CN108863977A - The class diphenyl ethene compounds and its synthetic method of a kind of thiazole ring containing bromo and application - Google Patents
The class diphenyl ethene compounds and its synthetic method of a kind of thiazole ring containing bromo and application Download PDFInfo
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- CN108863977A CN108863977A CN201810630849.5A CN201810630849A CN108863977A CN 108863977 A CN108863977 A CN 108863977A CN 201810630849 A CN201810630849 A CN 201810630849A CN 108863977 A CN108863977 A CN 108863977A
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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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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses the class diphenyl ethene compounds and its synthetic method of a kind of thiazole ring containing bromo and applications.The synthesis process of the compound is as follows：First 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole reacted under reflux state with triethyl phosphite, TLC is monitored to after reaction, extra triethyl phosphite is sloughed in concentration, solvent DMF, sodium hydroxide and substituted benzaldehyde are added in gained concentrate, it reacts at room temperature, it is post-treated after reaction that the class diphenyl ethene compounds containing thiazole ring are made；Again by containing thiazole ring class diphenyl ethene compounds and N- bromo-succinimide in acetonitrile solvent, bromo-reaction is carried out at 0 ~ 100 DEG C, be made the thiazole ring containing bromo class diphenyl ethene compounds.The present invention by using above-mentioned technology, synthesis obtain it is a kind of it is novel (E) the bromo- 4- of -5- (2,6- difluorophenyl) -2- substituted phenylethylene base thiazole compound, the preparation of such compound is simple, shows certain anticancer and antifungal activity.
Description
Technical field
The present invention relates to (E) the bromo- 4- of -5- (2,6- difluorophenyl) -2- substituted phenylethylene base thiazole compound and its answer
With.
Background technique
Diphenylethylene compounds are widespread in nature as phytoalexin, as polygonaceae plant hair black false hellebore, what
The tuber of multiflower knotweed, polygonum cuspidate, Liliaceae chinaroot greenbrier platymiscium Smilax perfoliate, Cassia, Mulberry Roots etc..The diphenylethylene compounds of natural source have
Multiple biological activities and the extensive concern for causing people, have a very important role in new drug development field.For example, in medicine
Field has antitumor (J Agr Food Chem, 2011,59 (16):8632-8638), immunity of organisms (BBA- is improved
Biomembranes, 1985, 837(2):209-212), anti-inflammatory (J Agr Food Chem, 2017,65 (51):
11179-11191), AntiHIV1 RT activity (J Pharm Sci, 2004,93 (10):2448-2457) isoreactivity；Have in pesticide field
Desinsection (Chem PharmBull, 1992,40 (5):1130-1136), mosquitocide (Chem Biodivers, 2016,13:
1165-1177), antimycotic (Med Chem Res, 2013,22 (5):2196-2206), molten algae (J Agr Food Chem,
2015, 63(5):1370-1377) isoreactivity.Meanwhile thiazole heterocycle compound also has wide spectrum biological activity, answers extensively
For medicine and pesticide field, such as there is anti-inflammatory (European Journal of Medicinal in field of medicaments
Chemistry, 2010, 45(9):3692-3701), antimycotic (Eur J Med Chem, 2011,46 (9): 3681-
3689), anticancer (Bioorg Med Chem Lett, 2011,21 (7):The bioactivity such as 1965-1968)；In pesticide field
With weeding (Bioorg Med Chem Lett, 2010,20 (11):3348-3351), desinsection (organic chemistry, 2009,
29(12):2000-2004), (J Agr Food Chem, 2009,57 (10) are sterilized:The bioactivity such as 4279-4286),
And there are many fungicide (pesticide, 2004,43 (11) are commercialized: 515-517).In addition, studies have reported that halogenic substituent
The activity that can enhance drug is introduced, drug design field (Expert Opin Drug Dis, 2012,7 (5) are widely used in:
375-383)。
Good bioactivity is all had based on diphenylethylene and thiazole heterocycle class compound, the present invention is sub- using activity
The method that structures to form and biological isostere replace by the active fluorine-containing phenyl thiazole group of screening (organic chemistry,
2009, 29(12): 2000-2004；Pesticide Science journal, 2010,12 (4):Talan skeleton 463-467) is introduced, it will
A phenyl ring in talan skeleton is replaced with fluorine-containing phenyl thiazole, then bromine atom is introduced on thiazole ring, design synthesis one
The class diphenyl ethene compounds of the novel thiazole ring containing bromo of class.This kind of compound contains thiazole ring, halogen simultaneously（Fluorine and bromine）And
Class talan structure is expected to have preferable bioactivity.
Series (E) -5- bromo- 4- (2,6- difluorophenyl) -2- substituted phenylethylene base thiazoles that the present invention designs and synthesizes
Compound, structure and bioactivity research are showed no document report.
Summary of the invention
In order to solve the above-mentioned technical problem, the purpose of the present invention is to provide a kind of class talan of thiazole ring containing bromo
Compound and its synthetic method and application, the preparation of such compound is simple, shows certain anticancer and antifungal activity.
The class diphenyl ethene compounds of a kind of thiazole ring containing bromo, shown in structure such as formula (I)：
In formula (I), it is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；
The integer that n is 0 ~ 5, preferably 1 ~ 2 integer indicate the number of substituent R on phenyl ring；When n=0, the H on phenyl ring is indicated
It is not substituted；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2 ~ 5, it is more to indicate that the H on phenyl ring is substituted base R
Replace, the substituent R on different the position of substitution is same or different；
The substituent R is hydrogen, the halogenated alkyl of the alkyl of C1 ~ C8 or C1 ~ C8, the alkoxy of C1 ~ C3, halogen, nitro or cyanogen
Base.
