CN110367265A - A kind of application of the diphenyl ethylene analogue of the structure containing phenyl thiazole as fungicide - Google Patents
A kind of application of the diphenyl ethylene analogue of the structure containing phenyl thiazole as fungicide Download PDFInfo
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- CN110367265A CN110367265A CN201910791653.9A CN201910791653A CN110367265A CN 110367265 A CN110367265 A CN 110367265A CN 201910791653 A CN201910791653 A CN 201910791653A CN 110367265 A CN110367265 A CN 110367265A
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- thiazole
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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 structure of application the invention discloses a kind of diphenylethylene compounds of structure containing phenyl thiazole as fungicide, the diphenylethylene compounds of the structure containing phenyl thiazole is as shown in the formula (I):
Description
Technical field
Application the present invention relates to the diphenyl ethylene analogue of the structure containing phenyl thiazole as fungicide.
Background technique
According to the literature, diphenylethylene compounds are present in mountain Kashihara (Chinese medicine journal, 2015,30 (07): 1010-
1013), chinaroot greenbrier (CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2016,41 (03): 446-450), tree beans leaf (tropical and subtropical plant journal, 2019,
27 (01): 115-120), polygonum cuspidate (contemporary Chinese Chinese medicine, 2017,19 (12): 1688-1691, drug evaluation research, 2016,39
) etc. (02): 317-321 in various plants.Diphenylethylene compounds have multiple biological activities, have such as in field of medicaments
Antitumor (J.Agric.Food Chem., 2019,67 (17): 4709-4717, Journal of the Fourth Military Medical University, 2008,29 (23):
2141-2143, tumour, 2009,29 (01): 26-30), it is blood pressure lowering (Microvasc.Res., 2019,123:42-29), anti-dynamic
Pulse atherosclerosis (J.Agric.Food Chem., 2019,67, (14): 3909-3918), it is anti-inflammatory (J.Agric.Food Chem,
2017,65 (51): 11179-11191), anti-oxidant (J.Bi ol.Chem., 2001,276 (25): 22586-22594) etc. it is living
Property；Related its pesticide activity research is relatively fewer, has desinsection (J.Pest.Sci., 2018,91 (2): 897- according to the literature
906), antimycotic (P lant Dis., 2019,103 (7): 1674-1684), kill algae (J.Agric.Food Chem.2008,
56:9140-9145) isoreactivity.The early-stage study of the applicant shows that diphenylethylene compounds also have mosquitocide
(Chem.Biodiversity 2016,13,1165-1177) isoreactivity.
Thiazole compound is because have good bioactivity and pharmacological activity with unique aromatic heterocyclic structure, example
As anticancer (Eur.J.Med.Chem., 2015,92 (6): 866-875, Biomedi cine&Pharmacotherapy, 2016,
82:555-560), antibacterial (Bioorg.Med.Chem.Let t., 2012,22 (24): 7719-7725, J.Anti., 2014,68
(4): 259-66, Drug Metab.Pharmacok, 2017,1 (32): S96), anti-inflammatory (Comput.Biol.Chem., 2016,
61:86-96), medicinal activities such as anti-oxidant (ChemistrySelect, 2019,4 (19): 5570-5576)；And desinsection
(J.Agric.Food Chem, 2011,59 (9): 2932-2937), (2009,29 (6): organic chemistry 924-928), kills for weeding
The pesticide activities such as bacterium (US 20030203949,2003).Currently, many pesticides containing thiazole structure are successfully commercialized, such as
Fungicide goes out pest azoles, rice can be rich；Herbicide thiazopyr, benazolin；Insecticide moth worm nitrile, clothianidin etc..The applicant is in early period
In work, design has synthesized fluorine phenyl thiazole acrylonitrile compound (organic chemistry, 2009,29 (12): 2000-
2004；Pesticide Science journal, 2010,12 (4): 463-467), experiments have shown that having preferable desinsection and bactericidal activity.
Styrene compound and thiazole heterocycle class compound all have good pesticide activity, but in the prior art simultaneously
There is not document to disclose the chemical structure of the diphenyl ethylene analogue of the structure containing phenyl thiazole, and to the hexichol of the structure containing phenyl thiazole
The bioactivity of ethylene analog has not been reported.
