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CN103819464A - Thiochroman compounds, synthesis method thereof and application thereof in preparing antifungal medicines - Google Patents

Thiochroman compounds, synthesis method thereof and application thereof in preparing antifungal medicines Download PDF

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Publication number
CN103819464A
CN103819464A CN201410087557.3A CN201410087557A CN103819464A CN 103819464 A CN103819464 A CN 103819464A CN 201410087557 A CN201410087557 A CN 201410087557A CN 103819464 A CN103819464 A CN 103819464A
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formula
hydrogen
compound
sulphur chroman
sulphur
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CN103819464B (en
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肖涛
田欣
李松
王小明
陈正伟
王锦堂
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Nanjing Tech University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
    • A01N43/647—Triazoles; Hydrogenated triazoles
    • A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4

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  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a thiochroman compound which can be applied to preparing antifungal medicaments and has a structural formula:wherein Z is sulfur, sulfinyl or sulfonyl; y is carbon or nitrogen; r5 and R8 are respectively or simultaneously selected from hydrogen, fluorine, chlorine, bromine or iodine; r6 is selected from fluorine, chlorine, bromine, iodine, hydrogen, C1-C3 oxyl or C1-C4 hydrocarbyl, amino, five-membered or six-membered nitrogen-containing heterocyclic ring; particularly preferred are: r7 is selected from fluorine or C1-C3R5, R6 and R8 are each hydrogen. The compound has wide antifungal physiological activity, and can be used for preparing broad-spectrum, low-toxicity and high-efficiency antifungal medicines and agricultural and horticultural plant bactericides.

Description

Sulphur chroman compound and synthetic method thereof and the application of preparing antifungal drug
Technical field
The present invention relates to the synthetic method of a kind of antimycotic sulphur chroman compound, this compound and in the application of preparing in antifungal drug.
Background technology
The diseases such as the ringworm of the foot, ringworm, candidiasis and crypotococcal result from fungi infestation more.In recent years, due to being widely used of Broad spectrum antibiotics, immunosuppressor and all kinds of hormone medicines, in addition the many reasons such as application and infected by HIV of the methods for the treatment of such as chemicotherapy, organ transplantation, cause human immune system's function reduction, the chance of fungal infection increases, and causes the M & M of Mycophyta disease constantly to rise.In addition, the problem such as resistance and narrow antimicrobial spectrum existing in clinical treatment, has also aggravated the treatment difficulty of fungi infestation disease.Therefore in the urgent need to the novel antifungal drugs of developing wide spectrum, efficient, low toxicity for clinical treatment.
Antifungal drug is divided into the classifications such as polyenoid class, nitrogen azole, allylamine and Thiourea conventionally, thiochromanone is the sulfur-bearing antifungal drug developing rapidly in recent years, research shows, it has stronger inhibition activity to several important pathogeny bacterium such as Cryptococcus neoformans, yeast, sporule silk bacterium, mould and trichophytons.The chemical structural formula of thiochromanone is:
Figure BDA0000475460140000011
For the antifungal drug of research and development high-efficiency low-toxicity, at present the structural modification of sulphur look (expiring) ketone is mainly concentrated to 1,3,4.Wherein, modify for 1 and generate sulphur look (expire) ketone 1,1-dioxide, 3 modifiers comprise beta-amino ketones compound, 3-benzyl-6-chlorine thiochromanone and 3-benzyl-thiochromanone, 4 modify current more be the modification of heteroatoms and amido-containing group.Through the above thiochromone derivative obtaining of modifying, its anti-mycotic activity has raising in various degree, or certain class fungi is had to higher activity.But sulphur look (expiring) ketone antifungal drug is far above in this, the present invention is according to the structure effect relation of sulphur look (expiring) ketone compounds, and further research acquisition anti-mycotic activity is more excellent, the more sulphur look of kind (expiring) ketone compounds.
