CN104530027B - A kind of 1,2,3 triazoles join 1,3,4 oxadiazole class compounds and its application - Google Patents

A kind of 1,2,3 triazoles join 1,3,4 oxadiazole class compounds and its application Download PDF

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CN104530027B
CN104530027B CN201410795532.9A CN201410795532A CN104530027B CN 104530027 B CN104530027 B CN 104530027B CN 201410795532 A CN201410795532 A CN 201410795532A CN 104530027 B CN104530027 B CN 104530027B
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oxadiazole
triazole
chlorobenzyls
methyl isophthalic
yls
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CN104530027A (en
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王宇光
朱冰春
董慧婵
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A01N43/82—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 three ring hetero atoms

Abstract

A kind of 1,2,3 triazoles connection 1,3,4 oxadiazole class compounds and its application, described 1,2,3 triazoles connection 1,3,4 oxadiazole class compounds are 2 R (5 (1 (2 chlorphenyl) 5 methyl 1H 1 shown in formula (I), the yl of 2,3 triazole 4) 1,3, the thioether of 4 oxadiazole 2), wherein R substituent is C1 C12 alkyl, COOR1、‑R2COOR3Or CH (R4)COR5, wherein R1C1 C4 alkyl or benzyl selected from H, side chain or side chain；R2C1 C4 alkylidenes selected from straight or branched, R3C1 C4 alkyl selected from H or straight or branched；R4Selected from H or the triazolyls of 1H 1,2,4；R5Substituent on C1 C4 alkyl or substituted-phenyl selected from straight or branched, substituted-phenyl is one or more, and the substituent is each independently selected from halogen or 3 chlorophenoxies.Described 2 R (thioether of 5 (yl of 1 1,2,3 triazoles of (2 chlorphenyl) 5 methyl 1H 4) 1,3,4 oxadiazole 2) can be applied to prepare antiseptic.2 R (5 (1 (2 chlorphenyl) 5 methyl 1H 1 that the present invention is provided, 2, the yl of 3 triazole 4) 1,3, the thioether of 4 oxadiazole 2) there is inhibitory action to a variety of thalline bacterium (bacillus subtilis, Escherichia coli, aspergillus fumigatus), and synthesis technique is simple, it is easy to industrialization.

Description

A kind of 1,2,3- triazoles connection 1,3,4- oxadiazole class compounds and its application
(1) technical field
The present invention relates to a kind of new 1,2,3- triazoles connection 1,3,4- oxadiazole class compounds and its application.
(2) background technology
Antibacterials are most popular class medicines in current pharmaceuticals industry, are also drug development and the emphasis of research One of field.Antibacterials species clinically has beta-lactam, sulfamido, Tetracyclines, aminoglycoside, big ring at present Lactone, quinolones and in the past few years clinically oxazolidinones etc..
But due to the abuse of antibacterials, cause germ drug resistance increasingly to increase, the death rate also rises and causes complete therewith The Health risk of ball.At present, drug resistance problems of antimicrobial and how improving have turned into the antibacterial activity of drug-resistant bacteria In the urgent need to the problem of concern.For this, existing many researchers are directed to the effort of this aspect, and such as scientific research works out one A little measures be used to preventing abusing antimicrobial so as to reduce the appearance of drug-fast bacteria, the target position of existing medicine is modified or transformed, The reason for inquiring into drug-fast bacteria drug resistance and mechanism etc..The emphasis of these work is all to prevent the appearance of drug-fast bacteria, still The new antimicrobial of exploitation can be more essential solve the problems, such as, including transformation to existing antibacterials structure and brand new is anti- The research and development of bacterium medicine.The antimicrobial of brand new may have different targetings to germ, be expected in certain journey The medicine drug resistance problems of bacterium are solved on degree, strengthen antibacterial activity.
1,2,3-triazoles analog derivative is as being one of common structure in natural products, with multiple biological activities and life Thing compatibility, while being expected to can solve the problem that antimicrobial because its chemical constitution is different with the antimicrobial clinically used at present again Drug resistance problems.
The present invention is generated containing 1,2,3-triazoles connection 1 by click reaction generation 1,2,3-triazoles, then by multistep reaction, 3,4- oxadiazole derivatives, these compounds are a kind of inhibitor medicaments with notable antibacterial activity, are the sieve of antibacterials Choosing provides Research foundation.
