CN1346827A - 1,2,3-thiadiazole compounds, and their preparing process and bioactivity - Google Patents

1,2,3-thiadiazole compounds, and their preparing process and bioactivity Download PDF

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CN1346827A
CN1346827A CN 01136684 CN01136684A CN1346827A CN 1346827 A CN1346827 A CN 1346827A CN 01136684 CN01136684 CN 01136684 CN 01136684 A CN01136684 A CN 01136684A CN 1346827 A CN1346827 A CN 1346827A
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thiadiazole
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CN1166650C (en
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李正名
赵卫光
杨炤
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Nankai University
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Nankai University
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Abstract

The present invention relates to a process for preparing 1,2,3-thiadiazole compounds, which can be used to prevent and treat hepatitis B and plant viruses.

Description

1,2,3-thiadiazole compound and preparation method thereof and biological activity
Technical field
The present invention relates to the preparation of thiadiazole compound, it can be applied to treat and/or prevent the control that is used for plant virus in hepatitis B and the agricultural.
Background technology
Hepatitis B virus (Hepatitis B Virus; HBV) be a sizable public health problem, because this virus has the acute and chronically infected ability that causes.Chronic HBV infection can cause liver cirrhosis and primary hepatocellular carcinoma.Although hepatitis B virus vaccine comes out for many years, however the present effective treatment means that does not also have control chronic HBV infection that can be successful.The whole world still has 300,000,000 populations to infect HBV, and wherein China accounts for 75%, they can't in be benefited in the existing commercially available vaccine.Existing HBV treatment means effect or has serious toxic side effect not enough, as generally acknowledge the Interferon, rabbit that clear and definite curative effect is arranged only have 25% to 40% efficient, also have 10% to 40% patient to produce severe side effect simultaneously.The effective means of therefore treating HBV is the task of top priority.
Plant virus also is that one in the agriculture production endangers greatly, nearly all farm crop and cash crop all are subjected to 2～3 kinds of virus harm, the title that " plant cancer " arranged, because control difficulty, cause great loss to agriculture production, for example, the nineteen eighty-three agricultural losses that cause because of plant virus of Japan reach 80,000,000,000 yen.
In order to prevent and treat plant virus, people have carried out many-sided research, from the seventies in 20th century, Schuster discovery compound in triazine class (DHT) has had since the good inhibitory effect to plant virus, the chemist has found that multiple compound has and has suppressed the plant virus activity preferably up to now, as tremble epidemic disease rhzomorph, virazole, Citrinin, purine and pyrimidine, plant hormone and some natural anti-virus materials, yet also there is different problems in they, have limited their application.As tremble the epidemic disease rhzomorph and do not have interior absorption, can not be organized absorption; Then there is the shortcoming that the lasting period is short, poisoning is serious and cost is high in virazole; There are the serious problem of poisoning equally in pyrimidine and purine, and invalid fully sometimes; And if plant hormone class drug main stimulates plant growth, and is inoperative to the propagation of virus.
Summary of the invention
The purpose of this invention is to provide a kind of 1,2, the 3-thiadiazole compound, it can be used for to anti-hepatitis B virus with to Antiphytoviral.
The present invention is the compound of following structural formula (I): R wherein 1Be hydrogen, halogen, alkyl, substituted aryl, alkoxyl group, substituted aryloxy, alkylthio, replacement arylthio, amino, alkylamino radical, aryl amine, contain five Yuans or six element heterocycles of N, S element; R 2Be hydrogen, alkyl, substituted aryl, alkoxyl group, substituted aryloxy, amino, alkylamino radical, substituted aromatic amines base, contain five Yuans or six element heterocycles of N, S element; R 3Be hydrogen, alkyl, substituted aryl, alkoxyl group, substituted aryloxy, alkylamino radical, substituted aromatic amines base, substituted benzyl, replacement virtue ethyl, contain N, S element five Yuans or six element heterocycles or its heterocyclic methyl, ethyl; X is O, S, CH 2, CHR ', NH, NR '; R ' is hydrogen, alkyl or aryl; Y is O, S, SO, SO 2, NH, NR '; Y also can be five Yuans or six element heterocycles that contain N, S element.
Preferred class group of the present invention is the compound of structure (II):
Wherein
Y is oxygen, sulphur, NH, NR ', SO or SO 2R ' is hydrogen, alkyl or aryl
R 3Be hydrogen, alkyl, substituted aryl, alkoxyl group, substituted aryloxy, alkylamino radical, substituted aromatic amines base, substituted benzyl, replacement virtue ethyl, contain N, S element five Yuans or six element heterocycles or its heterocyclic methyl, ethyl;
The example and the physico-chemical constant thereof of some structures (II) compound are shown in Table 1.
" aryl " speech used herein refers to any compound that comprises or be made of one or more aromatic nucleus, and aromatic nucleus can be carbocyclic ring, heterocycle or pseudo aromaticity, and can be list or multi-loop system, and preferably contains 3-20 carbon atom.Aromatic nucleus also can contain the heteroatoms of one or more selections from N, S, O and P.The example of suitable ring comprises, but be not limited to, benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetraline, the 1-benzyl naphthalene, anthracene, anthracene dihydride, benzanthrene, dibenzanthracene, luxuriant and rich with fragrance, pyridine, the 4-phenylpyridine, the 3-phenylpyridine, thiophene, thionaphthene, chromene, the pyrroles, imidazoles, pyrazine, pyrimidine, pyridazine, triazine, indoles, isoindole, purine, quinoline, isoquinoline 99.9, quinoxaline, pteridine, carbazole, phenanthridines, azophenlyene, furans, thiophene, the pyrroles, isothiazole isoxazole, triazole, thiadiazoles oxadiazole etc., comprise that also above-mentioned any two kinds of aromatic nucleus are directly continuous or pass through C, O, the situation that atoms such as N link to each other, every kind of all optional being substituted." pseudo aromaticity " speech refers to a kind of loop systems, though its aromaticity is not strict, and because of the delocalizationization of electronics is stablized, and similar to the behavior of aromatic nucleus.The example of false aromatic nucleus includes, but are not limited to: furans, thiophene, pyrroles etc.
Alkyl refers to straight C 1-30Alkyl or side chain C 1-30The C of alkyl and branching or non-branching 3-30Cycloalkyl, these groups can be saturated or unsaturated.
Alkoxyl group refers to straight C 1-30Alkoxyl group or side chain C 1-30The C of alkoxyl group and branching or non-branching 3-30Cycloalkyloxy, these groups can be saturated or unsaturated.
Basic preparation method of the present invention is described below:
Figure A0113668400061
A, alpha-chloro dicarbonyl compound (1) be dissolved in solvent methanol, ethanol, acetonitrile, chloroform, methylene dichloride,, among ether, dipropyl ether, DMF or the DMSO, temperature adds carbazic acid ethyl ester or p-toluene sulfonyl hydrazide between 0 ℃ to 80 ℃, temperature continued reaction after 0.5 to 20 hour between 0 ℃ to 80 ℃, vacuum is sloughed partial solvent, recrystallization gets thick liquid or solid target product (2).