Summary of the invention
The object of this invention is to provide a kind of sulphur chroman class antifungal compound, this compound all has stronger inhibition activity to common pathomycete and deep fungal, and has the features such as toxicity is low, good stability, anti-fungus spectra is wide, security is good.The present invention also provides the preparation method of this sulphur chroman class antifungal compound and the application in the medicine of preparing transplantation in treating systemic fungi infestation thereof.
A kind of sulphur chroman compound, chemical structure is suc as formula (I):
Figure BDA0000475460140000021
In formula (I):
Z is selected from sulphur (S), sulfinyl or alkylsulfonyl
Figure BDA0000475460140000023
Y is selected from carbon or nitrogen;
R 6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C 1-C 3-oxyl or C 1-C 4alkyl;
R 5, R 8respectively independently selected from hydrogen, fluorine, chlorine, bromine or iodine;
R 7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C 1-C 3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
Figure BDA0000475460140000024
Wherein:
W, V, M, G are respectively independently selected from hydrogen, C 1-C 4alkyl, hydroxyl, C 1-C 4-oxyl or amino, the one or more hydrogen in described amino can be by C 1-C 4alkyl replaces;
L is selected from hydrogen, C 1-C 4alkyl, hydroxyl or C 1-C 4-oxyl.
In described formula (I) sulphur chroman compound, preferred scheme is: Z is alkylsulfonyl; Y is selected from carbon or nitrogen; R7 is selected from fluorine or C 1-C 3-oxyl; R5, R6, R8 are hydrogen.
Sulphur chroman compound synthetic method of the present invention, press step:
Take formula II compound as raw material, in polar solvent, under the effect of hydride ion reductive agent, reaction acquisition formula (Ia) solid chemical compound, Z is selected from formula (I) the sulphur chroman compound product of sulphur; Described polar solvent is selected from least one in methyl-sulphoxide, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, water; Described hydride ion reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, lithium aluminum hydride, aluminum isopropylate or diborane or their derivative, and its reaction formula is as follows:
Wherein Y is selected from carbon or nitrogen;
R 6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C 1-C 3-oxyl or C 1-C 4alkyl;
R 5, R 8respectively independently selected from hydrogen, fluorine, chlorine, bromine or iodine;
R 7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C 1-C 3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
Figure BDA0000475460140000032
W, V, M, G are respectively independently selected from hydrogen, C 1-C 4alkyl, hydroxyl, C 1-C 4-oxyl or amino, the one or more hydrogen in described amino can be by C 1-C 4alkyl replaces.
By the formula of gained (Ia) compound elder generation and acetic anhydride, protection hydroxyl, then add the oxygenant of 0.9-1.1 equivalent, under the effect of oxygenant, there is oxidizing reaction, obtain oxo sulphur chroman compound, finally in sodium hydroxide solution, be hydrolyzed suc as formula the oxo sulphur chroman compound of (Ib), it is formula (I) the sulphur chroman compound product that Z is selected from sulfinyl; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
Figure BDA0000475460140000033
By the formula of step 1 gained (Ia) compound elder generation and acetic anhydride, protection hydroxyl, then add oxygenants more than 2 equivalents, oxidizing reaction obtains oxo sulphur chroman compound, finally in sodium hydroxide solution, be hydrolyzed suc as formula (Ic) compound, be formula (I) the sulphur chroman compound product that Z is selected from alkylsulfonyl; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
Figure BDA0000475460140000041
The invention provides described sulphur chroman compound the people of preparation treatment fungi infestation disease with the application in medicine or medicine for animal.
In described medicine, except containing activeconstituents sulphur chroman compound, also contain and pharmaceutically acceptable carrier, auxiliary agent and/or thinner composition composition.
The formulation of described medicine is solution, creme, suppository, ointment or solution.
The present invention also provides the application of described sulphur chroman compound as agricultural and horticultural bactericides.
In described sterilant, except containing activeconstituents sulphur chroman compound, also contain and pharmaceutically acceptable carrier, auxiliary agent and/or thinner composition composition.
