CN102838593B - 2-(4-methyl-1,2,3-thiadiazole)-5-(substituent)-1,3,4-oxa(thia)diazole derivative and application thereof - Google Patents

2-(4-methyl-1,2,3-thiadiazole)-5-(substituent)-1,3,4-oxa(thia)diazole derivative and application thereof Download PDF

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CN102838593B
CN102838593B CN201210377140.1A CN201210377140A CN102838593B CN 102838593 B CN102838593 B CN 102838593B CN 201210377140 A CN201210377140 A CN 201210377140A CN 102838593 B CN102838593 B CN 102838593B
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thiadiazoles
base
isophthalic acid
methyl isophthalic
benzyl
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CN102838593A (en
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徐维明
杨松
薛伟
金林红
陈卓
贺鸣
黎世泽
陈妍
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Guizhou University
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Abstract

The invention provides a 2-(4-methyl-1,2,3-thiadiazole)-5-(substituent)-1,3,4-oxa(thia)diazole derivative with better crop virus disease resistant activity. A target compound has a novel structure; and a commercial 2-(4-methyl-1,2,3-thiadiazole)-5-(substituent)-1,3,4-oxa(thia)diazole derivative is not available on a pesticide market; therefore, cross resistance cannot be generated between the 2-(4-methyl-1,2,3-thiadiazole)-5-(substituent)-1,3,4-oxa(thia)diazole derivative and the traditional antiviral agent; and better application prospects are obtained.

Description

2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative and application thereof
Technical field
The present invention relates to chemical industry and agricultural chemicals, concrete technology is 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative and application thereof.
Background technology
Tobacco mosaic virus (TMV) (Tobacco mosaic virus, abridge: pathogenic agent TMV) being tobacco mosaic disease etc., belong to Tobamovirus group, its host range is very wide, 36 section 350 kind of plant such as Cruciferae, Solanaceae, composite family, Chenopodiaceae and Amaranthaceae can be infected, comprise tobacco, tomato, eggplant, capsicum, spinach etc.As finding at first in the world and the virus determined, had the history of more than 100 year, the tobacco mosaic disease caused by it generally occurs in Ge Yan district of the world.After tobacco plant is caught an illness, young leaflet tablet lateral vein and offshoot tissue are translucent shape, i.e. bright arteries and veins, and vein both sides mesophyll tissue is gradually in light green.Virus is bred in a large number in leaf tissue, and make part mesophyll cell increase or increase, occur that blade thin and thick is irregular, color is yellowish green alternate, in floral leaf shape.The mottled degree of rear floral leaf strengthens, and existing big area Vandyke brown necrotic plaque, middle and lower part Lao Ye more so, the heavy leaf-shrinkage of morbidity, deformity, distortion.The plant shortened internodes of early stage morbidity, seriously downgrades, poor growth, normally can not blossom and bear fruit, and easily come off.Little and the shrinkage of developable shady fruit, grain weight is few and little, how can not germinate.Tobacco mosaic virus (TMV) has that host range is wide, strong stress resistance and the feature such as the harm that causes on producing is large, all generation is had in cigarette district, north and south of China, especially Main Tobacco-growing Regions In South morbidity is heavier, field strain sickness rate general 5% ~ 20%, indivedual field can up to 90% ~ 100%, the loss of early stage morbidity can reach 50% ~ 70%, even loses receipts.In addition, sick leaf is irregular colour after roasting solarization, and smoke is poor, and quality greatly reduces.The financial loss that the whole world causes because of TMV is every year just more than 100,000,000 dollars.Due to virus once invade host, its propagation just combines together with the metabolism of host, and the medicament of virus replication is difficult to not injure host, and therefore, the control of this virus disease is the difficult point of control of plant disease all the time.(Li Caihua, Ling Shouheng, Shen Li, circumference is flat, and Huangshi is prosperous. several Chemicals preventing and treating tobacco mosaic disease, Agriculture of Anhui science, 2009,37 (34): 16909-16910) and, in the urgent need to developing the antiviral agent of some novel structures.
Sulfone compound has a wide range of applications in fields such as agricultural chemicals, as the biological activity of desinsection, sterilization, weeding, tuberculosis, anti-inflammatory, anti-proliferate, anti-HIV-1, anti-infective, anticancer, anti-consumptive disease, the wide spectrum such as antitumor.In early-stage Study, this seminar design and synthesis a series of newly containing 1,3,4-Evil (thiophene) di azoly sulfone (sulfoxide) derivative, adopt growth rate method, with the former bacterium of tuber of pinellia damping-off ( r. solani), fusarium graminearum ( g. zeae), the former bacterium of gray mold of cucumber ( b. cinerea), Sclerotinia sclerotiorum ( s. sclerotiorum) etc. soil-borne disease and migrating property Plant diseases be tested object, bacteriostatic activity research has been carried out to partial target compound, find partial target compound have good bacteriostatic activity [ bioorg. Med. Chem. 2007, 15, 3981; bioorg. & Med. Chem. 2008, 16,3632].At present, find after further composition optimizes that partial target compounds exhibit goes out good anti-crop virus activity.
Summary of the invention
The object of the invention is initiative, to crop virosis evil, there is efficient, eco-friendly Novel antiviral agent, synthesize that a class formation is novel, agricultural chemicals does not have on the market, 2-(the 4-methyl isophthalic acid of cross resistance can not be produced with existing agricultural chemicals, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative.