B, the thionyl chloride that in reaction flask, adds 1～20 times of amount or sulfur dichloride, temperature will go up step product (2) under stirring and join in the reaction flask in batches between-15 ℃ to 35 ℃, finish, rise to 0 ℃ to 120 ℃ reaction 5～48 hours, impouring alkali is (as KOH, NaOH, K 2CO 3, Na 2CO 3, NaHCO 3Deng) the aqueous solution in, have a large amount of solids to separate out, suction filtration is used the appropriate solvent recrystallization, target product (3).
C, with the compound dissolution of hydroxyl, ammonia (amine) base, sulfydryl in suitable organic solvent (methyl alcohol, ethanol, acetonitrile, chloroform, methylene dichloride, ethyl acetate, ether, dipropyl ether, acetone, butanone, DMF or DMSO), the alkali that adds 0.8 to 5 times of amount (can be KOH, NaOH, K 2CO 3, Na 2CO 3, NaHCO 3Deng mineral alkali, also can be organic basess such as triethylamine, three positive fourth peaces, pyridine, DMAP), temperature adds the compound (3) of 0.8～3 times of amount between 0 ℃ to 80 ℃, after reaction finishes, vacuum boils off solvent, the resistates drip washing of on silicagel column, reducing pressure, solid target product (4).Can be synthetic when nitrogen that Y is oxygen, sulphur, nitrogen etc. on atom or five Yuans or six element heterocycles with similar method.
D, when Y is S, structural formula (4) compound dissolution is in suitable organic solvent (water, methyl alcohol, ethanol, acetonitrile, acetate, chloroform, methylene dichloride, ethyl acetate, ether, dipropyl ether, acetone, butanone, DMF or DMSO), the oxygenant that adds 0.9～5 times of amount, between-15 ℃ to 60 ℃, reacted 1～48 hour, after sloughing solvent, use the appropriate solvent recrystallization, can obtain Y is structural formula (5) compound of SO.Reacted 0.5～24 hour between 5 ℃ to 100 ℃, then can obtain Y is SO 2Structural formula (5) compound.
Structural formula (I) compound is used for the treatment of and/or prevents prevents and treats plant virus in the hepatitis b virus infected and agricultural.The purposes of the derivative that the salt of structural formula (I) compound and pharmacology thereof are allowable and in the agriculture purposes aspect viral of control.
Structural formula (I) or structural formula (II) compound demonstrate quite high activity in the resistance of hepatitis B check.These compounds demonstrate quite high activity in the resisting tobacco mosaic virus check simultaneously.
The compounds of this invention further can be used for making the medicine of treatment or prevention HBV.Therefore, preferably pharmacology is allowable to the invention provides the salt of structural formula (I) or structural formula (II) compound, but know that its non-pharmacology salt allowable also belongs within the scope of the invention, in the preparation process of pharmacology salt allowable because they are useful as intermediates.Pharmacology salt allowable comprises: the common non-toxic salt or the quaternary ammonium salt of compound, such as preparing from organic or mineral acid or alkali. the example of acid-adducting salt comprises, but be not limited to, coming from pharmacology for example acetate, propionic acid, citric acid, lactic acid, METHAPHOSPHORIC ACID, toluenesulphonic acids, Phenylsulfonic acid, Whitfield's ointment, xitix, hydrochloric acid, ortho-phosphoric acid, sulfuric acid and Hydrogen bromide, alkali salt allowable comprises, but be not limited to, come from pharmacology positively charged ion allowable such as sodium, potassium, lithium, calcium, magnesium, ammonia and alkanamine.Compound with proper metal hydroxide treatment structural formula (I) is prepared it, by some reagent, such as methane, ethane, propane and the butane of lower halogenated alkane such as chloro, Australia's generation and iodo; Sulfuric acid dialkyl such as methyl-sulfate and diethyl ester; And other also can be quaternized with nitrogenous basic group.
The compounds of this invention can be crystalline state or solvate (such as hydrate), and two states all belongs to and the scope of the invention.The solvation method is widely known by the people in the prior art.
Pharmacology derivative allowable can comprise any pharmacology salt allowable, hydrate.
Structural formula (I) or structural formula (II) compound have unsymmetrical structure, and therefore can exist the steric isomer above.Every kind of form of these isomer and composition thereof has been contained in the present invention, comprises racemoid.Isomer generally can or utilize resolving agent to separate by chromatography.Alternatively, the preparation of each isomer can be by having used the asymmetric synthesis of chiral intermediate or enzyme.
Structural formula of the present invention (I) or structural formula (II) compound further can be used for preventing and treating preparation or the mixture of plant virus.
Structural formula (I) or structural formula (II) compound also have plant growth regulating activity and simultaneously to the characteristic of plant safety except that having good activity of resisting tobacco mosaic virus, this be other most of agricultural antiviral agents can not possess simultaneously.
The present invention 1,2, and the 3-thiadiazole compound is easy to synthesize, cost is low, and animal virus and plant virus are all had good inhibitory effect, and novel structure, at present known virus is had do not see to have in the better inhibiting compound and contain 1,2, the report of 3-thiadiazoles ring.The present invention is from designing, produce the requirement that application all meets environmental friendliness and Green Chemistry.
Embodiment
In order further to understand the present invention, provide embodiment.Specific material and used condition are intended to illustrate of the present invention, its reasonable range are not construed as limiting.
The reagent of not mentioning is buied from the market and is used with former state, except as otherwise noted.
All temperature all are degree centigrade.
Scheme:
Figure A0113668400071
Embodiment 1:
Synthesizing of alpha-chloro acetoacetyl methylamine-N-ethoxycarbonyl hydrazone
Alpha-chloro acetoacetyl methylamine 21g (90%) (0.125mol) is dissolved in the 60mL dehydrated alcohol, slowly drip 12.9g (0.125mol) carbazic acid ethyl ester under the room temperature, room temperature reaction 18h, vacuum is sloughed partial solvent, recrystallization, get white solid 21g, productive rate 71%, fusing point: 120-121 ℃.Ultimate analysis: measured value, C:40.78, H:5.51, N:17.64; Calculated value: C:40.77, H:5.99, N:17.83. 1H?NMR(CDCl 3)：1.30(t，J＝7.2，3H，CH 3)，1.90(s，3H，CH 3)，2.87(d，J＝4.6，3H，NCH 3)，4.25(q，J＝7.0，2H，OCH 2)，5.11(s，1H，CH)，6.76(br，1H，NH)，7.90(br，1H，NH)。
Embodiment 2:
Alpha-chloro-1,2,3-thiadiazoles acetyl methylamine synthetic
In reaction flask, add the 25mL thionyl chloride, be cooled to 5 ℃, will go up step product 21g under stirring and join in the reaction flask in batches, controlled temperature is no more than 10 ℃, finish, rise to room temperature reaction 48h, in the impouring yellow soda ash saturated aqueous solution, there are a large amount of solids to separate out, suction filtration is used ethyl alcohol recrystallization, gets product 14.5g, productive rate 85%, fusing point: 144-145 ℃.Ultimate analysis: measured value, C:31.45, H:2.89, N:21.77; Calculated value: C:31.34, H:3.16, N:21.93. 1HNMR(CDCl 3)：2.93(d，J＝4.8，3H，NCH 3)，5.91(s，1H，CH)，6.96(br，1H，NH)，8.67(s，1H，thiadiazole-H)。
Embodiment 3:
Alpha-substitution phenoxy group-1,2,3-thiadiazoles acetyl methylamine (II-3a) synthetic
P bromophenol 0.87g (4mmol) is dissolved in the 10mL methyl alcohol, add sodium hydroxide 0.24g (5mmol), stir after 10 minutes under the room temperature and add alpha-chloro-1,2,3-thiadiazoles acetyl methylamine 0.77g (4mmol), stirring at room 48h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, (v: v=1: 5) decompression drip washing gets pure product 0.6g to resistates with the eluent ethyl acetate/petroleum ether on silicagel column.
