CN100503587C - Benzo [1,2,3] thiadiazole derivative, its synthesis method and use - Google Patents
Benzo [1,2,3] thiadiazole derivative, its synthesis method and use Download PDFInfo
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- CN100503587C CN100503587C CNB2005101223385A CN200510122338A CN100503587C CN 100503587 C CN100503587 C CN 100503587C CN B2005101223385 A CNB2005101223385 A CN B2005101223385A CN 200510122338 A CN200510122338 A CN 200510122338A CN 100503587 C CN100503587 C CN 100503587C
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Abstract
The present invention provides a kind of benzothiobiazole substituent formamidine derivative and benzothiobiazole methanamide derivative, their synthesis method and application. Said invention also provides their structure formulae in which 10 formamidine derivatives containing benzo [1,2,3] thiobiazole substituent and 10 substituted benzo [1,2,3] thiobiazole-7-methanamide derivatives. These compounds have the activity for resisting tobacco mosaic virus and inducing tobacco to resist tobacco mosaic virus and microbiostatic action for inhibiting agricultural fungi.
Description
Technical field
Technical scheme of the present invention relates to the heterogeneous ring compound that contains 1,2-diazole of condensed with carbocyclic ring, is specifically related to diazosulfide derivative.
Background technology
Plant inducing anti-disease activator mechanism of action novelty, environmentally friendly, belong to the environment friendly agricultural category, now researched and developed successful principal item S-methyl benzo [1 has been arranged, 2,3] (english abbreviation is BTH to thiadiazoles-7-carbothioic acid ester, english common name: acibenzolar-S-methyl), 2,6-dichloro-isonicotinic acid and beta-aminobutyric acid, methyl jasmonate, allyl isothiazole and tiadinil (Bao Lili such as (english common name: Tiadinil are called for short TDL), Liu Fengli, Fan Zhijin has active lead compound of plant inducing anti-disease and structural modification thereof, the Pesticide Science journal, 2005,7 (3): 201-209; Michiko Yasuda; HideoNakashita; Shigeo Yoshida; Tiadinil, a novel class of activator of systemic acquired resistance, induces defense gene expression and disease resistance in tobacco.Japanese Pesticide Science, 2004,29:46-49).The contriver had once set up the screening system of plant inducing anti-disease activator inducing anti-disease activity, about the report situation of the research of diazosulfide inducing anti-disease activity and patent documentation has been summarised in the contriver recently in the background technology of the patent document of application, simultaneously, the contriver has synthesized the derivative of some BTH, part of compounds demonstrates the evoking tobacco resisting tobacco mosaic virus activity (Fan Zhijin etc. of (being called for short TMV), the screening of diazosulfide derivative and synthetic method thereof and inducing anti-disease activity, People's Republic of China's national inventing patent, application number: 200510013111.7, publication number: CN1680342A; Fan Zhijin etc., the activity of diazosulfide derivative and synthetic method thereof and evoking tobacco resisting tobacco mosaic virus, People's Republic of China's national inventing patent, application number: 200510014378.8), the general structure of this compounds can represent as:
At home and abroad in the disclosed diazosulfide derivative of patent documentation, except the patent of applicant oneself application, all do not relate to its evoking tobacco resisting tobacco mosaic virus activity of (being called for short TMV), do not carry out the research of relevant inducing anti-disease bioactivity screening yet, in order further to seek novel B TH derivative with higher induced activity, for structure activity relationship (QSAR) research lays the foundation, patent of the present invention is carried out structural modification in a basic enterprising step of early-stage Study, 10 new compounds of not seeing bibliographical information have been synthesized, we have cultivated monocrystalline with BLLB14 wherein, and reported structure (the Bao Lili of its monocrystalline, Fan Zhijin, Song Haibin, Nie Kaisheng.N-Phenyl-N '-(1,3-thiazol-2-yl)-1,2,3-benzothiadiazole-7-carboxamidine.Acta Crystallographica E, 61 (11): o3817~o3818.), but do not report the The selection result of its synthetic method and inducing anti-disease activity.
