CN116253703A - Bromofuranone C-30 sustained release agent and preparation method and application thereof - Google Patents

Bromofuranone C-30 sustained release agent and preparation method and application thereof Download PDF

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CN116253703A
CN116253703A CN202310126915.6A CN202310126915A CN116253703A CN 116253703 A CN116253703 A CN 116253703A CN 202310126915 A CN202310126915 A CN 202310126915A CN 116253703 A CN116253703 A CN 116253703A
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bromofuranone
release agent
sustained release
silicon dioxide
nano silicon
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周志刚
喻丽娟
夏锐
杨雅麟
药园园
张震
冉超
丁倩雯
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Feed Research Institute of Chinese Academy of Agricultural Sciences
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/58—One oxygen atom, e.g. butenolide
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
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    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • A23K20/126—Lactones
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/195—Antibiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/10—Shaping or working-up of animal feeding-stuffs by agglomeration; by granulation, e.g. making powders
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K40/00—Shaping or working-up of animal feeding-stuffs
    • A23K40/30—Shaping or working-up of animal feeding-stuffs by encapsulating; by coating
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
    • Y02A40/80—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in fisheries management
    • Y02A40/81—Aquaculture, e.g. of fish

Abstract

The invention discloses a bromofuranone C-30 sustained release agent, a preparation method and application thereof. The invention dissolves bromofuranone in ethyl acetate, adds silicon dioxide to prepare fine particles, and then coats palm wax on the fine particles to obtain the bromofuranone C-30 slow release agent. The bromofuranone C-30 sustained release agent effectively improves the stability of the bromofuranone C-30, avoids the absorption of the bromofuranone C-30 in animal stomach, prolongs the action time of the bromofuranone C-30 in intestinal tracts, and can be applied to livestock, poultry and aquatic animal feeds. The preparation method of the bromofuranone C-30 sustained release agent provided by the invention has the advantages of simple process and low production cost.

Description

Bromofuranone C-30 sustained release agent and preparation method and application thereof
Technical Field
The invention belongs to the technical field of feed additives, and particularly relates to a bromofuranone C-30 sustained release agent, a preparation method and application thereof.
Background
Bacteria secrete polysaccharide, protein, DNA and other polymer substances through a quorum sensing system under the control of signal molecules, and wrap the bacteria in the polysaccharide, protein, DNA and other polymer substances to form a biological film. The sound bacteria of the quorum sensing system can form a typical biofilm that can resist bactericides. The antibiotics which cannot penetrate through the biological film are difficult to contact with bacteria in the biological film or difficult to reach the concentration required by antibiosis, so that the antibacterial effect cannot be exerted, great difficulty is brought to prevention, control and treatment of animal diseases, and abuse of the antibiotics in animal disease treatment and massive appearance of drug-resistant strains are indirectly triggered. Thus, the establishment of new antimicrobial therapies during animal farming is urgent. It is estimated that more than 60% of refractory microbial infections are associated with the formation of bacterial biofilms. Thus, inhibition of bacterial biofilm formation by interfering with quorum sensing systems is highly likely to be an effective antimicrobial therapy.
The halofuranone is a novel antibacterial component which is paid attention in recent years, and researches show that the halofuranone can control the formation of a bacterial biological film by blocking the information transmission passage of a quorum sensing system for most gram-positive bacteria and gram-negative bacteria, thereby playing a role in resisting bacteria, generating no bacterial drug resistance, having high biological safety and no cytotoxicity and genetic toxicity. The research shows that the natural or artificially synthesized bromofuranone can effectively inhibit a bacterial quorum sensing system and reduce bacterial pathogenicity. Among them, the in vitro antibacterial activity of the artificially synthesized bromofuranone C-30 is very high, but the antibacterial activity in animals is not known yet. If the bromofuranone C-30 is directly used as a feed additive, the bromofuranone C-30 can be rapidly absorbed in the stomach of animals, and the drug effect of the bromofuranone C-30 for treating bacterial infection is reduced. In addition, the bromofuranone is not high-temperature resistant, so that the bromofuranone is extremely easy to degrade and has serious loss in the feed production process. The synthetic yield of the bromofuranone C-30 is lower, the first reaction yield is only 40% -66%, and the second reaction yield is only 11% -54%. Therefore, there is a need to improve the yield of the synthetic method of bromofuranone C-30, overcome the defects of instability, easy absorption in animal stomach and the like, promote the replacement of antibiotics, and be widely applied in the field of animal cultivation.