Embodiment 4:
α-(β-naphthyloxy)-1,2,3-thiadiazoles acetyl methylamine (II-4) synthetic
2-Naphthol 0.72g (5mmol) is dissolved in the 10mL methyl alcohol, add sodium hydroxide 0.24g (6mmol), add alpha-chloro-1,2 after the stirring and dissolving, 3-thiadiazoles acetyl methylamine 0.77g (3mmol), stirring at room 48h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, (v: v=1: 5) decompression drip washing gets pure product 0.32g to resistates with the eluent ethyl acetate/petroleum ether on silicagel column.
Embodiment 5:
Alpha-substitution thiophenyl-1,2,3-thiadiazoles acetyl methylamine (II-5a) synthetic
With alpha-chloro-1,2,3-thiadiazoles acetyl methylamine 1.53g (8mmol) is dissolved in the 20mL acetonitrile, adds Anhydrous potassium carbonate 1.39g (10mmol) and phase-transfer catalyst 0.01g, drip 2 under the stirring at room, 5-thiophenol dimethyl benzene 1.4g (10mmol), stirring at room reaction 6h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, resistates dehydrated alcohol recrystallization gets pure product 1.59g.
Embodiment 6:
α-(4-chloro benzylthio-)-1,2,3-thiadiazoles acetyl methylamine (II-6) synthetic
With alpha-chloro-1,2,3-thiadiazoles acetyl methylamine 1.53g (8mmol) is dissolved in the 20mL acetonitrile, adds Anhydrous potassium carbonate 1.4g (10mmol) and phase-transfer catalyst 0.01g, drips under the stirring at room chloro benzyl mercaptan 1.45g (8mmol), stirring at room reaction 6h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, resistates dehydrated alcohol recrystallization gets pure product 1.6g.
Embodiment 7:
Alpha-substitution benzenesulfinyl-1,2,3-thiadiazoles acetyl methylamine (II-7e) synthetic
With α-to chlorobenzene sulfenyl-1,2,3-thiadiazoles acetyl methylamine 0.53g (1.8mmol) adds in the 10mL acetate, after the heating for dissolving, be cooled to 25～30 ℃, drip the hydrogen peroxide (30%) of 3.5mmol, leave standstill 2h after shaking up, stirring at room 24h, add water 20mL, leave standstill, suction filtration, with gained solid dehydrated alcohol recrystallization, get pure product 0.30g.
Embodiment 8:
Alpha-substitution benzyl sulfinyl-1,2,3-thiadiazoles acetyl methylamine (II-8) synthetic
With α-to benzyl chloride sulfenyl-1,2,3-thiadiazoles acetyl methylamine 0.53g (1.7mmol) adds in the 10mL acetate, after the heating for dissolving, be cooled to 25～30 ℃, drip the hydrogen peroxide (30%) of 3.5mmol, leave standstill 2h after shaking up, stirring at room 24h, add water 20mL, leave standstill, suction filtration, with gained solid dehydrated alcohol recrystallization, get pure product 0.30g.
Embodiment 9:
Alpha-substitution benzenesulfonyl-1,2,3-thiadiazoles acetyl methylamine (II-9a) synthetic
With α-2,5-dimethyl benzene sulfenyl-1,2,3-thiadiazoles acetyl methylamine 0.50g (1.7mmol) adds in the 10mL acetate, drip the hydrogen peroxide (30%) of 7mmol, be heated to 80 ℃, reaction 6h, be cooled to room temperature, add water 20mL, leave standstill, suction filtration, with gained solid dehydrated alcohol recrystallization, get pure product 0.35g.
Embodiment 10:
Alpha-substitution benzyl alkylsulfonyl-1,2,3-thiadiazoles acetyl methylamine (II-10) synthetic
With α-to benzyl chloride sulfenyl-1,2,3-thiadiazoles acetyl methylamine 0.53g (1.7mmol) adds in the 10mL acetate, drips the hydrogen peroxide (30%) of 7mmol, be heated to 80 ℃, reaction 6h is cooled to room temperature, adds water 20mL, leave standstill, suction filtration with gained solid dehydrated alcohol recrystallization, gets pure product 0.39g.
Embodiment 11:
α-[2-(1-methyl-3-ethyl pyrazoles-5-yl)-1,3,4-oxadiazole-5-sulfydryl]-1,2,3-thiadiazoles acetyl methylamine (II-11) synthetic
With alpha-chloro-1,2,3-thiadiazoles acetyl methylamine 0.55g (2.9mmol) is dissolved in the 10mL acetonitrile, add Anhydrous potassium carbonate 0.42g (3mmol) and phase-transfer catalyst 0.01g, add 2-(1-methyl-3-ethyl pyrazoles-5-yl)-5-sulfydryl-1,3 under the stirring at room, 4-oxadiazole 0.66g (2.9mmol), stirring at room reaction 6h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, resistates dehydrated alcohol recrystallization gets pure product 0.16g.
Embodiment 12:
α-[2-(1-methyl-3-methyl-5-methylthio group pyrazoles-4-yl)-1,3,4-thiadiazoles-5-sulfydryl]-1,2,3-thiadiazoles acetyl methylamine (II-12) synthetic
With alpha-chloro-1,2,3-thiadiazoles acetyl methylamine 0.55g (2.6mmol) is dissolved in the 10mL acetonitrile, add Anhydrous potassium carbonate 0.38g (2.7mmol) and phase-transfer catalyst 0.01g, add 2-(1-methyl-3-methyl-5-methylthio group pyrazoles-4-yl)-5-sulfydryl-1,3 under the stirring at room, 4-thiadiazoles 0.70g (2.7mmol), stirring at room reaction 6h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, resistates dehydrated alcohol recrystallization gets pure product 0.43g.
