CN108863977B - Stilbene compound containing bromothiazole ring and synthesis method and application thereof - Google Patents
Stilbene compound containing bromothiazole ring and synthesis method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- 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
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- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses a stilbene compound containing a bromothiazole ring and a synthesis method and application thereof. The synthesis process of the compound is as follows: firstly, 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole and triethyl phosphite react under the reflux state, TLC monitors until the reaction is finished, excessive triethyl phosphite is removed by concentration, solvent DMF, sodium hydroxide and substituted benzaldehyde are added into the obtained concentrated solution, the reaction is carried out at room temperature, and the stilbene compound containing the thiazole ring is prepared by post-treatment after the reaction is finished; and then carrying out bromination reaction on the stilbene compound containing the thiazole ring and N-bromosuccinimide in an acetonitrile solvent at 0-100 ℃ to prepare the stilbene compound containing the bromothiazole ring. The invention synthesizes and obtains a novel product (A) by adopting the technologyE) The-5-bromo-4- (2, 6-difluorophenyl) -2-substituted styryl thiazole compound is simple to prepare and shows certain anticancer and antifungal activities.
Description
Technical Field
The invention relates toE) -5-bromo-4- (2, 6-difluorophenyl) -2-substituted styryl thiazole compounds and application thereof.
Background
Stilbene compounds as phytoalexins widely exist in nature, such as rhizoma et radix Veratri, Polygoni Multiflori radix, rhizoma Polygoni Cuspidati of Polygonaceae, rhizoma Smilacis chinensis, semen Cassiae, and mulberry root of Smilax of Liliaceae. The stilbene compounds of natural sources have various biological activities, thereby causing wide attention of people and having very important function in the field of research and development of new drugs. For example, in the field of medicine, it has activities such as anti-tumor (J Agr Food Chem, 2011, 59(16): 8632-; in the field of agricultural chemicals, the pesticide composition has activities of killing insects (Chem pharmBull, 1992, 40(5): 1130-. Meanwhile, the thiazole heterocyclic compound also has broad-spectrum bioactivity and is widely applied to the fields of medicines and pesticides, such as biological activities of anti-inflammation (European Journal of medicinal chemistry, 2010, 45(9): 3692-; in the field of pesticides, the compounds have biological activities such as weeding (Bioorg Med Chem Lett, 2010, 20(11): 3348-. In addition, studies report that the introduction of halogen substituent can enhance the activity of drugs, and the halogen substituent is widely applied to the field of Drug design (Expert Opin Drug Dis, 2012, 7(5): 375-.
Based on that stilbene and thiazole heterocyclic compounds have good biological activity, the invention adopts a method of active substructure splicing and biological isostere substitution to introduce a screened active fluorophenyl thiazole-containing group (organic chemistry, 2009,29(12): 2000-2004; agricultural and pharmaceutical science, 2010, 12(4): 463-467) into a stilbene skeleton, substitute a benzene ring in the stilbene skeleton with fluorine-containing phenylthiazole, and introduce bromine atoms into a thiazole ring, thereby designing and synthesizing a novel stilbene-like compound containing a bromothiazole ring. The compound contains thiazole ring, halogen (fluorine and bromine) and stilbene-like structure, and is expected to have better biological activity.
The research on the structure and the bioactivity of the series of (E) -5-bromo-4- (2, 6-difluorophenyl) -2-substituted styryl thiazole compounds designed and synthesized by the invention is not reported in documents.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a stilbene compound containing a bromothiazole ring, a synthesis method and an application thereof, and the stilbene compound is simple to prepare and shows certain anticancer and antifungal activities.
The structure of the stilbene compound containing the bromothiazole ring is shown as the formula (I):
in the formula (I), H on a benzene ring is mono-substituted, multi-substituted or unsubstituted by a substituent R;
n is an integer of 0 to 5, preferably an integer of 1 to 2, and represents the number of substituents R on the benzene ring; n =0, represents that H on the phenyl ring is unsubstituted; n =1, represents H on the phenyl ring monosubstituted by a substituent R; when n = 2-5, the H on the benzene ring is substituted by a substituent R in multiple ways, and the substituent R on different substituted positions is the same or different;
the substituent R is hydrogen, alkyl of C1-C8, halogenated alkyl of C1-C8, alkoxy of C1-C3, halogen, nitro or cyano.
The stilbene compound containing the bromothiazole ring is characterized in that the substituent R is hydrogen, alkyl of C1-C5, halogenated alkyl of C1-C5, methoxy or halogen, preferably hydrogen, methyl, tert-butyl, trifluoromethyl, methoxy, F, Cl or Br.
The stilbene compound containing the bromothiazole ring is characterized in that R (n) is hydrogen, o-methyl, m-methyl, p-methyl, o-methoxy, p-methoxy, m-methoxy, p-tert-butyl, p-trifluoromethyl, p-fluorine, o-chlorine, p-chlorine, o-bromine, m-bromine or 2, 4-dichloro.
The synthesis method of the stilbene compound containing the bromothiazole ring is characterized by comprising the following steps of:
1) reacting 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole with triethyl phosphite under a reflux state, monitoring by TLC (thin layer chromatography) until the reaction is finished, concentrating to remove redundant triethyl phosphite, adding DMF (dimethyl formamide), sodium hydroxide and substituted benzaldehyde shown as a formula (IV) into the obtained concentrated solution, reacting at room temperature, and performing post-treatment after the reaction is finished to obtain a stilbene compound containing a thiazole ring shown as a formula (II);
2) carrying out bromination reaction on a stilbene compound containing a thiazole ring shown in a formula (II) and N-bromosuccinimide shown in a formula (III) in an acetonitrile solvent at 0-100 ℃ to prepare a stilbene compound containing a bromothiazole ring shown in a formula (I);
in the formula (II), H on a benzene ring is mono-substituted, multi-substituted or not substituted by a substituent R;
n is an integer of 0 to 5, preferably an integer of 1 to 2, and represents the number of substituents R on the benzene ring; n =0, represents that H on the phenyl ring is unsubstituted; n =1, represents H on the phenyl ring monosubstituted by a substituent R; when n = 2-5, the H on the benzene ring is substituted by a substituent R in multiple ways, and the substituent R on different substituted positions is the same or different;
the substituent R is hydrogen, alkyl of C1-C8, halogenated alkyl of C1-C8, alkoxy of C1-C3, halogen, nitro or cyano.
