CN1300082C - Phloroglucinol acetyl derivative and its synthesis method and uses - Google Patents

Phloroglucinol acetyl derivative and its synthesis method and uses Download PDF

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CN1300082C
CN1300082C CN 200510044250 CN200510044250A CN1300082C CN 1300082 C CN1300082 C CN 1300082C CN 200510044250 CN200510044250 CN 200510044250 CN 200510044250 A CN200510044250 A CN 200510044250A CN 1300082 C CN1300082 C CN 1300082C
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phloroglucinol
acetyl derivative
ethanoyl
reaction
compound
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CN1730456A (en
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高永超
孔学
杨合同
王加宁
陈贯虹
聂玉敏
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Biologic Inst., Shandong Prov. Academy of Sciences
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Biology Institute of Shandong Academy of Sciences
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Abstract

The present invention relates to phloroglucinol acetyl derivative, a synthesis method thereof and application, which belongs to the technical field of phloroglucinol acetyl derivative of biologic antibiotics. The compound formula of the phloroglucinol acetyl derivative is shown at the right, wherein R1 is-CH2 CH3 or-CH2 CH2 CH3. The compound is prepared through one step of alkylation reaction at the presence of Friedel catalyst by using 2-acetyl phloroglucinol as raw material. The compound of the present invention is used for preventing and treating plant diseases, such as cotton drooping diseases, wheat sharp eyespot, verticillium, ring rot of apple, gray mold of grape, blight, bead fungus, black rot, helminthosporium sativum, genlian fungus disease fungus, etc.

