow solid, namely (E) -4- (4-fluorophenyl) -2-o-bromophenylvinyl thiazole (which is marked as a compound Il), wherein the yield is 44.9%. m.p. 94-96 ℃;
1H NMR(500MHz,CDCl3)δ7.92(dd,J＝8.5,5.5Hz,2H),7.82(d,J＝16.5Hz,1H),7.70(dd,J＝7.5,1.5Hz,1H),7.63(dd,J＝8.0,1.0Hz,1H),7.41–7.27(m,3H),7.14(m,4H).HRMS(ESI)calcd C17H11BrFNS[M+H]+359.9852,found 359.9857。
example 13 synthesis of compound Im (r (n) ═ m-bromo):
5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) was added to triethyl phosphite (32.4g,195.0mmol), heated to reflux for reaction, TLC checked for reaction progress, and reaction was complete after about 3.0 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (26.1g), m-bromobenzaldehyde (5.5g,30mmol) and sodium hydroxide (1.9g,47mmol) to react at room temperature. TLC detects the reaction progress, the reaction is finished within about 3.5 hours, the reaction liquid is poured into ice water (319g), solid is separated out by stirring, the filtration is carried out, and a filter cake is recrystallized by ethyl acetate to obtain 1.4g of yellow solid, namely (E) -4- (4-fluorophenyl) -2-m-bromophenylvinylthiazole (which is marked as a compound Im), and the yield is 45.8%. m.p. 142-145 ℃;
1H NMR(500MHz,CDCl3)δ7.92(dd,J＝8.5,5.5Hz,2H),7.72(s,1H),7.47(t,J＝7.5Hz,2H),7.41(d,J＝16.5Hz,1H),7.37(s,1H),7.33(d,J＝16.5Hz,1H),7.27(t,J＝8.0Hz,1H),7.14(t,J＝8.5Hz,2H).HRMS(ESI)calcd C17H11BrFNS[M+H]+359.9852,found 359.9854。
example 14 synthesis of compound In (r (n) ═ 2, 4-dichloro):
adding 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole (2.9g,10mmol) into triethyl phosphite (33.2g,200.0mmol), heating to reflux for reaction, detecting the reaction progress by TLC, after about 3 hours of reaction, concentrating to remove redundant triethyl phosphite to obtain a concentrated solution; to the resulting concentrated solution were added DMF (29.0g), 2, 4-dichlorobenzaldehyde (5.2g,30mmol) and sodium hydroxide (2.0g,50mmol) to react at room temperature. And (3) detecting the reaction progress by TLC (thin layer chromatography), finishing the reaction within about 4 hours, pouring the reaction liquid into ice water (435g), stirring, separating out a solid, filtering, recrystallizing a filter cake by using ethyl acetate to obtain 1.3g of a yellow solid, namely (E) -4- (4-fluorophenyl) -2- (2, 4-dichlorostyryl) thiazole (which is marked as a compound In), and calculating the yield to be 44.3%. m.p. 131-133 ℃;
1H NMR(500MHz,CDCl3)δ7.92(dd,J＝8.5,5.5Hz,2H),7.78(d,J＝16.0Hz,1H),7.64(d,J＝8.5Hz,1H),7.45(d,J＝1.5Hz,1H),7.39(s,1H),7.33(d,J＝16.0Hz,1H),7.30–7.26(m,1H),7.14(t,J＝9.0Hz,2H).HRMS(ESI)calcd C17H10Cl2FNS[M+H]+349.9968,found 349.9967。
example 15 antifungal activity test:
test targets: wheat scab fungus Fusahum graminearum, corn small spot pathogen Helminthosporium maydis, cucumber anthracnose pathogen Mycosphaerella melonis, rice sheath blight fungus Thanatephorum cucumeris, cucumber downy mildew fungus Pseudoperonospora cubensis and the like.
The (E) -4- (4-fluorophenyl) -2-substituted styryl thiazole compounds synthesized in the examples 1-14 are marked as test compounds. The bactericidal activity of the target bacteria is determined on a compound to be detected, a control medicament and a distilled water blank by adopting a medicament-containing potato agar medium (PDA) method or a suspended spore spraying method, and the common sieve concentration of the compound to be detected and the control medicament is 200 mg/L.