Summary of the invention
Technical problem to be solved by this invention is: diazosulfide derivative and the synthetic method and the active screening of the anti-TMV of evoking tobacco of evoking tobacco resisting tobacco mosaic virus are provided, and its screening system comprises the screening of induced activity of stripped screening and live body and the screening of active mensuration of phenylalanine ammonia lyase (PAL) and bacteriostatic activity.
The present invention solves this technical problem the technical scheme that is adopted: the chemical structure of general formula of the diazosulfide derivative of evoking tobacco resisting tobacco mosaic virus is:
Wherein: R
1Be sec.-propyl, phenyl;
R
2Be hydrogen;
Work as R
1When being sec.-propyl, R
3Be phenyl, 1,3-thiazoles-2-base, p-nitrophenyl, 5-methyl isophthalic acid, 3,4-thiadiazoles-2 base, 2,6-two fluoro-3,5-two chloro-4 bases; Work as R
1When being phenyl, R
3Be p-methylphenyl, 1,4,5-trichlorophenyl, 1,3-thiazoles-2-base, phenyl, to bromophenyl.
Its concrete chemical structural formula is expressed as follows:
Contain the substituent formamidine derivative of benzo [1,2,3] thiadiazoles:
The synthetic method of the diazosulfide derivative of evoking tobacco resisting tobacco mosaic virus of the present invention is as follows:
Specifically be divided into following steps:
A. the preparation of benzo [1,2,3] thiadiazoles-7-formyl chloride:
The benzo [1 that in the there-necked flask of 500mL, adds aequum, 2,3] thiadiazoles-7-formic acid, and the toluene of the no water treatment of process, DMF and thionyl chloride, every gram benzo [1,2,3] thiadiazoles-7-formic acid adds the toluene of 7.4mL through no water treatment approximately, 0.037mL DMF and the thionyl chloride of 0.7mL, slow intensification degree to 80~90 ℃, keep this temperature to continue reaction 6 hours, cooled and filtered, the filtrate decompression steaming removes unnecessary thionyl chloride and precipitation and gets product benzo [1,2,3] thiadiazoles-7-formyl chloride, product need not purifying and are kept at and get single step reaction in the moisture eliminator ready and directly use;
B. the preparation of the benzo of evoking tobacco resisting tobacco mosaic virus [1,2,3] thiadiazoles derivative:
I. benzo [1,2,3] preparation of thiadiazoles-7-carboxamides derivatives: in the there-necked flask of 100mL, add 5mmol amine, absolute anhydrous tetrahydro furan 25mL and 6mmol sodium hydride, the sodium salt suspension for preparing corresponding amine, refluxed 3 hours and cooling mixture, Dropwise 5 mmol benzo [1 under ice bath, 2,3] the absolute anhydrous tetrahydrofuran solution of 15mL of thiadiazoles-7-formyl chloride, cooling was stirred 2 hours down, heated up gradually and reflux 6 hours, cooled and filtered, filtrate is concentrating under reduced pressure on Rotary Evaporators, get pure product with purification by silica gel column chromatography, used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 3:1, and the consumption of above-claimed cpd can or dwindle by corresponding proportion expansion;
II. contain benzo [1,2,3] preparation of the substituent formamidine derivative of thiadiazoles: in the there-necked flask of 100mL, add 5mmol diazosulfide-7-methane amide, the 5mmol phosphorus pentachloride, mixing post-heating to 120 ℃ also reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add aminated compounds under the stirring at room in batches, heated up gradually and reflux 6 hours, and added 5mL water after being cooled to 90 ℃, stirred 1 hour, use the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth inferior then, separate organic phase, organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product, and purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, their volume ratio is 3:1, and the consumption of above-claimed cpd can or dwindle by corresponding proportion expansion;
The screening method of diazosulfide derivative evoking tobacco activity of resisting tobacco mosaic virus of the present invention is as follows:
I. the selection of standard plant inducing anti-disease activator: selecting diazosulfide (BTH) and tiadinil (TDL) is the plant inducing anti-disease activator of standard, and vitro Screening adopts 500 μ g/mL; The Evaluation on effect of inducing live body adopts the concentration of 100 μ g/mL or 0.1mol/L;