2-of the present invention (4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative, has following general formula:
Formula (I) formula II
In formula:
X is O (oxygen) or S (sulphur), the ， Wei oxadiazole compounds when X is O (oxygen); When X is S (sulphur), it is thiadiazole compound;
R is selected from hydrogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxyl group, C2-C5 thiazolinyl, the ester group of C2-C5, benzyl or substituted benzyl.
Described halogen atom is fluorine, chlorine, bromine or iodine,
Described C1-C5 alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or neo-pentyl,
Described C1-C2 haloalkyl is fluoroform alkyl, methyl chlorofluoride base, trichloromethane base, methylene fluoride base, methylene chloride-based, a fluoromethane base, 1,2-C2H4F2 C2H4F2 base, 1,2-Tetrafluoroethane base, 1,2-ethylene dichloride base or 1,2-tetrachloroethane base,
Described C1-C3 alkoxyl group is methoxyl group, oxyethyl group or positive propoxy,
The thiazolinyl of described C2-C5 is vinyl, propenyl, allyl group, butenyl, isobutenyl, pentenyl, isopentene group or new pentenyl,
The ester group of described C2-C5 is methyl-formiate base, group-4 ethyl formate, propyl formate base, methyl acetate base, ethyl acetate base or propyl acetate base,
Described substituted benzyl is 4-methyl-benzyl, 3-methyl-benzyl, 2-methyl-benzyl, 3,4-dimethyl benzyl, 2,4-dimethyl benzyl, 2,6-dimethyl benzyl, 4-luorobenzyl, 3-luorobenzyl, 2-luorobenzyl, 3,4-difluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichloro benzyl, 2,4-dichloro benzyl, 2,6-dichloro benzyls, 4-methoxy-benzyl, 3-methoxy-benzyl, 2-methoxy-benzyl, 3,4-dimethoxy-benzyls, 2,4-dimethoxy-benzyl, 2,6-dimethoxy-benzyls.
Part of compounds is:
i 1 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(Dimethyl sulfide base)-1,3,4-oxadiazoles;
i 2 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(dibenzylsulfide ether)-1,3,4-oxadiazoles;
i 3 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(3-chloro benzyl sulfur ether)-1,3,4-oxadiazoles;
i 4 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl thioether base)-1,3,4-oxadiazoles;
i 5 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(4-nitrobenzyl thioether group)-1,3,4-oxadiazoles;
i 6 :2-(carbethoxymethylene thioether)-5-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-1,3,4-oxadiazoles;
II 1 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(methyl sulfuryl)-1,3,4-oxadiazoles;
II 2 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(benzyl sulfuryl)-1,3,4-oxadiazoles;
II 3 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(3-chlorobenzyl sulfuryl)-1,3,4-oxadiazoles;
II 4 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl sulfuryl)-1,3,4-oxadiazoles;
iII 1 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(dibenzylsulfide ether)-1,3,4-thiadiazoles;
iII 2 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl thioether base)-1,3,4-thiadiazoles;
iII 3 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(adjacent luorobenzyl thioether group)-1,3,4-thiadiazoles;
iII 4 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(allyl sulfide ether)-1,3,4-thiadiazoles;
iII 5 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(Dimethyl sulfide base)-1,3,4-thiadiazoles;
iV 1 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(benzyl sulfuryl)-1,3,4-thiadiazoles;
iV 2 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl sulfuryl)-1,3,4-thiadiazoles;
iV 3 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(adjacent luorobenzyl sulfuryl)-1,3,4-thiadiazoles;
iV 4 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(allyl group sulfuryl)-1,3,4-thiadiazoles;
iV 5 :2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(methyl sulfuryl)-1,3,4-thiadiazoles.
Described 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative, for control or suppression crop virosis evil.
Described 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative is used for control or suppresses tobacco mosaic virus disease evil, Cucumber Mosaic Virus evil, oryza virus 3 disease, rice dwarf virus disease virus disease, maize rough dwarf virus virus disease, rice black-streaked dwarf virus disease, tomato virus virus disease.
Described 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1, the formulation of 3,4-Evil (thiophene) diazoles derivative is missible oil, micro emulsion, water and milk, suspension agent, seed coat agent, seed dressing, wettable powder, sustained-release granular formulation, controlled release granule, water dispersible granules, dry suspension or granule.
In the formulation of described preparation, effective constituent 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative accounts for 1% ~ 90% of total formulation weight amount, and content is 10% ~ 85% more specifically.
Described 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative maybe needs to prevent and treat the purposes in the material of virus attack, crop, region, soil, seed or space for the treatment of virus, viral habitat.
embodiment: the synthesis of target compound
The synthesis of 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-oxadiazole analog derivative
The synthesis of intermediate ethyl carbazate
By diethyl carbonate (11.8g, 0.1mol) He 80% hydrazine hydrate (5.9g, 0.095 mol) is thrown in 100 mL there-necked flasks, and room temperature (23 DEG C) stirs 4h, TCL follows the tracks of reaction (iodine develops the color, V sherwood oil: V ethyl acetate=3:1).The de-second alcohol and water of decompression, separate out clear crystal, pumping rate obtains product 9g, fusing point 44 ~ 45 DEG C (45 ~ 46 DEG C, Fan, Z. J., et al, 2009), yield 87%.