(3) content of the invention
Resist it is an object of the present invention to provide a kind of new 1,2,3- triazoles connection 1,3,4- oxadiazole class compounds and its preparing Application in microbial inoculum, such compound has inhibitory action to a variety of thalline bacterium, and synthesis technique is simple, it is easy to industrialization.
The technical solution adopted by the present invention is as follows：
Join 1,3,4- oxadiazole class compounds, its chemical entitled 2-R- (5- (1- (2- the invention provides 1,2,3-triazoles Chlorobenzyl) -5- methyl isophthalic acids H-1,2,3- triazole-4-yls) -1,3,4- oxadiazole -2- thioethers), shown in structure such as formula (I)：
R substituent is C1-C12 alkyl ,-COOR1、-R2COOR3Or-CH (R4)COR5, wherein R1Selected from H, side chain or branch The C1-C4 alkyl or benzyl of chain；R2C1-C4 alkylidenes selected from straight or branched, R3C1-C4 selected from H or straight or branched Alkyl；R4Selected from H or 1H-1,2,4- triazolyls；R5On C1-C4 alkyl or substituted-phenyl selected from straight or branched, substituted-phenyl Substituent to be one or more, the substituent is each independently selected from halogen or 3- chlorophenoxies.
Further, the preferred Cl of halogen.
Further, R1C1-C4 alkyl selected from side chain or side chain；R2C1-C4 alkylidenes selected from straight or branched, R3 C1-C4 alkyl selected from straight or branched；R4Selected from H；R5Substituent on substituted-phenyl, substituted-phenyl is one or many Individual, the substituent is each independently selected from chlorine or 3- chlorophenoxies.
Again further, described 2-R- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acids H-1,2,3- triazole-4-yls) -1,3, 4- oxadiazole -2- thioethers) selected from one of following：
Of the present invention to be prepared by a conventional method, its reaction equation is as follows：
The invention provides the 2-R- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3, 4- oxadiazole -2- thioethers) application in antiseptic is prepared.
Further, described antiseptic is the inhibitor for bacillus subtilis, Escherichia coli or aspergillus fumigatus.
Further, the inhibitor for bacillus subtilis being directed to for preparing is chemical compounds I -11.
Further, the inhibitor for Escherichia coli being directed to for preparing is compound I-1, I-4 or I-6.
Further, the inhibitor for aspergillus fumigatus being directed to for preparing is compound I-4, I-6, I-7 or I-8.
Compared with prior art, the beneficial effects of the present invention are：2-R- that the present invention is provided (5- (1- (2- chlorobenzyls)- 5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazole -2- thioethers) to a variety of thalline bacterium (bacillus subtilis, large intestines Bacillus, aspergillus fumigatus) there is inhibitory action, and synthesis technique is simple, it is easy to industrialization.
(4) embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in This：
It is prepared by intermediate：
1) preparation of 1- (2- chlorine) -5- methyl isophthalic acid H-1,2,3- triazole -4- methyl formates (3)
Weigh 1.60g o-chloro benzyl chloride 1 (10mmol) and 0.98g NaN3(15mmol) is added in the DMF containing 8ml, often Temperature stirring, TCL tracking, after reaction terminates, plus 20ml dichloromethane, it is washed with water (20ml × 3), the anhydrous MgSO of organic phase4It is dry Dry, vacuum concentrated by rotary evaporation obtains product, clear colorless liquid, 1.6g, yield 95.8%；By 1.6g o-chlorobenzyls nitrine 2 (9.58mmol) is added in 100ml round-bottomed flasks, adds 1.11g methyl acetoacetates (9.58mmol), adds 1.45g K2CO3(9.58 × 1.1=10.84mmol) and 10ml acetone, is heated to reflux, TCL tracking, after reaction terminates, cooling down, mistake Filter obtains liquid, and vacuum concentrated by rotary evaporation, solid is washed with dichloromethane, and dichloromethane solution is mixed with concentrate, and add water washing (15ml × 3), organic anhydrous MgSO of addition4Dry, be concentrated to give 1- (2- chlorine) -5- methyl isophthalic acids H-1,2,3- triazole -4- formic acid Methyl esters 3, faint yellow solid, 2.36g, yield 92.9%.