Embodiment 13:
α-[2-(1-methyl-3-methyl-5-methylthio group pyrazoles-4-yl)-1,3,4-oxadiazole-5-sulfydryl]-1,2,3-thiadiazoles acetyl methylamine (II-12) synthetic
With alpha-chloro-1,2,3-thiadiazoles acetyl methylamine 0.50g (2.6mmol) is dissolved in the 10mL acetonitrile, add Anhydrous potassium carbonate 0.38g (2.7mmol) and phase-transfer catalyst 0.01g, add 2-(1-methyl-3-methyl-5-methylthio group pyrazoles-4-yl)-5-sulfydryl-1,3 under the stirring at room, 4-oxadiazole 0.63g (2.6mmol), stirring at room reaction 6h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, resistates dehydrated alcohol recrystallization gets pure 0.17g.
Embodiment 14:
α-(5,7-dimethyl-1,2,4-triazole [1,5-a] pyrimidine-2-sulfydryl)-1,2,3-thiadiazoles acetyl methylamine (II-13) synthetic
With alpha-chloro-1,2,3-thiadiazoles acetyl methylamine 0.85g (4.4mmol) is dissolved in the 10mL acetonitrile, add Anhydrous potassium carbonate 0.69g (5mmol) and phase-transfer catalyst 0.01g, add 2-sulfydryl-5,7-dimethyl-1 under the stirring at room, 2,4-triazole [1,5-a] pyrimidine 0.6g (5mmol), stirring at room reaction 6h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, resistates dehydrated alcohol recrystallization gets pure product 0.64g.
Embodiment 15:
α-(1,2, the 4-triazol-1-yl)-1,2,3-thiadiazoles acetyl methylamine (II-14) synthetic
With alpha-chloro-1,2,3-thiadiazoles acetyl methylamine 0.19g (1mmol) is dissolved in the 10mL acetonitrile, add Anhydrous potassium carbonate 0.2g (1.4mmol) and phase-transfer catalyst 0.005g, add 1,2 under the stirring at room, 4-triazole 0.1g (1.4mmol), stirring at room reaction 48h, vacuum boils off solvent, with 10mL water washing solid, suction filtration, (V: V=1: 1) purify, and gets pure product 0.08g by the decompression column chromatography with ethyl acetate/petroleum ether for resistates.
Table 1: the materialization data of structural formula (II) compound
Compound ????Y ???R 3 Proterties Fusing point ℃ Productive rate
??II-3a ????O ???p-Br-C 6H 4 ????White?solid ???140-142 ???46
??II-3b ????O ???2-Cl-5-Me-C 6H 3 ????White?solid ???13II-135 ???27
??II-3c ????O ???p-I-C 6H 4 ????White?solid ???157-158 ???23
??II-3d ????O ???o-Br-C 6H 4 ????White?solid ???148-149 ???29
??II-3e ????O ???C 6H 5 ????White?solid ???140-141 ???29
??II-3f ????O ???p-Me-C 6H 4 ????White?solid ???130-132 ???15
??II-3g ????O ???m-Me-C 6H 4 ????White?solid ???127-128 ???38
??II-3h ????O ???3-Me-3-Me-C 6H 3 ????White?solid ???116-117 ???63
??II-3i ????O ???m-Cl-C 6H 4 ????White?solid ???118-119 ???27
??II-4 ????O ???naphthoxy ????White?solid ???172-173 ???27
??II-5a ????S ???2-Me-5-Me-C 6H 3 ????White?solid ???139-140 ???68
??II-5b ????S ???p-F-C 6H 4 ????White?solid ???126-127 ???62
??II-5c ????S ???p-Cl-C 6H 4 ????White?solid ???140-141 ???52
??II-5d ????S ???2-Cl-5-Cl-C 6H 3 ????White?solid ???170-172 ???45
??II-5e ????S ???p-OMe-C 6H 4 ????White?solid ???110-111 ???74
??II-5f ????S ???o-F-C 6H 4 ????White?solid ???135-137 ???68
??II-5g ????S ???p-NH 2-C 6H 4 ????White?solid ???139-141 ???77
??II-6 ????S ???p-Cl-C 6H 4CH 2 ????White?solid ???143-143 ???64
??II-7a ????SO ???2-Me-5-Me-C 6H 3 ????White?solid ???160-161.5 ???94
??II-7b ????SO ???p-F-C 6H 4 ????White?solid ???157.5-159 ???51
??II-7c ????SO ???p-Cl-C 6H 4 ????White?solid ???126-129 ???62
??II-7d ????SO ???2-Cl-5-Cl-C 6H 3 ????White?solid ???170-172 ???57
??II-7e ????SO ???p-OMe-C 6H 4 ????White?solid ???163-165 ???38
??II-7f ????SO ???o-F-C 6H 4 ????White?solid ???170-172 ???72
??II-8 ????SO ???p-Cl-C 6H 4CH 2 ????White?solid ???126-129 ???53
??II-9a ????SO2 ???2-Me-5-Me-C 6H 3 ????White?solid ???176-178 ???63
??II-9b ????SO2 ???p-F-C 6H 4 ????White?solid ???156-158 ???92
??II-9c ????SO2 ???p-Cl-C 6H 4 ????White?solid ???196-198 ???87
??II-9d ????SO2 ???2-Cl-5-Cl-C 6H 3 ????White?solid ???172-174 ???53
??II-9e ????SO2 ???p-OMe-C 6H 4 ????White?solid ???178-179.5 ???94
Table 2: the ultimate analysis data of structural formula (II) compound
Compound Ultimate analysis
Calculated value (%) Measured value (%)
??C ???H ???N ???C ???H ????N
??II-3a ??40.26 ???3.07 ???12.80 ???40.41 ???2.77 ????12.61
??II-3b ??48.40 ???4.06 ???14.11 ???48.54 ???3.91 ????13.90
??II-3c ??35.21 ???2.69 ???11.20 ???35.08 ???2.55 ????11.29