II. the screening method of direct antiviral activity exsomatizes: test compound is mixed with the 500 μ g/mL solution that contain micro-tensio-active agent soil temperature 80, with phosphoric acid buffer TMV virus crude extract is diluted to suitable concentration, behind the frictional inoculation TMV, with blade along in arteries and veins to cuing open, about half leaf immerse respectively in test compound solution and the clear water, representative is handled and blank respectively, take out after 30 minutes, put the cultivation of preserving moisture under 23 ± 1 ℃ the illumination, observe them after 3 days and produce the quantity of withered spot, the record incidence, be calculated as follows out the directly relative effect of the anti-TMV of test compound, 3 repetitions are established in each processing, standard chemicals treatment contrast again except that blank; The relative effect of test compounds is divided into 4 grades: A, B, C, D, concrete data are the A level: relative effect〉50%, for excellent; The B level: relative effect 30~50%, for very; The C level: relative effect 20~30%, in; The D level: relative effect<20%, for poor,
Wherein, X is direct inhibiting rate or the relative effect of compound to TMV, unit: %
CK is the average withered spot number that clear water contrasts half leaf, unit: individual
A is the average withered spot number of chemicals treatment half leaf, unit: individual;
III. the screening method of live body inducing anti-disease cytotoxic activity: with the common cigarette of seedling age unanimity, 3 basins are one group, cigarette seedling respectively at inoculation pre-treatment in preceding 7 days, processing mode comprises: spray test compound solution 2 to 3 times, each 20mL, the 7th day frictional inoculation TMV on the tobacco leaf that newly grows, place its growth optimal temperature and the following cultivation of illumination after 3 days the cigarette seedling, check incidence, comprehensive scab number is calculated as follows out the inducing anti-disease toxic effect fruit of test compound to TMV, 3 repetitions are established in each processing, and contrast divides blank and standard chemicals treatment to contrast 2 kinds; The relative effect of test compounds is divided into 4 grades: A, B, C, D, concrete data are the A level: induce effect〉70%, for excellent; B level: induce effect 70~50%, for very; C level: induce effect 30~50%, for poor; The D level: induce effect<30% to be considered as not having and induce effect,
Wherein, R is the induce effect of new compound to the anti-TMV of tobacco, unit: %
CK is the average withered spot number of clear water contrast blade, unit: individual
I is for inducing the average withered spot number of handling rear blade, unit: individual through compound;
IV. the screening method of fungicidal activity: adopt thalli growth rate assay method (Mycelium growth rate test), detailed process is, get the 5mg sample dissolution in an amount of dimethyl formamide, then with containing the medicament that a certain amount of polysorbas20 emulsifier aqueous solution is diluted to 500 μ g/mL, reagent agent is respectively drawn 1mL under aseptic condition inject in the culture dish, add the 9mL substratum more respectively, make 50 μ g/mL pastille flat boards after shaking up, do blank with the flat board that adds the 1mL aqua sterilisa, punch tool with diameter 4mm cuts the bacterium dish along the mycelia outer rim, move on the pastille flat board, be equilateral triangle and put, every processing repeats 3 times, culture dish is placed on cultivation in 24 ± 1 ℃ of constant incubators, " Invest, Then Investigate " was respectively handled bacterium dish expansion diameter in 48 hours, averaged, and relatively calculated relative bacteriostasis rate with blank.Comprise gibberella saubinetii (Gibberellazeae), tomato early epidemic disease (Alternaria), asparagus stem withered (Phoma asparagi solani), apple wheel line (Physalosporapiricola) and peanut foxiness (Cercospora arachidicola) for the examination pathogenic fungi.