2) system of 5- (1- (2- chlorobenzenes) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazole -2- mercaptan (5) It is standby
Excessive hydrazine hydrate is added by the 8 of 2.36g, using hydrazine hydrate as solvent, 5h is heated to reflux, TCL tracking is reacted, instead After should terminating, cool, stand overnight, be filtrated to get solid, (20ml × 3) are washed with water in solid, obtain compound 1- (2- chlorine Benzene) -5- methyl isophthalic acids H-1,2,3- triazole -4- hydrazides, white solid, 2.24g, yield 95.0%；By 2.24g 4 (8.45mmol) It is dissolved in 95% ethanol, 1.35ml CS is slowly added under ice-water bath2(25.35mmol) and 0.56g KOH (10mmol), are stirred 10min is mixed, removes ice-water bath, 12h, TCL tracking reactions is heated to reflux.After reaction terminates, cooling, vacuum revolving sloughs solvent, Obtain solid 50ml H2O is dissolved, filtering, and liquid adjusts pH value to 3-4 with 1M HCl, is filtrated to get solid, and filter cake drying is used Recrystallizing methanol obtains pure product, 5- (1- (2- chlorobenzenes) -5- methyl isophthalic acids H-1,2,3- triazole-4-yls) -1, and 3,4- oxadiazoles - 2- mercaptan (5), white solid, 2.21g, yield 85.32%.
Embodiment 1：2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazoles -2- Thioether) methyl acetate (I -1)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.076g (0.5mmol) methyl bromoacetate are added into 50ml round bottoms to burn In bottle, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH is added, heated To 80 DEG C, 5h is stirred, TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, through silica gel flaggy Analysis separates to obtain final pure product 2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- Evil bis- Azoles -2- thioethers) methyl acetate (I -1), 0.153g, yield 80.8%.
1H NMR(600MHz,CDCl3,ppm-1) δ 7.45 (d, J=8.0Hz, 1H), 7.31 (t, J=7.7Hz, 1H), 7.24 (t, J=7.6Hz, 1H), 6.87 (d, J=7.7Hz, 1H), 5.71 (s, 2H), 4.13 (s, 2H), 3.81 (s, 3H), 2.58 (s,3H).IR(KBr,cm-1):2963,1741,1624,1554,1431,1301,744.HRMS(ESI):m/z calcd for C15H15ClN5O3S+[M+H]+:380.0579,found:380.0585.
Embodiment 2：2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazoles -2- Thioether) -3 Methylbutanoic acid ethyl ester (I -2)
Reaction equation is as follows：
The bromo- 3 Methylbutanoic acid ethyl esters of compound 0.153g 5 (0.5mmol) and 0.104g (0.5mmol) 2- are added to In 50ml round-bottomed flasks, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) is added NaOH, is heated to 80 DEG C, stirs 5h, and TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, Through silica gel plate chromatography obtain finally pure product 2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) - 1,3,4- oxadiazole -2- thioethers) -3 Methylbutanoic acid ethyl ester (I -2), 0.177g, yield 81.7%.
1H NMR(600MHz,CDCl3,ppm-1) δ 7.34 (d, J=7.9Hz, 1H), 7.21 (t, J=7.6Hz, 1H), 7.14 (t, J=7.5Hz, 1H), 6.78 (d, J=7.6Hz, 1H), 5.61 (s, 2H), 4.27 (d, J=6.4Hz, 1H), 4.18- (dd, J=21.2,6.8Hz, the 6H) of 4.12 (m, 2H), 2.49 (s, 3H), 1.17 (dt, J=20.7,7.1Hz, 4H), 1.0513C NMR(150MHz,CDCl3)δ169.92,163.11,159.90,135.58,132.55,131.62,131.51,129.96, 129.82,128.61,127.60,61.85,56.92,49.13,31.20,19.95,19.69,14.09,8.91.IR(KBr, cm-1):2921,1737,1642,1385,1376,745.HRMS(ESI):m/z calcd for C19H23ClN5O3S+[M+H]+: 436.1205,found:436.1205. embodiment 3：2- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -5- (isopropyl thioether) -1,3,4- oxadiazoles (I -3)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.061g (0.5mmol) 2- N-Propyl Bromides are added to 50ml round-bottomed flasks In, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH is added, is heated to 80 DEG C, 5h is stirred, TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, through silica gel plate layer chromatography Separate finally pure product 2- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -5- (isopropyl thioether) - 1,3,4- oxadiazoles (I -3), 0.156g, yield 89.8%.