Summary of the invention
In order to solve above-mentioned technical problem of the existing technology, the purpose of the present invention is to provide one kind to contain phenyl thiazole
Application of the diphenylethylene compounds of structure as fungicide, the diphenylethylene compounds of the structure containing phenyl thiazole are (E)-
4- (4- fluorophenyl) -2- substituted phenylethylene base thiazole compound.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
Shown in the structure such as formula (I) of the diphenylethylene compounds of the structure containing phenyl thiazole:
In formula (I), it is monosubstituted or polysubstituted that the H on phenyl ring is substituted base R；N be 1~5 integer, preferably 1~2 it is whole
Number, n indicate the number of substituent R on phenyl ring；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2~5, table
Show that the substituted base R of H on phenyl ring is polysubstituted, the substituent R on different the position of substitution is same or different；The substituent R is
C1~C8 alkyl, C1~C8 halogenated alkyl, C1~C3 alkoxy, halogen, nitro or cyano.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
The substituent R is C1~C5 alkyl, C1~C5 halogenated alkyl, methoxyl group or halogen, preferably methyl, tert-butyl, fluoroform
Base, methoxyl group, F, Cl or Br.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
In formula (I), R (n) be adjacent methyl, methyl, to methyl, O-methoxy, meta-methoxy, to methoxyl group, to tert-butyl, to trifluoro
Methyl, to fluorine, adjacent chlorine, to one of chlorine, adjacent bromine, bromine and 2,4- dichloro.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
The diphenylethylene compounds of the structure containing phenyl thiazole, which are used to prepare, inhibits corn southern leaf blight germ, cucumber anthracnose disease
The fungicide of bacterium, Rhizoctonia solani Kuhn or bacterium of downy mildew of cucumber.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
The synthetic methods of the diphenylethylene compounds of the structure containing phenyl thiazole the following steps are included:
1) the bromo- 2- of 5- (bromomethyl) -4- (4- fluorophenyl) thiazole as shown in formula (II) and the phosphorous as shown in formula (III)
Triethylenetetraminehexaacetic acid ester is reacted under reflux state, and TLC is monitored to after reaction, and extra triethyl phosphite is sloughed in concentration,
Obtain concentrate；
2) solvent DMF, sodium hydroxide and the substituted benzaldehyde as shown in formula (IV) is added in the concentrate obtained by step 1),
It reacts at room temperature, TLC, which is monitored to reaction, to be terminated, last post-treated to be made as shown in formula (I) containing phenyl thiazole structure
Diphenylethylene compounds；
In formula (IV), it is monosubstituted or polysubstituted that the H on phenyl ring is substituted base R；The integer that n is 1~5, preferably 1~2
Integer, n indicate the number of substituent R on phenyl ring；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2~5,
Indicate that the substituted base R of H on phenyl ring is polysubstituted, the substituent R on different the position of substitution is same or different；Taking in formula (IV)
It is C1~C8 alkyl, C1~C8 halogenated alkyl, C1~C3 alkoxy, halogen, nitro or cyano for base R.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
The bromo- 2- of 5- (bromomethyl) -4- (4- fluorophenyl) thiazole, the triethyl phosphite as shown in formula (III) as shown in formula (II), such as
The ratio between amount for the substance that feeds intake of substituted benzaldehyde shown in formula (IV) and sodium hydroxide is 1:10.0~30.0:1.0~8.0:
1.0~20.0, preferably 1:15.0~20.0:1.0~3.0:1.0~5.0.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
The bromo- 2- of 5- (bromomethyl) -4- (4- fluorophenyl) thiazole and the mass ratio of solvent DMF as shown in formula (II) are 1:2.0~20, excellent
It is selected as 1:4.0~10.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
The reaction time of step 1) is 1~3 hour, and the reaction time of step 2) is 1~4 hour.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
Step 2) last handling process is as follows: a large amount of ice water is added after reaction, in reaction solution, stir, if there is solid precipitation, and filtering,
The recrystallization purification of filter cake organic solvent obtains the diphenylethylene compounds of the structure containing phenyl thiazole as shown in formula (I)；If
No solid is precipitated, then is extracted with ethyl acetate, after precipitation, and residual liquid uses column chromatography to obtain as shown in formula (I) containing benzene
The diphenylethylene compounds of base thiazole structure；Wherein, 5- bromo- 2- (the bromine first that the addition quality Yu step 1) of ice water are added
Base) -4- (4- fluorophenyl) thiazole mass ratio be 50~150:1.
A kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that
Recrystallizing organic solvent used is ethyl alcohol, ethyl acetate or n-hexane；It is ethyl acetate and petroleum ether that column, which chromatographs eluant, eluent used,
Mixed liquor, the volume ratio of ethyl acetate and petroleum ether is 1:3~5.
During preparing the diphenylethylene compounds of the ring structure of the invention containing thiazole, it is necessary to control phosphorous acid three
The dosage and reaction temperature of ethyl ester in a certain range, this is because triethyl phosphite have certain reproducibility, if phosphorous
When the dosage of triethylenetetraminehexaacetic acid ester is more and reaction temperature higher (reflux temperature), containing for the structure as shown in formula (I) can be prepared
The diphenylethylene compounds of phenyl thiazole structure.
Compared with prior art, the beneficial effects of the present invention are embodied in:
1) present invention utilizes the method for active substructure splicing and biological isostere substitution by one in talan skeleton
A phenyl ring is replaced with fluorine-containing phenyl thiazole, and design has synthesized the diphenylethylene compounds of a kind of novel structure containing phenyl thiazole,
And it is intended to find its new pesticide activity.
2) the present invention provides the diphenylethylene compounds of a kind of novel structure containing phenyl thiazole as killing answering for agent
With especially suitable for fusarium graminearum, corn southern leaf blight germ, cucumber anthracnose germ, Rhizoctonia solani Kuhn and cucumber cream
The fungies such as mildew bacterium show under 200mg/L concentration, thiophene containing phenyl of the invention from the antibacterial activity test result of embodiment
The diphenylethylene compounds of azoles structure to for examination target show certain inhibitory activity, wherein compound Ia, Ic, If,
Ii to fusarium graminearum inhibiting rate up to 50% or more, compound Ik to cucumber anthracnose germ inhibiting rate up to 50% with
On, compound Ih, up to 50% or more, shows medium inhibitory activity to cucumber downy mildew germ inhibiting rate.Wherein, compound Ia
To fusarium graminearum inhibiting rate up to 95%, preferable inhibitory activity is shown.
Specific embodiment
The present invention is further explained in the light of specific embodiments, but the scope of protection of the present invention is not limited thereto.
The synthesis of 1 compound Ia of embodiment (R (n)=neighbour's methyl):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (24.9g, 150.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 1.0h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；DMF (11.6g), o-tolualdehyde are added in gained concentrate
(1.2g, 10mmol) and sodium hydroxide (0.4g, 10mmol) react at room temperature.TLC detects reaction process, about 1.0 hours
Reaction terminates, and reaction solution is poured into ice water (145g), and stirring has solid precipitation, filters, filter cake recrystallizes yellow with n-hexane
Color solid 1.4g, as (E) -4- (4- fluorophenyl) -2- o-methyl styrene base thiazole (being marked as compound Ia), yield
57.4%.M.p.:71~75 DEG C；
1H NMR(500MHz,CDCl3) δ 7.94 (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。
The synthesis of 2 compound Ib of embodiment (R (n)=methyl):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (3.5g, 10mmol)
It in (24.9g, 150.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 1.0h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；DMF (11.6g), tolyl aldehyde are added in gained concentrate
(1.2g, 10mmol) and sodium hydroxide (0.4g, 10mmol) react at room temperature.TLC detects reaction process, about 1.0 hours
Reaction terminates, and reaction solution is poured into ice water (145g), and stirring has solid precipitation, filters, filter cake recrystallizes yellow with n-hexane
Color solid 1.3g, as (E) -4- (4- fluorophenyl) -2- m-methyl styrene base thiazole (being marked as compound Ib), yield
44.5%.M.p.:148~149 DEG C；
1H NMR(500MHz,CDCl3) δ 7.93 (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。