The invention has the beneficial effects as follows: diazosulfide is a kind of plant inducing anti-disease activator of standard, utilize the last patent of invention of applicant to set up the screening system, successfully inducing tobacco plant TMV to be produced on the basis of good antiviral activity, the further successful application of the present invention this system carry out the screening of inducing anti-disease activity, step of going forward side by side is carried out the screening of bacteriostatic activity, and The selection result finds that part of compounds has the activity of evoking tobacco resisting tobacco mosaic virus preferably and suppresses the activity of pathogenic fungi growth.
The present invention will more specifically describe the synthetic and biological activity of diazosulfide analog derivative by specific preparation and biological activity determination embodiment, but described embodiment only is used for specific description the present invention and unrestricted the present invention, and concrete embodiment is as follows:
Embodiment 1
The preparation of benzo [1,2,3] thiadiazoles-7-formyl chloride:
Add 27.0g benzo [1,2,3] thiadiazoles-7-formic acid in the there-necked flask of 500mL, 200mL is through the toluene of no water treatment, the DMF of 1mL, the SOCl of 20mL
2, slowly degree of intensification is to 80~90 ℃, keeps this temperature to continue reaction 6 hours, cooled and filtered, and the filtrate decompression precipitation gets product benzo [1,2,3] thiadiazoles-7-formyl chloride 28g, and product need not purifying and is kept at and gets single step reaction in the moisture eliminator ready and directly use.
Embodiment 2
Synthetic and the structure of BLLB1 is identified:
In the there-necked flask of 100mL, add 1g diazosulfide-7-formyl Isopropylamine, 0.94g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add 0.43g 2-aminopyridine under the stirring at room in batches, heated up gradually and reflux 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, use the dichloromethane extraction organic phase after being cooled to room temperature, add 5mL 28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.87g, yield 65.2%, purification by silica gel column chromatography get pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, their volume ratio is 3:1, measure fusing point and
1H NMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M+1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at 317.0nm and 268.0nm place.
Embodiment 3
Synthetic and the structure of BLLB2 is identified:
In the there-necked flask of 100mL, add 1g diazosulfide-7-formyl Isopropylamine, 0.94g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add the 0.46g thiazolamine under the stirring at room in batches, heated up gradually and reflux 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.45g, yield 33.0%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 8:1.Measure fusing point and
1H NMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M+1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at 317.0nm and 239.0nm place.
Embodiment 4
Synthetic and the structure of BLLB4 is identified:
In the there-necked flask of 100mL, add 1g diazosulfide-7-formyl Isopropylamine, 0.94g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add the 0.62g p-Nitroaniline under the stirring at room in batches, heated up gradually and reflux 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.41g, yield 26.1%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 3: 1.Measure fusing point and
1H NMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M+1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at 336.0nm and 217.0nm place.
Embodiment 5
Synthetic and the structure of BLLB6 is identified:
In the there-necked flask of 100mL, add 1g diazosulfide-7-formyl Isopropylamine, 0.94g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add the amino thiadiazoles of 0.52g 5-methyl-2 under the stirring at room in batches, heated up gradually and reflux 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.36g, yield 25.0%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 1.5:1.Measure fusing point and
1HNMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M+1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at 380.0nm and 280.0nm place.
Embodiment 6
Synthetic and the structure of BLLB7 is identified:
In the there-necked flask of 100mL, add 1g diazosulfide-7-formyl Isopropylamine, 0.94g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add 0.89g 4-amino-3 under the stirring at room in batches, 5-two chloro-2, the 6-difluoro pyridine heated up gradually and refluxes 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.36g, yield 21.1%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 5:1.Measure fusing point and
1HNMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M+1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at 315.0nm and 266.0nm place.
Embodiment 7
Synthetic and the structure of BLLB12 is identified:
In the there-necked flask of 100mL, add 0.76g diazosulfide-7-formylaniline, 1.25g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add 0.32g under the stirring at room in batches, heated up gradually and reflux 6 hours monomethylaniline, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.33g, yield 32.1%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 8:1.Measure fusing point and
1H NMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M+1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at the 380.0nm place.