The synthesis of condensation intermediate
By methyl aceto acetate (6.5g, 0.05 mol) and methylene dichloride (35 mL) throw in 100 mL there-necked flasks, by ethyl carbazate (5.2g, 0.05 mol) be dissolved in methylene dichloride (17 mL) and slowly drip afterwards in there-necked flask, within about 30 minutes, dropwise.TCL follows the tracks of reaction (iodine develops the color, V sherwood oil: V ethyl acetate=3:1), and reaction in 6 hours terminates.Decompression desolventizing obtains white powder solid, and recrystallization obtains product 5.5g (ethanol: water=3:1), fusing point 64 ~ 67 DEG C (65-66 DEG C, Fan, Z. J., et al., 2009), yield 85%.
Intermediate 4-methyl isophthalic acid, the synthesis of 2,3-thiadiazoles-5-ethyl formate
Sulfur oxychloride 25 mL is thrown in 50 mL there-necked flasks, under ice bath, keeps temperature lower than 10 DEG C; Condensation product (6 g, 46 mmol) is dissolved in methylene dichloride (20 mL) slowly drip afterwards in reaction flask, keeps temperature lower than 10 DEG C; Within 1 hour, dropwise, continue to stir at lower than 10 DEG C after 2 hours and move to room temperature (lower than 20 DEG C) reaction 20 hours.Change water distilling apparatus after completion of the reaction into and steam methylene dichloride and water, then underpressure distillation (collecting 136 ~ 140 DEG C of cuts), obtains the liquid of yellowish, quality 5.2 g (Fan, Z. J., et al., 2009), yield 64%.
Intermediate 4-methyl isophthalic acid, the synthesis of 2,3-thiadiazoles-5-formyl hydrazine
By 4-methyl isophthalic acid, 2,3-thiadiazoles-5-ethyl formate (5g, 29 mmol) and dehydrated alcohol (40 mL) throw in 100 mL there-necked flasks, 80% hydrazine hydrate (2 g are dripped under room temperature, 32 mmol) after be warming up to backflow, TCL follows the tracks of reaction, 5 hours reaction terminate.Decompression desolventizing obtains yellow solid, and dehydrated alcohol recrystallization obtains yellow solid.Quality 3.7 g, fusing point 113 ~ 115 DEG C, (Yang Zhiguang etc., 2001), yield 81%.
The synthesis of intermediate 2-sulfydryl-5-(4-methyl isophthalic acid, 2,3-thiadiazoles)-1,3,4-oxadiazoles
By 4-methyl isophthalic acid, 2,3-thiadiazoles-5-formyl hydrazine (3 g, 19 mmol), potassium hydroxide (1.3 g, 19 mmol) and ethanol (30 mL) are thrown in l00 mL there-necked flask, and stirring at room temperature is dissolved.Be warming up to 77 ~ 78 DEG C of back flow reaction after slowly adding dithiocarbonic anhydride (2.1 g, 28 mmol) to terminate for 6 hours.Decompression is sloughed ethanol and is obtained yellow solid, washes out with water (100 mL), adjusts pH=6 with 3% dilute hydrochloric acid, leave standstill and obtain white fluffy solid, suction filtration after 1 hour, 95% ethyl alcohol recrystallization obtains 2-sulfydryl-5-(4-methyl isophthalic acid, 2,3-thiadiazoles)-1,3,4-oxadiazole 2.4 g, white crystal, fusing point: 144 ~ 148 DEG C, yield 63% 1h NMR (500 MHz, CDCl 3) δ: 11.23 (s, 1H, SH), 3.27 (s, 3H, CH 3).