The class diphenyl ethene compounds of a kind of thiazole ring containing bromo, it is characterised in that the substituent R is hydrogen, C1
The alkyl of ~ C5 or halogenated alkyl, methoxyl group or the halogen of C1 ~ C5, preferably hydrogen, methyl, tert-butyl, trifluoromethyl, methoxyl group,
F, Cl or Br.
A kind of class diphenyl ethene compounds of the thiazole ring containing bromo, it is characterised in that R (n) be hydrogen, adjacent methyl,
Methyl, to methyl, O-methoxy, to methoxyl group, meta-methoxy, to tert-butyl, to trifluoromethyl, to fluorine, adjacent chlorine, to chlorine, neighbour
Bromine, bromine or 2,4- dichloro.
The synthetic method of the class diphenyl ethene compounds of the thiazole ring containing bromo, it is characterised in that including walking as follows
Suddenly：
1）2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole is reacted under reflux state with triethyl phosphite, TLC prison
Survey to after reaction, extra triethyl phosphite is sloughed in concentration, be added in gained concentrate solvent DMF, sodium hydroxide and
The substituted benzaldehyde as shown in formula (IV), reacts at room temperature, and post-treated be made contains as shown in formula (II) after reaction
The class diphenyl ethene compounds of thiazole ring；
2）Class diphenyl ethene compounds as shown in formula (II) containing thiazole ring and the N- bromo succinyl as shown in formula (III) are sub-
Amine carries out bromo-reaction in acetonitrile solvent at 0 ~ 100 DEG C, and the class hexichol of the thiazole ring containing bromo as shown in formula (I) is made
Vinyl compound；
In formula (II), it is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；
The integer that n is 0 ~ 5, preferably 1 ~ 2 integer indicate the number of substituent R on phenyl ring；When n=0, the H on phenyl ring is indicated
It is not substituted；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2 ~ 5, it is more to indicate that the H on phenyl ring is substituted base R
Replace, the substituent R on different the position of substitution is same or different；
The substituent R is hydrogen, the halogenated alkyl of the alkyl of C1 ~ C8 or C1 ~ C8, the alkoxy of C1 ~ C3, halogen, nitro or cyanogen
Base.
The synthetic method of the class diphenyl ethene compounds of the thiazole ring containing bromo, it is characterised in that step 1）In, 2-
(bromomethyl) -4- (2,6- difluorophenyl) thiazole, triethyl phosphite, substituted benzaldehyde and hydroxide as shown in formula (IV)
The ratio between amount for the substance that feeds intake of sodium 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；
2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole and the mass ratio of solvent DMF are 1:2.0~20, preferably 1:
4.0~10.
The synthetic method of the class diphenyl ethene compounds of the thiazole ring containing bromo, it is characterised in that as shown in formula (II)
Class diphenyl ethene compounds containing thiazole ring and the N- bromo-succinimide as shown in formula (III) the substance that feeds intake amount it
Than being 1:1.0 ~ 20.0, preferably 1: 1.0~5.0；
The mass ratio of the class diphenyl ethene compounds and acetonitrile solvent as shown in formula (II) containing thiazole ring is 1: 2.0
~20, preferably 1:4.0~10.
The synthetic method of the class diphenyl ethene compounds of the thiazole ring containing bromo, it is characterised in that step 2）In, instead
Answering temperature is 20 ~ 50 DEG C, and the reaction time is 0.5 ~ 6 hour.
The synthetic method of the class diphenyl ethene compounds of the thiazole ring containing bromo, it is characterised in that step 2）Reaction knot
Ice water is added in reaction solution in Shu Hou, stirs, if there is solid precipitation, recrystallization purification is obtained such as formula（I）Shown in contain bromethiazole
The class diphenyl ethene compounds of ring；If no solid is precipitated, it is extracted with ethyl acetate, precipitation, residual liquid column chromatography for separation obtains
To such as formula（I）Shown in the thiazole ring containing bromo class diphenyl ethene compounds, the addition volume of ice water and 2- (bromomethyl) -4-
The mass ratio of (2,6- difluorophenyl) thiazole is 33-50:1, volume unit mL, mass unit g, since DMF amount is fewer,
The precipitation that a large amount of water energys guarantee product is added.
The synthetic method of the class diphenyl ethene compounds of the thiazole ring containing bromo, it is characterised in that recrystallization is used molten
Agent is the mixed liquor of one or more of ethyl alcohol, ethyl acetate, n-hexane, petroleum ether；Column chromatographs eluant, eluent used
The mixed liquor of ethyl acetate and n-hexane, or the mixed liquor for ethyl acetate and petroleum ether.
Application of the class diphenyl ethene compounds of the thiazole ring containing bromo as anti-tumor drug or antibacterial agent.