Specifically, the test method refers to "evaluation of biological Activity of pesticides SOP". Wheat scab pathogen, corn small spot pathogen, cucumber anthracnose pathogen and rice sheath blight pathogen adopt a medicine-containing culture medium method: adding 2mL of the liquid medicine containing the to-be-detected compound or the control drug with the concentration of 1000mg/L into 8mL of PDA culture medium cooled to 45 ℃ to prepare a drug-containing culture medium plate with the final concentration of the to-be-detected compound or the control drug of 200 mg/L. A6.5 mm diameter piece of hyphae was then removed from the edge of the cultured test pathogen colony and transferred to a drug-containing media plate for 4 replicates per treatment (4 tests per sample were performed using the same procedure, and the average inhibition was finally calculated). After the treatment, the cells were cultured in a constant temperature biochemical incubator at 28 ℃ for 4 days, and the diameter of the colonies was measured to calculate the growth inhibition rate.
The cucumber downy mildew is sprayed by using a suspended spore spraying method: dissolving the compound to be detected or the reference medicament with DMF to prepare a mother solution with the mass concentration of 5%, and diluting the mother solution with distilled water to prepare the spray medicament with the final concentration of the compound to be detected or the reference medicament of 200 mg/L. Then selecting potted cucumber seedlings with consistent growth vigor, adopting the prepared spraying agent to spray the potted cucumber seedlings, naturally drying the potted cucumber seedlings, dipping distilled water by using a writing brush after 24 hours, washing the sporocysts on the backs of diseased leaves to prepare a sporangium suspension (2-3 multiplied by 10)5One per ml), uniformly spraying the sporangium suspension on cucumber leaves by using an inoculation sprayer (the pressure is 0.1MPa), and then transferring the inoculated cucumber seedlings into an artificial climate chamber (the relative humidity is 100%, the temperature is 21-23 ℃, and the light-dark period is 14h/10h) for culture. Maintaining relative humidity of about 90% after 24 hr, and keeping moisture for 7-8 daysAnd (5) carrying out result investigation on the morbidity of the rearview blank control, and calculating the growth inhibition rate.
The above-mentioned medicated culture medium method and suspended spore spray method both adopt distilled water and respectively obtain blank control group result according to the same method. When the drug-containing culture medium method or the suspended spore spraying method is adopted to treat the compound to be tested, the growth inhibition rate is calculated in the following mode:
growth inhibition (%) of [ (blank colony diameter-treated colony diameter)/blank colony diameter ] × 100%
The test results are shown in Table 1.
TABLE 1200 bactericidal Activity of Compounds Ia-Io at mg/L concentration
Note: azoxystrobin is used as a control drug, and CK is distilled water blank control.
The bactericidal activity test result in Table 1 shows that at a concentration of 200mg/L, the (E) -4- (4-fluorophenyl) -2-substituted styryl thiazole compounds show certain inhibitory activity on test targets, wherein the inhibition rates of the compounds Ia, Ic, If and Ii on wheat scab pathogen are all more than 50%, the inhibition rate of Ik on cucumber anthracnose pathogen is all more than 50%, and the inhibition rate of Ih on cucumber downy mildew pathogen is more than 50%, so that the compounds show moderate inhibitory activity. Wherein, the inhibition rate of Ia on wheat scab germ reaches 95%, and the Ia shows better inhibition activity.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (9)
1. The application of the stilbene compound containing the phenylthiazole structure as the bactericide is characterized in that the structure of the stilbene compound containing the phenylthiazole structure is shown as the formula (I):
the substituent R (n) is o-methyl; the stilbene compound containing the phenylthiazole structure is used for preparing a bactericide for preventing and treating wheat scab.
2. The application of the stilbene compound containing the phenylthiazole structure as the bactericide as claimed in claim 1, wherein the synthesis method of the stilbene compound containing the phenylthiazole structure comprises the following steps:
1) reacting 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole shown as a formula (II) with triethyl phosphite shown as a formula (III) in a reflux state, and concentrating and removing redundant triethyl phosphite after TLC monitoring is carried out until the reaction is finished to obtain a concentrated solution;
2) adding a solvent DMF, sodium hydroxide and substituted benzaldehyde shown as a formula (IV) into the concentrated solution obtained in the step 1), reacting at room temperature, monitoring by TLC until the reaction is finished, and finally carrying out post-treatment to obtain a toluylene compound shown as a formula (I) and containing a phenylthiazole structure;
the substituent R (n) is o-methyl.