Disclosure of Invention
The invention aims to provide a bromofuranone C-30 sustained release agent, a preparation method and application thereof, which effectively improves the stability of the bromofuranone C-30, avoids the absorption of the bromofuranone C-30 in animal stomach, prolongs the action time of the bromofuranone C-30 in intestinal tracts, and can be used as a bacterial quorum sensing inhibitor to be added into feed for livestock, poultry and aquatic animals to reduce bacterial pathogenicity; meanwhile, the preparation method of the sustained release agent has simple process and low production cost.
In order to achieve the above purpose, the present invention provides the following technical solutions:
in a first aspect, the invention provides a method for preparing bromofuranone C-30, comprising the following steps:
s1, carrying out bromination reaction on levulinic acid and liquid bromine in the presence of a catalyst and a solvent to obtain 3, 5-dibromo-4-oxo-pentanoic acid;
s2, carrying out a ring closure reaction on the 3, 5-dibromo-4-oxo-pentanoic acid in the presence of a dehydrating agent to obtain the bromofuranone C-30.
The bromofuranone C-30 has the following structure:
Figure BDA0004082434750000021
the synthetic route of the bromofuranone C-30 is as follows:
Figure BDA0004082434750000022
in the step S1, the catalyst is selected from one or more of hydrogen bromide acetic acid solution, hydrogen bromide water solution and dilute hydrochloric acid; preferably 40% hydrogen bromide in acetic acid.
In step S1, the solvent is selected from one or more of dichloromethane, chloroform and petroleum ether.
In step S1, the molar ratio of levulinic acid to catalyst is 1: (0.01 to 0.05), preferably 1: (0.04-0.05).
In step S1, the molar ratio of levulinic acid to liquid bromine is 1: (0.9 to 1.1), preferably 1:1.
in step S1, the reaction conditions of the bromination reaction are as follows:
the temperature is 30-80 ℃, preferably 45-55 ℃; the specific method can be oil bath;
the reflux time is 50 to 120min, preferably 85 to 95min.
In the step S1, after the reaction is finished, the reaction solution is washed by water, extracted, washed by anhydrous sodium sulfite solution, concentrated under reduced pressure and dried to obtain the 3, 5-dibromo-4-oxo-pentanoic acid.
In step S2, the dehydrating agent is one or more selected from concentrated sulfuric acid, phosphorus pentoxide, calcium chloride and magnesium sulfate, preferably concentrated sulfuric acid.
In the step S2, the molar ratio of the 3, 5-dibromo-4-oxo-pentanoic acid to the dehydrating agent is 1: (2 to 40), preferably 1: (30-40).
In step S2, the reaction conditions of the ring-closing reaction are as follows:
the temperature is 80 to 150 ℃, preferably 95 to 105 ℃, such as 100 ℃;
the time is 10 to 50min, preferably 15 to 25min.
In the step S2, after the reaction is finished, the reaction liquid is cooled, solid is separated out, filtered, dichloromethane is dissolved, and a proper amount of petroleum ether is added for rotary evaporation, so that the bromofuranone C-30 is obtained.
In a second aspect, the invention further provides a sustained release preparation of bromofuranone C-30, which comprises the following components: the core material and the packing material are coated on the outer surface of the core material;
the core material consists of nano silicon dioxide and bromofuranone C-30 embedded in the pores of the nano silicon dioxide;
the packing material is made of palm wax.