The synthesis (I) of 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-substituting group thioether group-1,3,4-oxadiazole
By 2-sulfydryl-5-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-1,3,4-oxadiazole (5 mmol), sodium hydroxide (0.2 g, 5 mmol) and water (20 mL) are thrown in l00 mL there-necked flask, and stirring at room temperature is dissolved.Slowly add methyl-sulfate (0.82 g, 6.5 mmol), Benzyl Chloride or replace Benzyl Chloride (6.5 mmol) room temperature (22 DEG C) reaction end in 1 hour afterwards.Suction filtration obtains faint yellow solid, 95% ethyl alcohol recrystallization.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(Dimethyl sulfide base)-1,3,4-oxadiazole (I 1 )
Clear crystal, m.p. 132 ~ 134 DEG C; Yield 65.6%; 1h NMR (500 MHz, CDCl 3) δ: 3.12 (s, 3H, CH 3), 3.45 (s, 3H, SCH 3). 13c NMR (125 MHz, CDCl 3) δ: 159.99,157.75,153.42,131.58,29.57,14.32; Anal. Calcd for C 6h 6n 4oS 2: C 33.63, H 2.82, N 26.15; Found:C 33.51, H 2.51, N 25.75.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(dibenzylsulfide ether)-1,3,4-oxadiazole (I 2 )
Clear crystal, m.p. 71 ~ 72 DEG C; Yield 78.2%; 1h NMR (500 MHz, CDCl 3) δ: 7.47 ~ 7.31 (m, 5H, benzyl-H), 4.55 (s, 2H, CH 2s), 3.05 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 166.02,159.39,158.55,135.11,131.67,129.25,128.99,128.41,36.96,14.33; IR (KBr, cm -1) ν:3031,2917,1566,1506,1326,705; Anal. Calcd for C 12h 10n 4oS 2c 49.64, H 3.47, N 19.30; Found:C 49.66, H 3.52, N 19.22.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(3-chloro benzyl sulfur ether)-1,3,4-oxadiazoles (I 3 )
Clear crystal, m.p. 61 ~ 63 oc; Yield 80.8%; 1h NMR (500 MHz, CDCl 3) δ: 7.47 ~ 7.29 (m, 4H, benzyl-H), 4.51 (s, 2H, CH 2-S), 3.06 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 165.57,159.45,158.71,137.26,134.75,131.57,130.21,129.29,128.65,127.45,36.17,14.34; IR (KBr, cm -1) ν:3037,2927,1557,1456,1357,1172; Anal. Calcd for C 12h 9clN 4oS 2: C 44.37, H 2.79, N 17.25; Found:C 44.18, H 2.64, N 17.04;
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl thioether base)-1,3,4-oxadiazole (I 4 )
White crystal, m.p. 43 ~ 45 DEG C; Yield 72.3%; 1h NMR (500 MHz, CDCl 3) δ:3.64 (q, j=7.45,2H, CH 2), 3.06 (s, 3H, CH 3), 1.53 (t, j=7.45,3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 159.81,158.24,152.24,151.43,132.73,23.43,6.94; IR (KBr, cm -1) ν:2916,1566,1506,1426,705; Anal. Calcd for C 7h 8n 4oS 2: C 36.83, H 3.53, N 24.54; Found:C 36.73, H 3.54, N 24.77.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(4-nitrobenzyl thioether group)-1,3,4-oxadiazoles (I 5 )
Colourless powdery solid, m.p. 92 ~ 94 DEG C; Yield 72.5%; 1h NMR (500 MHz, CDCl 3) δ: 8.22 ~ 7.68 (m, 4H, benzyl-H), 4.61 (s, 2H, CH 2-S), 3.06 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 165.09,159.53,158.96,147.81,142.86,131.38,130.26,124.11,35.69,14.37; IR (KBr, cm -1) ν:3031,2909,1588,1537,1462,702; Anal. Calcd for C 12h 9n 5o 3s 2: C 42.98, H 2.70, N 20.88; Found:C 42.34, H 2.67, N 20.31.
2-(carbethoxymethylene thioether)-5-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-1,3,4-oxadiazoles (I 6 )
Clear crystal, m.p. 75 ~ 76 oc; Yield 80.8%; 1h NMR (500 MHz, CDCl 3) δ: 4.28 (q, j=6.9,2H, cH 2 cH 3), 4.14 (s, 2H, CH 2-S), 3.07 (s, 3H, CH 3), 1.31 (t, j=7.45,3H, CH 2 cH 3 ); 13c NMR (125 MHz, CDCl 3) δ: 167.09,159.52,158.84,165.07,131.55,62.77,34.48,14.34,14.19; IR (KBr, cm -1) ν:2985,2939,1534,1432,667; Anal. Calcd for C 9h 10n 4o 3s 2: C 37.75, H 3.52, N 19.57; Found:C 37.51, H 3.77, N 19.27.
The synthesis (II) of 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-substituting group sulfuryl-1,3,4-oxadiazole
2-Dimethyl sulfide base-5-(4-methyl isophthalic acid, 2,3-thiadiazoles)-1,3,4-oxadiazoles (0.70 g, 3.27 mmol) and glacial acetic acid (10 mL) are thrown in 50 mL there-necked flasks, 22 DEG C of stirring and dissolving.Slowly add that to join be the KMnO of 5% aqueous solution 4(0.62 g, 3.9 mmol).TCL follows the tracks of, and decolour with saturated sodium bisulfite after completion of the reaction, pour in frozen water and namely separate out solid, dehydrated alcohol recrystallization obtains target compound.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(methyl sulfuryl)-1,3,4-oxadiazoles (iI 1 )
Clear crystal, m.p. 132-134 DEG C; Yield 70.5%; 1h NMR (500 MHz, CDCl 3) δ: 3.12 (s, 3H, CH 3), 3.45 (s, 3H, SO 2cH 3). 13c NMR (125 MHz, CDCl 3) δ: 159.99,157.75,153.42,131.58,29.57,14.32; IR (KBr, cm -1) ν:2909,1546,1423,676; Anal. Calcd for C 6h 6n 4o 3s 2: C 29.26, H 2.46, N 22.75; Found:C 29.16, H 2.73, N 22.44.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(benzyl sulfuryl)-1,3,4-oxadiazoles (iI 2 )
Clear crystal, m.p. 131 ~ 132 DEG C; Yield 82.6%; 1h NMR (500 MHz, CDCl 3) δ: 7.40 ~ 7.35 (m, 5H, benzyl-H), 4.83 (s, 2H, CH 2-SO 2), 3.01 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 162.12,161.12,159.52,131.34,130.16,130.03,129.42,124.58,62.39,14.40; IR (KBr, cm -1) ν:3033,2937,1575,1458,1355,1155; Anal. Calcd for C 12h 10n 4o 3s 2: C 44.71, H 3.13, N 17.38; Found:C 44.91, H 3.04, N 17.29.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(3-chlorobenzyl sulfuryl)-1,3,4-oxadiazoles (iI 3 )
Clear crystal, m.p. 143 ~ 144 DEG C; Yield 82.6%; 1h NMR (500 MHz, CDCl 3) δ: 7.44 ~ 7.32 (m, 4H, benzyl-H), 5.01 (s, 2H, CH 2-SO 2), 3.06 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 165.71,159.12,157.03,138.45,135.66,131.34,131.02,130.47,129.67,128.74,51.65,14.31; IR (KBr, cm -1) ν:3034,2937,1575,1429,1357,1157; Anal. Calcd for C 12h 9clN 4o 3s 2: C 40.39, H 2.54, N 15.70; Found:C 40.79, H 2.54, N 15.11.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl sulfuryl)-1,3,4-oxadiazoles (iI 4 )
Clear crystal, m.p. 108 ~ 110 DEG C; Yield 82.6%; 1h NMR (500 MHz, CDCl 3) δ:3.71 (q, j=7.45,2H, CH 2), 3.04 (s, 3H, CH 3), 1.55 (t, j=7.45,3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 162.27,159.43,151.32,151.77,133.38,52.17,6.94; IR (KBr, cm -1) ν:3032,2902,1575,1506,1344,1155; Anal. Calcd for C 7h 8n 4o 3s 2: C 32.30, H 3.10, N 21.52; Found:C 32.54, H 3.03, N 21.79.