The method for synthesizing the stilbene compound containing the bromothiazole ring is characterized in that in the step 1), the mass ratio of the 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole to the triethyl phosphite to the substituted benzaldehyde shown as the formula (IV) and the sodium hydroxide is 1: 1.0-30.0: 1.0-8.0: 1.0-20.0, preferably 1: 5.0-20.0: 1.0-3.0: 1.0-5.0;
the mass ratio of the 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole to the DMF solvent is 1: 2.0-20, preferably 1: 4.0-10.
The synthesis method of the stilbene compound containing the bromothiazole ring is characterized in that the amount ratio of the stilbene compound containing the thiazole ring shown in the formula (II) to the N-bromosuccinimide shown in the formula (III) is 1: 1.0-20.0, preferably 1: 1.0-5.0;
the mass ratio of the stilbene compound containing the thiazole ring shown in the formula (II) to the acetonitrile solvent is 1: 2.0-20, and preferably 1: 4.0-10.
The synthesis method of the stilbene compound containing the bromothiazole ring is characterized in that in the step 2), the reaction temperature is 20-50 ℃, and the reaction time is 0.5-6 hours.
The synthesis method of the stilbene compound containing the bromothiazole ring is characterized in that after the reaction in the step 2), ice water is added into reaction liquid, the mixture is stirred, and if solid is separated out, the mixture is recrystallized and purified to obtain the stilbene compound containing the bromothiazole ring shown in the formula (I); and if no solid is precipitated, extracting with ethyl acetate, desolventizing, and separating by using a residual liquid column chromatography to obtain a stilbene compound containing a bromothiazole ring shown in the formula (I), wherein the mass ratio of the adding volume of ice water to the 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole is 33-50:1, the volume unit is mL, the mass unit is g, and a large amount of water can ensure the precipitation of the product due to the fact that the amount of DMF is small.
The method for synthesizing the stilbene compound containing the bromothiazole ring is characterized in that a solvent used for recrystallization is a mixed solution of one or more than two of ethanol, ethyl acetate, normal hexane and petroleum ether; the eluent used for column chromatography is a mixed solution of ethyl acetate and n-hexane, or a mixed solution of ethyl acetate and petroleum ether.
The stilbene compound containing the bromothiazole ring is applied to an antitumor drug or an antibacterial agent.
Compared with the prior art, the invention has the following beneficial effects:
the present invention provides a new type ofE) The-5-bromo-4- (2, 6-difluorophenyl) -2-substituted styryl thiazole compound is simple to prepare and shows certain anticancer and antifungal activities. In the examples, the anti-tumor activity of the synthesized compounds was determined by DNA loosening testThe experimental result shows that most compounds have certain antitumor activity at the concentration of 50 mu M; under the concentration of 100 mg/L, the (E) -5-bromo-4- (2, 6-difluorophenyl) -2-substituted styryl thiazole compound shows certain inhibitory activity on a test target, wherein the inhibitory rates of the compounds Ia, Ib and Id on wheat scab pathogen are all over 50%, and the inhibitory rate of the compound Id on cucumber sphaleria solani is 56.7%, so that the compound shows moderate inhibitory 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 derivative Ia (r (n) = H):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 15 mL (86.8mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 1 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 20 mL of DMF, benzaldehyde (1.3g, 12 mmol) and sodium hydroxide (0.9 g, 22 mmol) to react. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 3 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using ethyl acetate to obtain 1.6 g of a yellow solid, namely the (E) -4- (2, 6-difluorophenyl) -2-styrylthiazole, wherein the yield is calculated to be 54.7%. m.p. of 79-80 ℃;
1H NMR (500 MHz, Chloroform-d) 7.56 (d,J= 7.5 Hz, 2H), 7.50 –7.37 (m, 5H), 7.37 – 7.26 (m, 2H), 7.02 (t,J= 8.0 Hz, 2H)；
HRMS (ESI) calcd C17H11F2NS [M+H]+300.0688, found 300.0662。
(E) -4- (2, 6-difluorophenyl) -2-styrylthiazole (3.0 g,10 mmol) prepared as described above and N-bromosuccinimide (2.14 g, 12 mmol) were dissolved in 15 mL of acetonitrile and reacted with stirring at 20 ℃. The reaction process was checked by TLC, and after about 2.5 hours, ice water was added to the reaction solution, followed by stirring to precipitate a solid, filtration and recrystallization from ethyl acetate to obtain 1.9 g of a yellow solid with a yield of 50.2%. m.p. 103-105 ℃;
1H NMR (500 MHz, Chloroform-d)7.54 (d, J = 7.5 Hz, 2H), 7.49–7.33(m, 5H), 7.27 (d, J = 16.5 Hz, 1H), 7.09–7.00 (m, 2H)；
HRMS (ESI) calcd C17H10BrF2NS [M+H]+ 377.9765, found 377.9759。
example 2 synthesis of derivative Ib (r (n) = o-chloro):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 9.0 mL (50.0mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 1.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 25mL of DMF, o-chlorobenzaldehyde (1.4g, 10 mmol) and sodium hydroxide (1.3g, 32 mmol) to react. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction within about 3.5 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using ethanol to obtain 1.4g of a yellow solid, namely the (E) -4- (2, 6-difluorophenyl) -2-o-chlorostyrenyl thiazole, wherein the calculated yield is 40.6%. m.p. 87-89 ℃;