??II-3d ??40.26 ???3.07 ???12.08 ???40.29 ???3.08 ????12.90
??II-3e ??53.00 ???4.45 ???16.86 ???53.18 ???4.46 ????16.60
??II-3f ??54.74 ???4.98 ???15.96 ???54.46 ???4.97 ????15.97
??II-3g ??54.74 ???4.98 ???15.96 ???54.68 ???4.70 ????15.95
??II-3h ??56.30 ???5.45 ???15.15 ???56.20 ???5.54 ????15.06
??II-3i ??46.56 ???3.55 ???14.81 ???46.39 ???3.30 ????14.86
??II-4 ??60.18 ???4.38 ???14.04 ???60.07 ???4.31 ????13.86
??II-5a ??53.22 ???5.15 ???14.32 ???53.08 ???4.98 ????14.14
??II-5b ??46.63 ???3.56 ???14.83 ???46.77 ???3.54 ????14.81
??II-5c ??44.07 ???3.36 ???14.02 ???43.94 ???3.41 ????13.88
??II-5d ??39.53 ???2.71 ???12.57 ???39.26 ???2.93 ????12.78
??II-5e ??48.79 ???4.44 ???14.23 ???48.82 ???4.44 ????14.18
??II-5f ??46.63 ???3.56 ???14.83 ???46.56 ???3.55 ????14.68
??II-5g ??47.12 ???4.31 ???19.98 ???47.25 ???4.20 ????19.90
??II-6 ??45.93 ???3.85 ???13.39 ???45.71 ???3.63 ????13.36
??II-7a ??50.46 ???4.89 ???13.58 ???50.38 ???4.90 ????13.46
??II-7b ??44.14 ???3.37 ???14.04 ???44.16 ???3.17 ????13.85
??II-7c ??41.84 ???3.19 ???13.31 ???41.54 ???3.04 ????13.09
????II-7d ????37.72 ????2.59 ????12.00 ????37.52 ?????2.81 ????12.29
????II-7e ????46.29 ????4.21 ????13.49 ????46.16 ?????4.16 ????13.42
????II-7f ????44.14 ????3.37 ????14.04 ????44.00 ?????3.38 ????13.85
????II-8 ????43.70 ????3.67 ????12.74 ????43.66 ?????3.39 ????12.50
????II-9a ????47.98 ????4.65 ????12.91 ????47.74 ?????4.40 ????12.91
????II-9b ????41.90 ????3.20 ????13.33 ????41.66 ?????3.14 ????13.17
????II-9c ????39.82 ????3.04 ????12.66 ????39.63 ?????3.10 ????12.44
????II-9d ????36.07 ????2.48 ????11.47 ????36.14 ?????2.48 ????11.44
????II-9e ????44.02 ????4.00 ????12.84 ????44.04 ?????3.91 ????12.86
????II-9f ????41.90 ????3.20 ????13.30 ????41.66 ?????3.03 ????13.28
????II-10 ????41.68 ????3.50 ????12.15 ????41.40 ?????3.75 ????12.39
????II-11 ????42.73 ????4.14 ????26.83 ????42.63 ?????3.95 ????26.69
????II-12 ????37.75 ????3.66 ????23.71 ????37.89 ?????3.12 ????23.81
????II-13 ????39.28 ????3.80 ????24.67 ????39.37 ?????3.64 ????24.69
????II-14 ????42.97 ????3.91 ????29.23 ????42.83 ?????3.70 ????29.54
????II-15 ????37.49 ????3.60 ????37.48 ????37.25 ?????3.43 ????37.36
Table 3: structural formula (II) compound 1H NMR data
Compound ???????????????????????????????????????????1H?NMR(CDCl3，ppm)
???II-3a ?2.91(d，J＝4.8，3H，NCH3)，6.12(s，1H，CH)，6.94(br，1H，NH)，6.85-7.38(m， ?4H，Ph)，8.63(s，1H，thiadiazole-H)
???II-3b ?2.29(s，3H，CH3)，2.91(d，J＝4.9，3H，NCH3)，6.11(s，1H，CH)，6.96(br，1H， ?NH)，6.68-7.24(m，3H，Ph)，8.62(s，1H，thiadiazole-H)
???II-3c ?2.91(d，J＝4.8，3H，NCH3)，6.12(s，1H，CH)，6.92(br，1H，NH)，6.74-7.57(m， ?4H，Ph)，8.62(s，1H，thiadiazole-H)
???II-3d ?2.95(d，J＝5.0，3H，NCH3)，6.24(s，1H，CH)，7.28(br，1H，NH)，6.91-7.58(m， ?4H，Ph)，8.66(s，1H，thiadiazole-H)
???II-3e ?2.91(d，J＝5.0，3H，NCH3)，6.16(s，1H，CH)，6.95-7.30(m，5H，Ph)，8.62(s，1H， ?thiadiazole-H)
???II-3f ?2.26(s，3H，CH3)，2.92(d，J＝5.0，3H，NCH3)，6.11(s，1H，CH)，7.02(br，1H， ?NH)，6.84-7.08(m，4H，Ph)，8.59(s，1H，thiadiazole-H)
???II-3g ?2.29(s，3H，CH3)，2.91(d，J＝5.1，3H，NCH3)，6.15(s，1H，CH)，6.98(br，1H， ?NH)，6.80-7.14(m，4H，Ph)，8.61(s，1H，thiadiazole-H)
???II-3h ?2.15(s，3H，CH3)，2.18(s，3H，CH3)，2.91(d，J＝4.6，3H，NCH3)，6.11(s，1H， ?CH)，6.71-7.02(m，4H，Ph+NH)，8.60(s，1H，thiadiazole-H)
???II-3i ?2.89(d，J＝4.6，3H，NCH3)，6.16(s，1H，CH)，6.88-7.23(m，5H，Ph+NH)，8.66(s， ?1H，thiadiazole-H)
???II-4 ?2.94(d，J＝4.8，3H，NCH3)，6.33(s，1H，CH)，7.04(br，1H，NH)，7.20-7.79(m， ?7H，naphthalene)，8.67(s，1H，thiadiazole-H)
???II-5a ?2.24(s，3H，CH3)，2.27(s，3H，CH3)，2.84(d，J＝4.7，3H，NCH3)，5.34(s，1H， ?CH)，6.88(br，1H，NH)，6.92-7.15(m，3H，Ph)，8.46(s，1H，thiadiazole-H)
???II-5b ?2.82(d，J＝5.0，3H，NCH3)，5.41(s，1H，CH)，6.90-7.34(m，5H，Ph+NH)，8.52(s， ?1H，thiadiazole-H)
???II-5c ?2.84(d，J＝5.0，3H，NCH3)，5.42(s，1H，CH)，6.92(br，1H，NH)，7.22-7.40(m， ?4H，Ph)，8.53(s，1H，thiadiazole-H)
???II-5d ?2.82(d，J＝4.4，3H，NCH3)，5.48(s，1H，CH)，7.04?(br，1H，NH)，7.14-7.32(m， ?3H，Ph)，8.58(s，1H，thiadiazole-H)
???II-5e ?2.81(d，J＝4.5，3H，NCH3)，3.73(s，3H，CH3)，5.30(s，1H，CH)，6.84(br，1H， ?NH)，6.72-7.23?(m，4H，Ph)，8.40(s，1H，thiadiazole-H)
???II-5g ?2.84(d，J＝4.2，3H，NCH3)，5.49(s，1H，CH)，6.96(br，1H，NH)，7.05-7.33(m， ?4H，Ph)，8.57(s，1H，thiadiazole-H)
???II-5h ?2.88(d，J＝4.8，3H，NCH3)，2.76(br，2H，NH2)，5.30(s，1H，CH)，6.92?(br，1H， ?NH)，6.55-7.14(m，4H，Ph)，8.43(s，1H，thiadiazole-H)
???II-6 ?2.80(d，J＝4.8，3H，NCH3)，3.75，3.79(q，AB，2H，CH2)，5.30(s，1H，CH)，6.84 ?(br，1H，NH)，6.72-7.23(m，4H，Ph)，8.40(s，1H，thiadiazole-H)