Description

Phloroglucinol acetyl derivative and synthetic method thereof and application
(1) technical field
The present invention relates to a kind of phloroglucinol acetyl derivative and synthetic method thereof and application, belong to biological microbiotic phloroglucinol acetyl derivative technical field.
(2) background technology
2,4-diacetyl Phloroglucinol is a kind of polyketide with broad-spectrum sterilization effect that is produced by Pseudomonas fluorescence, bacterium, fungi, virus and worm there is the intensive killing activity, also higher plant there is certain toxicity, referring to patent " Pseudomonas fluorescence, be used for fresh-keeping microbial inoculum of fruits and vegetables diseases prevention and production technique thereof " notification number 1403568; Class's moral etc., the polyketide that the plant Pseudomonas fluorescence produces, Plant Pathology, 37 volume 175-196,1999 (Bender, C.L., et.al.1999.Polyketide production by plant-associated Pseudomonas.Ann.Rev.Phytopathol.37:175-196); Wang Ye produces microbiotic 2, the isolation identification of 4-diacetyl Phloroglucinol Pseudomonas fluorescens and the clone of synthetic gene thereof, calendar year 2001 Ph D dissertation.
About 2,4-diacetyl Phloroglucinol synthetic method report is more, is raw material with the Phloroglucinol how, is acylating reagent with acid anhydrides or acyl chlorides, with BF 3Or ZnCl 2Be catalyzer, prepare by Fu Shi (Friedel-Crafts) acylation reaction.As Japanese Patent the 04th, 128, authorize for No. 220 a day 1992.4.28 (Jpn.Kokai Tokkyo Koho JP 04,128,220[92,128,220], 28Apr 1992, Appl.90/246,424,17 Sep 1990) to disclose with Phloroglucinol and acetate at BF 3-Et 2Under the O catalysis, reaction synthesis of diacetyl base Phloroglucinol method under argon shield, biological activity test finds that it has greater activity to simplexvirus.People such as Ma Chade; 2; 4-diacetyl Phloroglucinol; the easy of a kind of natural antibiotics of take-all synthesized; the agricultural food product The Chemicals, 48 volume 1882-1887,2000 (Marchand; Patrice; et.al, J.Agric.Convenient Synthesis of2,4-Diacetylphloroglucinol; a Natural Antibiotic Involved in the Control of Take-all Disease ofWheat; Food Chem., 2000,48 (5); 1882-1887) reported that with 2-ethanoyl Phloroglucinol be raw material, with diacetyl oxide at BF 3-Et 2Synthetic 2 under the O catalysis, the method for 4-diacetyl Phloroglucinol, yield is 90%.Studies show that, Phloroglucinol series acyl derivative, especially the C-acyl derivative has multiple anti-microbial activity, and its activity is different with the change of acyl group chain length and the acyl group number that had.Do not appear in the newspapers about diacetyl Phloroglucinol modification after product synthetic method and biological activity test in the pertinent literature.
(3) summary of the invention
At the deficiencies in the prior art, the invention provides a kind of phloroglucinol acetyl derivative and synthetic method thereof and application, by changing the compound of acyl group carbon chain lengths acquisition than high bacteriostatic activity, promptly a kind of new bio microbiotic.
The invention provides the phloroglucinol acetyl derivative shown in the general formula (1):
R wherein 1For-CH 2CH 3Or-CH 2CH 2CH 3
The synthetic method of above-claimed cpd: in the presence of Fu Shi (Friedel-Crafts) catalyzer, be that raw material is through the acylation reaction one-step synthesis with 2-ethanoyl Phloroglucinol.
The acylating reagent of above-mentioned acylation reaction is an acid anhydrides, can select propionic anhydride or butyryl oxide according to reaction product, and reaction formula is as follows:
Figure C20051004425000041
Wherein the Fu Shi catalyzer can be selected BF 3, raw material 2-ethanoyl Phloroglucinol and catalyst B F 3Molar ratio range is 1: 3-4, and the molar ratio range of raw material 2-ethanoyl Phloroglucinol and acylating reagent acid anhydrides is 1: 1-1.5 is a solvent with the ether, and this is reflected in the ice-water bath and carries out, temperature of reaction-2～5 ℃, 0～2 ℃ is good, the reaction times is controlled at 24-30h.BF 3Facile hydrolysis generates boric acid, avoid having in the reaction system water as far as possible.
The preparation products therefrom can adopt the separation method of prior art, removes as underpressure distillation and desolvates, and by product is removed in recrystallization, filtration, and column chromatography separation method, gets the product of purifying.