In the bromofuranone C-30 sustained release agent, the mass fraction of the bromofuranone C-30 is 40% -44%, and can be 40%, 42% or 44% specifically.
In a third aspect, the invention further provides a preparation method of the bromofuranone C-30 sustained release agent, which comprises the following steps:
(1) Dissolving the bromofuranone C-30 in a solvent to prepare a saturated solution, and adding the nano silicon dioxide to prepare a core material;
(2) And adding the palm wax solution into the core material to prepare the bromofuranone C-30 slow release agent.
In the step (1), the solvent is one or more selected from ethyl acetate, dichloromethane and petroleum ether.
In the step (1), the particle size of the nano silicon dioxide is 30-500 nm, preferably 50-200nm, and particularly can be 50nm, 100nm or 200nm.
In the step (1), the addition amount of the nano silicon dioxide is 20-80% of the mass of the bromofuranone C-30, and can be specifically 20%, 50% or 80%.
In the step (1), the stirring temperature is room temperature, and the stirring time is 5-20 h, specifically 8h, 12h or 16h.
In the step (1), adding the nano silicon dioxide into a saturated solution containing the bromofuranone C-30, stirring, filtering and drying to obtain a core material.
In the step (2), the mass fraction of the palm wax in the palm wax solution is 0.5% -1.25%, and specifically may be 0.5%, 0.75% or 1.25%.
In the step (2), the addition amount of the palm wax solution is 10% -100% of the mass of the nano silicon dioxide, and specifically can be 30%, 50% or 100%.
In the step (2), the stirring temperature is room temperature, and the stirring time is 10-30 min, specifically 10min, 20min or 30min.
In the step (2), the palm wax solution is added into the core material, and the bromofuranone C-30 slow release agent is prepared by stirring and drying.
In a fourth aspect, the invention further provides the use of the extended release formulation of bromofuranone C-30 as a bacterial quorum sensing inhibitor in feed for livestock, poultry and aquatic animals.
The aquatic animal is one of zebra fish, tilapia, carp, micropterus salmoides and prawns.
The addition amount of the bromofuranone C-30 slow release agent is 0.00001-2.27 kg/t of feed, preferably 0.0001-0.02 kg/t of feed, more preferably 0.0001-0.0003 kg/t of feed.
Compared with the prior art, the invention has the following characteristics:
1) The preparation method of the bromofuranone C-30 provided by the invention is simple to operate, and the yield of synthesizing the bromofuranone C-30 is high. In the existing artificial synthesis method, the reaction yield of the first step is only 40% -66%, and the reaction yield of the second step is only 11% -54%; in the preparation method provided by the invention, the yield of the 3, 5-dibromo-4-oxopentanoic acid obtained in the step S1 reaches 80% -85%, and the yield of the bromofuranone C-30 obtained in the step S2 reaches 70% -80%.
2) The bromofuranone C-30 slow release agent provided by the invention can resist high temperature treatment, and is suitable for granulating feed.
3) The bromofuranone C-30 sustained release agent provided by the invention has strong stability and is not easy to decompose in the storage process.
4) The bromofuranone C-30 sustained release agent provided by the invention has low release rate in animal stomach, can be released continuously in intestinal tracts, and has long action time which can reach 72 hours.
5) The preparation method of the bromofuranone C-30 sustained release agent provided by the invention has the advantages of simple equipment, low reagent toxicity, simple operation and convenience for industrial production.
6) The bromofuranone C-30 slow release agent provided by the invention can be used as a bacterial quorum sensing inhibitor to be added into feeds of livestock, poultry and aquatic animals, so that bacterial pathogenicity is reduced; the optimal addition amount of the bromofuranone C-30 slow release agent is 0.0001-0.0003 kg/t, the cost is not obviously increased under the dosage, and the germ resistance of fishes and shrimps can be effectively improved.
Drawings
FIG. 1 shows the effect (48 h) of the addition level of the bromofuranone C-30 slow release agent provided by the invention on the death rate of zebra fish.