By measuring minimum inhibitory concentration MIC (being the concentration of compound energy inhibition test microorganism growth), the anti-mycotic activity of sulphur chroman compound of the present invention is carried out to in-vitro evaluation.Test confirms, sulphur chroman compound of the present invention has broad-spectrum antifungal activity, in human body and animal (particularly Mammals) body, there is pharmacological activity, can mix mutually with the acceptable diluent or carrier of common chemotherapy, or with other vehicle, make the formulations such as solution, creme, suppository, ointment, solution, carry out partial smearing use with the form of medicine.Also can be simultaneously and other antiseptic-germicide, as mixing, amphotericin B, fungistatin, trichomycin, variotin or Mycosporin etc. use, there is obvious curative effect for fungi infestation disease.Except using or animal antifungal drug beyond the region of objective existence for the preparation of antimycotic people, sulphur chroman compound of the present invention also can be used for the bactericide of agricultural and gardening, to various phytopathogen diseases, as the hat rust of the rust of the powder mildew of the powder mildew of rice blast, barley and wheat and other various host plants (as cucumber, apple, grape), wheat, oat and other various hosts' rust, the control that the late blight of tomato and the pathogenicity bo of other host plants are rotted etc. is very effective.
Embodiment
Below by embodiment, foregoing of the present invention is further elaborated.It should be noted that, scope of the present invention is not limited by embodiment, and is as the criterion with claim.
Embodiment 1:3-(1H-1,2,4-triazol-1-yl) the synthetic preparation feedback formula of-4-hydroxyl sulphur chroman (formula I a1) is as follows:
Figure BDA0000475460140000051
Press step preparation:
Get 2-ethylmercapto group-3-(1H-1,2,4-triazol-1-yl) thiochromone compound 22.4mmol, be dissolved in 50% 50mL ethanol; 89.6mmol sodium borohydride is added in above-mentioned solution in batches, under room temperature, stir and spend the night, underpressure distillation is except desolventizing, and 50mL ethyl acetate and the extraction of 50mL water for solid, get ethyl acetate layer, wash with water twice (50mL × 2), reclaim organic layer evaporate to dryness, obtain formula (I a1) product 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman 19.3mmol, yield 86%.
1H NMR(CDCl 3):8.77(s,1H),8.06(s,1H),7.26-7.32(m,3H),7.14(t,1H),5.17(d,1H),4.50(d,1H),4.42-4.44(m,1H),3.30-3.34(m,1H),3.06-3.08(m,1H).
Embodiment 2-embodiment 19: (I is the preparation of sulphur chroman compound a) for formula
Take formula II compound as raw material, prepare product formula (I is compound (target product is the each compound of formula (I a2)～formula (I a19) in table 1) a), and reaction formula is as follows:
Preparation process is as follows:
Get 22.4mmol formula II compound and be dissolved in polar solvent, 89.6mmol reductive agent is added in solution in batches, under room temperature, stir and spend the night, by embodiment 1 method processing, obtain the each sulphur chroman compound of formula (I a2)～formula (I a19).
In embodiment 2～embodiment 19, product formula (select and prepare with reagent and detect data and all list in table 1 by I a) the each group of sulphur chroman compound.
Table 1
Figure BDA0000475460140000061
Figure BDA0000475460140000081
Embodiment 20:3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl-1-sulfur oxide chroman synthetic
With 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman is raw material, prepares target product (I b1) sulphur chroman compound.
Preparation feedback formula is as follows:
Figure BDA0000475460140000082
Preparation process is as follows:
Get raw material 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman 19.3mmol, add in 35mL diacetyl oxide solvent, there is acetylization reaction protection hydroxyl, reaction finishes rear underpressure distillation and removes diacetyl oxide solvent.Add 30mL saturated sodium bicarbonate solution and 30mL ethyl acetate, isolate ethyl acetate layer; Water layer is with merging organic layer after the extraction of 20mL ethyl acetate, at room temperature drip wherein again the hydrogen peroxide 3.4g(20mmol of 30% concentration) generation oxidizing reaction, reaction finishes rear use respectively 10mL saturated sodium bisulfite solution and 30mL water washing, separates organic layer evaporate to dryness.Finally add the sodium hydroxide solution of 20mL20% concentration and the mixed solution of 20mL ethanol, heating hydrolysis at 50 ℃, solvent evaporated after complete reaction, with getting organic layer after 20mL water and the washing of 20mL ethyl acetate, after evaporate to dryness, obtain product sulfoxide compound 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl-1-sulfur oxide chroman (13.8mmol), yield 72%.