Compared with the existing technology, beneficial effects of the present invention are as follows：
The present invention provides it is a kind of it is novel (E) the bromo- 4- of -5- (2,6- difluorophenyl) -2- substituted phenylethylene base thiazoles chemical combination
Object, the preparation of such compound is simple, shows certain anticancer and antifungal activity.It is loosely tested with DNA in embodiment pair
The compound of synthesis has carried out antitumor cytolytic activity, DNA it is loose the experimental results showed that, majority of compounds is in 50 μM of concentration
There is certain anti-tumor activity；Under 100 mg/L concentration, (E) -5- bromo- 4- (2,6- difluorophenyl) -2- of the invention is taken
For styryl thiazole compound, certain inhibitory activity is shown to for examination target, wherein compound Ia, Ib, Id couple
For fusarium graminearum inhibiting rate 50% or more, compound Id is 56.7% to the inhibiting rate of cucumber didymella bryoniae, is shown
Deng inhibitory activity.
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 derivative I a of embodiment (R (n)=H)：
It is sub- that 15 mL (86.8 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 1 h.Extra phosphorous triethylenetetraminehexaacetic acid is sloughed in concentration
Ester obtains concentrate；20 mL DMF, benzaldehyde (1.3g, 12 mmol) and sodium hydroxide (0.9 are added in gained concentrate
G, 22 mmol) reaction.TLC detects reaction process, and about 3 hour reactions terminate, reaction solution is poured into 150 mL ice water, is stirred
It mixes, there is solid precipitation, filter, then obtain 1.6 g of yellow solid, as (E) -4- (2,6- difluorobenzenes with re-crystallizing in ethyl acetate
Base) -2- styryl thiazole, calculating its yield is 54.7%.m.p.:79~80 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- styryl thiazole that will be prepared according to the above method（3.0 g, 10 mmol）
With N- bromo-succinimide（2.14 g, 12 mmol）It is dissolved in 15 mL acetonitriles, is stirred to react at 20 DEG C.TLC inspection
Reaction process is surveyed, about 2.5 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, filters, then uses
Re-crystallizing in ethyl acetate obtains 1.9 g of yellow solid, yield 50.2%.m.p.:103~105 DEG C；
1H NMR (500 MHz, Chloroform-d)δ7.54 (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。
The synthesis of 2 derivative I b of embodiment (R (n)=neighbour's chlorine)：
It is sub- that 9.0 mL (50.0 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 1.5 h.Extra phosphorous acid three is sloughed in concentration
Ethyl ester obtains concentrate；25mL DMF, o-chlorobenzaldehyde (1.4g, 10 mmol) and sodium hydroxide are added in gained concentrate
(1.3 g, 32 mmol) reaction.TLC detects reaction process, and about 3.5 hour reactions terminate, and reaction solution is poured into 150 mL ice
Water, stirring, there is solid precipitation, filters, then obtains 1.4 g of yellow solid, as (E) -4- (2,6- difluorobenzenes with ethyl alcohol recrystallization
Base) -2- ortho-chlorostyrene base thiazole, calculating its yield is 40.6%. m.p.:87~89 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- ortho-chlorostyrene base thiazole that will be prepared according to the above method（3.34 g, 10
mmol）With N- bromo-succinimide（5.34 g, 30 mmol）It is dissolved in 30 mL acetonitriles, is stirred to react at 45 DEG C.
TLC detects reaction process, and about 1.0 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, filters,
Then 2.5 g of yellow solid, yield 60.6% are obtained with ethyl alcohol recrystallization；m.p.:144~147 DEG C；
1H NMR (500 MHz, Chloroform-d)δ7.74 (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。
The synthesis of 3 derivative I c of embodiment (R (n)=to chlorine)：
It is sub- that 12 mL (69.5 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 3 h.Extra phosphorous triethylenetetraminehexaacetic acid is sloughed in concentration
Ester obtains concentrate；22 mL DMF, p-chlorobenzaldehyde (2.8 g, 20 mmol) and sodium hydroxide are added in gained concentrate
(2.0 g, 50 mmol) reaction.TLC detects reaction process, and about 2.5 hour reactions terminate, and reaction solution is poured into 150 mL ice
Water, stirring, there is solid precipitation, filters, then recrystallizes to obtain 1.9 g of yellow solid, as (E) -4- (2,6- difluoros with n-hexane
Phenyl) -2- p-chlorostyrene base thiazole, calculating its yield is 56.1%. m.p.:91~93 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- p-chlorostyrene base thiazole that will be prepared according to the above method（3.34 g, 10
mmol）With N- bromo-succinimide（2.67 g, 15 mmol）It is dissolved in 25 mL acetonitriles, is stirred to react at 25 DEG C.