Embodiment 8
Synthetic and the structure of BLLB13 is identified:
In the there-necked flask of 100mL, add 0.76g diazosulfide-7-formylaniline, 1.25g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add 0.59g2 under the stirring at room in batches, 4, the 5-trichloroaniline heated up gradually and refluxes 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.42g, yield 32.4%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 8:1.Measure fusing point and
1HNMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M+1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at the 320.0nm place.
Embodiment 9
Synthetic and the structure of BLLB16 is identified:
In the there-necked flask of 100mL, add 0.76g diazosulfide-7-formylaniline, 1.25g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add 0.27g aniline under the stirring at room in batches, heated up gradually and reflux 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.49g, yield 49.5%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 10:1.Measure fusing point and
1H NMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M-1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at 318.0nm and 232.0nm place.
Embodiment 10
Synthetic and the structure of BLLB17 is identified:
In the there-necked flask of 100mL, add 0.76g diazosulfide-7-formylaniline, 1.25g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add the 0.5g para-bromoaniline under the stirring at room in batches, heated up gradually and reflux 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.52g, yield 43.7%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 10:1.Measure fusing point and
1H NMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M-1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at 317.0nm and 235.0nm place.
Embodiment 11
Synthetic and the structure of BLLB14 is identified:
In the there-necked flask of 100mL, add 0.76g diazosulfide-7-formylaniline, 1.25g phosphorus pentachloride, keeping temperature of reaction behind the mixing is 120 ℃, reacted 20 hours, to be cooled to room temperature, add the 2mL pyridine, add the 0.33g thiazolamine under the stirring at room in batches, heated up gradually and reflux 6 hours, add 5mL water after being cooled to 90 ℃, stirred 1 hour, and used the dichloromethane extraction organic phase after being cooled to room temperature, add the 5mL28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product 0.34g, yield 31.1%, purification by silica gel column chromatography gets pure product, and used eluent is 60~90 ℃ sherwood oil and an ethyl acetate, and their volume ratio is 8:1.Measure fusing point and
1H NMR, its chemical structural formula and physical and chemical parameter see Table 1 and table 2, by table 1 and table 2 as seen, and this compound
1H NMR shows and the corresponding chemical shift of its structure that the number of H and its structure are coincide, and MS measures the m/z peak that corresponding M+1 occurs, and corresponding skeleton absorption peak appears in IR, and the maximum absorption band of UV scanning appears at 380.0nm and 250.0nm place.
Embodiment 12
The effect of benzo of the present invention [1,2,3] thiadiazoles derivative evoking tobacco resisting tobacco mosaic virus:
The biological tobacco determination test the results are shown in Table 3, table 3 shows, the plant inducing anti-disease activator BTH of standard and tiadinil and most of benzo [1 of the present invention, 2,3] all to TMV unrestraint effect, but BTH and tiadinil can produce the good resistance of TMV by evoking tobacco thiadiazoles derivative under isolated condition; Preliminary bioassay results shows, benzo of the present invention [1,2,3] thiadiazoles derivative BLLB2, BLLB12, have direct restraining effect, but do not have the inductive activity all about 50% the direct action effect of the TMV that exsomatizes; BLLB4, BLLB13, BLLB17 have 80%, 95% and 60% induced activity respectively.
Embodiment 13
The bacteriostatic activity of benzo of the present invention [1,2,3] thiadiazoles derivative:
Thalli growth rate method measurement result sees Table 4, and table 4 shows that synthetic majority of compounds of the present invention does not all have bacteriostatic activity.
The physical and chemical parameter of table 1 The compounds of this invention
Table 2 The compounds of this invention
1H NMR and MS and IR data
The activity of the compound evoking tobacco resisting tobacco mosaic virus among table 3 the present invention
Annotate: data are average results of 3 experiments in the table
The bacteriostatic activity of the compound among table 4 the present invention
Claims (4)
1. diazosulfide derivative is characterized in that it is the compound of structural formula (I):
Wherein: R
1Be sec.-propyl, phenyl;
R
2Be hydrogen;
Work as R
1When being sec.-propyl, R
3Be phenyl, 1,3-thiazoles-2-base, p-nitrophenyl, 5-methyl isophthalic acid, 3,4-thiadiazoles-2 base, 2,6-two fluoro-3,5-two chloro-4-pyridyl; Work as R
1When being phenyl, R
3Be p-methylphenyl, phenyl, to bromophenyl.