1H NMR(CDCl 3):8.71(s,1H),8.03(s,1H),7.51-7.55(m,3H),7.38(t,1H),5.19(s,1H),4.55(d,1H),4.18-4.22(m,1H),3.30-3.34(m,1H),3.09-3.13(m,1H).
Embodiment 21-embodiment 38: sulfoxide type sulphur chroman (b) synthetic of I
Take formula (I a) sulphur chroman compound as raw material, prepare general formula (I b) sulphur chroman compound product (target product is the formula I b2～formula I b19 in table 2, and preparation process is with embodiment 20.Reaction formula is as follows:
The formula of embodiment 21～embodiment 38 (select and prepare with reagent and detect data and all list in table 2 by I b) the each group of sulphur chroman compound.
Table 2
Figure BDA0000475460140000092
Figure BDA0000475460140000101
Embodiment 39:3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl-1,1-sulfurous gas chroman (formula I c1) synthetic
With 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman is raw material, prepares target product (I c1) compound, reaction formula is as follows:
By 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl sulphur chroman (19.3mmol) adds in 35mL diacetyl oxide solvent, and acetylization reaction protection hydroxyl occurs, and reaction finishes rear underpressure distillation and removes diacetyl oxide solvent.Add saturated sodium bicarbonate 30mL solution and ethyl acetate 30mL, separate ethyl acetate layer, water layer is with merging organic layer after the extraction of 20mL ethyl acetate, at room temperature drip wherein again 30% excessive hydrogen peroxide 13.6g(80mmol) generation oxidizing reaction, reaction finishes rear use respectively 10mL saturated sodium bisulfite solution and 30mL water washing, separates organic layer evaporate to dryness.Finally add the sodium hydroxide solution of 20mL20% and the mixed solution of 20mL ethanol, heating hydrolysis at 50 ℃, solvent evaporated after complete reaction, with getting organic layer after 20mL water and the washing of 20mL ethyl acetate, after evaporate to dryness, obtain sulfone compound 3-(1H-1,2,4-triazol-1-yl)-4-hydroxyl-1,1-sulfurous gas chroman (14.1mmol), yield 73%.
1H NMR(CDCl 3):8.73(s,1H),8.09(s,1H),7.81(d,1H),7.68(d,1H),7.51(t,1H),7.35(t,1H),5.19(s,1H),4.45(d,1H),4.19-4.24(m,1H),3.96-4.01(m,1H),3.79-3.84(m,1H).
Embodiment 40～embodiment 57: sulfone class sulphur chroman (c) synthetic of formula I
Take formula, (a) sulphur chroman compound is as raw material for I, and by embodiment 39 same procedure, (I is sulphur chroman compound product (object product is the formula I c2～formula I c19 in table 3) c) to prepare general formula.Reaction formula is as follows:
Figure BDA0000475460140000131
The formula of embodiment 40～embodiment 57 (select and prepare with reagent and detect data and all list in table 3 by I c) the each group of sulphur chroman compound.
Table 3
Figure BDA0000475460140000132
Figure BDA0000475460140000141
Figure BDA0000475460140000151
Embodiment 58: extracorporeal antifungal activity experiment
1, test bacterial strain
Candida parapsilosis, sporothrix, saccharomyces cerevisiae aspergillus tubigensis,, Candida albicans, Candida glabrata, Oidium tropicale, trichophyton, Penicillium notatum, Trichophyton verrucosum, Trichophyton violaceum, cryptococcus neoformans, gram Rou Shi candidiasis, acrothesium floccosum, trichophyton gypseum.