FIG. 2 shows the effect of the addition level of the bromofuranone C-30 sustained release agent provided by the invention on the growth of zebra fish.
FIG. 3 shows the effect of the addition level of the bromofuranone C-30 sustained release agent provided by the invention on the intestinal immunity of zebra fish.
FIG. 4 shows the effect of the addition level of the bromofuranone C-30 sustained release agent provided by the invention on the oxidation resistance of zebra fish intestinal tracts.
FIG. 5 shows the effect (72 h) of the addition level of the bromofuranone C-30 slow release agent provided by the invention on the death rate of zebra fish.
Detailed Description
The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The starting materials are available from published commercial sources unless otherwise specified.
The specifications and sources of reagents used in the following examples are as follows:
levulinic acid, methylene dichloride, 40% hydrogen bromide acetic acid solution, liquid bromine, anhydrous sodium sulfite, concentrated sulfuric acid and ethyl acetate are purchased from Shanghai national pharmaceutical chemicals, inc., and are all analytically pure reagents.
Nano silicon dioxide and palm wax are purchased from Shanghai Meilin Biochemical technology Co., ltd, and are all analytically pure reagents.
Example 1 preparation of (Z) -4-bromo-5-bromomethylene-2 (5H) -furanone C-30
(1) 69.6g levulinic acid (0.6 mol) was weighed into a 2000mL flask, 600mL of methylene chloride (9.36 mol) and 12 drops of 40% hydrogen bromide acetic acid solution were added, stirred, 210g of liquid bromine (0.6 mol) and 240mL of methylene chloride (3.74 mol) were added to a constant pressure dropping funnel, the liquid in the constant pressure funnel was slowly dropped into the flask, and after the dropping was completed, the oil bath was heated to 50℃and refluxed for 1.5 hours.
After the reaction is finished, 800mL of water is used for washing, dichloromethane extraction is used, anhydrous sodium sulfite solution is added for washing, dichloromethane extraction is used for extracting water phase, and organic phases are combined and concentrated to obtain white solid, and the yield is 80%;
through nuclear magnetic detection, the specific detection result is as follows: 1 H NMR(CHCl 3 TMS,400 MHz) δ=3.05 (dd, j=8.0, 20.0hz,1 h), 3.37 (dd, j=8.0, 20.0hz,1 h), 4.18 (d, j=12.0 hz,1 h), 4.38 (d, j=12.0 hz,1 h), 5.01 (t, j=8.0 hz,1 h). The obtained product was confirmed to be 3, 5-dibromo-4-oxopentanoic acid.
(2) 100g of 3, 5-dibromo-4-oxopentanoic acid (0.37 mol) was taken in a 1000mL flask, 650mL of concentrated sulfuric acid (12.2 mol) was added, and the mixture was heated to 100℃and stirred for 20min; standing to room temperature, pouring into crushed ice, precipitating a large amount of yellow solid, filtering, dissolving with dichloromethane, adding a proper amount of petroleum ether, and rotary steaming to obtain a large amount of yellow solid, namely the pure product (Z) -4-bromo-5-bromomethylene-2 (5H) -furanone, wherein the yield is 80%.
Through nuclear magnetic detection, the specific detection result is as follows: 1 H NMR(CHCl 3 TMS,400 MHz): δ=6.51 (s, 1H), 6.42 (s, 1H). The obtained product was confirmed to be (Z) -4-bromo-5-bromomethylene-2 (5H) -furanone C-30.