1H NMR (500 MHz, Chloroform-d) 7.83 (d,J= 16.0 Hz, 1H), 7.74 –7.67 (dd,J= 7.5, 1.5 Hz, 1H), 7.50 (s, 1H), 7.48 – 7.38 (m, 2H), 7.38 –7.20 (m, 3H), 7.02 (t,J= 8.5 Hz, 1H)；
HRMS (ESI) calcd C17H10ClF2NS [M+H]+334.0263, found 334.0250。
(E) -4- (2, 6-difluorophenyl) -2-o-chlorostyrylthiazole (3.34 g,10 mmol), prepared as described above, and N-bromosuccinimide (5.34 g, 30mmol) were dissolved in 30 mL of acetonitrile and reacted with stirring at 45 ℃. Detecting the reaction process by TLC (thin layer chromatography), finishing the reaction within about 1.0 hour, adding ice water into the reaction solution, stirring, separating out solids, filtering, and then recrystallizing with ethanol to obtain yellow solids 2.5 g, wherein the yield is 60.6%; m.p. 144-147 ℃;
1H NMR (500 MHz, Chloroform-d)7.74 (d, J = 16.0 Hz, 1H), 7.70–7.64(m, 1H), 7.48–7.38 (m, 2H), 7.33–7.24 (m, 3H), 7.11–6.98 (m, 2H)；
HRMS (ESI) calcd C17H9BrClF2NS [M+H]+ 411.9368, found 411.9380。
example 3 synthesis of derivative Ic (r (n) = p-chloro):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 12 mL (69.5mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 3 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 22 mL of DMF, p-chlorobenzaldehyde (2.8 g, 20 mmol) and sodium hydroxide (2.0 g, 50 mmol) to react. And (3) detecting the reaction process by TLC (thin layer chromatography), ending the reaction for about 2.5 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using n-hexane to obtain 1.9 g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2-p-chlorostyrylthiazole, wherein the calculated yield is 56.1%. m.p. 91-93 ℃;
1H NMR (500 MHz, Chloroform-d) 7.50 – 7.45 (m, 3H), 7.40 (d,J=16.0 Hz, 1H), 7.38 – 7.29 (m, 4H), 7.02 (t,J= 8.0 Hz, 2H)；
HRMS (ESI) calcd C17H10ClF2NS [M+H]+334.0263, found 334.0254。
(E) -4- (2, 6-difluorophenyl) -2-p-chlorostyrylthiazole (3.34 g,10 mmol), prepared as described above, and N-bromosuccinimide (2.67 g, 15mmol) were dissolved in 25mL of acetonitrile and reacted with stirring at 25 ℃. The reaction process was checked by TLC, and after about 2.0 hours, ice water was added to the reaction mixture, and the mixture was stirred to precipitate a solid, which was then filtered and recrystallized from petroleum ether to give 2.4 g of a yellow solid with a yield of 58.2%. m.p. 110-119 ℃;
1H NMR (500 MHz, Chloroform-d) 7.46 (d, J = 8.5 Hz, 2H), 7.43-7.40(m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 16.0 Hz, 1H), 7.22 (d, J =16.0 Hz, 1H), 7.04 (m, J = 8.5Hz, 2H)；
HRMS (ESI) calcd C17H9BrClF2NS [M+H]+ 411.9368, found 411.9384。
example 4 Synthesis of derivative Id (R (n) = p-trifluoromethyl)
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 16 mL (92.6mmol) triethyl phosphite and heated to reflux and the reaction was monitored by TLC after about 2 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 30 mL of DMF, p-trifluoromethylbenzaldehyde (5.3 g, 30mmol) and sodium hydroxide (1.2 g, 30mmol) to react. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 2 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using a mixed solution of ethyl acetate and petroleum ether (V ethyl acetate: V petroleum ether = 1: 1) to obtain 2.3g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2-p-trifluoromethylstyryl thiazole, wherein the yield is calculated to be 62.4%. 117-119 ℃ in m.p.;
1H NMR (500 MHz, Chloroform-d) 7.65 (s, 4H), 7.52 (s, 1H), 7.47(s, 2H), 7.39 – 7.30 (m, 1H), 7.03 (t,J= 8.0 Hz, 2H)；
HRMS (ESI) calcd C18H10F5NS [M+H]+368.0527, found 368.0511。
(E) -4- (2, 6-difluorophenyl) -2-p-trifluoromethylstyrylthiazole (3.68 g,10 mmol) prepared as described above and N-bromosuccinimide (7.12 g, 40 mmol) were dissolved in 50 mL of acetonitrile and reacted with stirring at 25 ℃. The reaction process was checked by TLC, and after about 2.5 hours, ice water was added to the reaction solution, followed by stirring to precipitate a solid, filtration and recrystallization from n-hexane to give 2.9 g of a yellow solid with a yield of 65.0%. m.p. 89-91 ℃;
1H NMR (500 MHz, Chloroform-d) 7.70 – 7.59 (dd,J = 8.5, 5.0 Hz 4H),7.44 (m, 1H), 7.39 (d, J = 16.5 Hz, 1H), 7.33 (d, J = 16.5 Hz, 1H), 7.09 –7.01 (m, 2H)；
HRMS (ESI) calcd C18H9BrF5NS [M+H]+ 445.9632, found 445.9643。
example 5 synthesis of derivative Ie (r (n) = p-methoxy):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 35 mL (200 mmol) of triethyl phosphite and heated to reflux and the reaction was monitored by TLC after about 1 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 15 mL of DMF, p-methoxybenzaldehyde (3.4 g, 25 mmol) and sodium hydroxide (1.6 g, 40 mmol) to react. And detecting the reaction process by TLC (thin layer chromatography), finishing the reaction within about 1.5 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using ethanol to obtain 2.2 g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2-p-methoxystyryl thiazole, wherein the calculated yield is 68.0%. m.p. 132-133 ℃;
1H NMR (500 MHz, Chloroform-d) 7.51 (d,J= 8.5 Hz, 2H), 7.43 (s,1H), 7.41 (d,J= 16.0 Hz, 1H), 7.37 – 7.31 (m, 1H), 7.28 (d,J= 16.0 Hz,1H), 7.02 (t,J= 8.0 Hz, 2H), 6.93 (d,J= 8.5 Hz, 2H), 3.85 (s, 3H)；
HRMS (ESI) calcd C18H13F2NOS [M+H]+330.0759, found 330.0747。