TLC detects reaction process, and about 2.0 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, filters,
Then 2.4 g of yellow solid, yield 58.2% are recrystallized to obtain with petroleum ether.m.p.:110~119 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 4 derivative I d of embodiment (R (n)=to trifluoromethyl)
It is sub- that 16 mL (92.6 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 2 h.Extra phosphorous triethylenetetraminehexaacetic acid is sloughed in concentration
Ester obtains concentrate；30 mL DMF, p-trifluoromethyl benzaldehyde (5.3 g, 30 mmol) and hydrogen are added in gained concentrate
Sodium oxide molybdena (1.2 g, 30 mmol) reaction.TLC detects reaction process, and about 2 hour reactions terminate, and reaction solution is poured into 150
ML ice water, stirring, there is solid precipitation, filters, and then uses ethyl acetate and petroleum ether mixed liquor（V ethyl acetate:V petroleum ether=
1 : 1）Recrystallize to obtain 2.3 g of yellow solid, as (E) -4- (2,6- difluorophenyl) -2- p-trifluoromethylstyrene base thiophene
Azoles, calculating its yield is 62.4%.m.p.:117~119 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- p-trifluoromethylstyrene base thiazole that will be prepared according to the above method（3.68
g, 10 mmol）With N- bromo-succinimide（7.12 g, 40 mmol）It is dissolved in 50 mL acetonitriles, is stirred at 25 DEG C
Mix reaction.TLC detects reaction process, and about 2.5 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid analysis
Out, it filters, then recrystallizes to obtain 2.9 g of yellow solid, yield 65.0% with n-hexane.m.p.:89~91 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 5 derivative I e of embodiment (R (n)=to methoxyl group)：
35 mL (200 mmol) phosphorous is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethylenetetraminehexaacetic acid ester, is heated to flowing back, TLC detection is reacted, end of reaction after about 1 h.Extra triethyl phosphite is sloughed in concentration,
Obtain concentrate；15 mL DMF, P-methoxybenzal-dehyde (3.4 g, 25 mmol) and sodium hydroxide are added in gained concentrate
(1.6 g, 40 mmol) reaction.TLC detects reaction process, and about 1.5 hour reactions terminate, and reaction solution is poured into 150 mL ice
Water, stirring, there is solid precipitation, filters, then obtains 2.2 g of yellow solid, as (E) -4- (2,6- difluorobenzenes with ethyl alcohol recrystallization
Base) for -2- to methoxyl-styrene thiazole, calculating its yield is 68.0%.m.p.:132~133 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
By (E) -4- (2,6- the difluorophenyl) -2- prepared according to the above method to methoxyl-styrene thiazole（3.30 g,
10 mmol）With N- bromo-succinimide（3.56 g, 20 mmol）It is dissolved in 35 mL acetonitriles, is stirred at 35 DEG C anti-
It answers.TLC detects reaction process, and about 1.5 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, mistake
Then ethyl alcohol and petroleum ether mixed liquor are used in filter（V ethyl alcohol:Petroleum ether=2 V: 1）Recrystallize to obtain 2.7 g of yellow solid, yield
66.1%.m.p.:102~107 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 6 derivative I f of embodiment (R (n)=2,4- dichloro)：
It is sub- that 11 mL (63.7 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 3 h.Extra phosphorous triethylenetetraminehexaacetic acid is sloughed in concentration
Ester obtains concentrate；18 mL DMF, 2,4 dichloro benzene formaldehyde (3.4 g, 25 mmol) and hydrogen-oxygen are added in gained concentrate
Change sodium (0.8 g, 20 mmol) reaction.TLC detects reaction process, and about 3 hour reactions terminate, and reaction solution is poured into 150 mL
Ice water, stirring, there is solid precipitation, filters, then recrystallizes to obtain 1.8 g of yellow solid, as (E) -4- (2,6- bis- with hexamethylene
Fluorophenyl) -2- (2,4- dichlorostyrene base) thiazole, calculating its yield is 48.2%.m.p.:107~108 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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 = 16.0 Hz,
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 dichloro benzene vinyl) thiazole that will be prepared according to the above method（3.69
g, 10 mmol）With N- bromo-succinimide（6.23 g, 35 mmol）It is dissolved in 45 mL acetonitriles, is stirred at 50 DEG C
Mix reaction.TLC detects reaction process, and about 1 hour reaction terminates, ice water is added in reaction solution, stirs, there is solid precipitation,
Filtering, then obtains 2.6 g of yellow solid, yield 58.1% with re-crystallizing in ethyl acetate.m.p.:96~100 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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 = 16.5 Hz,
1H), 7.04 (t, J = 8.5, 2H)；
HRMS (ESI) calcd C17H8BrCl2F2NS [M+H]+ 445.8986, found 445.8981。
The synthesis of 7 derivative I g of embodiment (R (n)=to methyl)
It is sub- that 10 mL (57.9 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 1 h.Extra phosphorous triethylenetetraminehexaacetic acid is sloughed in concentration
Ester obtains concentrate；20 mL DMF, p-tolyl aldehyde (1.5 g, 12 mmol) and hydroxide are added in gained concentrate
Sodium (0.4 g, 10 mmol) reaction.TLC detects reaction process, and about 4 hour reactions terminate, and reaction solution is poured into 150 mL ice
Water, stirring, there is solid precipitation, filters, then recrystallizes to obtain 2.1 g of yellow solid, as (E) -4- (2,6- difluoros with petroleum ether
Phenyl) -2- p-methylstyrene base thiazole, yield 66.3%.m.p.:149~150 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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 = 8.0 Hz,
2H), 2.38 (s, 3H)；
HRMS (ESI) calcd C18H13F2NS [M+H]+ 314.0810, found 314.0804。
(E) -4- (2,6- the difluorophenyl) -2- p-methylstyrene base thiazole that will be prepared according to the above method（3.14 g,
10 mmol）With N- bromo-succinimide（2.50 g, 14 mmol）It is dissolved in 20 mL acetonitriles, is stirred at 30 DEG C anti-
It answers.TLC detects reaction process, and about 3 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, filters,
Then 2.5 g of yellow solid, yield 63.7% are recrystallized to obtain with petroleum ether.m.p.:144~148 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 8 derivative I h of embodiment (R (n)=to tert-butyl)：
26 mL (150 mmol) phosphorous is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethylenetetraminehexaacetic acid ester, is heated to flowing back, TLC detection is reacted, end of reaction after about 3 h.Extra triethyl phosphite is sloughed in concentration,
Obtain concentrate；20 mL DMF, p-t-Butylbenzaldehyde (2.5 g, 15 mmol) and sodium hydroxide are added in gained concentrate
(0.8 g, 20 mmol) reaction.TLC detects reaction process, and about 3.5 hour reactions terminate, and reaction solution is poured into 150 mL ice
Water, stirring, there is solid precipitation, filters, then recrystallizes to obtain 1.5 g of yellow solid, as (E) -4- (2,6- difluoros with petroleum ether
Phenyl) -2- p-tert-butylstyrene base thiazole, yield 43.5%.m.p.:55~60 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- p-tert-butylstyrene base thiazole that will be prepared according to the above method（3.56 g,
10 mmol）With N- bromo-succinimide（4.45 g, 25 mmol）It is dissolved in 30 mL acetonitriles, is stirred at 20 DEG C anti-
It answers.TLC detects reaction process, and about 5 hour reactions terminate, ice water is added in reaction solution, stirs, is extracted with ethyl acetate,
Precipitation, residual liquid are chromatographed with column（Eluant, eluent used is the mixed liquor of ethyl acetate and n-hexane, V ethyl acetate:V just oneself
Alkane=1: 5）Separate to obtain 2.8 g of yellow liquid, yield 64.4%.