The synthesis of 3 compound Ic of embodiment (R (n)=to methyl):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (24.9g, 150.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 1.0h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；DMF (14.5g), p-tolyl aldehyde are added in gained concentrate
(1.4g, 12mmol) and sodium hydroxide (0.4g, 10mmol) react at room temperature.TLC detects reaction process, about 1.0 hours
Reaction terminates, and reaction solution is poured into ice water (145g), and stirring has solid precipitation, filters, filter cake recrystallizes yellow with n-hexane
Color solid 1.4g, as (E) -4- (4- fluorophenyl) -2- p-methylstyrene base thiazole (being marked as compound Ic), yield
57.3%.M.p.:164~167 DEG C；
1H NMR(500MHz,CDCl3) δ 7.92 (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。
The synthesis of 4 compound Id of embodiment (R (n)=O-methoxy):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (27.4g, 165.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 1.5h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；DMF (14.5g), o-methoxybenzaldehyde are added in gained concentrate
(2.0g, 15mmol) and sodium hydroxide (0.6g, 15mmol) react at room temperature.TLC detects reaction process, about 1.5 hours
Reaction terminates, and reaction solution is poured into ice water (145g), and stirring is extracted with ethyl acetate, after precipitation, the residue column of precipitation
Chromatography (eluant, eluent used is the mixed liquor of ethyl acetate and petroleum ether, V ethyl acetate: V petroleum ether=1:3) separate yellow is solid
Body 1.3g, as (E) -4- (4- fluorophenyl) -2- o-methoxystyrene base thiazole (being marked as compound Id), yield
50.9%.M.p.:73~76 DEG C；
1H NMR(500MHz,CDCl3) δ 7.93 (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。
The synthesis of 5 compound Ie of embodiment (R (n)=meta-methoxy):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (3.5g, 10mmol)
It in (27.4g, 165.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 1.5h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；DMF (17.4g), m-methoxybenzaldehyde are added in gained concentrate
(2.0g, 15mmol) and sodium hydroxide (0.6g, 15mmol) react at room temperature.TLC detects reaction process, about 1.5 hours
Reaction terminates, and reaction solution is poured into ice water (145g), and stirring is extracted with ethyl acetate, after precipitation, the residue column of precipitation
Chromatography (eluant, eluent used is the mixed liquor of ethyl acetate and petroleum ether, V ethyl acetate: V petroleum ether=1:5) separate yellow is solid
Body 1.4g, as (E) -4- (4- fluorophenyl) -2- meta-methoxy styryl thiazole (being marked as compound Ie), yield
52.6%.M.p.:115~116 DEG C；
1H NMR(500MHz,CDCl3) δ 7.92 (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。
The synthesis of 6 compound If of embodiment (R (n)=to methoxyl group):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (27.4g, 165.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 1.5h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；DMF (17.4g), P-methoxybenzal-dehyde are added in gained concentrate
(2.0g, 15mmol) and sodium hydroxide (0.6g, 15mmol) react at room temperature.TLC detects reaction process, about 1.5 hours
Reaction terminates, and reaction solution is poured into ice water (145g), and stirring has solid precipitation, filters, and filter cake is obtained with re-crystallizing in ethyl acetate
Yellow solid 1.6g, as (E) -4- (4- fluorophenyl) -2- to methoxyl-styrene thiazole (being marked as compound If),
Calculating its yield is 59.9%.M.p.:124~129 DEG C；
1H NMR(500MHz,CDCl3) δ 7.92 (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。
The synthesis of 7 Compound Ig per of embodiment (R (n)=to tert-butyl):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (29.1g, 175.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 2.0h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；DMF (20.3g), p-t-Butylbenzaldehyde are added in gained concentrate
(2.4g, 15mmol) and sodium hydroxide (0.8g, 20mmol) react at room temperature.TLC detects reaction process, about 2.0 hours
Reaction terminates, and reaction solution is poured into ice water (232g), and stirring has solid precipitation, filters, and filter cake is obtained with re-crystallizing in ethyl acetate