2, reagent and material
Test material:
Improvement Martin substratum, 96 well culture plates, DMSO
Control drug: fluconazole
3, test method
(1) preparation of antibacterial liquid
Tested medicine is dissolved with DMSO respectively, be made into the solution of 25.6g/L, save backup below in one 20 ℃.Before test, the tested liquid of deepfreeze is taken out, in 35 ℃ of thermostat containers, melt, with 10 times of RPMI1640 dilutions, for subsequent use.
(2) preparation of inoculation liquid
Each tested beads bacterial strain (Candida albicans, Candida glabrata, Oidium tropicale, Candida parapsilosis) is transferred species on improvement Martin substratum, and being used massfraction is that 0.85% Sterile Saline is made suspension.Count spore with blood cell counting plate, adjust bacteria containing amount, making colony forming unit is 1 × 10 6～5 × 10 6cFU/mL.When inoculation, diluted after 200 times with RPMI-1640 nutrient solution, 10 times of redilution, CFU value is adjusted to 0.5 × 10 3～6.0 × 10 3cFU/mL, for subsequent use.
(3) preparation of MIC plate
Under aseptic technique, add RPMI-1640 nutrient solution 100 μ L in No. 1 hole of 96 hole polystyrene plates of sterilizing, as blank.No. 2 hole adds bacterium liquid 190 μ L, and 3-12 hole adds the bacterium liquid 100 μ L that configure.Then in No. 2 holes, add the tested liquid of 10 μ L, by the concentration in 10 grades of doubling dilution 2-11 holes, the ultimate density that makes each hole is 128,64,32,16,8,4,2,1,0.5,0.25mg/L, and No. 12 hole does not add tested liquid as growth control.Each MIC plate is airtight to be placed in 35 ℃ of normal air incubators, hatches full 24h judged result.
(4) result judgement
The OD value of surveying each hole with enzyme micro-plate reader in 620nm, the minimum concentration declining more than 80% using OD value is as MIC value.When MIC value is counted ﹥ 128mg/L during higher than 128mg/L; As MIC value count≤0.25mg/L during lower than 0.25mg/L.
(5) repeated observation and statistics
Above-mentioned test needs at least in triplicate, in the time there is the single jumping of MIC value hole, is recorded as maximum anti-bacteria concentration, in the time that MIC value occurs that two or more jump hole, re-starts test.
4, antimycotic sensitivity test result
Measure and find by preliminary MIC, test-compound has broad-spectrum antifungal activity, wherein the sulphur chroman compound Antifungi activity of embodiment 1, embodiment 4, embodiment 5, example 9, embodiment 10, embodiment 11, embodiment 13, embodiment 14, embodiment 15, embodiment 20～embodiment 57 is more remarkable, and the MIC value of above strain subject is all less than to 2mg/L.

Claims (10)

1. a sulphur chroman compound, it is characterized in that chemical structure suc as formula (
Figure 810918DEST_PATH_IMAGE001
):
Formula ( ) in:
Z be selected from sulphur (S), sulfinyl (
Figure 93498DEST_PATH_IMAGE003
) or alkylsulfonyl (
Figure 976003DEST_PATH_IMAGE004
);
Y is selected from carbon or nitrogen;
R 6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C 1-C 3-oxyl or C 1-C 4alkyl;
R 5, R 8respectively independently selected from hydrogen, fluorine, chlorine, bromine or iodine;
R 7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C 1-C 3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
；
Wherein:
W, V, M, G are respectively independently selected from hydrogen, C 1-C 4alkyl, hydroxyl, C 1-C 4-oxyl or amino, the one or more hydrogen in described amino can be by C 1-C 4alkyl replace;
L is selected from hydrogen, C 1-C 4alkyl, hydroxyl or C 1-C 4-oxyl.
2. sulphur chroman compound according to claim 1, it is characterized in that described formula ( ) in sulphur chroman compound, Z is alkylsulfonyl; Y is selected from carbon or nitrogen; R7 is selected from fluorine or C 1-C 3-oxyl; R5, R6, R8 are hydrogen.