1H NMR(600MHz,CDCl3,ppm-1) δ 7.34 (d, J=8.0Hz, 1H), 7.20 (t, J=7.7Hz, 1H), 7.13 (t, J=7.6Hz, 1H), 6.78 (d, J=7.7Hz, 1H), 5.62 (s, 2H), 3.88 (dq, J=13.5,6.8Hz, 1H), 2.50 (s, 3H), 1.43 (d, J=6.8Hz, 6H)13C NMR(150MHz,CDCl3)δ162.95,158.49,134.41, 131.52,130.71,130.63,128.93,128.61,127.54,126.59,48.11,38.03,22.30,7.94.IR (KBr,cm-1):2955,1638,1472,1383,1374,1151,1050,752.HRMS(ESI):m/z calcd for C15H17ClN5OS+[M+H]+:350.0837,found:350.0840.
Embodiment 4：3- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazoles -2- Thioether) methyl butyrate (I -4)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.096g (0.5mmol) 3- bromobutyrates are added to 50ml round bottoms In flask, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH is added, plus Heat stirs 5h to 80 DEG C, and TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, through silica gel plate Chromatography obtains finally pure product 3- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- Evil Diazole -2- thioethers) methyl butyrate (I -4), 0.185g, yield 87.9%.
1H NMR(600MHz,CDCl3) δ 7.44 (d, J=7.9Hz, 1H), 7.31 (t, J=8.1Hz, 1H), 7.24 (t, J =7.5Hz, 1H), 6.89 (d, J=7.6Hz, 1H), 5.71 (s, 2H), 4.41 (t, J=6.8Hz, 1H), 4.24 (q, J= 7.1Hz, 2H), 2.60 (s, 3H), 2.11 (m, 2H), 1.28 (t, J=7.1Hz, 3H), 1.11 (d, J=7.4Hz, 3H) .HRMS (ESI):m/z calcd for C18H21ClN5O3S+[M+H]+:422.1048,found:422.1051.
Embodiment 5：2- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -5- (dodecyl thioether) - 1,3,4- oxadiazoles (I -5)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.124g (0.5mmol) N-dodeeyl bromide are added to 50ml round bottoms In flask, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH is added, plus Heat stirs 5h to 80 DEG C, and TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, through silica gel plate Chromatography obtains finally pure product 2- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -5- (n-dodecanes Base thioether) -1,3,4- oxadiazoles (I -5), 0.211g, yield 89.1%.
1H NMR(600MHz,CDCl3,ppm-1) 7.45 (dd, J=8.0,1.1Hz, 1H), 7.30 (td, J=7.8, 1.5Hz, 1H), 7.23 (td, J=7.6,1.1Hz, 1H), 6.86 (d, J=8.9Hz, 1H), 5.71 (s, 2H), 3.31-3.28 (m, 2H), 2.58 (s, 3H), 1.83 (dt, J=15.1,7.5Hz, 2H), 1.48-1.43 (m, 2H), 1.29 (s, 16H), 0.88 (t, J=7.0Hz, 3H) .IR (KBr, cm-1):2922,1621,1473,1443,1253,1165,1055,746.HRMS(ESI): m/z calcd for C24H35ClN5OS+[M+H]+:476.2245,found:476.2241.
Embodiment 6：S-5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazoles -2- Base O- Ethyl formates thioether (I -6)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.076g (0.5mmol) 1- bromine Ethyl formates are added to 50ml round bottoms In flask, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH is added, plus Heat stirs 5h to 80 DEG C, and TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, through silica gel plate Chromatography obtains finally pure product S-5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- Evil bis- Azoles -2- base O- Ethyl formates thioethers (I -6), 0.152g, yield 80.4%.
1H NMR(600MHz,CDCl3,ppm-1) δ 7.45 (d, J=8.0Hz, 1H), 7.31 (t, J=7.7Hz, 1H), 7.24 (t, J=7.6Hz, 1H), 6.87 (d, J=7.7Hz, 1H), 5.71 (s, 2H), 4.13 (s, 2H), 3.81 (s, 3H), 2.58 (s,3H).IR(KBr,cm-1):3011,2901,1739,1650,1438,1021,953,745.HRMS(ESI):m/z calcd for C15H15ClN5O3S+[M+H]+:380.0579,found:380.0581.
Embodiment 7：2- (butyl thioether) -5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3, 4- oxadiazoles (I -7)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.068g (0.5mmol) bromination of n-butane are added into 50ml round bottoms to burn In bottle, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH is added, heated To 80 DEG C, 5h is stirred, TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, through silica gel flaggy Analysis separate finally pure product 2- (butyl thioether) -5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) - 1,3,4- oxadiazoles (I -7), 0.161g, yield 88.9%.