Yellow solid 1.6g, as (E) -4- (4- fluorophenyl) -2- p-tert-butylstyrene base thiazole (being marked as Compound Ig per),
Yield 56.6%.M.p.:146~148 DEG C；
1H NMR(500MHz,CDCl3) δ 7.93 (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。
The synthesis of 8 compound Ih of embodiment (R (n)=to trifluoromethyl):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
(30.2g, 185.0mmol) is heated to reflux and is reacted, and TLC detects reaction process, end of reaction after about 2h, and concentration is sloughed
Extra triethyl phosphite, obtains concentrate；DMF (20.3g), p-trifluoromethyl benzaldehyde are added in gained concentrate
(3.5g, 20mmol) and sodium hydroxide (1.0g, 25mmol) react at room temperature.TLC detects reaction process, about 2.5 hours
Reaction terminates, and reaction solution is poured into ice water (232g), and stirring is extracted with ethyl acetate, after precipitation, the residue column of precipitation
Chromatography (eluant, eluent used is the mixed liquor of ethyl acetate and petroleum ether, V ethyl acetate: V petroleum ether=1:5) separate yellow is solid
Body 1.8g, as (E) -4- (4- fluorophenyl) -2- p-trifluoromethylstyrene base thiazole (being marked as compound Ih), yield
61.4%.M.p.:111~115 DEG C；
1H NMR(500MHz,CDCl3) δ 7.93 (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。
The synthesis of 9 compound Ii of embodiment (R (n)=to fluorine):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (32.4g, 195.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 2.5h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；In gained concentrate be added DMF (23.2g), 4-Fluorobenzaldehyde (2.5g,
20mmol) reacted at room temperature with sodium hydroxide (1.2g, 30mmol).TLC detects reaction process, and about 3 hour reactions terminate,
Reaction solution is poured into ice water (232g), stirs, there is solid precipitation, is filtered, filter cake recrystallizes to obtain yellow solid with n-hexane
1.2g, as (E) -4- (4- fluorophenyl) -2- pfluorostyrene base thiazole (being marked as compound Ii), calculating its yield is
49.0%.M.p.:146~149 DEG C；
1H NMR(500MHz,CDCl3) δ 7.92 (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。
The synthesis of 10 compound Ij of embodiment (R (n)=neighbour's chlorine):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (32.4g, 195.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 2.5h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；In gained concentrate be added DMF (23.2g), o-chlorobenzaldehyde (2.8g,
20mmol) reacted at room temperature with sodium hydroxide (1.6g, 40mmol).TLC detects reaction process, about 3.0 hour reaction knots
Beam pours into reaction solution in ice water (232g), and stirring has solid precipitation, filters, and filter cake obtains yellow solid with ethyl alcohol recrystallization
1.5g, as (E) -4- (4- fluorophenyl) -2- ortho-chlorostyrene base thiazole (being marked as compound Ij), calculating its yield is
58.5%.M.p.:95~98 DEG C；
1H NMR(500MHz,CDCl3) δ 7.93 (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。
The synthesis of 11 compound Ik of embodiment (R (n)=to chlorine):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (32.4g, 195.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 2.5h.Concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；In gained concentrate be added DMF (23.2g), p-chlorobenzaldehyde (2.8g,
20mmol) reacted at room temperature with sodium hydroxide (1.6g, 40mmol).TLC detects reaction process, about 3.0 hour reaction knots
Beam pours into reaction solution in ice water (232g), and stirring has solid precipitation, filters, and filter cake recrystallizes to obtain yellow solid with n-hexane
1.3g, as (E) -4- (4- fluorophenyl) -2- p-chlorostyrene base thiazole (being marked as compound Ik), calculating its yield is
48.3%.M.p.:171~175 DEG C；
1H NMR(500MHz,CDCl3) δ 7.92 (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。
The synthesis of 12 compound Il of embodiment (R (n)=neighbour's bromine):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (32.4g, 195.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 3.0h, concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；In gained concentrate be added DMF (23.2g), o-bromobenzaldehye (5.5g,