(E) -4- (2, 6-difluorophenyl) -2-p-methoxystyrylthiazole (3.30 g,10 mmol), prepared as described above, and N-bromosuccinimide (3.56 g, 20 mmol) were dissolved in 35 mL of acetonitrile and reacted with stirring at 35 ℃. The reaction process was checked by TLC for about 1.5 hours, ice water was added to the reaction solution, and the mixture was stirred to precipitate a solid, filtered, and recrystallized from a mixture of ethanol and petroleum ether (vuthanol: vu petroleum ether = 2: 1) to give 2.7 g of a yellow solid with a yield of 66.1%. m.p. 102-107 ℃;
1H NMR (500 MHz, Chloroform-d) 7.48 (d, J = 9.0 Hz, 2H), 7.43 (m, ,1H), 7.31 (d, J = 16.0 Hz, 1H), 7.14 (d, J = 16.0 Hz, 1H), 7.07 – 7.00 (m,2H), 6.93 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H)；
HRMS (ESI) calcd C18H12BrF2NOS [M+H]+, 407.9864 found. 445.9884。
example 6 synthesis of derivative If (r (n) =2, 4-dichloro):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 11 mL (63.7mmol) triethyl phosphite and heated to reflux and the reaction was monitored by TLC after about 3 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 18 mL of DMF, 2, 4-dichlorobenzaldehyde (3.4 g, 25 mmol) and sodium hydroxide (0.8 g, 20 mmol) to react. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 3 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using cyclohexane to obtain 1.8 g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2- (2, 4-dichlorostyryl) thiazole, wherein the calculated yield is 48.2%. m.p. 107-108 ℃;
1H NMR (500 MHz, Chloroform-d) 7.72 (d,J= 16.0 Hz, 1H), 7.60 (d,J= 8.5 Hz, 1H), 7.50 (s, 1H), 7.41 (d,J= 2.0 Hz, 1H), 7.36 (d,J= 16.0Hz, 1H), 7.34 – 7.28 (m, 1H), 7.25 (dd,J= 8.5, 2.0 Hz, 1H), 7.01 (t,J=8.0 Hz, 1H)；HRMS (ESI) calcd C17H9Cl2F2NS [M+H]+367.9874, found 367.9873。
(E) -4- (2, 6-difluorophenyl) -2- (2, 4-dichlorostyryl) thiazole (3.69 g,10 mmol) prepared as described above and N-bromosuccinimide (6.23 g, 35 mmol) were dissolved in 45 mL of acetonitrile and reacted with stirring at 50 ℃. The reaction process was checked by TLC, and after about 1 hour, ice water was added to the reaction mixture, and the mixture was stirred to precipitate a solid, which was then filtered and recrystallized from ethyl acetate to give 2.6 g of a yellow solid with a yield of 58.1%. m.p. 96-100 ℃;
1H NMR (500 MHz, Chloroform-d) 7.66 (d, J = 16.5 Hz, 1H), 7.60 (d,J = 8.5 Hz,1H), 7.46 – 7.41 (m, 2H), 7.30 – 7.28 (m, 1H), 7.25 (d, J = 16.5Hz, 1H), 7.04 (t, J = 8.5, 2H)；
HRMS (ESI) calcd C17H8BrCl2F2NS [M+H]+ 445.8986, found 445.8981。
example 7 synthesis of the derivative Ig (r (n) = p-methyl)
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 10 mL (57.9mmol) triethyl phosphite and heated to reflux and the reaction was monitored by TLC after about 1 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 20 mL of DMF, p-tolualdehyde (1.5 g, 12 mmol) and sodium hydroxide (0.4 g,10 mmol) to react. And detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 4 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using petroleum ether to obtain 2.1 g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2-p-methylstyrene thiazole, wherein the yield is 66.3%. m.p. 149-150 ℃;
1H NMR (500 MHz, Chloroform-d) 7.50 – 7.41 (m, 4H), 7.37 (d,J=16.0 Hz, 1H), 7.35 – 7.28 (m, 1H), 7.21 (d,J= 8.0 Hz, 2H), 7.02 (t,J= 8.0Hz, 2H), 2.38 (s, 3H)；
HRMS (ESI) calcd C18H13F2NS [M+H]+314.0810, found 314.0804。
(E) -4- (2, 6-difluorophenyl) -2-p-methylstyrene isothiazole (3.14 g,10 mmol) prepared in the above-mentioned manner and N-bromosuccinimide (2.50 g, 14 mmol) were dissolved in 20 mL of acetonitrile and reacted with stirring at 30 ℃. The reaction process is detected by TLC, about 3 hours of reaction is finished, ice water is added into the reaction liquid, stirring is carried out, solid is separated out, filtering is carried out, and then petroleum ether is used for recrystallization to obtain yellow solid 2.5 g, and the yield is 63.7%. m.p. 144-148 ℃;
1H NMR (500 MHz, Chloroform-d) 7.46 (d, J = 8.0 Hz, 2H), 7.44 (d,J = 16.5 Hz, 1H), 7.37 (d, J = 16.5 Hz, 1H), 7.35 – 7.31 (m, 1H), 7.21 (d, J= 8.0 Hz, 2H), 7.02 (t, J = 8.0 Hz, 2H), 2.39 (s, 3H)；
HRMS (ESI) calcd C18H12BrF2NS [M+H]+ 391.9915, found 391.9941。
example 8 synthesis of derivative Ih (r (n) = p-tert-butyl):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 26 mL (150 mmol) of triethyl phosphite and heated to reflux and the reaction was monitored by TLC after about 3 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 20 mL of DMF, p-tert-butylbenzaldehyde (2.5 g, 15mmol) and sodium hydroxide (0.8 g, 20 mmol) to react. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction within about 3.5 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using petroleum ether to obtain 1.5 g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2-p-tert-butylvinyl thiazole with the yield of 43.5%. m.p. 55-60 ℃;
1H NMR (500 MHz, Chloroform-d) 7.51 (d,J= 8.0 Hz, 2H), 7.47 –7.41 (m, 4H), 7.39 (d,J= 16.0 Hz, 1H), 7.36 – 7.29 (m, 1H), 7.02 (t,J=8.0 Hz, 2H), 1.36 (s, 9H)；
HRMS (ESI) calcd C21H19F2NS [M+H]+356.1206, found 356.1119。
(E) -4- (2, 6-difluorophenyl) -2-p-tert-butylmethylvinylthiazole (3.56 g,10 mmol) prepared as described above and N-bromosuccinimide (4.45 g, 25 mmol) were dissolved in 30 mL of acetonitrile and reacted with stirring at 20 ℃. TLC detection reaction process, about 5 hours reaction completion, reaction liquid added with ice water, stirring, ethyl acetate extraction, desolventizing, residual liquid by column chromatography (eluent is ethyl acetate and n-hexane mixed liquid, V ethyl acetate: V n-hexane = 1: 5) separation of yellow liquid 2.8 g, yield 64.4%.