The synthesis of 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-mercaptan-1,3,4-thiadiazoles
By 4-methyl isophthalic acid, 2,3-thiadiazoles-5 formyl hydrazine (1.9 g, 0.012 mol) is thrown in 50 mL tri-neck round-bottomed flasks, adds dehydrated alcohol (20 mL), potassium hydroxide (0.92g, 0.013 mol), stirring and dissolving.Control temperature is room temperature (21 DEG C), drips (1.1 g, 0.014 mol) dithiocarbonic anhydride, rapid stirring 5 h.Suction filtration, with absolute ethanol washing, obtains white solid.Add in 10 mL sulfuric acid by sylvite (2 g, 7.3 mmol) after infrared drying, under agitation reaction is violent, a large amount of heat release, temperature control <3 DEG C.After adding, treat that all solids dissolves, then stir 90 minutes, then reactant is slowly poured into thread shape in the frozen water of 200 mL, product Precipitation, suction filtration, washs by suitable quantity of water, solid 10% sodium hydroxide solution dissolves, and elimination insolubles uses 5% hcl acidifying again, obtains white solid.Ethyl alcohol recrystallization, obtains colourless acicular crystal 1.1g.Fusing point 191 ~ 192 DEG C, yield 70%. 1H NMR(500 MHz, CDCl 3) δ: 11.24 (s, 1H, SH), 3.13(s, 3H, CH 3)。
The synthesis (III) of 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-substituting group thioether-1,3,4-thiadiazoles
By 2-sulfydryl-5-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-1,3,4-thiadiazoles (0.6g, 2.79mmol), sodium hydroxide (0.11 g, 2.79mmol) throw in l00mL there-necked flask with water (20mL), stirring at room temperature is dissolved.Slowly add room temperature (22 DEG C) the reaction end in 4 hours afterwards of methyl-sulfate (0.52g, 4.18mmol), ethyl sulfate (0.52g, 4.18mmol) or halohydrocarbon (2.79mmol).Suction filtration obtains faint yellow solid, and 95% ethyl alcohol recrystallization obtains target compound.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(dibenzylsulfide ether)-1,3,4-thiadiazoles (iII 1 )
Clear crystal, m.p. 114 ~ 116 DEG C; Yield 91.6%; 1h NMR (500 MHz, CDCl 3) δ: 7.46 ~ 7.29 (m, 5H, benzyl-H), 4.64 (s, 2H, CH 2), 2.94 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 167.91,157.02,155.63,139.35,135.38,129.36,128.96,128.28,38.42,14.44; IR (KBr, cm -1) ν:3033,2974,1571,1352,1047,698; Anal. Calcd for C 12h 10n 4s 3: C 47.03, H 3.29, N 18.28; Found:C 46.71, H 3.14, N 18.04.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl thioether base)-1,3,4-thiadiazoles (iII 2 )
Clear crystal, m.p. 74 ~ 76 DEG C; Yield 81.9%; 1h NMR (500 MHz, CDCl 3) δ:3.46 (q, j=6.85,2H, CH 2), 2.97 (s, 3H, CH 3), 1.52 (t, j=6.9,3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 168.81,156.98,155.10,139.23,28.88,14.55,14.43; IR (KBr, cm -1) ν:2932,1558,1354,694; Anal. Calcd for C 7h 8n 4s 3: C 34.41, H 3.30, N 22.93; Found:C 34.21, H 3.15, N 22.71.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(adjacent luorobenzyl thioether group)-1,3,4-thiadiazoles (iII 3 )
Clear crystal, m.p. 125 ~ 127 DEG C; Yield 80.1%; 1h NMR (500 MHz, CDCl 3) δ: 7.54 ~ 7.07 (m, 4H, benzyl-H), 4.68 (s, 2H, CH 2), 2.95 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 167.55,156.98,155.64,139.21,131.57,130.29,130.22,124.48,115.87,115.70,31.59,14.43; IR (KBr, cm -1) ν:2927,1583,1487,1446,1350,692; Anal. Calcd for C 12h 9fN 4s 3: C 44.43, H 2.80, N 17.27; Found:C 44.26, H 2.55, N17.11.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(allyl sulfide ether)-1,3,4-thiadiazoles (iII 4 )