1H NMR(600MHz,CDCl3,ppm-1) δ 7.30 (dd, J=8.7,5.6Hz, 1H), 7.18 (t, J=5.5Hz, 1H), 7.13-7.08 (m, 1H), 6.76 (d, J=7.7Hz, 1H), 5.58 (s, 2H), 3.18 (d, J=7.1Hz, 2H), 2.48 (s, 3H), 1.70 (d, J=4.4Hz, 2H), 1.37 (d, J=6.0Hz, 2H), 0.83 (dd, J=10.7,7.3Hz, 3H) .HRMS (ESI):m/z calcd for C16H19ClN5OS+[M+H]+:364.0993,found:364.0989.
Embodiment 8：2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazoles -2- Thioether) ethyl propionate (I -8)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.090g (0.5mmol) 2 bromopropionic acid ethyl ester are added to 50ml round bottoms In flask, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH is added, plus Heat stirs 5h to 80 DEG C, and TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, through silica gel plate Chromatography obtains finally pure product 2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- Evil Diazole -2- thioethers) ethyl propionate (I -8), 0.175g, yield 85.7%.
Faint yellow solid, fusing point：79.6-82.2℃.1H NMR(600MHz,CDCl3,ppm-1) δ 7.37 (d, J= 7.4Hz, 1H), 7.23 (t, J=7.7Hz, 1H), 7.16 (t, J=8.1Hz, 1H), 6.80 (d, J=8.8Hz, 1H), 5.64 (s, 2H), 4.44 (q, J=7.3Hz, 1H), 4.16 (qd, J=7.1,2.2Hz, 2H), 2.51 (s, 3H), 1.66 (d, J=7.3Hz, 3H), 1.20 (t, J=7.1Hz, 3H) .IR (KBr, cm-1):3033,2932,2854,1621,1556,1470,1255,1165, 1051,744.HRMS(ESI):m/z calcd for C17H19ClN5O3S+[M+H]+:408.0892,found:408.0895.
Embodiment 9：2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazoles -2- Thioether) acetic acid (I -9)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.069g (0.5mmol) bromoacetic acid are added in 50ml round-bottomed flasks, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.042g (1.05mmol) NaOH is added, is heated to 80 DEG C, 5h is stirred, TCL tracking after reaction terminates, adjusts pH value to be 6.0, separate organic layer, vacuum concentrated by rotary evaporation is obtained slightly with 1MHCl Product, finally pure product 2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acids H-1,2,3- triazole -4- is obtained through silica gel plate chromatography Base) -1,3,4- oxadiazole -2- thioethers) acetic acid (I -9), 0.152g, yield 83.4%.
1H NMR(600MHz,CDCl3,ppm-1) δ 9.11 (s, 1H), 7.45 (d, J=8.0Hz, 1H), 7.31 (t, J= 7.6Hz, 1H), 7.26 (s, 2H), 7.24 (t, J=7.6Hz, 1H), 6.88 (d, J=7.7Hz, 1H), 5.69 (s, 2H), 2.47 (s,3H).IR(KBr,cm-1):1733,1559,1471,1371,1345,1264,1199,1052,989,854,750.HRMS (ESI):m/z calcd for C14H13ClN5O3S+[M+H]+:366.0422,found:366.0427.
Embodiment 10：2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazoles - 2- thioethers) -1- (2,4 dichloro benzene base) ethyl ketone (I -10)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.133g (0.5mmol) 2- bromo- 1- (2,4 dichloro benzene base) ethyl ketone is added Enter into 50ml round-bottomed flasks, add 5ml water and 5ml toluene, add 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH, is heated to 80 DEG C, stirs 5h, and TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation is obtained To crude product, finally pure product 2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acids H-1,2,3- tri- are obtained through silica gel plate chromatography Azoles -4- bases) -1,3,4- oxadiazole -2- thioethers) -1- (2,4 dichloro benzene base) ethyl ketone (I -10), 0.194g, yield 78.9%.
1H NMR(600MHz,CDCl3) δ 7.70 (d, J=8.4Hz, 1H), 7.48 (d, J=1.9Hz, 1H), 7.45 (d, J =8.0Hz, 1H), 7.36 (dd, J=8.4,1.9Hz, 1H), 7.31 (t, J=7.7Hz, 1H), 7.24 (t, J=7.6Hz, 1H), 6.87 (d, J=7.7Hz, 1H), 5.71 (s, 2H), 4.79 (s, 2H), 2.57 (s, 3H) .IR (KBr, cm-1):2923,2852, 1733,1662,1635,1576,1558,1473,1446,1262,1123,865.HRMS(ESI):m/z calcd for C20H15Cl3N5O2S+[M+H]+:494.0007,found:494.0011.