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 9 derivative I i of embodiment (R (n)=to fluorine)：
It is sub- that 17 mL (98.43 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 1.5 h.Extra phosphorous acid three is sloughed in concentration
Ethyl ester obtains concentrate；28 mL DMF, 4-Fluorobenzaldehyde (2.3 g, 18 mmol) and hydroxide are added in gained concentrate
Sodium (1.2 g, 30 mmol) reaction.TLC detects reaction process, and about 3 hour reactions terminate, and reaction solution is poured into 150 mL ice
Water, stirring, there is solid precipitation, filters, then obtains 1.7 g of yellow solid, as (E) -4- (2,6- difluorobenzenes with ethyl alcohol recrystallization
Base) -2- pfluorostyrene base thiazole, yield 55.3%.m.p.:95~99 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- pfluorostyrene base thiazole that will be prepared according to the above method（3.18 g, 10
mmol）With N- bromo-succinimide（2.67 g, 15 mmol）It is dissolved in 35 mL acetonitriles, is stirred to react at 30 DEG C.
TLC detects reaction process, and about 3 hour reactions terminate, ice water is added in reaction solution, stirs, has a large amount of solids to be precipitated, mistake
Then ethyl acetate and n-hexane mixed liquor are used in filter（V ethyl acetate:N-hexane=2 V: 1）Recrystallize to obtain yellow solid 2.3
G, yield 58.0%. m.p.:105~106 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 10 derivative I j of embodiment (R (n)=neighbour's methyl)：
It is sub- that 10 mL (57.9 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 2.5 h.Extra phosphorous acid three is sloughed in concentration
Ethyl ester obtains concentrate；20 mL DMF, o-tolualdehyde (2.6 g, 22 mmol) and hydrogen-oxygen are added in gained concentrate
Change sodium (0.8 g, 20 mmol) reaction.TLC detects reaction process, and about 2.5 hour reactions terminate, and reaction solution is poured into 100
ML ice water, stirring, ethyl acetate extraction, then column chromatographs（Eluant, eluent used is the mixed liquor of ethyl acetate and n-hexane, V second
Acetoacetic ester:N-hexane=1 V: 4）Separate to obtain 2.1 g of yellow liquid, as (E) -4- (2,6- difluorophenyl) -2- o-methyl-benzene
Vinylthiazole, yield 67.6%.
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- o-methyl styrene base thiazole that will be prepared according to the above method（3.14 g,
10 mmol）With N- bromo-succinimide（7.12 g, 40 mmol）It is dissolved in 25 mL acetonitriles, is stirred at 30 DEG C anti-
It answers.TLC detects reaction process, and about 2.5 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, mistake
Filter, then obtains 2.1 g of yellow solid, yield 53.5% with ethyl alcohol recrystallization.m.p.:128~132 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 11 derivative I k of embodiment (R (n)=methyl)：
It is sub- that 18 mL (104.2 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 3 h.Extra phosphorous triethylenetetraminehexaacetic acid is sloughed in concentration
Ester obtains concentrate；20 mL DMF, tolyl aldehyde (1.8 g, 15 mmol) and hydroxide are added in gained concentrate
Sodium (1.6 g, 40 mmol) reaction.TLC detects reaction process, and about 2.5 hour reactions terminate, and reaction solution is poured into 100 mL
Then ice water, stirring, ethyl acetate extraction are chromatographed with column（Eluant, eluent used is the mixed liquor of ethyl acetate and n-hexane, V second
Acetoacetic ester:N-hexane=1 V: 5）Separate to obtain 1.8 g of yellow liquid, methylbenzene between as (E) -4- (2,6- difluorophenyl) -2-
Vinylthiazole, yield 57.3%.1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- m-methyl styrene base thiazole that will be prepared according to the above method（3.14 g,
10 mmol）With N- bromo-succinimide（3.56 g, 20 mmol）It is dissolved in 35 mL acetonitriles, is stirred at 40 DEG C anti-
It answers.TLC detects reaction process, and about 2.0 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, mistake
Filter, then recrystallizes to obtain 2.4 g of yellow solid, yield 61.1% with petroleum ether.m.p.:65~70 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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, 7.5
Hz, 2H), 2.39 (s, 3H)；
HRMS (ESI) calcd C18H12BrF2NS [M+H]+ 391.9915, found 391.9928。
The synthesis of 12 derivative I l of embodiment (R (n)=bromine)：
It is sub- that 10 mL (57.9 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 2 h.Extra phosphorous triethylenetetraminehexaacetic acid is sloughed in concentration
Ester obtains concentrate；24 mL DMF, 3-bromobenzaldehyde (3.7 g, 20 mmol) and sodium hydroxide are added in gained concentrate
(1.6 g, 40 mmol) reaction.TLC detects reaction process, and about 4 hour reactions terminate, and reaction solution is poured into 100 mL ice
Then water, stirring, ethyl acetate extraction are chromatographed with column（Eluant, eluent used is the mixed liquor of ethyl acetate and n-hexane, V acetic acid
Ethyl ester:Petroleum ether=1 V: 3）Separate to obtain 1.7 g of yellow liquid, bromstyrol between as (E) -4- (2,6- difluorophenyl) -2-
Base thiazole, yield 45.2%.