Clear crystal, m.p. 104 ~ 106 DEG C; Yield 78.3%; 1h NMR (500 MHz, CDCl 3) δ: 6.04 ~ 5.97 (m, 1H, CH=CH 2), 5.29 (m, 2H, CH=CH 2), 4.05 (d, j=6.9 Hz, 2H, CH 2-S), 2.97 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 167.74,159.28,155.36,139.33,131.49,120.32,36.94,14.46; IR (KBr, cm -1) ν:2909,1543,1423,677; Anal. Calcd for C 8h 8n 4s 3: C 37.48, H 3.15, N 21.85; Found:C 36.77, H 2.93, N 21.75.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(Dimethyl sulfide base)-1,3,4-thiadiazoles (iII 5 )
Clear crystal, m.p. 108 ~ 110 DEG C; Yield 83.7%; 1h NMR (500 MHz, CDCl 3) δ: 2.97 (s, 3H, CH 3), 2.88 (s, 3H, SCH 3). 13c NMR (125 MHz, CDCl 3) δ: 169.63,156.99,155.22,139.36,16.60,14.43; IR (KBr, cm -1) ν:2931,1519,1350,657; Anal. Calcd for C 6h 6n 4s 3: C 31.29, H 2.63, N 24.32; Found:C 30.88, H 2.67, N 24.31.
The synthesis (IV) of 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-substituting group sulfuryl-1,3,4-thiadiazoles
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(benzyl sulfuryl)-1,3,4-thiadiazoles (iV 1 )
Clear crystal, m.p. 147 ~ 149 DEG C; Yield 89.6%; 1h NMR (500 MHz, CDCl 3) δ: 7.46 ~ 7.29 (m, 5H, benzyl-H), 4.85 (s, 2H, CH 2), 2.94 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 168.66,161.11,158.41,137.93,131.36,129.78,128.95,125.68,62.06,14.63; IR (KBr, cm -1) ν:3030,2923,1558,1456,1373,1149; Anal. Calcd for C 12h 10n 4o 2s 3: C 42.59, H 2.98, N 16.55; Found:C 42.75, H 2.81, N 17.10.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl sulfuryl)-1,3,4-thiadiazoles (iV 2 )
Clear crystal, m.p. 84 ~ 86 DEG C; Yield 79.2%; 1h NMR (500 MHz, CDCl 3) δ: 3.67 (q, j=6.85,2H, cH 2 cH 3), 3.04 (s, 3H, CH 3), 1.52 (t, j=7.45,3H, CH 2 cH 3 ); 13c NMR (125 MHz, CDCl 3) δ: 169.13,160.78,158.45,137.97,50.36,14.72,7.19; IR (KBr, cm -1) ν:3027,2918,1558,1508,1456,1328,1143; Anal. Calcd for C 7h 8n 4o 2s 3: C 30.42, H 2.92, N 20.27; Found:C 29.71, H 2.69, N 19.80.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(adjacent luorobenzyl sulfuryl)-1,3,4-thiadiazoles (iV 3 )
Clear crystal, m.p. 153 ~ 155 DEG C; Yield 86.5%; 1h NMR (500 MHz, CDCl 3) δ: 7.41 ~ 7.07 (m, 4H, benzyl-H), 4.93 (s, 2H, CH 2), 2.97 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 168.31,161.25,158.35,137.70,133.02,132.21,125.00,116.23,55.51,14.68; IR (KBr, cm -1) ν:3032,2917,1583,1492,1454,1332,1155; Anal. Calcd for C 12h 9fN 4o 2s 3: C 40.44, H 2.55, N 15.72; Found:C 40.27, H 2.54, N 15.50.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(allyl group sulfuryl)-1,3,4-thiadiazoles (iV 4 )
Clear crystal, m.p. 125 ~ 127 DEG C; Yield 88.4%; 1h NMR (500 MHz, CDCl 3) δ: 8.21 ~ 7.66 (m, 2H, CH 2), 4.71 (s, 1H, CH), 2.95 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 166.46,156.96,143.39,130.27,124.07,36.88,14.45; IR (KBr, cm -1) ν:2923,1565,1433,1357,1143; Anal. Calcd for C 8h 8n 4o 2s 3: C, 33.32, H, 2.80, N, 19.43; Found:C 33.98, H 2.41, N 19.11.
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(methyl sulfuryl)-1,3,4-thiadiazoles (iV 5 )
Clear crystal, m.p. 99 ~ 101 DEG C; Yield 76.7%; 1h NMR (500 MHz, CDCl 3) δ: 3.54 (s, 3H, SCH 2), 3.04 (s, 3H, CH 3); 13c NMR (125 MHz, CDCl 3) δ: 169.87,160.70,158.47,137.79,126.54,118.67,43.27,14.71; IR (KBr, cm -1) ν:3005,2918,1573,1411,1328,1143; Anal. Calcd for C 6h 6n 4o 2s 3: C 27.47, H 2.31, N 21.36; Found:C 27.38, H 2.23, N 21.28.