Above-mentioned raw materials 2-ethanoyl Phloroglucinol synthetic method can with reference to people such as Gu Laiti " 2-ethanoyl Phloroglucinol ", see organic synthesis 15 volume, 70 pages.(K.C.Gulati，S.R.Seth，and K.Venkataraman.Organic Syntheses，Vol.15，p.70)。
The present invention also measures the antimicrobial spectrum activity of above-mentioned ethanoyl Phloroglucinol derivative; kind of pathogenic bacteria surplus having adopted ten; antimicrobial spectrum activity to above-claimed cpd is measured; the result shows 2-ethanoyl-4-propionyl Phloroglucinol and the 2-ethanoyl-4-butyryl radicals Phloroglucinol has good fungistatic effect, and minimum inhibitory concentration is lower.These two kinds of compounds adopt the inhibition 50% effective concentration (Ec50) of damping-off, gray mold, three kinds of pathogenic bacterias mensuration of banded sclerotial blight respectively all below 70ug/ml.Pathogenic bacteria is upright withered bacterium, and experimental subjects is pot experiment and the field plot trial of cotton, and the result shows that these two kinds of compounds are all having good preventive effect first week, and effect is better than contrasting the medicament derosal.Under the field test condition, the pathogenic bacteria morbidity is lighter, and the effect and the derosal of 2-ethanoyl-4-butyryl radicals Phloroglucinol are suitable.Field test to wheat powdery mildew shows, all variant significance between above-mentioned two kinds of compounds and the contrast, and 2-ethanoyl-4-propionyl Phloroglucinol is better than triazolone to the preventive effect of Powdery Mildew.
Compound 2-ethanoyl of the present invention-4-propionyl Phloroglucinol and 2-ethanoyl-4-butyryl radicals Phloroglucinol is used for the control of Plant diseases; specifically be used for cotton seedling blight; wheat hypochnus, verticillium; ring rot of apple, the control of pathogenic fungies such as grape grey mould, blight, beading bacterium, Black Rotten, Helminthosporium sp., root sickle bacterium.Working concentration is 100ug/ml-300ug/ml, sprays.
(4) embodiment
Embodiment 1:
2-ethanoyl-4-propionyl Phloroglucinol, molecular formula is:
Synthesizing of 2-ethanoyl-4-propionyl Phloroglucinol:
In the 250ml there-necked flask of whipping appts and reflux exchanger is housed; add 10g (0.060mol) 2-ethanoyl Phloroglucinol; under nitrogen protection; (0.071mol drips 22.6ml (25.5g) boron trifluoride-diethyl ether solution under the 9.30g) propionic anhydride, agitation condition slowly to drip 9.2ml; boron trifluoride 0.18mol wherein; after dropwising, add the 10ml anhydrous diethyl ether again, this reaction system is stirring reaction 24h in ice-water bath.After reaction finishes, add 100ml distilled water, stir 5-10min, separating reaction liquid, water layer 50ml ethyl acetate extraction, ester layer and reaction solution merge the back underpressure distillation except that desolvating, the gained solid obtains the product crude product after with 60% ethanol/water recrystallization, and thick product yield is 78.9%.Select 3: 1 n-hexane/ethyl acetate solution of developping agent for use, above-mentioned thick product is separated obtaining yellow needle-like crystal product with silica gel chromatographic column, M.P.129-131 ℃, yield is 66%.
Product structure further confirms with mass spectrum, m/z:224 (M +), 182 (M +-COCH 3), 168 (M +-COCH 2CH 3), 153 (M +-COCH 3-CH 2CH 3).
Embodiment 2:
2-ethanoyl-4-butyryl radicals Phloroglucinol, molecular formula is:
Synthesizing of 2-ethanoyl-4-butyryl radicals Phloroglucinol:
In the 250ml there-necked flask of whipping appts and reflux exchanger is housed; add 5g (0.03mol) 2-ethanoyl Phloroglucinol; there-necked flask is placed the cryosel water-bath, make temperature of reaction not be higher than 5 ℃, slowly add 5.8ml (0.036mol; 5.65g) butyryl oxide; add 13.1ml (14.79g) boron trifluoride-diethyl ether solution again, boron trifluoride 0.104mol wherein is after dropwising; add the 10ml anhydrous diethyl ether again reactant is dissolved fully, keep temperature of reaction-2～2 ℃ stirring reaction 24h.After reaction finishes, add 15ml distilled water, violent stirring adds 1: 1 methanol 30ml again, careful adding 10gK 2CO 3, make pH value of solution=7-8, add 1: 1 methanol 10ml again, stir 6h under the room temperature, add 10% hydrochloric acid and regulate pH=5-6, gained solution reduces pressure below 50 ℃ and steams methyl alcohol, wet residue adds 200ml water and stirs the 5min filtration, and washing removes freshen, 80 ℃ of dryings of the thick product that obtains.Thick product is with 60% ethanol/water recrystallization, and slightly product yield is 82%.Select 4: 1 n-hexane/ethyl acetate solution of developping agent for use, above-mentioned thick product is separated with silica gel chromatographic column, obtain 2-ethanoyl-4-butyryl radicals Phloroglucinol, yield is 17.9%.