30mmol) reacted at room temperature with sodium hydroxide (1.9g, 47mmol).TLC detects reaction process, about 3.5 hour reaction knots
Beam pours into reaction solution in ice water (319g), and stirring has solid precipitation, filters, and filter cake obtains yellow with re-crystallizing in ethyl acetate and consolidates
Body 1.3g, as (E) -4- (4- fluorophenyl) -2- bromophenyl vinylthiazole (being marked as compound Il), yield
44.9%.M.p.:94~96 DEG C；
1H NMR(500MHz,CDCl3) δ 7.92 (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。
The synthesis of 13 compound Im of embodiment (R (n)=bromine):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (32.4g, 195.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 3.0h.Concentration
Extra triethyl phosphite is sloughed, concentrate is obtained；In gained concentrate be added DMF (26.1g), 3-bromobenzaldehyde (5.5g,
30mmol) reacted at room temperature with sodium hydroxide (1.9g, 47mmol).TLC detects reaction process, about 3.5 hour reaction knots
Beam pours into reaction solution in ice water (319g), and stirring has solid precipitation, filters, and filter cake obtains yellow with re-crystallizing in ethyl acetate and consolidates
Bromstyrol base thiazole (being marked as compound Im) between body 1.4g, as (E) -4- (4- fluorophenyl) -2-, yield
45.8%.M.p.:142~145 DEG C；
1H NMR(500MHz,CDCl3) δ 7.92 (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。
The synthesis of 14 compound In of embodiment (R (n)=2,4- dichloro):
Triethyl phosphite is added in 5- bromo- 2- (bromomethyl) -4- (4- fluorophenyl) thiazole (2.9g, 10mmol)
It in (33.2g, 200.0mmol), is heated to reflux and is reacted, TLC detects reaction process, end of reaction after about 3h, and concentration takes off
Extra triethyl phosphite is removed, concentrate is obtained；DMF (29.0g), 2,4 dichloro benzene formaldehyde are added in gained concentrate
(5.2g, 30mmol) and sodium hydroxide (2.0g, 50mmol) react at room temperature.TLC detects reaction process, and about 4 hours are anti-
It should terminate, reaction solution is poured into ice water (435g), stir, there is solid precipitation, filter, filter cake is obtained yellow with re-crystallizing in ethyl acetate
Color solid 1.3g, as (E) -4- (4- fluorophenyl) -2- (2,4- dichlorostyrene base) thiazole (being marked as compound In),
Calculating its yield is 44.3%.M.p.:131~133 DEG C；
1H NMR(500MHz,CDCl3) δ 7.92 (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。
The test of 15 antifungal activity of embodiment:
Test target: fusarium graminearum FusaHum graminearum, corn southern leaf blight germ
Helminthosporium maydis, cucumber anthracnose germ Mycosphaerella melonis, Rhizoctonia solani Kuhn
The fungies such as Thanatephorus cucumeris and bacterium of downy mildew of cucumber Pseudoperonospora cubensisi.
(E) -4- (4- the fluorophenyl) -2- substituted phenylethylene base thiazole compound synthesized in embodiment 1~14 is marked
For untested compound.Using drug containing potato agar culture medium (PDA) method or suspension spore spray-on process to untested compound, control
Drug and distilled water blank have carried out the bactericidal activity measurement of above-mentioned target fungus, untested compound and the general sieve concentration of control drug
It is 200mg/L.
Specifically, test method is referring to " pesticide bioactivity evaluates SOP ".Wheat scab germ, corn southern leaf blight disease
Bacterium, cucumber anthracnose germ, rice sheath blight disease germ use pastille culture medium method: taking the untested compound of the concentration containing 1000mg/L
Or the medical fluid 2mL of control drug, it is added in the PDA culture medium for the 8mL for being cooled to 45 DEG C, untested compound or control drug is made
Final concentration of 200mg/L pastille culture medium plate.Then 6.5mm diameter bacterium is taken from cultured test germ colony edge
Silk block, moves on pastille culture medium plate, and (same program test 4 times of each sample finally calculates average 4 repetitions of every processing
Inhibiting rate).It is disposed, is placed in 28 DEG C of constant temperature biochemical cultivation case and cultivates, colony diameter is measured after 4 days, calculate growth suppression
Rate processed.