Target compound resisting tobacco mosaic virus is tested
Virus purification
Adopt Gooding method (Gooding; Et al., 1967), choose inoculation more than 3 weeks, TMV systemic infection host Nicotiana glutinosa (Nicotiana glutinosa L.) plant upper blade, homogenate in phosphoric acid buffer, double gauze filters, 1000 rpm are centrifugal, through 2 polyoxyethylene glycol process, more centrifugal, precipitation phosphoric acid buffer suspends, and namely obtains the crude extract of TMV.Whole test is carried out under 4 ° of C.The absorbance of 260 nm wavelength is measured, according to formulae discovery virus concentration with ultraviolet spectrophotometer.
Virus concentration (mg ∕ mL)=(A 260× extension rate) ∕ E 0.1% 1 cm 260 nm
Wherein E represents optical extinction coefficient, and namely during wavelength 260 nm, concentration is the suspension of 0.1% (1 mg ∕ mL), photoabsorption (optical density(OD)) value when light path is l cm.The E of TMV 0.1% 1 cm 260 nm3.1.
The live body therapeutic action that medicament infects TMV
Select the Nicotiana glutinosa that growing way is consistent, first dip viral juice with writing brush, full leaf virus inoculation, rinses with clear water after inoculation.After blade is dry, spread medicament at Zuo Banye, the solvent that right half leaf spreads matched doses compares.In illumination box, moisturizing is cultivated subsequently, and control temperature 23 ± 1 ° of C, illumination 10000 Lux, observe after 3-4 d and record the number producing withered spot.Every chemicals treatment establishes 3 strains, every strain 3 ~4 leaves.Every medicament carries out 3 repetitions as stated above.
Each process be with second half in contrast, then reference is done in the process arranging one group of Ningnanmycin.On half leaf of blank, present obvious withered spot, at experiment 3-4 d " Invest, Then Investigate ", record the withered spot number of left and right half leaf of every sheet leaf respectively, press column count and go out the inhibiting rate of test compound to tobacco mosaic virus (TMV), i.e. relative efficacy.
Method for expressing: Y=(C-A)/C × 100%
Wherein: Y is the inhibiting rate of compound to tobacco mosaic virus (TMV); C is control group (right half leaf) withered spot number, and A is the withered spot number of control group (Zuo Banye).
Adopt the withered spot method of half leaf to carry out the therapeutic activity test of resisting tobacco mosaic virus (TMV) to part of compounds, test result is shown in table 1.
From table 1raw active testing result of surveying can be found out, when concentration is 500 μduring g/mL, institute's test compounds between 31 ~ 55%, has certain inhibit activities, wherein chemical compounds I to the treatment inhibiting rate of tobacco mosaic virus (TMV) (TMV) 3,i 4 with II 1 treatment inhibiting rate be respectively 48%, 47% and 47%, chemical compounds I 1treatment inhibiting rate be 55%, with contrast medicine Ningnanmycin effect substantially quite (56%), due to target compound novel structure, agricultural chemicals does not have commercial 2-(4-methyl isophthalic acid, 2 on the market, 3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative, therefore, cross resistance can not be produced with existing antiviral agent, there is good application prospect.
The embodiment of the present invention is aided with technical scheme of the present invention, but the content of embodiment is not limited thereto.
Conclusion, effect
1,2-(4-methyl isophthalic acid, 2,3-the thiadiazoles)-5-(substituting group)-1 of crop virosis evil is prevented and treated, 3,4-Evil (thiophene) diazoles derivative, effective, most widely used antiviral agent (Ningnanmycin) is suitable on the market at present for fundamental sum.
2,2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative is for preventing and treating crop tobacco mosaic disease, novel structure, and agricultural chemicals does not have 2-(4-methyl isophthalic acid on the market, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative, therefore, cross resistance can not be produced with existing agricultural chemicals.
3,2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative control crop Micobial Disease, can be prepared into several formulations, be easy to be converted into practical application.

Claims (5)

1. a class 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil/(thiophene) diazoles derivative is prevented and treated or is suppressed the purposes of tobacco mosaic virus disease evil, Cucumber Mosaic Virus evil, oryza virus 3 disease, rice dwarf virus disease virus disease, maize rough dwarf virus virus disease, rice black-streaked dwarf virus disease, tomato virus disease, it is characterized in that compound has following general formula:
In formula:
X is O or S, the ， Wei oxadiazole compounds when X is O; When X is S, it is thiadiazole compound;
R is selected from hydrogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxyl group, C2-C5 thiazolinyl, the ester group of C2-C5, benzyl or substituted benzyl;
Described substituted benzyl is 4-methyl-benzyl, 3-methyl-benzyl, 2-methyl-benzyl, 3,4-dimethyl benzyl, 2,4-dimethyl benzyl, 2,6-dimethyl benzyl, 4-luorobenzyl, 3-luorobenzyl, 2-luorobenzyl, 3,4-difluorobenzyl, 2,4-difluorobenzyl, 2,6-difluorobenzyl, 4-chlorobenzyl, 3-chlorobenzyl, 2-chlorobenzyl, 3,4-dichloro benzyl, 2,4-dichloro benzyl, 2,6-dichloro benzyls, 4-methoxy-benzyl, 3-methoxy-benzyl, 2-methoxy-benzyl, 3,4-dimethoxy-benzyls, 2,4-dimethoxy-benzyl or 2,6-dimethoxy-benzyl.