Embodiment 11：1- (the chloro- 4- of 2- (3- chlorobenzenes ether) phenyl) -2- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2, 3- triazole-4-yls) -1,3,4- oxadiazole -2- thioethers) ethyl ketone (I -11)
Reaction equation is as follows：
By compound 0.153g 5 (0.5mmol) and the bromo- 1- of 0.178g (0.5mmol) 2- (the chloro- 4- of 2- (3- chlorobenzenes ether) benzene Base) ethyl ketone is added in 50ml round-bottomed flasks, adds 5ml water and 5ml toluene, add 0.016g (0.05mmol) PTC with 0.022g (0.55mmol) NaOH, is heated to 80 DEG C, stirs 5h, and TCL tracking after reaction terminates, separates organic layer, vacuum revolving Crude product is concentrated to give, finally pure product 1- (the chloro- 4- of 2- (3- chlorobenzenes ether) phenyl) -2- (5- are obtained through silica gel plate chromatography (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazole -2- thioethers) ethyl ketone (I -11), 0.224g, yield 76.9%.
1H NMR(600MHz,CDCl3,ppm-1) δ 7.70 (dd, J=8.7,1.5Hz, 1H), 7.32 (d, J=7.1Hz, 1H), 7.26 (d, J=8.8Hz, 2H), 7.18 (t, J=7.1Hz, 1H), 7.12 (d, J=6.8Hz, 1H), 6.92 (dd, J= 8.8,2.2Hz, 2H), 6.88 (d, J=1.2Hz, 1H), 6.81 (dd, J=8.7,2.4Hz, 1H), 6.77 (d, J=7.7Hz, 1H), 5.58 (s, 2H), 4.76 (d, J=1.9Hz, 2H), 2.46 (d, J=2.3Hz, 3H) .IR (KBr, cm-1):3069,1674, 1627,1576,1464,1383,1169,1059,841,805,742.HRMS(ESI):m/z calcd for C26H19Cl3N5O3S+[M+H]+:586.0269,found:586.0276.
Embodiment 12：O- phenyl-S-5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- Evil Diazole -2- bases thioether (I -12)
Reaction equation is as follows：
Compound 0.153g 5 (0.5mmol) and 0.107g (0.5mmol) bromo benzyl formate are added to 50ml round bottoms In flask, 5ml water and 5ml toluene are added, 0.016g (0.05mmol) PTC and 0.022g (0.55mmol) NaOH is added, plus Heat stirs 5h to 80 DEG C, and TCL tracking after reaction terminates, separates organic layer, vacuum concentrated by rotary evaporation obtains crude product, through silica gel plate Chromatography obtains finally pure product O- phenyl-S-5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1, 3,4- oxadiazole -2- bases thioethers (I -12), 0.113g, yield 51.3%.
1H NMR(600MHz,CDCl3,ppm-1) δ 7.48-7.43 (m, 3H), 7.37-7.26 (m, 5H), 7.23 (td, J= 7.6,1.1Hz,1H),5.70(s,2H),4.53(s,2H),2.57(s,3H).HRMS(ESI):m/z calcd for C20H17ClN5O3S+[M+H]+:442.0735,found:442.0739.
Embodiment 13：1- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazoles - 2- thioethers) -3,3- dimethyl -1- (1H-1,2,4- triazol-1-yls) -2- butanone (I -13)
Reaction equation is as follows：
By compound 0.153g 5 (0.5mmol) and the bromo- 3,3- dimethyl -1- of 0.122g (0.5mmol) 1- (1H-1,2, 4- triazol-1-yls) -2- butanone is added in 50ml round-bottomed flasks, and 5ml water and 5ml toluene are added, 0.016g is added (0.05mmol) PTC and 0.022g (0.55mmol) NaOH, is heated to 80 DEG C, stirs 5h, and TCL tracking after reaction terminates, is separated Organic layer, vacuum concentrated by rotary evaporation obtains crude product, and finally pure product 1- (5- (1- (2- benzyl chlorides are obtained through silica gel plate chromatography Base) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- oxadiazole -2- thioethers) -3,3- dimethyl -1- (1H-1,2,4- tri- Azoles -1- bases) -2- butanone (I -13), 0.182g, yield 77.4%.