1H NMR (500 MHz, Chloroform-d) δ 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。
By bromstyrol base thiazole between (E) -4- (2,6- the difluorophenyl) -2- prepared according to the above method（3.79 g, 10
mmol）With N- bromo-succinimide（4.45 g, 25 mmol）It is dissolved in 35 mL acetonitriles, is stirred to react at 30 DEG C.
TLC detects reaction process, and about 4.5 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, filters,
Then 2.5 g of yellow solid, yield 54.6% are obtained with ethyl alcohol recrystallization.m.p.:84~87 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 13 derivative I m of embodiment (R (n)=neighbour's bromine)：
It is sub- that 13 mL (75.2 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 2.5 h.Extra phosphorous acid three is sloughed in concentration
Ethyl ester obtains concentrate；20 mL DMF, o-bromobenzaldehye (2.8 g, 15 mmol) and hydroxide are added in gained concentrate
Sodium (1.2 g, 30 mmol) reaction.TLC detects reaction process, and about 3 hour reactions terminate, and reaction solution is poured into 150 mL ice
Water, stirring, there is solid precipitation, filters, and then uses ethyl acetate and n-hexane mixed liquor（V ethyl acetate:N-hexane=2 V:
1）Recrystallize to obtain 1.8 g of yellow solid, as (E) -4- (2,6- difluorophenyl) -2- bromophenyl vinylthiazole, yield
48.4%.m.p.:75~77 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- bromophenyl vinylthiazole that will be prepared according to the above method（3.79 g, 10
mmol）With N- bromo-succinimide（6.23 g, 35 mmol）It is dissolved in 40 mL acetonitriles, is stirred to react at 20 DEG C.
TLC detects reaction process, and about 5.5 hour reactions terminate, ice water is added in reaction solution, stirs, there is solid precipitation, filters,
Then ethyl acetate and petroleum ether mixed liquor are used（V ethyl acetate:Petroleum ether=2 V: 1）2.4 g of yellow solid is recrystallized to obtain,
Yield 52.5%.m.p.:141~148 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 14 derivative I n of embodiment (R (n)=meta-methoxy)：
It is sub- that 15 mL (86.8 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 1.5 h.Extra phosphorous acid three is sloughed in concentration
Ethyl ester obtains concentrate；20 mL DMF, m-methoxybenzaldehyde (2.5 g, 18 mmol) and hydrogen are added in gained concentrate
Sodium oxide molybdena (1.0 g, 25 mmol) reaction.TLC detects reaction process, and about 1.5 hour reactions terminate, reaction solution is poured into
150 mL ice water, stirring, there is solid precipitation, filter, then recrystallize to obtain 2.2 g of yellow solid, as (E) -4- with petroleum ether
(2,6- difluorophenyl) -2- meta-methoxy styryl thiazole, yield 67.4%.m.p.:60~62 DEG C；
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- meta-methoxy styryl thiazole that will be prepared according to the above method（3.30 g,
10 mmol）With N- bromo-succinimide（3.56 g, 20 mmol）It is dissolved in 45 mL acetonitriles, is stirred at 25 DEG C anti-
It answers.TLC detects reaction process, and about 2.5 hour reactions terminate, ice water is added in reaction solution, stirs, ethyl acetate extraction,
Then it is chromatographed with column（Eluant, eluent used is the mixed liquor of ethyl acetate and n-hexane, V ethyl acetate:N-hexane=1 V: 5）
Separate to obtain 1.9 g of yellow liquid, yield 46.5%.
1H NMR (500 MHz, Chloroform-d) δ 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。
The synthesis of 15 derivative I o of embodiment (R (n)=O-methoxy)：
It is sub- that 10 mL (57.9 mmol) is added in 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole (2.9 g, 10 mmol)
It in triethyl phosphate, is heated to flowing back, TLC detection is reacted, end of reaction after about 2.5 h.Extra phosphorous acid three is sloughed in concentration
Ethyl ester obtains concentrate；20 mL DMF, o-methoxybenzaldehyde (2.1 g, 15 mmol) and hydrogen are added in gained concentrate
Sodium oxide molybdena (1.2 g, 30 mmol) reaction.TLC detects reaction process, and about 2 hour reactions terminate, and reaction solution is poured into 100
Then mL ice water, stirring, ethyl acetate extraction are chromatographed with column（Eluant, eluent used is the mixed liquor of ethyl acetate and petroleum ether, V
Ethyl acetate:Petroleum ether=1 V: 5）Separate to obtain 1.6 g of yellow liquid, as (E) -4- (2,6- difluorophenyl) -2- neighbour's methoxy
Base styryl thiazole, yield 50.1%.