1H NMR (500 MHz, Chloroform-d) 7.48 (d, J = 8.5 Hz, 2H), 7.44 –7.39 (m, 3H), 7.35 (d, J = 16.5 Hz, 1H), 7.25 (d, J = 16.5 Hz, 1H), 7.08 –7.01 (t, J = 8.5 Hz, 2H), 1.35 (s,9H)；
HRMS (ESI) calcd C21H18BrF2NS [M+H]+ 434.0384, found 434.0411。
Example 9 synthesis of derivative Ii (r (n) = p-fluoro):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 17 mL (98.43mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 1.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrate were added 28 mL of DMF, p-fluorobenzaldehyde (2.3 g, 18mmol) and sodium hydroxide (1.2 g, 30mmol) and reacted. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 3 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using ethanol to obtain 1.7 g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2-p-fluorostyrylthiazole, wherein the yield is 55.3%. m.p. 95-99 ℃;
1H NMR (500 MHz, Chloroform-d) 7.52 (dd,J= 8.5, 5.0 Hz, 2H), 7.46(s, 1H), 7.41 (d,J= 16.0 Hz, 1H), 7.36 – 7.27 (m, 2H), 7.08 (t,J= 8.5 Hz,2H), 7.01 (t,J= 8.5 Hz, 2H)；
HRMS (ESI) calcd C17H10F3NS [M+H]+318.0559, found 318.0552。
(E) -4- (2, 6-difluorophenyl) -2-p-fluorostyrylthiazole (3.18 g,10 mmol) prepared as described above and N-bromosuccinimide (2.67 g, 15mmol) were dissolved in 35 mL of acetonitrile and reacted with stirring at 30 ℃. The reaction process was checked by TLC for about 3 hours, ice water was added to the reaction solution, and the reaction solution was stirred to precipitate a large amount of solid, filtered, and recrystallized with a mixture of ethyl acetate and n-hexane (V ethyl acetate: V n-hexane = 2: 1) to obtain 2.3g of yellow solid with a yield of 58.0%. m.p. 105-106 ℃;
1H NMR (500 MHz, Chloroform-d) 7.51 (dd, J = 5.5, 8.5 Hz, 2H),7.43 (m, 1H), 7.33 (d, J = 16.0Hz, 1H), 7.18 (d, J = 16.0 Hz, 1H), 7.09 (t, J= 8.5 Hz, 2H), 7.04 (t, J = 8.5 Hz, 2H)；
HRMS (ESI) calcd C17H9BrF3NS [M+H]+ 395.9664, found 395.9688。
example 10 synthesis of derivative Ij (r (n) = o-methyl):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 10 mL (57.9mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 2.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 20 mL of DMF, o-methylbenzaldehyde (2.6 g, 22 mmol) and sodium hydroxide (0.8 g, 20 mmol) to react. The reaction process is detected by TLC (thin layer chromatography), the reaction is finished within about 2.5 hours, the reaction solution is poured into 100mL of ice water, stirred, extracted by ethyl acetate, and then separated by column chromatography (eluent is mixed solution of ethyl acetate and n-hexane, V ethyl acetate: V n-hexane = 1: 4) to obtain 2.1 g of yellow liquid, namely (E) -4- (2, 6-difluorophenyl) -2-o-methylstyrene thiazole, and the yield is 67.6%.
1H NMR (500 MHz, Chloroform-d) 7.72 (d,J= 16.0 Hz, 1H), 7.68 –7.60 (m, 1H), 7.47 (s, , 1H), 7.37 – 7.30 (m,2H), 7.28 – 7.20 (m, 3H), 7.07 –6.99 (t,J= 8.0 Hz, 2H), 2.49 (s, 3H)；
HRMS (ESI) calcd C18H13F2NS [M+H]+314.0810, found 314.0802。
(E) -4- (2, 6-difluorophenyl) -2-o-methylstyrene thiazole (3.14 g,10 mmol), prepared as described above, and N-bromosuccinimide (7.12 g, 40 mmol) were dissolved in 25mL of acetonitrile and reacted with stirring at 30 ℃. The reaction process was checked by TLC, and after about 2.5 hours, ice water was added to the reaction solution, followed by stirring to precipitate a solid, filtration and recrystallization from ethanol to give 2.1 g of a yellow solid with a yield of 53.5%. m.p. 128-132 ℃;
1H NMR (500 MHz, Chloroform-d) 7.64 – 7.58 (m, 2H), 7.43 (m, , 1H),7.30 – 7.16 (m, 4H), 7.08 – 7.01 (m, 2H), 2.47 (s, 3H)；
HRMS (ESI) calcd C18H12BrF2NS [M+H]+ 391.9915, found 391.9912。
example 11 synthesis of derivative Ik (r (n) = m-methyl):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 18 mL (104.2mmol) triethyl phosphite and heated to reflux and the reaction was monitored by TLC after about 3 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 20 mL of DMF, m-tolualdehyde (1.8 g, 15mmol) and sodium hydroxide (1.6 g, 40 mmol) to react. The reaction process is detected by TLC, the reaction is finished within about 2.5 hours, the reaction solution is poured into 100mL of ice water, stirred and extracted by ethyl acetate, and then is separated by column chromatography (eluent is mixed solution of ethyl acetate and n-hexane, V ethyl acetate: V n-hexane = 1: 5) to obtain 1.8 g of yellow liquid, namely (E) -4- (2, 6-difluorophenyl) -2-m-methylstyrene thiazole, and the yield is 57.3%.1H NMR (500 MHz, Chloroform-d) 7.46 (s, 1H),7.43 (d,J= 3.0 Hz, 2H), 7.38 (d,J= 6.5 Hz, 2H), 7.31 (m, 2H), 7.16 (d,J= 7.5 Hz, 1H), 7.02 (t,J= 8.5 Hz, 2H), 2.39 (s, 3H)；
HRMS (ESI) calcd C18H13F2NS [M+H]+314.0810, found 314.0788。
(E) -4- (2, 6-difluorophenyl) -2-m-methylstyrene isothiazole (3.14 g,10 mmol) prepared as described above and N-bromosuccinimide (3.56 g, 20 mmol) were dissolved in 35 mL of acetonitrile and reacted with stirring at 40 ℃. The reaction process was checked by TLC, and after about 2.0 hours, ice water was added to the reaction mixture, and the mixture was stirred to precipitate a solid, which was then filtered and recrystallized from petroleum ether to give 2.4 g of a yellow solid with a yield of 61.1%. m.p. 65-70 ℃;
1H NMR (500 MHz, Chloroform-d) 7.47 – 7.39 (m, 1H), 7.37 – 7.32 (m,3H), 7.31 – 7.24 (m, 2H), 7.17 (d, J = 7.5 Hz, 1H), 7.04 (dd, J = 8.5, 7.5Hz, 2H), 2.39 (s, 3H)；
HRMS (ESI) calcd C18H12BrF2NS [M+H]+ 391.9915, found 391.9928。
example 12 synthesis of derivative Il (r (n) = m-bromo):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 10 mL (57.9mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 2 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrate were added 24 mL of DMF, m-bromobenzaldehyde (3.7 g, 20 mmol) and sodium hydroxide (1.6 g, 40 mmol) and reacted. TLC detection reaction process, about 4 hours reaction end, reaction liquid poured into 100mL ice water, stirring, ethyl acetate extraction, then column chromatography (eluent is ethyl acetate and n-hexane mixed liquid, V ethyl acetate: V petroleum ether = 1: 3) separation to obtain yellow liquid 1.7 g, namely (E) -4- (2, 6-difluorophenyl) -2-m-bromophenylvinyl thiazole, yield 45.2%.