2. the synthetic method of the described diazosulfide derivative of claim 1 is characterized in that total synthetic route is:
Wherein: R
1Be sec.-propyl, phenyl;
R
2Be hydrogen;
Work as R
1When being sec.-propyl, R
3Be phenyl, 1,3-thiazoles-2-base, p-nitrophenyl, 5-methyl isophthalic acid, 3,4-thiadiazoles-2 base, 2,6-two fluoro-3,5-two chloro-4-pyridyl; Work as R
1When being phenyl, R
3Be p-methylphenyl, phenyl, to bromophenyl;
Specifically be divided into following steps:
A. the preparation of benzo [1,2,3] thiadiazoles-7-formyl chloride:
The benzo [1 that in 500 milliliters there-necked flask, adds aequum, 2,3] thiadiazoles-7-formic acid, and the toluene of the no water treatment of process, DMF and thionyl chloride, every gram benzo [1,2,3] thiadiazoles-7-formic acid adds 7.4 milliliters of toluene through no water treatment, 0.037 the DMF of milliliter and 0.7 milliliter thionyl chloride, slowly intensification degree to 80~90 are spent, keep this temperature to continue reaction 6 hours, cooled and filtered, the filtrate decompression steaming removes unnecessary thionyl chloride and precipitation and gets product benzo [1,2,3] thiadiazoles-7-formyl chloride, product need not purifying and are kept at and get single step reaction in the moisture eliminator ready and directly use;
B. the preparation of benzo [1,2,3] thiadiazoles derivative:
I. the preparation of benzo [1,2,3] thiadiazoles-7-carboxamides derivatives: in 100 milliliters there-necked flask, add 5 mmole amine NH
2R
125 milliliters of absolute anhydrous tetrahydro furans and 6 mmole sodium hydrides, the sodium salt suspension for preparing corresponding amine, refluxed 3 hours and cooling mixture, Dropwise 5 mmole benzo [1 under ice bath, 2,3] 15 milliliters of absolute anhydrous tetrahydrofuran solutions of thiadiazoles-7-formyl chloride, cooling was stirred 2 hours down, heated up gradually and reflux 6 hours, cooled and filtered, filtrate is concentrating under reduced pressure on Rotary Evaporators, get pure product with purification by silica gel column chromatography, used eluent is the sherwood oil and the ethyl acetate of 60~90 degree, and their volume ratio is 3:1, and the consumption of above-claimed cpd can or dwindle by corresponding proportion expansion;
II. contain benzo [1,2,3] preparation of the substituent formamidine derivative of thiadiazoles: in 100 milliliters there-necked flask, add 5 mmoles diazosulfide-7-carboxamides derivatives, 5 mmole phosphorus pentachlorides, mixing post-heating to 120 ℃ also reacted 20 hours, to be cooled to room temperature, add 2 milliliters of pyridines, add NHR under the stirring at room in batches
2R
3Aminated compounds, heated up gradually and reflux 6 hours, be cooled to 90 degree backs and add 5 ml waters, stirred 1 hour, use the dichloromethane extraction organic phase after being cooled to room temperature, add 5 milliliter of 28% strong aqua in the organic phase, stirred 1 hour, water is given a baby a bath on the third day after its birth time then, separates organic phase, and organic phase concentrating under reduced pressure desolventizing on Rotary Evaporators gets crude product, purification by silica gel column chromatography gets pure product, used eluent is the sherwood oil and the ethyl acetate of 60~90 degree, and their volume ratio is 3:1, and the consumption of above-claimed cpd can or dwindle by corresponding proportion expansion.