1H NMR (500 MHz, Chloroform-d) δ 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- the difluorophenyl) -2- o-methoxystyrene base thiazole that will be prepared according to the above method（3.30 g,
10 mmol）With N- bromo-succinimide（5.34 g, 30 mmol）It is dissolved in 30 mL acetonitriles, is stirred at 40 DEG C anti-
It answers.TLC detects reaction process, and about 1.5 hour reactions terminate, ice water is added in reaction solution, stirs, ethyl acetate extraction,
Then it is chromatographed with column（Eluant, eluent used is the mixed liquor of ethyl acetate and petroleum ether, V ethyl acetate:Petroleum ether=1 V: 4）
Separate to obtain 2.2 g yellow liquids, yield 53.8%.
1H NMR (500 MHz, Chloroform-d) δ 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。
The test of 16 anti-tumor activity of embodiment：
Experiment loosely tests (E) -5- bromo- 4- (2,6- the difluorophenyl) -2- for testing and synthesizing in embodiment 1~15 using DNA
Substituted phenylethylene base thiazole compound is to topoisomerase I（TOP I ）Inhibitory activity, test concentrations be 50 μM.
Specific experiment process is as follows：Reaction system (20 μ L)：0.2 μ g negative supercoiling type plasmid p322 DNA, 1 μ L,
The TOP I 1 μ L of 0.5 U, 50 μM of 1 μ L of untested compound, buffer solution (20 7.5,0.1 mM of mM Tris, pH
EDTA, 10 Mm MgCl2, 100 Mm KCl, 50 μ g/mL acetylated BSA) and supply volume.
After having configured sample, half an hour is incubated at 37 DEG C.4 μ L6 × Loading are added after incubation
Buffer mixing, is added in the sample well of 0.8% Ago-Gel, 4.6 V/cm electrophoresis 1.5 hours.After electrophoresis, by fine jade
Sepharose is put into the aqueous solution of 1 × gel red and dyes 0.5 hour, photograph.
Test result is shown in Table 1.
The anti-tumor activity of 1 50 μM of table lower compound Ia-Io
Infuse a：TOPI（Topoisomerase I）DNA test inhibitory activity loosely with CPT（Camptothecine）（Positive control medicine pair
TOP1 has inhibitory activity）As a control group.For the data obtained relative to 50 μM of CPT, quantificational expression method is as follows：++++, table
Show 80% or more activity；+++ indicates between 40% to 79%；++it indicates between 10% to 39%；+, the activity less than 10%.
As shown in Table 1, under 50 μM of concentration, compound represented of embodiment of the present invention Ia-Io has certain antitumor
Activity.
The test of 17 antifungal activity of embodiment：
Test target：Fusarium graminearum FusaHum graminearum, cucumber didymella bryoniae Mycosphaerella
Melonis, botrytis cinerea Botrytis cinerea, Rhizoctonia solani Kuhn Thanatephorus cucumeris.
Embodiment 1~15 is synthesized using drug containing potato agar culture medium (PDA) method 15 bromo- 4- of (E) -5- (2,
6- difluorophenyl) -2- substituted phenylethylene base thiazole compound and blank medicament carried out the bactericidal activity of above-mentioned target fungus
Measurement, general sieve concentration are 100 mg/L.
Specifically, test method reference《Pesticide bioactivity evaluates SOP》.Using pastille culture medium method：Take each 500 mg/
2 mL of L compound medical fluid, addition are cooled in 45 DEG C of the PDA of 8 mL, and the pastille culture medium of final concentration of 100 mg/L is made
Plate.Then 6.5 mm diameter mycelia blocks are taken from cultured test germ colony edge, moved in pastille culture medium, every processing
4 repetitions（Same program test 4 times of each sample, finally calculates average inhibition）.It is disposed, it is raw to be placed in 28 DEG C of constant temperature
Change and cultivated in incubator, colony diameter is measured after 4 days, calculates growth inhibition ratio.
Growth inhibition ratio (%)=[(blank control colony diameter-processing colony diameter)/blank control colony diameter]
×100 %；
Test result is shown in Table 2.
The condition of the present embodiment blank control is free from the culture medium of medicine, other operating conditions are the same.
The bactericidal activity of compound Ia-Io under 2 100 mg/L of table
Note：Fluoxastrobin is control drug, and CK is blank control.
2 bactericidal activity test result of table shows under 100 mg/L concentration, (E) -5- bromo- 4- (2,6- difluoros of the invention
Phenyl) -2- substituted phenylethylene base thiazole compound, certain inhibitory activity is shown to for examination target, wherein compound
To fusarium graminearum inhibiting rate 50% or more, compound Id is to the inhibiting rate of cucumber didymella bryoniae by Ia, Ib, Id
56.7%, show medium inhibitory activity.
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, protection scope of the present invention is also only in those skilled in the art's root
According to present inventive concept it is conceivable that equivalent technologies mean.