Product structure further confirms with mass spectrum, m/z:238 (M +), 223 (M+-CH 3), 210 (M +-CH 2CH 3), 195 (M +-COCH 3), 168 (M +-COCH 2CH 2CH 3), 153 (M +-COCH 3-CH 2CH 2CH 3), 126 (M +-COCH 3-COCH 2CH 2CH 3).
Embodiment 3:
As described in embodiment 1, different is to add 2-ethanoyl Phloroglucinol 0.060mol, propionic anhydride 0.085mol, boron trifluoride 0.24mol (diethyl ether solution).Thick product yield is 82.4%, and with thick product separation, getting pure product yield is 68%.
Embodiment 4: the antimicrobial spectrum determination of activity
The pathogenic bacteria of test is ten kinds of isolated from the common disease in field pathogenic fungies, is respectively damping-off, banded sclerotial blight, verticillium, ring rot of apple, gray mold, blight, beading bacterium, Black Rotten, Helminthosporium sp., root sickle bacterium.Experimental technique is that the compound with embodiment 1 and embodiment 2 mixes substratum, make that this compound concentrations reaches 50ppm and 100ppm respectively in the substratum, then fall dull and stereotyped, the above-mentioned pathogenic bacteria of inoculation after the condensation, each is handled 4 times and repeats, 28 ℃ of constant temperature culture are measured a pathogenic bacteria bacterial plaque diameter every 24h, till the bacterial plaque of blank covers with flat board.
The result shows that the compound of embodiment 1 and embodiment 2 all has very high bacteriostatic activity to above-mentioned ten kinds of pathogenic bacterias; wherein the inhibiting rate to ring rot of apple is the highest, and the inhibiting rate to ring spot under 2-ethanoyl-4-butyryl radicals Phloroglucinol 50ppm concentration can reach 100%.Inhibition effect to other pathogenic bacterias is also fairly obvious, and inhibiting rate is all more than 85%.
Embodiment 5: the mensuration that suppresses 50% effective concentration (Ec50)
Three kinds of pathogenic bacterias of test are to separate to obtain from common field disease, are respectively: dry thread Pyrenomycetes (damping-off), cereal rhizoctonia (banded sclerotial blight), Botrytis cinerea (gray mold).Experimental technique is the compound dissolve with ethanol with embodiment 1 and embodiment 2, adds in the substratum, makes this compound concentrations in the substratum reach 5 different concns in minimum inhibitory concentration and the blank scope.2,4-diacetyl Phloroglucinol is a lead compound, as the compound activity reference just of embodiment 1 and embodiment 2.Culture temperature is 28 ℃, and every 24h record pathogenic bacteria bacterial plaque growth diameter is till the dull and stereotyped bacterial plaque of blank covers with.Calculate the inhibiting rate of this compound, carry out regression analysis, draw the inhibition 50% effective concentration (Ec50) of this compound with statistical software.Measurement result such as following table:
Compound EC50(ug/ml)
Upright withered bacterium Botrytis cinerea The withered bacterium of line
2,4-diacetyl Phloroglucinol 2-ethanoyl-4-butyryl radicals Phloroglucinol 2-ethanoyl-4-propionyl Phloroglucinol 20.54 32.3 66.06 25.12 29.24 56.76 25.23 39.18 68.6
The result shows that embodiment 1 and 2 two kinds of compounds of embodiment adopt the inhibition 50% effective concentration (Ec50) of damping-off, gray mold, three kinds of pathogenic bacterias mensuration of banded sclerotial blight respectively all below 70ug/ml.

Claims (2)

1. the preparation method of a phloroglucinol acetyl derivative is that raw material is at Fu Shi catalyst B F with 2-ethanoyl Phloroglucinol 3Exist down through the acylation reaction one-step synthesis;
The acylating reagent of acylation reaction is an acid anhydrides, catalyst B F 3Add with boron trifluoride-diethyl ether solution, acylation reaction carries out under nitrogen protection;
Phloroglucinol and catalyst B F 3Molar ratio range is 1: 3-4, and the mol ratio of Phloroglucinol and acylating reagent is 1: 1.0～1.5, and temperature of reaction is controlled at-2～5 ℃, and the reaction times is 24～30h.
2. the preparation method of phloroglucinol acetyl derivative according to claim 1 is characterized in that described acid anhydrides is propionic anhydride or butyryl oxide.
CN 200510044250 2005-08-12 2005-08-12 Phloroglucinol acetyl derivative and its synthesis method and uses Expired - Fee Related CN1300082C (en)

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