1H NMR(600MHz,CDCl3) δ 8.63 (s, 1H), 7.91 (s, 1H), 7.46 (s, 1H), 7.38 (d, J=8.0Hz, 1H), 7.24 (t, J=8.3Hz, 1H), 7.17 (t, J=5.8Hz, 1H), 6.81 (d, J=7.7Hz, 1H), 5.63 (s, 2H), 2.50(s,3H),1.16(s,9H).IR(KBr,cm-1):2852,1651,1475,1423,1366,1310,1121,1106, 951,751.HRMS(ESI):m/z calcd for C20H22ClN8O2S+[M+H]+:473.1269,found:473.1273.
Embodiment 14：The measure of antibacterial activity
(1) preparation of culture medium
Broth bouillon：Beef extract 1g, peptone 2g, NaCl 1g, plus the dissolving of 180ml water, pH value is adjusted with 1N NaOH 7.0, add water and be settled to 200ml, 121 DEG C of sterilizing 20min.
Agar medium：Beef extract 1g, peptone 2g, NaCl 1g, agar 4g, plus the dissolving of 180ml water, are adjusted with 1N NaOH PH value 7.0, adds water and is settled to 200ml, 121 DEG C of sterilizing 20min.
PDA solid mediums：Potato 30g, glucose 2g, agar 1.5-2g, water 100ml, natural ph, 121 DEG C go out Bacterium 20min.
PDA liquid medium：Potato 30g, glucose 2g, water 100ml, natural ph, 121 DEG C of sterilizing 20min.
(2) Determination of Antibacterial Activity
1) preparation of bacterium solution
The similar bacterium colony to be checked of picking form (Escherichia coli, bacillus subtilis, staphylococcus aureus) 3-5, connect Plant in 5ml broth mediums, 37 DEG C of culture 2-6h after thalline breeding, determine its OD630Value, controls its OD630Value exists 0.1 or so, it is standby with 100 times of culture medium dilution.
It is a small amount of (aspergillus fumigatus, aspergillus niger) from picking fungi pearl bacterium in the PDA culture medium of 4 DEG C of preservations with inoculation circle, it is seeded to 5ml PDA nutrient solutions, in 37 DEG C, in constant incubator culture 18-25h.
2) preparation of test medicine
Treat that reagent thing is made into 6.4mg/ml solution with DMSO, 6.4mg samples and 1ml DMSO added in 1.5ml EP pipes, - 20 DEG C of preservations are placed in after dissolving, before experiment, decoction 37 DEG C of incubators of taking-up is taken out and melts standby.
3) preparation of drug sensitive plate
Sterile 96 orifice plate is taken, adds the 184 fresh bacterium solutions of μ l in every No. 1 hole of row, 2~No. 12 holes respectively add the bacterium solution of Fresh 100μl；No. 1 hole adds 16 μ l decoctions.2~No. 11 10 grades of doubling dilutions, make the drug concentration in each hole be respectively 512,256, 128th, 64,32,16,8,4,2,1 and 0.5 μ g/ml, No. 12 holes not drug containing, make positive control, and it is DMSO as sky separately to have one group White control, each drug sensitive plate is in 37 DEG C of cultures.
4)IC50Value judges
Escherichia coli, hay bacillus and staphylococcus aureus cultivate 18h in 37 DEG C, and aspergillus fumigatus, aspergillus tamarii are in 37 DEG C 20h is cultivated, OD is surveyed with ELIASA630.Contrasted with No. 12 holes, the medicine declined with OD values in more than 50% least concentration hole is dense Spend for IC50(concentration when fungi or bacterial growth 50% are suppressed).As the IC of measure50During higher than maximum concentration, be designated as "> 512μg/mL”；IC50When value is less than least concentration, be designated as "<0.5μg/mL”.
Compound is tested as stated above respectively made from embodiment 1-13, as a result as follows：
As seen from table, compound I-11 shows the resistance as Norfloxacin to bacillus subtilis；Compound I- 1st, I-4, I-6 show preferable inhibitory activity to Escherichia coli, and compound I-10 is preferable to the inhibition of bacillus subtilis. Test active testing result to fungi shows that wherein compound I-4, I-6, I-7, I-8 inhibition is better than Fluconazole.