Comparative example 1 preparation of bromofuranone C-30 by the existing method
(1) 12.34g (106.3 mmol) of levulinic acid was dissolved in 100mL of methylene chloride, placed in a 250mL three-necked flask, warmed, stirred electromagnetically, cooled to 0℃in an ice bath, and 10 drops of a 90% aqueous solution of hydrogen bromide in glacial acetic acid were added dropwise. 35.78g of bromine was dissolved in 20mL of methylene chloride to prepare a solution, which was added dropwise to a three-necked flask at 0 ℃. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours, washed with 50mL of water, and then with 0.5M Na 2 S 2 O 3 The aqueous phases were washed, combined, extracted with 60mL portions 2 times, the organic phases combined and dried over anhydrous sodium sulfate. Filtering, rotary evaporating and concentrating filtrate, adding petroleum ether (60-90 deg.c), stirring to separate out great amount of white solid, filtering, washing with petroleum ether to obtain white solid in 14.01g and yield of 48%.
(2) The white solid 4.0g was dissolved in 20mL of concentrated sulfuric acid, stirred at room temperature, reacted at 110℃for 20min, cooled to room temperature, poured into crushed ice and vigorously stirred, yellow insoluble matter separated out, extracted 4 times with 200mL of methylene chloride, washed to neutrality with saturated sodium chloride solution, combined with aqueous phase, extracted 2 times with 100mL of methylene chloride, combined with organic phase, and dried over anhydrous sodium sulfate. Suction filtration and rotary evaporation of the filtrate gave 2.76g of a tan solid which was recrystallized 2 times from methylene chloride and petroleum ether (60-90 ℃ C.) to give 0.42g of pale yellow needle crystals with a yield of 11.2%.
EXAMPLE 2 preparation of Bromofuranone C-30 sustained release agent
40g of bromofuranone C-30 (prepared in example 1) is dissolved in 100mL of ethyl acetate, 8g of 50nm nano silicon dioxide is added, stirred for 8 hours, filtered and dried to obtain fine particles; and adding 4g of 1.25% palm wax solution into the fine particles, stirring for 20min, and drying to obtain the bromofuranone C-30 sustained release agent with the drug loading of 44%.
EXAMPLE 3 preparation of Bromofuranone C-30 sustained release agent
40g of bromofuranone C-30 (prepared in example 1) is dissolved in 100mL of ethyl acetate, 20g of 100nm nano silicon dioxide is added, stirred for 12h, filtered and dried to obtain fine particles; and adding 10g of 0.5% palm wax solution into the fine particles, stirring for 30min, and drying to obtain the bromofuranone C-30 sustained release agent with the drug loading rate of 42%.
EXAMPLE 4 preparation of Bromofuranone C-30 sustained release agent
40g of bromofuranone C-30 (prepared in example 1) is dissolved in 100mL of ethyl acetate, 32g of 200nm nano silicon dioxide is added, stirred for 16h, filtered and dried to obtain fine particles; then 32g of 0.75% palm wax solution is added into the fine particles, stirred for 10min and dried to obtain the bromofuranone C-30 sustained release agent, and the drug loading rate is 40%.
Comparative example 2 preparation of Bromofuranone C-30 sustained release agent Using Talc Carrier
40g of bromofuranone C-30 (prepared in example 1) is dissolved in 100mL of ethyl acetate, 20g of talcum powder is added, stirring is carried out for 12 hours, and the powder sample is obtained after filtration and drying; then 32g of 0.75% palm wax solution is added into the powder sample, stirred for 10min and dried to obtain the bromofuranone C-30 sustained release agent with the drug loading rate of 10%.
The results show that: the obtained sustained release agent has low drug loading, thereby indicating that the nano silicon dioxide is used as a carrier to have the advantage of high drug loading.
Comparative example 3 preparation of Bromofuranone C-30 sustained-release agent Using sodium alginate coating Material
40g of bromofuranone C-30 (prepared in example 1) is dissolved in 100mL of ethyl acetate, 8g of 50nm nano silicon dioxide is added, stirred for 8 hours, filtered and dried to obtain fine particles; and adding 4g of 1.25% sodium alginate solution into the fine particles, stirring for 20min, and drying to obtain the bromofuranone C-30 sustained release agent with the drug loading of 44%.
The results show that: the obtained sustained release agent has serious caking phenomenon and poor coating uniformity, thereby indicating that the palm wax is used as the coating material and has the advantages of high uniformity and dispersibility.