Bacterium of downy mildew of cucumber uses suspension spore spray-on process: untested compound or control drug being dissolved with DMF and prepare matter
The mother liquor that concentration is 5% is measured, which is diluted with distilled water again, and the final concentration of of untested compound or control drug is made
The spraying medicament of 200mg/L.Then the consistent potting cucumber seedling of growing way is selected, using the spraying medicament of above-mentioned preparation to potting Huang
Melon seedling carries out naturally dry after spraying treatment, dips distillation washing with writing brush after 24 hours and takes disease leaf back sporangium, is made into spore
Ascus suspension (2-3 × 105A/ml), sporangia suspension is uniformly sprayed on Huang with inoculation sprayer (pressure 0.1MPa)
Cucumber seedling after inoculation on melon blade, then moves in artificial climate room to (relative humidity 100%, temperature are 21-23 DEG C, light
The dark period is 14h/10h) culture.90% or so moisturizing of relative humidity is maintained to induce afterwards for 24 hours, the morbidity of backsight blank control in 7-8 days
Situation carries out result investigation, calculates growth inhibition ratio.
Above-mentioned pastille culture medium method and suspension spore spray-on process are obtained after the same method respectively using distilled water
Blank control group result.It is raw when above-mentioned use pastille culture medium method or suspension spore spray-on process handle untested compound
The calculation of long inhibiting rate carries out in the following manner:
Growth inhibition ratio (%)=[(blank control colony diameter-processing colony diameter)/blank control colony diameter] ×
100%
Test result is shown in Table 1.
The bactericidal activity of compound Ia-Io under 1 200mg/L concentration of table
Note: Fluoxastrobin is control drug, and CK is distilled water blank control.
1 bactericidal activity test result of table shows that under 200mg/L concentration, (E) -4- (4- fluorophenyl) -2- of the invention takes
For styryl thiazole compound, certain inhibitory activity is shown to for examination target, wherein compound Ia, Ic, If, Ii
To fusarium graminearum inhibiting rate up to 50% or more, Ik to cucumber anthracnose germ inhibiting rate up to 50% or more, Ih to Huang
Melon downy mildew germ inhibiting rate shows medium inhibitory activity up to 50% or more.Wherein, Ia is equal to fusarium graminearum inhibiting rate
Up to 95%, preferable inhibitory activity is shown.
Content described in this specification is only to enumerate to inventive concept way of realization, and protection scope of the present invention is not answered
When the concrete form for being seen as limited by embodiment and being stated.
Claims (10)
1. a kind of application of the diphenylethylene compounds of structure containing phenyl thiazole as fungicide, it is characterised in that thiophene containing phenyl
The structure of the diphenylethylene compounds of azoles structure is as shown in the formula (I):
In formula (I), it is monosubstituted or polysubstituted that the H on phenyl ring is substituted base R；The integer that n is 1 ~ 5, preferably 1 ~ 2 integer, n table
Show the number of substituent R on phenyl ring；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2 ~ 5, indicate on phenyl ring
H be substituted base R it is polysubstituted, the substituent R on different the position of substitution is same or different；The substituent R is C1 ~ C8 alkane
Base, C1 ~ C8 halogenated alkyl, C1 ~ C3 alkoxy, halogen, nitro or cyano.
2. a kind of application of the diphenylethylene compounds of the structure containing phenyl thiazole as described in claim 1 as fungicide,
It is characterized in that the substituent R is C1 ~ C5 alkyl, C1 ~ C5 halogenated alkyl, methoxyl group or halogen, preferably methyl, tertiary fourth
Base, trifluoromethyl, methoxyl group, F, Cl or Br.
3. a kind of application of the diphenylethylene compounds of the structure containing phenyl thiazole as described in claim 1 as fungicide,
It is characterized in that in formula (I), R (n) be adjacent methyl, methyl, to methyl, O-methoxy, meta-methoxy, to methoxyl group, to uncle
Butyl, to trifluoromethyl, to fluorine, adjacent chlorine, to one of chlorine, adjacent bromine, bromine and 2,4- dichloro.
4. a kind of application of the diphenylethylene compounds of the structure containing phenyl thiazole as described in claim 1 as fungicide,
It is characterized in that the diphenylethylene compounds of the structure containing phenyl thiazole, which are used to prepare, inhibits corn southern leaf blight germ, cucumber
The fungicide of anthracnose germ, Rhizoctonia solani Kuhn or bacterium of downy mildew of cucumber.