???II-7a ?2.24(s，3H，CH3)，2.27(s，3H，CH3)，2.84(d，J＝4.7，3H，NCH3)，5.34(s，1H， ?CH)，6.88?(br，1H，NH)，6.92-7.15(m，3H，Ph)，8.46(s，1H，thiadiazole-H)
???II-7b ?2.86(d，3H，NCH3)，5.44(s，1H，CH)，6.96(br，1H，NH)，7.05-7.34(m，5H，Ph)， ?8.65(s，1H，thiadiazole-H)
???II-7c * ?3.30(s，3H，NCH3)，5.69(s，1H，CH)，6.92(br，1H，NH)，7.3?1-7.52(m，4H，Ph)， ?9.15(s，1H，thiadiazole-H)
???II-7d ?2.85(d，J＝4.6，3H，NCH3)，5.38(s，1H，CH)，6.95(br，1H，NH)，7.07-7.37(m， ?4H，Ph)，8.75(s，1H，thiadiazole-H)
???II-7e ?2.90(s，3H，NCH3)，3.81(s，3H，CH3)，5.46(s，1H，CH)，6.84-7.21(m，5H， ?Ph+NH)，8.56(s，1H，thiadiazole-H)
???II-7f ?2.94(d，J＝4.5，3H，NCH3)，5.62(s，1H，CH)，6.80(br，1H，NH)，7.07-7.44(m， ?4H，Ph)，8.69(s，1H，thiadiazole-H)
???II-8 ?2.88(d，J＝4.2，3H，NCH3)，3.88，3.92(q，AB，2H，CH2)，5.23(s，1H，CH)，6.96 ?(br，1H，NH)，7.15-7.36(m，4H，Ph)，8.79(s，1H，thiadiazole-H)
???II-9a ?2.21(s，3H，CH3)，2.55(s，3H，CH3)，2.94(d，J＝4.7，3H，NCH3)，5.91(s，1H， ?CH)，7.12-7.29(m，4H，Ph+NH)，8.89(s，1H，thiadiazole-H)
???II-9b ?2.91(d，J＝4.8，3H，NCH3)，5.99(s，1H，CH)，7.13-7.66(m，6H，Ph+NH)，8.92 ?(s，1H，thiadiazole-H)
???II-9c ?2.93(d，J＝4.8，3H，NCH3)，5.88(s，1H，CH)，7.07(br，1H，NH)，7.28-7.60(m， ?4H，Ph)，8.90(s，1H，thiadiazole-H)
???II-9d ?2.95(d，J＝4.2，3H，NCH3)，6.42(s，1H，CH)，7.06(br，1H，NH)，7.10-7.62(m， ?4H，Ph)，9.07(s，1H，thiadiazole-H)
???II-9e ?2.93(s，3H，NCH3)，3.83(s，3H，CH3)，5.94(s，1H，CH)，7.17(br，1H，NH)，6.86- ?7.51(m，4H，Ph)，8.90(s，1H，thiadiazole-H)
???II-9f ?2.93(d，J＝4.4，3H，NCH3)，6.15(s，1H，CH)，7.11-7.63(m，5H，Ph+NH)，8.69 ?(s，1H，thiadiazole-H)
???II-10 ?2.87(d，J＝4.2，3H，NCH3)，4.28，4.40(q，AB，2H，CH2)，5.63(s，1H，CH)，7.12 ?(br，1H，NH)，7.21-7.42(m，4H，Ph)，8.91(s，1H，thiadiazole-H)
???II-11 ?1.23(t，J＝6.9，3H，CH3)，2.64(q，J＝7.2，2H，CH2)，2.89(d，3H，NCH3)，4.16 ?(s，3H，pyrazole-CH3)，6.26(s，1H，CH)，6.57(s，1H，pyrazole-H)，7.14?(br，1H， ?NH)，8.96(s，1H，thiadiazole-H)
???II-12 * ?2.47(s，3H，SCH3)，2.59(s，3H，pyrazole-CH3)，3.31(s，3H，NCH3)，3.83(s，3H， ?pyrazole-CH3)，6.25(s，1H，CH)，9.16(s，1H，thiadiazole-H)
???II-13 * ?2.48(s，3H，SCH3)，2.62(s，3H，pyrazole-CH3)，3.33(s，3H，NCH3)，3.85(s，3H， ?pyrazole-CH3)，6.28(s，1H，CH)，9.16(s，1H，thiadiazole-H)
???II-14 * ?2.49(s，6H，2×CH3)，2.64(s，3H，NCH3)，6.31(s，1H，CH)，7.12(s，1H， ?pyrimidne-H)，8.64(br，1H，NH)，9.15(s，1H，thiadiazole-H)
???II-15 ?2.90(d，J＝4.4，3H，NCH3)，6.77(s，1H，CH)，6.88(br，1H，NH)，8.06(s，1H， ?triazole-H)，8.42(s，1H，triazole-H)，8.74(s，1H，thiadiazole-H)
*Solvent for use is acetone-d6.
Table 4: the MS and the IR data of structural formula (II) compound
Compound ?????IR(cm-1) ????MS(12eV)
???II-3a ?????3405，3145，1662，1580，1486，1443， ?????1412，1297，1229 ????329(M+，81Br，13)，327(M+，81Br，13)， ????272(81Br，7)，270(81Br，8)，174(81Br， ????29)，172(81Br，31)，156(6)，128(100)
???II-3b ?????3393，3088，1668，1621，1559，1481， ?????1409，1306，1235，1171 ????297(M+，34)，240(11)，156(4)，142(100)， ????128(82)
???II-5a ?????3382，3118，3000，1647，1546，1463， ?????1383，1332，1237，1209，1188 ????293(M+，25)，232(25)，234(21)，203(22)， ????175(30)，138(63)，105(68)，58(100)
???II-5b ?????3389，3138，2990，1645，1617，1582， ?????1484，1394，1289，1233，1190，1154 ????283(M+，27)，226(83)，193(22)，165(52)， ????128(77)，58(100)
???II-7f * ????299(M+，0.35)，156(6.0)，144(57)，143 ????(24)，128(67)，58(100)
???II-7c * ?????3391，3163，2929，1689，1556，1472， ?????1399，1279，1046
???II-8 * ?????3301，3130，2961，1664，1559，1489， ?????1406，1286，1231，1032
???II-9b ?????3384，3181，2931，1683，1585，1509， ?????1410，1318，1233，1146 ????251(10)，194(11)，128(100)，58(83)
???II-9c ????267(5.8)，210(8.4)，128(48)，58(100)
???II-10 ?3352，3124，1664，1590，1527，1488， ?1420，1332，1131
*The used electron bombardment ionization source of MS is 70eV
Embodiment 15:
Anti-hepatitis B virus (HBV) effect of structural formula (1) compound
Materials and methods:
A, cell in vitro model: HepG2 2.2.1.5
The toxicity of b, mtt assay test sample pair cell
C, EIA method (HBsAg of Huamei Bio-Engrg Co., and HbeAg diagnostic kit)
D, positive drug contrast: aciclovir (ACV)
Table 5: the resistance of hepatitis B toxic action of structural formula (II) compound
Compound Maximal non-toxic concentration TCD 0??(□mol/ml) To HBsAg inhibiting rate (%) To HBeAg inhibiting rate (%)
???II-3d ??0.6 ?＞55 ?15.5
???II-5f ??0.6 ?＞55 ?16.2
???II-7c ??0.6 ?48.5 ?0
???II-9b ??0.6 ?46.8 ?1.3
???II-13 ??0.4 ?＞55 ?7.1
ACV is 52.9% to the HBsAg inhibiting rate when 0.4 mol/ml, is 44.2% to the HBeAg inhibiting rate.