3. the screening method of the described diazosulfide derivative evoking tobacco of claim 1 activity of resisting tobacco mosaic virus:
The screening method of the system of diazosulfide derivative evoking tobacco activity of resisting tobacco mosaic virus is as follows:
I. the selection of standard plant inducing anti-disease activator: selecting diazosulfide (BTH) and thiophene acyl bacterium ammonia (TDL) is the plant inducing anti-disease activator of standard, and vitro Screening adopts 500 mcg/ml; The Evaluation on effect of inducing live body adopts the concentration of 100 mcg/ml or 0.1 mol;
II. the screening method of direct antiviral activity exsomatizes: test compound is mixed with the 500 mcg/ml solution that contain micro-tensio-active agent tween 80, with phosphoric acid buffer the tobacco mosaic virus (TMV) crude extract is diluted to suitable concentration, after the frictional inoculation tobacco mosaic virus (TMV), with blade along in arteries and veins to cuing open, about half leaf immerse respectively in test compound solution and the clear water, representative is handled and blank respectively, take out after 30 minutes, put the cultivation of preserving moisture under 23 ± 1 illumination of spending, observe them after 3 days and produce the quantity of withered spot, the record incidence, be calculated as follows out the directly relative effect of test compound resisting tobacco mosaic virus, 3 repetitions are established in each processing, standard chemicals treatment contrast again except that blank; The relative effect of test compounds is divided into 4 grades: A, B, C, D, concrete data are the A level: relative effect〉50%, for excellent; The B level: relative effect 30~50%, for very; The C level: relative effect 20~30%, in; The D level: relative effect<20%, for poor,
Wherein, X is direct inhibiting rate or the relative effect of compound to tobacco mosaic virus (TMV), unit: %
CK is the average withered spot number that clear water contrasts half leaf, unit: individual
A is the average withered spot number of chemicals treatment half leaf, unit: individual;
III. the screening method of live body inducing anti-disease cytotoxic activity: with the common cigarette of seedling age unanimity, 3 basins are one group, cigarette seedling respectively at inoculation pre-treatment in preceding 7 days, processing mode comprises: spray test compound solution 2 to 3 times, each 20 milliliters, the 7th day frictional inoculation tobacco mosaic virus (TMV) on the tobacco leaf that newly grows, place its growth optimal temperature and the following cultivation of illumination after 3 days the cigarette seedling, check incidence, comprehensive scab number is calculated as follows out the inducing anti-disease toxic effect fruit of test compound to tobacco mosaic virus (TMV), 3 repetitions are established in each processing, and contrast divides blank and standard chemicals treatment to contrast 2 kinds; The relative effect of test compounds is divided into 4 grades: A, B, C, D, concrete data are the A level: induce effect〉70%, for excellent; B level: induce effect 70~50%, for very; C level: induce effect 30~50%, for poor; The D level: induce effect<30% to be considered as not having and induce effect,
Wherein, R is the induce effect of compound to the tobacco resisting tobacco mosaic virus, unit: %
CK is the average withered spot number of clear water contrast blade, unit: individual
I is for inducing the average withered spot number of handling rear blade, unit: individual through compound.
4. the application of the application of the resisting tobacco mosaic virus of the described diazosulfide derivative of claim 1 or evoking tobacco resisting tobacco mosaic virus.
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Non-Patent Citations (4)
Title |
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N-phenyl-N'-(1,3-thiazol-2-yl)-1,2,3-benzothiadiazole-7-carboxamidine. Bao, Li Li et al.Acta Crystallographica, Section E: Structure Reports Online,Vol.E61 No.11. 2005 |
N-phenyl-N'-(1,3-thiazol-2-yl)-1,2,3-benzothiadiazole-7-carboxamidine. Bao, Li Li et al.Acta Crystallographica, Section E: Structure Reports Online,Vol.E61 No.11. 2005 * |
植物激活剂苯并噻二唑(BTH). 范志金等.四川师范大学学报(自然科学版,第27卷第4期. 2004 |
植物激活剂苯并噻二唑(BTH). 范志金等.四川师范大学学报 自然科学版,第27卷第4期. 2004 * |
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