1H NMR (500 MHz, Chloroform-d) 7.68 (s, 1H), 7.49 (s, 1H), 7.45 (t,J= 8.0 Hz, 2H), 7.36 (s, 2H), 7.35 – 7.29 (m, 1H), 7.24 (t,J= 8.0 Hz, 1H),7.02 (t,J= 8.0 Hz, 2H)；
HRMS (ESI) calcd C17H10BrF2NS [M+H]+377.9758, found 377.9753。
(E) -4- (2, 6-difluorophenyl) -2-m-bromostyrylthiazole (3.79 g,10 mmol), prepared as described above, and N-bromosuccinimide (4.45 g, 25 mmol) were dissolved in 35 mL of acetonitrile and reacted with stirring at 30 ℃. The reaction process was checked by TLC, and after about 4.5 hours, ice water was added to the reaction solution, followed by stirring to precipitate a solid, filtration and recrystallization from ethanol to give 2.5 g of a yellow solid with a yield of 54.6%. m.p. 84-87 ℃;
1H NMR (500 MHz, Chloroform-d) 7.68 (t, J = 2.0 Hz, 1H), 7.51 –7.39 (m, 3H), 7.33 – 7.20 (m, 3H), 7.04 (dd, J = 8.5, 7.5 Hz, 2H)；
HRMS (ESI) calcd C17H9Br2F2NS [M+H]+ 455.8863, found 455.8873。
example 13 synthesis of derivative Im (r (n) = ortho-bromo):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 13 mL (75.2mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 2.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 20 mL of DMF, o-bromobenzaldehyde (2.8 g, 15mmol) and sodium hydroxide (1.2 g, 30mmol) to react. And (3) detecting the reaction process by TLC (thin layer chromatography), ending the reaction for about 3 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using a mixed solution of ethyl acetate and n-hexane (V ethyl acetate: V n-hexane = 2: 1) to obtain 1.8 g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2-o-bromophenylvinyl thiazole with the yield of 48.4%. m.p. 75-77 ℃;
1H NMR (500 MHz, Chloroform-d) 7.77 (d,J= 16.0 Hz, 1H), 7.68 (dd,J= 7.5, 1.0 Hz, 1H), 7.60 (dd,J= 8.0, 1.0 Hz, 1H), 7.49 (s, 1H), 7.41 –7.27 (m, 3H), 7.17 (td,J= 8.0, 1.5 Hz, 1H), 7.01 (t,J= 8.0 Hz, 2H)；
HRMS (ESI) calcd C17H10BrF2NS [M+H]+377.9758, found 377.9755。
(E) -4- (2, 6-difluorophenyl) -2-o-bromobenzenethiazolium (3.79 g,10 mmol) prepared as described above and N-bromosuccinimide (6.23 g, 35 mmol) were dissolved in 40 mL of acetonitrile and reacted with stirring at 20 ℃. The reaction progress was checked by TLC, and after about 5.5 hours, ice water was added to the reaction solution, and the mixture was stirred to precipitate a solid, which was then filtered, followed by recrystallization from a mixture of ethyl acetate and petroleum ether (V ethyl acetate: V petroleum ether = 2: 1) to obtain 2.4 g of a yellow solid with a yield of 52.5%. m.p. 141-148 ℃;
1H NMR (500 MHz, Chloroform-d) 7.70 (d, J = 16.0 Hz, 1H), 7.66 (dd,J = 8.0, 1.5 Hz, 1H), 7.62 (dd, J = 8.0, 1.0 Hz, 1H), 7.43 (m,, 1H), 7.35 (t,J = 7.5 Hz, 1H), 7.27 – 7.17 (m, 2H), 7.04 (dd, J = 8.5, 7.5 Hz, 2H)；
HRMS (ESI) calcd C17H9Br2F2NS [M+H]+ 455.8863, found 455.8855。
example 14 synthesis of the derivative In (r (n) = m-methoxy):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 15 mL (86.8mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 1.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 20 mL of DMF, m-methoxybenzaldehyde (2.5 g, 18mmol) and sodium hydroxide (1.0 g, 25 mmol) to react. And detecting the reaction process by TLC (thin layer chromatography), finishing the reaction within about 1.5 hours, pouring the reaction liquid into 150 mL of ice water, stirring, separating out a solid, filtering, and recrystallizing by using petroleum ether to obtain 2.2 g of a yellow solid, namely (E) -4- (2, 6-difluorophenyl) -2-m-methoxystyrylthiazole, wherein the yield is 67.4%. m.p. 60-62 ℃;
1H NMR (500 MHz, Chloroform-d) 7.48 (s, 1H), 7.42 (s, 2H), 7.37 –7.27 (m, 2H), 7.16 (d,J= 8.0 Hz, 1H), 7.10 (t,J= 2.0 Hz, 1H), 7.02 (t,J= 8.5 Hz, 2H), 6.90 (dd,J= 8.0, 2.5 Hz, 1H), 3.85 (s, 3H)；
HRMS (ESI) calcd C18H13F2NOS [M+H]+330.0759, found 330.0749。
(E) -4- (2, 6-difluorophenyl) -2-m-methoxystyrylthiazole (3.30 g,10 mmol), prepared as described above, and N-bromosuccinimide (3.56 g, 20 mmol) were dissolved in 45 mL of acetonitrile and reacted with stirring at 25 ℃. The reaction process was checked by TLC for about 2.5 hours, ice water was added to the reaction solution, stirred, extracted with ethyl acetate, and then separated by column chromatography (eluent used was a mixture of ethyl acetate and n-hexane, V ethyl acetate: V n-hexane = 1: 5) to obtain 1.9 g of yellow liquid with a yield of 46.5%.