3. a sulphur chroman compound synthetic method for claim 1, is characterized in that according to the following steps:
Take formula II compound as raw material, in polar solvent, under the effect of hydride ion reductive agent, reaction acquisition formula (
Figure 771287DEST_PATH_IMAGE001
a) solid chemical compound, Z be selected from sulphur formula (
Figure 191904DEST_PATH_IMAGE001
) sulphur chroman compound product; Described polar solvent is selected from least one in methyl-sulphoxide, ethanol, methyl alcohol, Virahol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, water; Described hydride ion reductive agent is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, lithium aluminum hydride, aluminum isopropylate or diborane or their derivative, and its reaction formula is as follows:
Figure 664473DEST_PATH_IMAGE006
Wherein, Y is selected from carbon or nitrogen;
R 6be selected from fluorine, chlorine, bromine, iodine, hydrogen, C 1-C 3-oxyl or C 1-C 4alkyl;
R 5, R 8respectively independently selected from hydrogen, fluorine, chlorine, bromine or iodine;
R 7be selected from fluorine, chlorine, bromine, iodine, hydrogen, C 1-C 3-oxyl, amino or be selected from following five yuan or hexa-atomic nitrogen heterocyclic ring:
Figure 840240DEST_PATH_IMAGE005
，
W, V, M, G are respectively independently selected from hydrogen, C 1-C 4alkyl, hydroxyl, C 1-C 4-oxyl or amino, the one or more hydrogen in described amino can be by C 1-C 4alkyl replaces.
4. sulphur chroman compound synthetic method according to claim 3, it is characterized in that by the formula of gained (
Figure 765471DEST_PATH_IMAGE001
a) compound elder generation and acetic anhydride, protection hydroxyl, then adds the oxygenant of 0.9-1.1 equivalent, under the effect of oxygenant, oxidizing reaction occurs, and obtains oxo sulphur chroman compound, finally in sodium hydroxide solution, be hydrolyzed suc as formula (
Figure 989779DEST_PATH_IMAGE001
b) oxo sulphur chroman compound, its be the formula that Z is selected from sulfinyl (
Figure 113592DEST_PATH_IMAGE001
) sulphur chroman compound product; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
Figure 397943DEST_PATH_IMAGE007
。
5. sulphur chroman compound synthetic method according to claim 3, it is characterized in that by the formula of step 1 gained (
Figure 810470DEST_PATH_IMAGE001
a) compound elder generation and acetic anhydride, protection hydroxyl, then add oxygenants more than 2 equivalents, oxidizing reaction obtains oxo sulphur chroman compound, finally in sodium hydroxide solution, be hydrolyzed suc as formula (
Figure 900786DEST_PATH_IMAGE001
c) compound, be the formula that Z is selected from alkylsulfonyl (
Figure 82368DEST_PATH_IMAGE001
) sulphur chroman compound product; Described oxygenant is selected from Manganse Dioxide, hydrogen peroxide, benzoyl hydroperoxide, metachloroperbenzoic acid, magnesium monoperoxyphthalate or Peracetic Acid; Reaction formula is as follows:
。
Described in a claim 1 or 2 sulphur chroman compound the people of preparation treatment fungi infestation disease with the application in medicine or medicine for animal.
7. application according to claim 6, is characterized in that in described medicine, except containing activeconstituents sulphur chroman compound, also containing pharmaceutically acceptable carrier, auxiliary agent and/or thinner, composition composition.
8. application according to claim 7, the formulation that it is characterized in that described medicine is solution, creme, suppository, ointment or solution.
Described in a claim 1 or 2 sulphur chroman compound as agricultural and the application of horticultural bactericides.
10. application according to claim 9, is characterized in that in described sterilant, except containing activeconstituents sulphur chroman compound, also containing pharmaceutically acceptable carrier, auxiliary agent and/or thinner, composition composition.
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