5. a kind of application of the diphenylethylene compounds of the structure containing phenyl thiazole as described in claim 1 as fungicide,
It is characterized in that the synthetic method of the diphenylethylene compounds of the structure containing phenyl thiazole the following steps are included:
1) the bromo- 2- of 5- (bromomethyl) -4- (4- fluorophenyl) thiazole as shown in formula (II) and the phosphorous acid three as shown in formula (III)
Ethyl ester is reacted under reflux state, and TLC is monitored to after reaction, and extra triethyl phosphite is sloughed in concentration, is obtained dense
Contracting liquid；
2) solvent DMF, sodium hydroxide and the substituted benzaldehyde as shown in formula (IV) are added in the concentrate obtained by step 1), in room
The lower reaction of temperature, TLC, which is monitored to reaction, to be terminated, the last post-treated hexichol that the structure containing phenyl thiazole as shown in the formula is made
Ethylene compounds；
In formula (IV), it is monosubstituted or polysubstituted that the H on phenyl ring is substituted base R；The integer that n is 1 ~ 5, preferably 1 ~ 2 integer, n
Indicate the number of substituent R on phenyl ring；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2 ~ 5, phenyl ring is indicated
On H be substituted base R it is polysubstituted, the substituent R on different the position of substitution is same or different；
Substituent R in formula (IV) is C1 ~ C8 alkyl, C1 ~ C8 halogenated alkyl, C1 ~ C3 alkoxy, halogen, nitro or cyano.
6. a kind of application of the diphenylethylene compounds of the structure containing phenyl thiazole as claimed in claim 5 as fungicide,
It is characterized in that the bromo- 2- of 5- (bromomethyl) -4- (4- fluorophenyl) thiazole, the Asia as shown in formula (III) as shown in formula (II)
The ratio between amount for the substance that feeds intake of triethyl phosphate, the substituted benzaldehyde as shown in formula (IV) and sodium hydroxide be 1: 10.0~
30.0: 1.0~8.0: 1.0~20.0, preferably 1: 15.0~20.0: 1.0~3.0: 1.0~5.0.
7. a kind of application of the diphenylethylene compounds of the structure containing phenyl thiazole as claimed in claim 5 as fungicide,
It is characterized in that the bromo- 2- of 5- (bromomethyl) -4- (4- fluorophenyl) thiazole and the mass ratio of solvent DMF as shown in formula (II) are 1:
2.0~20, preferably 1: 4.0~10.
8. a kind of application of the diphenylethylene compounds of the structure containing phenyl thiazole as claimed in claim 5 as fungicide,
It is characterized in that the reaction time of step 1) is 1 ~ 3 hour, the reaction time of step 2 is 1 ~ 4 hour.
9. a kind of application of the diphenylethylene compounds of the structure containing phenyl thiazole as claimed in claim 5 as fungicide,
It is characterized in that step 2 last handling process is as follows: a large amount of ice water being added after reaction, in reaction solution, stir, if there is solid
It is precipitated, filtering, the recrystallization purification of filter cake organic solvent obtains the diphenylethylene of the structure as shown in the formula (I) containing phenyl thiazole
Compound；If no solid is precipitated, it is extracted with ethyl acetate, after precipitation, residual liquid uses column chromatography to obtain such as formula (I) institute
The diphenylethylene compounds for the structure containing phenyl thiazole shown；Wherein, the bromo- 2- of 5- that the addition quality Yu step 1) of ice water are added
The mass ratio of (bromomethyl) -4- (4- fluorophenyl) thiazole is 50 ~ 150:1.
10. a kind of diphenylethylene compounds answering as fungicide of the structure containing phenyl thiazole as claimed in claim 9
With, it is characterised in that recrystallizing organic solvent used is ethyl alcohol, ethyl acetate or n-hexane；It is acetic acid that column, which chromatographs eluant, eluent used,
The volume ratio of the mixed liquor of ethyl ester and petroleum ether, ethyl acetate and petroleum ether is 1:3 ~ 5.
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| CN113683608A (en) * | 2021-09-17 | 2021-11-23 | 深圳大学 | N-substituted-2-amino-4-saccharin substituted methyl thiazole compound with bactericidal activity, preparation method and application |
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