1H NMR (500 MHz, Chloroform-d) 7.47 – 7.39 (m, 1H), 7.36 – 7.29 (m,2H), 7.26 (d, J = 16.0 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.09 – 7.01 (m,3H), 6.91 (dd, J = 8.0, 2.5 Hz, 1H), 3.84 (s, 3H)；
HRMS (ESI) calcd C18H12BrF2NOS [M+H]+ 407.9864, found 407.9867。
Example 15 synthesis of derivative Io (r (n) = o-methoxy):
2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole (2.9 g,10 mmol) was added to 10 mL (57.9mmol) triethyl phosphite and heated to reflux and the reaction was checked by TLC after about 2.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added 20 mL of DMF, o-methoxybenzaldehyde (2.1 g, 15mmol) and sodium hydroxide (1.2 g, 30mmol) to react. TLC detection reaction process, about 2 hours reaction end, reaction liquid poured into 100mL ice water, stirring, ethyl acetate extraction, then column chromatography (eluent used is ethyl acetate and petroleum ether mixed liquid, V ethyl acetate: V petroleum ether = 1: 5) separation to obtain yellow liquid 1.6 g, namely (E) -4- (2, 6-difluorophenyl) -2-o-methoxy styryl thiazole, yield 50.1%.
1H NMR (500 MHz, Chloroform-d) 7.76 (d,J= 16.0 Hz, 1H), 7.58 (dd,J= 7.5, 1.5 Hz, 1H), 7.53 (d,J= 16.0 Hz, 1H), 7.44 (s, 1H), 7.34 – 7.25(m, 2H), 7.05 – 6.97 (m, 3H), 6.92 (d,J= 8.5 Hz, 1H), 3.89 (s, 3H)；
HRMS (ESI) calcd C18H13F2NOS [M+H]+330.0759, found 330.0745。
(E) -4- (2, 6-difluorophenyl) -2-o-methoxystyrylthiazole (3.30 g,10 mmol) prepared as described above and N-bromosuccinimide (5.34 g, 30mmol) were dissolved in 30 mL of acetonitrile and reacted with stirring at 40 ℃. The reaction progress was checked by TLC for about 1.5 hours, ice water was added to the reaction solution, stirring was performed, ethyl acetate was extracted, and then column chromatography (eluent used was a mixture of ethyl acetate and petroleum ether, V ethyl acetate: V petroleum ether = 1: 4) was performed to obtain 2.2 g of yellow liquid with a yield of 53.8%.
1H NMR (500 MHz, Chloroform-d) 7.42 (m,, 1H), 7.36 – 7.28 (m, 2H),7.26 (d, J = 16.5 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.09 – 7.00 (m, 3H),6.91 (dd, J = 8.0, 2.5 Hz, 1H), 3.83 (s, 3H)；
HRMS (ESI) calcd C18H12BrF2NOS [M+H]+ 407.9864, found 407.9869。
Example 16 antitumor activity assay:
experiment the inhibitory activity of (E) -5-bromo-4- (2, 6-difluorophenyl) -2-substituted styryl thiazole compounds synthesized in examples 1 to 15 on topoisomerase I (TOP I) was tested by a DNA loosening experiment at a test concentration of 50. mu.M.
The specific experimental process is as follows: reaction system (20 μ L): mu.l of 0.2. mu.g negative supercoiled plasmid p322 DNA, 1. mu.l of 0.5U TOP I, 1. mu.l of 50. mu.M test compound, buffer solution (20 mM Tris, pH 7.5, 0.1 mM EDTA, 10mM MgCl)2100 Mm KCl, 50. mu.g/mL acetylated BSA) make up the volume.
After the samples were prepared, they were incubated at 37 ℃ for half an hour. After incubation, 4. mu.L of 6 XLoadingbuffer was added and mixed, and added to a sample well of 0.8% agarose gel and electrophoresed at 4.6V/cm for 1.5 hours. After the electrophoresis was completed, the agarose gel was stained in an aqueous solution of 1 Xgel red for 0.5 hour, and photographed.
The test results are shown in Table 1.
Antitumor Activity of Compounds Ia-Io at Table 150 μ M
Note a: DNA relaxation assay inhibitory activity of TOPI (topoisomerase I) CPT (camptothecin), a positive control drug having inhibitory activity against TOP1, was used as a control group. The data obtained are quantified relative to CPT 50. mu.M as follows: + + + + +, indicating an activity of 80% or more; + + + + represents between 40% and 79%; + means between 10% and 39%; +, less than 10% activity.
As can be seen from Table 1, compounds Ia to Io shown in the examples of the present invention all had certain antitumor activity at a concentration of 50. mu.M.
Example 17 antifungal activity test:
test targets: wheat scab fungus Fusahum graminearum, cucumber Rhizoctonia solani Mycosphaerellaramelonis, Botrytis cinerea, and Rhizoctonia solani Thanatephorum cucumeris.
The bactericidal activity of the target germs was measured for 15 (E) -5-bromo-4- (2, 6-difluorophenyl) -2-substituted styryl thiazole compounds synthesized in examples 1 to 15 and a blank drug by a potato agar medium (PDA) method, and the concentration of the common sieve was 100 mg/L.