3. The application of the stilbene compound containing the phenylthiazole structure as the bactericide as claimed in claim 2, which is characterized in that the amount ratio of the feeding substances of the 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole shown as the formula (II), the triethyl phosphite shown as the formula (III), the substituted benzaldehyde shown as the formula (IV) and the sodium hydroxide is 1: 10.0-30.0: 1.0-8.0: 1.0-20.0.
4. The application of the stilbene compound containing the phenylthiazole structure as the bactericide as claimed in claim 3, which is characterized in that the amount ratio of the feeding substances of the 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole shown as the formula (II), the triethyl phosphite shown as the formula (III), the substituted benzaldehyde shown as the formula (IV) and the sodium hydroxide is 1: 15.0-20.0: 1.0-3.0: 1.0-5.0.
5. The application of the toluylene compound containing phenylthiazole structure as the bactericide of claim 2, is characterized in that the mass ratio of 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole shown in formula (II) to DMF (dimethyl formamide) is 1: 2.0-20.
6. The application of the toluylene compound containing phenylthiazole structure as the bactericide of claim 5, is characterized in that the mass ratio of 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole shown in formula (II) to DMF (dimethyl formamide) is 1: 4.0-10.
7. The application of the stilbene compound containing the phenylthiazole structure as the bactericide as claimed in claim 2, wherein the reaction time of the step 1) is 1-3 hours, and the reaction time of the step 2) is 1-4 hours.
8. The application of the toluylene compound containing benzothiazole structure as claimed in claim 2, characterized in that the post-treatment process in step 2) is as follows: after the reaction is finished, adding a large amount of ice water into the reaction liquid, stirring, separating out solids, filtering, and recrystallizing and purifying a filter cake by using an organic solvent to obtain a toluylene compound containing a phenylthiazole structure shown in the formula (I); if no solid is separated out, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography to obtain a stilbene compound containing a phenylthiazole structure shown in the formula (I); wherein the mass ratio of the added mass of the ice water to the 5-bromo-2- (bromomethyl) -4- (4-fluorophenyl) thiazole added in the step 1) is 50-150: 1.
9. The use of a stilbene compound having phenylthiazole structure as defined in claim 8 as a fungicide which comprises an organic solvent used for recrystallization which is ethanol, ethyl acetate or n-hexane; the eluent used for column chromatography is a mixed solution of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is 1: 3-5.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994008982A1 (en) * | 1992-10-13 | 1994-04-28 | Nippon Soda Co., Ltd. | Oxazole and thiazole derivatives |
| US5310746A (en) * | 1991-11-26 | 1994-05-10 | Roussel Uclaf | Alpha-methylene-6-styryl-acrylic acid derivatives |
| EP1103180A2 (en) * | 1999-11-25 | 2001-05-30 | Ciba SC Holding AG | Hydroxyphenylvinylthiazoles |
| CN101119723A (en) * | 2004-12-17 | 2008-02-06 | 迈科索尓公司 | Thiazolium compounds and uses thereof |
| CN108605949A (en) * | 2018-06-19 | 2018-10-02 | 浙江工业大学 | A kind of application of the class diphenyl ethene compounds as fungicide containing thiazole ring |
| CN108863977A (en) * | 2018-06-19 | 2018-11-23 | 浙江工业大学 | The class diphenyl ethene compounds and its synthetic method of a kind of thiazole ring containing bromo and application |
-
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5310746A (en) * | 1991-11-26 | 1994-05-10 | Roussel Uclaf | Alpha-methylene-6-styryl-acrylic acid derivatives |
| WO1994008982A1 (en) * | 1992-10-13 | 1994-04-28 | Nippon Soda Co., Ltd. | Oxazole and thiazole derivatives |
| EP1103180A2 (en) * | 1999-11-25 | 2001-05-30 | Ciba SC Holding AG | Hydroxyphenylvinylthiazoles |
| CN101119723A (en) * | 2004-12-17 | 2008-02-06 | 迈科索尓公司 | Thiazolium compounds and uses thereof |
| CN108605949A (en) * | 2018-06-19 | 2018-10-02 | 浙江工业大学 | A kind of application of the class diphenyl ethene compounds as fungicide containing thiazole ring |
| CN108863977A (en) * | 2018-06-19 | 2018-11-23 | 浙江工业大学 | The class diphenyl ethene compounds and its synthetic method of a kind of thiazole ring containing bromo and application |
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