Claims (9)

1. 2-R- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- Evil shown in a kind of formula (I) Diazole -2- thioethers)：
R substituent is C1-C12 alkyl ,-COOR1、-R2COOR3Or-CH (R4)COR5, wherein R1Selected from H, straight or branched C1-C4 alkyl or benzyl；R2C1-C4 alkylidenes selected from straight or branched, R3C1-C4 alkane selected from H or straight or branched Base；R4Selected from H or 1H-1,2,4- triazolyls；R5On C1-C4 alkyl or substituted-phenyl selected from straight or branched, substituted-phenyl Substituent is one or more, and the substituent is each independently selected from halogen or 3- chlorophenoxies.
2. 2-R- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- as claimed in claim 1 Oxadiazole -2- thioethers), it is characterised in that：Halogen is Cl.
3. 2-R- as claimed in claim 1 or 2 (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1, 3,4- oxadiazole -2- thioethers), it is characterised in that：R1C1-C4 alkyl selected from straight or branched；R2Selected from straight or branched C1-C4 alkylidenes, R3C1-C4 alkyl selected from straight or branched；R4Selected from H；R5Taking on substituted-phenyl, substituted-phenyl Dai Jiwei is one or more, and the substituent is each independently selected from chlorine or 3- chlorophenoxies.
4. 2-R- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- as claimed in claim 3 Oxadiazole -2- thioethers), it is characterised in that：Described 2-R- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazoles -4- Base) -1,3,4- oxadiazole -2- thioethers) selected from one of following：
5. 2-R- (5- (1- (2- chlorobenzyls) -5- methyl isophthalic acid H-1,2,3- triazole-4-yls) -1,3,4- as claimed in claim 1 Oxadiazole -2- thioethers) application in antiseptic is prepared.
6. application as claimed in claim 5, it is characterised in that：Described antiseptic is to be directed to bacillus subtilis, large intestine bar Bacterium or the inhibitor of aspergillus fumigatus.
7. application as claimed in claim 6, it is characterised in that：Being for preparing the inhibitor for bacillus subtilis Compound I -11,
8. application as claimed in claim 6, it is characterised in that：The inhibitor that Escherichia coli are directed to for preparing is compound I-1, I-4 or I-6,
9. application as claimed in claim 6, it is characterised in that：The inhibitor that aspergillus fumigatus is directed to for preparing is compound I- 4th, I-6, I-7 or I-8；
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1128996A (en) * 1993-06-29 1996-08-14 比克·古尔顿·劳姆贝尔格化学公司 Substituted arylthioalkylthiopyridines
CN101255142A (en) * 2008-03-11 2008-09-03 贵州大学 2-substituted sulfinyl-5-(3,4,5-trialkoxy phenyl)-1,3,4-oxadiazole derivatives as well as preparation method and uses thereof
CN103880836A (en) * 2014-04-04 2014-06-25 贵州大学 1-substituted-5-amino-4-pyrazol di-1,3,4-diazole sulfur ether or 1,3,4-diazole sulfone derivatives and application thereof

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
JP5007788B2 (en) * 2005-05-16 2012-08-22 日産化学工業株式会社 Dihydroazole-substituted benzamide compounds and pest control agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1128996A (en) * 1993-06-29 1996-08-14 比克·古尔顿·劳姆贝尔格化学公司 Substituted arylthioalkylthiopyridines
CN101255142A (en) * 2008-03-11 2008-09-03 贵州大学 2-substituted sulfinyl-5-(3,4,5-trialkoxy phenyl)-1,3,4-oxadiazole derivatives as well as preparation method and uses thereof
CN103880836A (en) * 2014-04-04 2014-06-25 贵州大学 1-substituted-5-amino-4-pyrazol di-1,3,4-diazole sulfur ether or 1,3,4-diazole sulfone derivatives and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
(3-苄基-4-芳酰基-1,2,4-三唑-5-基)(5-苯基-1,3,4-噁二唑-2-基)硫醚的合成;冯小明，等;《高等学校化学学报》;19931031;第14卷(第10期);第1383-1386页 *
含1,2,4-三氮唑和1,3,4-噁二唑的硫醚类衍生物的合成、表征及生物活性的测定;董保东;《郑州大学硕士学位论文》;20120929;第31-33页 *
水杨醛缩3-(5-取代苯基-1,3,4-噁二唑-2-亚甲硫基)-5-吡啶-3-基-1,2,4-三唑-4-胺席夫碱的合成及抗菌活性;胡国强，等;《化学试剂》;20060531;第28卷(第5期);第296-297页 *

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