Embodiment 16:
Structural formula (1) compound activity of resisting tobacco mosaic virus
Supply the prelibation source: tobacco mosaic virus (TMV) (TMV); Test plant: three lives cigarette (Nicotiana Tabacum cv, " Samsum ")
Test method: virus inoculation adopts the juice frictional inoculation method: the sick leaf of three lives cigarette of getting fresh typical TMV virus symptom, add phosphate buffer solution (0.01mol/L, pH7.2), in mortar, grind, the butt writing brush that boiled with boiling water dips in taking juice then, inoculate spreading on the blade face of silicon carbide, and get express developed, leave standstill moments later and move again with clear water.Behind sample preparation: TMV inoculation 1.5～2h, cut the inoculation blade, be cut into two along the blade master pulse and equate half leaf, a half vane soaks leaf with different compounds to be handled, and second half blade is dipped in clear water and compares, and the 72h " Invest, Then Investigate " is added up half leaf withered spot number.
Investigation statistics method: withered spot inhibiting rate (%)=(blank half leaf withered spot number-medicine sample is handled half leaf withered spot number)/blank half leaf withered spot number * 100%
The activity of resisting tobacco mosaic virus of structural formula (II) compound under 500ppm concentration sees Table 6.Wherein compound (II-15) inhibiting rate to tobacco mosaic virus (TMV) under 250ppm of α-triazole replacement is 42%.
Table 6: structural formula (II) compound is to the inhibition activity of tobacco mosaic virus (TMV)
Ethers The thioether class The sulfoxide class The sulfone class
Compound Inhibiting rate % Compound Inhibiting rate % Compound Inhibiting rate % ???No. Inhibiting rate %
?II-3d ?44 ?II-5a ?0 ?II-7a ?0 ???II-10 ?51
?II-3g ?5.5 ?II-5b ?33 ?II-8 ?20 ???II-9f ?82
?II-3h ?3 ?II-5d ?0 ?II-7c ?31 ???II-9a ?12
??II-3i ???53 ???II-5g ???37 ??II-7f * ???19 ??II-9e ???0
??II-3b ???56 ???II-5h ???15 ??II-7b ???11 ??II-9b ???19
??II-3a * ???64 ???II-6 ???35
??II-4 * ???22 ???II-5c ???42
???II-12 ???35
???II-13 ???5
The contrast medicament is a virus of A, and working concentration is 100ppm, and inhibiting rate is 71%.
*Contrast medicament inhibiting rate is 58%.
Embodiment 17:
The stripped weeding activity of structural formula (1) compound
We use barnyard grass little agar diffusion method of grass and rape Plating that its weeding activity is tested to institute's synthetic majority of compounds.
Table 7: the stripped weeding activity of structural formula (II) compound
Concentration ppm Ethers The thioether class The sulfoxide class The sulfone class
Compound Inhibiting rate % Compound Inhibiting rate % Compound Inhibiting rate % Compound Inhibiting rate %
The barnyard grass grass Rape The barnyard grass grass Rape The barnyard grass grass Rape The barnyard grass grass Rape
??100 ?II-3d ???44 ???35 ?II-5a ??21 ???39 II-7f ???0 ??0 II-10 ??23 ??89
??10 ???0 ???0 ??0 ???6 ???0 ??0 ??0 ??25
??100 ?II-3g ???22 ???20 ?II-5b ??17 ???29 II-7a ???13 ??0 II-9f ??27 ??23
??10 ???0 ???0 ??0 ???0 ???0 ??0 ??0 ??0
??100 ?II-3h ???35 ???30 ?II-5d ??12 ???10 II-8 ???35 ??0 II-9a ??20 ??10
??10 ???0 ???0 ??4 ???0 ???0 ??0 ??0 ??0
??100 ?II-3i ???34 ???17 ?II-5g ??14 ???0 II-7d ???8 ??14 II-9e ??0 ??0
??10 ???0 ???0 ??0 ???0 ???0 ??0 ??0 ??0
??100 ?II-3c ???13 ???64 ?II-5h ??19 ???4 II-7c ???0 ??0 II-9b ??24 ??0
??10 ???0 ???9 ??0 ???0 ???0 ??0 ??0 ??0
??100 ?II-6 ??12 ???6
??10 ??11 ???5
??100 ?II-12 ??20 ???41
??10 ??0 ???0
??100 ?II-13 ??0 ???11
??10 ??0 ???0
Embodiment 17:
The live body weeding activity of structural formula (II) compound
Part of compounds has been carried out potted plant weeding test.
Table 8: the live body weeding activity of structural formula (II) compound
Compound Soil treatment Cauline leaf is handled
The barnyard grass grass Lady's-grass Three-coloured amaranth Rape Clover The barnyard grass grass Lady's-grass Three-coloured amaranth Rape Clover
?II-3a ?0 ?0 ?21 ?0 ?17 ?0 ?62 ?0 ?0 ?20
?II-3b ?0 ?0 ?0 ?0 ?0 ?40 ?7 ?0 ?0
Embodiment 18:
The plant growth regulating activity of structural formula (II) compound
We have carried out the test of plant growth regulating activity to part of compounds.
Table 9: the growth regulating-activity of structural formula (II) compound
Tested object Concentration (ppm) ??????II-3a ??????II-3b ??????II-9f ??????II-7c
The elongation of wheat bud scale ??10 ???-1.9 ??- ???10 ??+
Cucumber cotyledons is taken root ??10 ???107.5 ??++ ???69.2 ??+ ??15.4 - ??61.5 ??+
The cucumber cotyledons expansion ??10 ???-2.2 ??- ???0 ??-
Rape hypocotyls ??10 ???6.5 ??- ???10.1 ??- ??10.2 - ??18.1 ??-

Claims (9)

1, a kind of 1,2, the 3-thiadiazole compound is characterized in that it is the compound of structural formula (I):
Wherein,
R 1Be hydrogen, halogen, alkyl, substituted aryl, alkoxyl group, substituted aryloxy, alkylthio, replacement arylthio, amino, alkylamino radical, aryl amine, contain five Yuans or six element heterocycles of N, S element;
R 2Be hydrogen, alkyl, substituted aryl, alkoxyl group, substituted aryloxy, amino, alkylamino radical, substituted aromatic amines base, contain five Yuans or six element heterocycles of N, S element;
R 3Be hydrogen, alkyl, substituted aryl, alkoxyl group, substituted aryloxy, alkylamino radical, substituted aromatic amines base, substituted benzyl, replacement virtue ethyl, contain N, S element five Yuans or six element heterocycles or its heterocyclic methyl, ethyl;
X is O, S, CH 2, CHR ', NH, NR ', R ' is hydrogen, alkyl or aryl;
Y is O, S, SO, SO 2, NH, NR ', R ' is hydrogen, alkyl or aryl; Y also can be five Yuans or six element heterocycles that contain N, S element.