Specifically, the test method refers to "evaluation of biological Activity of pesticides SOP". Adopting a medicine-containing culture medium method: 2 mL of each 500 mg/L compound solution was added to 8 mL of PDA cooled to 45 ℃ to prepare a drug-containing medium plate with a final concentration of 100 mg/L. A6.5 mm diameter piece of hyphae was then removed from the edge of the cultured test pathogen colony and transferred to the drug-containing medium 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.
Growth inhibition (%) = [ (blank control colony diameter-treated colony diameter)/blank control colony diameter ] × 100%;
the test results are shown in Table 2.
The blank of this example was prepared in the absence of drug, and the same conditions were used for the other operations.
Fungicidal Activity of Compounds Ia-Io at 2100 mg/L
Note: azoxystrobin was the control drug and CK was the blank control.
Table 2 shows bactericidal activity test results that at a concentration of 100 mg/L, the (E) -5-bromo-4- (2, 6-difluorophenyl) -2-substituted styryl thiazole compounds of the present invention all exhibit certain inhibitory activities on test targets, wherein the inhibitory rates of the compounds Ia, Ib, and Id on gibberella zeae are all above 50%, and the inhibitory rate of the compound Id on fusarium oxysporum f.sp.cubense is 56.7%, which exhibits moderate inhibitory activities.
The description is given for the sole purpose of illustrating embodiments of the inventive concept and should not be taken as limiting the scope of the invention to the particular forms set forth in the embodiments, but rather as being limited only to the equivalents thereof as may be contemplated by those skilled in the art based on the teachings herein.
Claims (11)
1. A stilbene compound containing a bromothiazole ring has a structure shown in a formula (I):
in the formula (I), R (n) is hydrogen, o-methyl, m-methyl, p-methyl, o-methoxy, p-methoxy, m-methoxy, p-tert-butyl, p-trifluoromethyl, p-fluorine, o-chlorine, p-chlorine, o-bromine, m-bromine or 2, 4-dichloro.
2. A method for synthesizing the benzhydryl-like compound containing the bromothiazole ring according to claim 1, which comprises the steps of:
1) reacting 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole with triethyl phosphite under a reflux state, monitoring by TLC (thin layer chromatography) until the reaction is finished, concentrating to remove redundant triethyl phosphite, adding DMF (dimethyl formamide), sodium hydroxide and substituted benzaldehyde shown as a formula (IV) into the obtained concentrated solution, reacting at room temperature, and performing post-treatment after the reaction is finished to obtain a stilbene compound containing a thiazole ring shown as a formula (II);
2) carrying out bromination reaction on a stilbene compound containing a thiazole ring shown in a formula (II) and N-bromosuccinimide shown in a formula (III) in an acetonitrile solvent at 0-100 ℃ to prepare a stilbene compound containing a bromothiazole ring shown in a formula (I);
in the formulas (II) and (IV), R (n) is hydrogen, o-methyl, m-methyl, p-methyl, o-methoxy, p-methoxy, m-methoxy, p-tert-butyl, p-trifluoromethyl, p-fluorine, o-chlorine, p-chlorine, o-bromine, m-bromine or 2, 4-dichloro.
3. The method for synthesizing a benzhydryl compound containing a bromothiazole ring according to claim 1, wherein in step 1), the ratio of the amounts of the 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole, the triethyl phosphite, the substituted benzaldehyde represented by formula (IV) and the sodium hydroxide is 1: 1.0-30.0: 1.0-8.0: 1.0-20.0;
the mass ratio of the 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole to the DMF solvent is 1: 2.0-20.
4. The method for synthesizing a benzhydryl compound containing a bromothiazole ring according to claim 1, wherein in step 1), the ratio of the amounts of the 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole, the triethyl phosphite, the substituted benzaldehyde represented by formula (IV) and the sodium hydroxide is 1: 5.0-20.0: 1.0-3.0: 1.0-5.0;
the mass ratio of the 2- (bromomethyl) -4- (2, 6-difluorophenyl) thiazole to the DMF solvent is 1: 4.0-10.
5. The method for synthesizing the stilbene compound containing the bromothiazole ring according to claim 1, which is characterized in that the amount ratio of the stilbene compound containing the thiazole ring shown in the formula (II) to the N-bromosuccinimide shown in the formula (III) is 1: 1.0-20.0;
the mass ratio of the thiazole ring-containing stilbene compound shown in the formula (II) to the acetonitrile solvent is 1: 2.0-20.
6. The method for synthesizing the stilbene compound containing the bromothiazole ring according to claim 1, which is characterized in that the amount ratio of the stilbene compound containing the thiazole ring shown in the formula (II) to the N-bromosuccinimide shown in the formula (III) is 1: 1.0-5.0;
the mass ratio of the thiazole ring-containing stilbene compound shown in the formula (II) to the acetonitrile solvent is 1: 4.0-10.
7. The method for synthesizing a stilbene compound having a bromothiazole ring according to claim 1, wherein the reaction temperature in the step 2) is 20 to 50 ℃ and the reaction time is 0.5 to 6 hours.
8. The method for synthesizing a bromothiazole ring-containing stilbene compound according to claim 1, wherein the method is characterized in that ice water is added into the reaction liquid after the reaction in the step 2), the mixture is stirred, and if solid is separated out, recrystallization purification is carried out to obtain the bromothiazole ring-containing stilbene compound shown in the formula (I); if no solid is separated out, extracting with ethyl acetate, desolventizing, and separating by residual liquid column chromatography to obtain the stilbene compound containing the bromothiazole ring shown in the formula (I).
9. The method for synthesizing a benzhydryl compound containing a bromothiazole ring according to claim 8, wherein the solvent used for recrystallization is one or a mixture of two or more of ethanol, ethyl acetate, n-hexane and petroleum ether; the eluent used for column chromatography is a mixed solution of ethyl acetate and n-hexane, or a mixed solution of ethyl acetate and petroleum ether.
10. The use of a benzhydrylidene-like compound containing a bromothiazole ring according to claim 1 wherein R (n) is hydrogen, p-trifluoromethyl, p-methoxy, p-tert-butyl, o-bromo, or o-methoxy, for the preparation of an antitumor agent for inhibiting topoisomerase I.
11. Use of the stilbene compounds containing bromothiazole rings according to claim 1 as antibacterial agents against fusarium graminearum, fusarium oxysporum, botrytis cinerea and rhizoctonia solani.
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