Claims (10)
1. the class diphenyl ethene compounds of a kind of thiazole ring containing bromo, shown in structure such as formula (I)：
In formula (I), it is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；
The integer that n is 0 ~ 5, preferably 1 ~ 2 integer indicate the number of substituent R on phenyl ring；When n=0, the H on phenyl ring is indicated
It is not substituted；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2 ~ 5, it is more to indicate that the H on phenyl ring is substituted base R
Replace, the substituent R on different the position of substitution is same or different；
The substituent R is hydrogen, the halogenated alkyl of the alkyl of C1 ~ C8 or C1 ~ C8, the alkoxy of C1 ~ C3, halogen, nitro or cyanogen
Base.
2. a kind of class diphenyl ethene compounds of thiazole ring containing bromo according to claim 1, it is characterised in that described to take
It is hydrogen, the halogenated alkyl of the alkyl of C1 ~ C5 or C1 ~ C5, methoxyl group or halogen, preferably hydrogen, methyl, tert-butyl, trifluoro for base R
Methyl, methoxyl group, F, Cl or Br.
3. a kind of class diphenyl ethene compounds of thiazole ring containing bromo according to claim 1, it is characterised in that R (n) is
Hydrogen, adjacent methyl, methyl, to methyl, O-methoxy, to methoxyl group, meta-methoxy, to tert-butyl, to trifluoromethyl, to fluorine,
Adjacent chlorine, to chlorine, adjacent bromine, bromine or 2,4- dichloro.
4. a kind of synthetic method of the class diphenyl ethene compounds of the thiazole ring according to claim 1 containing bromo, feature
It is to include the following steps：
1）2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole is reacted under reflux state with triethyl phosphite, TLC prison
Survey to after reaction, extra triethyl phosphite is sloughed in concentration, be added in gained concentrate solvent DMF, sodium hydroxide and
The substituted benzaldehyde as shown in formula (IV), reacts at room temperature, and post-treated be made contains as shown in formula (II) after reaction
The class diphenyl ethene compounds of thiazole ring；
2）Class diphenyl ethene compounds as shown in formula (II) containing thiazole ring and the N- bromo succinyl as shown in formula (III) are sub-
Amine carries out bromo-reaction in acetonitrile solvent at 0 ~ 100 DEG C, and the class hexichol of the thiazole ring containing bromo as shown in formula (I) is made
Vinyl compound；
In formula (II), it is monosubstituted, polysubstituted or be not substituted that H on phenyl ring is substituted base R；
The integer that n is 0 ~ 5, preferably 1 ~ 2 integer indicate the number of substituent R on phenyl ring；When n=0, the H on phenyl ring is indicated
It is not substituted；When n=1, it is monosubstituted to indicate that the H on phenyl ring is substituted base R；When n=2 ~ 5, it is more to indicate that the H on phenyl ring is substituted base R
Replace, the substituent R on different the position of substitution is same or different；
The substituent R is hydrogen, the halogenated alkyl of the alkyl of C1 ~ C8 or C1 ~ C8, the alkoxy of C1 ~ C3, halogen, nitro or cyanogen
Base.
5. the synthetic method of the class diphenyl ethene compounds of the thiazole ring according to claim 4 containing bromo, it is characterised in that
Step 1）In, 2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole, triethyl phosphite, the substituted benzoyl as shown in formula (IV)
The ratio between amount for the substance that feeds intake of aldehyde and 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；
2- (bromomethyl) -4- (2,6- difluorophenyl) thiazole and the mass ratio of solvent DMF are 1:2.0~20, preferably 1:
4.0~10.
6. the synthetic method of the class diphenyl ethene compounds of the thiazole ring according to claim 4 containing bromo, it is characterised in that
The throwing of class diphenyl ethene compounds as shown in formula (II) containing thiazole ring and the N- bromo-succinimide as shown in formula (III)
The ratio between amount of material matter is 1:1.0 ~ 20.0, preferably 1: 1.0~5.0；
The mass ratio of the class diphenyl ethene compounds and acetonitrile solvent as shown in formula (II) containing thiazole ring is 1: 2.0
~20, preferably 1:4.0~10.
7. the synthetic method of the class diphenyl ethene compounds of the thiazole ring according to claim 4 containing bromo, it is characterised in that
Step 2）In, reaction temperature is 20 ~ 50 DEG C, and the reaction time is 0.5 ~ 6 hour.
8. the synthetic method of the class diphenyl ethene compounds of the thiazole ring according to claim 4 containing bromo, it is characterised in that
Step 2）After reaction, ice water is added in reaction solution, stirs, if there is solid precipitation, recrystallization purification is obtained such as formula（I）It is shown
The thiazole ring containing bromo class diphenyl ethene compounds；If no solid is precipitated, it is extracted with ethyl acetate, precipitation, residual liquid
Column chromatography for separation is obtained such as formula（I）Shown in the thiazole ring containing bromo class diphenyl ethene compounds.
9. the synthetic method of the class diphenyl ethene compounds of the thiazole ring according to claim 8 containing bromo, it is characterised in that
Recrystallization solvent for use is the mixed liquor of one or more of ethyl alcohol, ethyl acetate, n-hexane, petroleum ether；Column chromatography
Eluant, eluent used is the mixed liquor of ethyl acetate and n-hexane, or the mixed liquor for ethyl acetate and petroleum ether.
10. the class diphenyl ethene compounds of any thiazole ring containing bromo are as anti-tumor drug according to claim 1 ~ 3
Or the application of antibacterial agent.
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