2, according to said 1,2 in the claim 1,3-thiadiazole compound compound is characterized in that it is structural formula (II) compound:
Figure A0113668400022
Wherein,
R 3Be hydrogen, alkyl, substituted aryl, alkoxyl group, substituted aryloxy, alkylamino radical, substituted aromatic amines base, alkylamino, substituted benzyl, replacement virtue ethyl, contain N, S element five Yuans or six element heterocycles or its heterocyclic methyl, ethyl;
Y is O, S, SO, SO 2, NH, NR ', R ' is hydrogen, alkyl or aryl; Y also can be five Yuans or six element heterocycles containing N, S element that replace.
3. claim 1 is said 1,2, and the preparation method of 3-thiadiazole compound is characterized in that it comprises the steps:
Figure A0113668400023
(1) alpha-chloro dicarbonyl compound (1) is dissolved in the organic solvent, at 0 ℃-80 ℃ hydrazides that add 0.8～10 times of amount down of temperature, continues reaction 0.5～20 hour, and vacuum is sloughed partial solvent, and recrystallization gets thick liquid or solid target product (2);
(2) in reaction flask, add the thionyl chloride or the sulfur dichloride of 1～20 times of amount, temperature is between-15 ℃ to 35 ℃, stir and join compound (2) in the reaction flask down in batches, finish, rise to 0 ℃ to 120 ℃ reaction 5～48 hours, in the impouring alkaline solution, there are a large amount of solids to separate out, suction filtration is used solvent recrystallization, gets target product (3);
(3) with the compound dissolution of hydroxyl, ammonia (amine) base, sulfydryl in suitable organic solvent, the alkali that adds 0.8 to 5 times of amount, temperature adds the compound (3) of 0.8～3 times of amount between 0 ℃ to 80 ℃, after reaction finishes, vacuum boils off solvent, the resistates drip washing of on silicagel column, reducing pressure, solid target product (4);
(4) when Y is S, structural formula (4) compound dissolution adds the oxygenant of 0.9～5 times of amount in suitable organic solvent, between-15 ℃ to 60 ℃, reacted 1～48 hour, after sloughing solvent, use solvent recrystallization, can obtain Y is structural formula (5) compound of SO.Reacted 0.5～24 hour between 5 ℃ to 100 ℃, then can obtain Y is SO 2Structural formula (5).
4. said 1,2 according to claim 3, the preparation method of 3-thiadiazole compound is characterized in that said alkali is KOH, NaOH, K 2CO 3, Na 2CO 3, NaHCO 3, triethylamine, tri-n-butylamine, pyridine or DMAP.
5. according to claim 3 said 1,2, the preparation method of 3-thiadiazole compound is characterized in that said organic solvent is single solvent or the mixed solvent of water, methyl alcohol, ethanol, acetonitrile, acetate, ethyl acetate, ether, dipropyl ether, chloroform, methylene dichloride, acetone, butanone, DMF or DMSO.
6. said 1,2 according to claim 3, the preparation method of 3-thiadiazole compound is characterized in that said oxygenant is H 2O 2, potassium permanganate or peroxidation acid.
7. claim 1 is said 1,2, and the 3-thiadiazole compound is used, and it is characterized in that it is used for the treatment of or prevents hepatitis b virus infected.
8. claim 1 is said 1,2, and the 3-thiadiazole compound is used, and it is characterized in that it makes mixture in agricultural or preparation comprises missible oil, pulvis, aqua or suspension agent, is used to prevent and treat plant virus.
9. said 1,2 according to claim 8, the 3-thiadiazole compound is used, and it is characterized in that it is used to prevent and treat the tobaccoization mosaic virus.
CNB011366842A 2001-10-26 2001-10-26 1,2,3-thiadiazole compounds, and their preparing process and bioactivity Expired - Fee Related CN1166650C (en)

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CN101250168B (en) * 2008-03-28 2011-12-14 南开大学 Thiadiazoles imine derivative as well as synthesis and uses thereof
CN103214475A (en) * 2013-05-02 2013-07-24 南开大学 Alpha-(substituted)oxyamide derivatives containing 4-methyl-1,2,3-thiadiazole and preparation methods and application thereof
CN103214476A (en) * 2013-05-02 2013-07-24 南开大学 Formamidine derivatives containing 4-methyl-1,2,3-thiadiazole, and preparation methods and uses
CN103214432A (en) * 2013-05-02 2013-07-24 南开大学 5-methyl-1,2,3-thiadiazole based alpha-(substituted)oxyamide derivatives and preparation methods and application thereof
CN103232448A (en) * 2013-05-02 2013-08-07 南开大学 4, 5-dihydro thiazole alcoholic ester derivative containing 4-methyl-1, 2, 3-thiadiazole and preparation method and application thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101250168B (en) * 2008-03-28 2011-12-14 南开大学 Thiadiazoles imine derivative as well as synthesis and uses thereof
CN103214475A (en) * 2013-05-02 2013-07-24 南开大学 Alpha-(substituted)oxyamide derivatives containing 4-methyl-1,2,3-thiadiazole and preparation methods and application thereof
CN103214476A (en) * 2013-05-02 2013-07-24 南开大学 Formamidine derivatives containing 4-methyl-1,2,3-thiadiazole, and preparation methods and uses
CN103214432A (en) * 2013-05-02 2013-07-24 南开大学 5-methyl-1,2,3-thiadiazole based alpha-(substituted)oxyamide derivatives and preparation methods and application thereof
CN103232448A (en) * 2013-05-02 2013-08-07 南开大学 4, 5-dihydro thiazole alcoholic ester derivative containing 4-methyl-1, 2, 3-thiadiazole and preparation method and application thereof
CN103214432B (en) * 2013-05-02 2015-08-26 南开大学 Based on 5-methyl isophthalic acid, α-(replacement) hydroxyamide derivatives of 2,3-thiadiazoles and its production and use
CN103214475B (en) * 2013-05-02 2016-01-20 南开大学 One class contains 4-methyl isophthalic acid, α-(replacement) hydroxyamide derivatives of 2,3-thiadiazoles and its production and use
CN103232448B (en) * 2013-05-02 2016-03-30 南开大学 One class contains 4-methyl isophthalic acid, 4,5-thiazoline carboxylic ester derivatives of 2,3-thiadiazoles and its production and use

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