2. a class 2-(4-methyl isophthalic acid according to claim 1,2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil/(thiophene) diazoles derivative is prevented and treated or is suppressed the purposes of tobacco mosaic virus disease evil, Cucumber Mosaic Virus evil, oryza virus 3 disease, rice dwarf virus disease virus disease, maize rough dwarf virus virus disease, rice black-streaked dwarf virus disease, tomato virus disease, it is characterized in that:
Described C1-C5 alkyl is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl or neo-pentyl,
Described C1-C2 haloalkyl is fluoroform alkyl, trichloromethane base, methylene fluoride base, methylene chloride-based, a fluoromethane base, 1,2-C2H4F2 C2H4F2 base, 1,2-Tetrafluoroethane base, 1,2-ethylene dichloride base or 1,2-tetrachloroethane base,
Described C1-C3 alkoxyl group is methoxyl group, oxyethyl group or positive propoxy,
The thiazolinyl of described C2-C5 is vinyl, propenyl, allyl group, butenyl, isobutenyl, pentenyl, isopentene group or new pentenyl,
The ester group of described C2-C5 is methyl-formiate base, group-4 ethyl formate, propyl formate base, methyl acetate base, ethyl acetate base or propyl acetate base,
Described substituted benzyl is 4-luorobenzyl, 3-luorobenzyl, 4-chlorobenzyl, 3-chlorobenzyl.
3. a class 2-(4-methyl isophthalic acid according to claim 1,2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative is prevented and treated or is suppressed the purposes of tobacco mosaic virus disease evil, Cucumber Mosaic Virus evil, oryza virus 3 disease, rice dwarf virus disease virus disease, maize rough dwarf virus virus disease, rice black-streaked dwarf virus disease, tomato virus disease, it is characterized in that compound is:
2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(Dimethyl sulfide base)-1,3,4-oxadiazole (I 1), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(dibenzylsulfide ether)-1,3,4-oxadiazole (I 2), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(3-chloro benzyl sulfur ether)-1,3,4-oxadiazoles (I 3), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl thioether base)-1,3,4-oxadiazole (I 4), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(4-nitrobenzyl thioether group)-1,3,4-oxadiazoles (I 5), 2-(carbethoxymethylene thioether)-5-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-1,3,4-oxadiazoles (I 6), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(methyl sulfuryl)-1,3,4-oxadiazole (II 1), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(benzyl sulfuryl)-1,3,4-oxadiazole (II 2), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(3-chlorobenzyl sulfuryl)-1,3,4-oxadiazoles (II 3), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl sulfuryl)-1,3,4-oxadiazole (II 4), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(dibenzylsulfide ether)-1,3,4-thiadiazoles (III 1), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl thioether base)-1,3,4-thiadiazoles (III 2), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(adjacent luorobenzyl thioether group)-1,3,4-thiadiazoles (III 3), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(allyl sulfide ether)-1,3,4-thiadiazoles (III 4), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(Dimethyl sulfide base)-1,3,4-thiadiazoles (III 5), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(benzyl sulfuryl)-1,3,4-thiadiazoles (IV 1), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(ethyl sulfuryl)-1,3,4-thiadiazoles (IV 2), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(adjacent luorobenzyl sulfuryl)-1,3,4-thiadiazoles (IV 3), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(allyl group sulfuryl)-1,3,4-thiadiazoles (IV 4), 2-(4-methyl isophthalic acid, 2,3-thiadiazoles-5-base)-5-(methyl sulfuryl)-1,3,4-thiadiazoles (IV 5).
4. a class 2-(4-methyl isophthalic acid according to claim 1, 2, 3-thiadiazoles)-5-(substituting group)-1, 3, 4-Evil/(thiophene) diazoles derivative is used for control or suppresses tobacco mosaic virus disease evil, Cucumber Mosaic Virus evil, oryza virus 3 disease, rice dwarf virus disease virus disease, maize rough dwarf virus virus disease, rice black-streaked dwarf virus disease, the preparation of tomato virus disease, described 2-(4-methyl isophthalic acid, 2, 3-thiadiazoles)-5-(substituting group)-1, 3, the formulation of 4-Evil/(thiophene) diazoles derivative formulations is missible oil, micro emulsion, water and milk, suspension agent, seed coat agent, seed dressing, wettable powder, sustained-release granular formulation, controlled release granule, water dispersible granules, dry suspension or granule.
5. preparation according to claim 4, is characterized in that, in the formulation of described preparation, effective constituent 2-(4-methyl isophthalic acid, 2,3-thiadiazoles)-5-(substituting group)-1,3,4-Evil (thiophene) diazoles derivative accounts for 1% ~ 90% of total formulation weight amount.
CN201210377140.1A 2012-10-08 2012-10-08 2-(4-methyl-1,2,3-thiadiazole)-5-(substituent)-1,3,4-oxa(thia)diazole derivative and application thereof Expired - Fee Related CN102838593B (en)

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