Example 5 Effect of the addition level of the Bromofuranone C-30 sustained release agent on the mortality of zebra fish
And adding 0, 0.227 mug/g, 2.27 mug/g and 22.7 mug/g of bromofuranone C-30 slow release agent (prepared in example 2 and having a drug loading rate of 44%) into basic feed, feeding February-age zebra fish for 14 days, and carrying out toxicity attack by vibrio parahaemolyticus ZB-1, and calculating the death rate.
As shown in figure 1, the addition of the bromofuranone C-30 slow release agent in the feed can effectively reduce the death rate of the zebra fish and improve the capability of the zebra fish in resisting the infection of vibrio parahaemolyticus ZB-1; wherein, when the bromofuranone C-30 slow release agent is not added, the death rate of the zebra fish is very high and reaches more than 40 percent in 20 hours; when the addition amount is 0.227 mug/g, the death rate of the zebra fish can be effectively reduced; when the addition amount is 2.27 mug/g, the death rate of the zebra fish can be obviously reduced, but the feed cost is higher; when the addition amount is 22.7 mug/g, the death rate of the zebra fish is improved; meanwhile, according to experiments, the use amount of the bromofuranone C-30 sustained release agent prepared by the invention is less than 0.00001kg/t (0.01 mug/g), and the capability of resisting bacteria of fishes and shrimps is not obviously improved. Comprehensively considering that the optimal adding amount of the bromofuranone C-30 slow release agent is between 0.0001 and 0.0003kg/t (0.1 to 0.3 mug/g), the cost is not obviously increased, and the germ resistance of fishes and shrimps can be effectively improved.
Example 6 Effect of Bromofuranone C-30 sustained Release agent on growth of zebra fish and intestinal health
And adding 0, 0.227 mug/g, 22.7 mug/g and 2270 mug/g of the bromofuranone C-30 slow release agent (prepared in example 2 and having a drug loading rate of 44%) into the basic feed, feeding the zebra fish of one month old for 4 weeks, and sampling and analyzing the influence of the bromofuranone C-30 slow release agent added into the feed on the growth and intestinal health of the zebra fish.
As shown in figure 2, when the bromofuranone C-30 slow release agent is not added, the weight gain rate of the zebra fish is about 175 percent; when the addition amount is 0.227 mug/g, the weight gain rate of the zebra fish is obviously improved by more than 200 percent; when the addition amount is 22.7 mug/g, the weight gain rate of the zebra fish is reduced; when the addition amount was 2270. Mu.g/g, the weight gain of the zebra fish was not substantially changed. Therefore, the feed can be added with 0.227 mu g/g of the bromofuranone C-30 slow release agent to obviously improve the growth performance of the zebra fish, and the weight gain rate is highest.
As shown in FIG. 3, when the bromofuranone C-30 sustained release agent is not added, the relative expression amount of the immunoglobulin is 1.0; when the addition amount is 0.227 mug/g, 22.7 mug/g and 2270 mug/g, the relative expression amount of the immunoglobulin is obviously improved, thus showing that when the addition amount in the feed is 0.227 mug/g, 22.7 mug/g and 2270 mug/g, the bromofuranone C-30 slow release agent can obviously improve the immunity of zebra fish intestinal tracts.
As shown in FIG. 4, when the sustained release agent of bromofuranone C-30 was not added, the relative expression amount of superoxide dismutase was 1.0; when the addition amount is 0.227 mug/g and 22.7 mug/g, the relative expression amount of the superoxide dismutase is obviously improved; when the addition amount was 2270. Mu.g/g, the relative expression amount of superoxide dismutase was unchanged. Therefore, when the addition amount of the bromofuranone C-30 slow release agent in the feed is 0.227 mug/g and 22.7 mug/g, the antioxidation capability of the intestinal tract of the zebra fish can be obviously improved.
EXAMPLE 7 high temperature resistance of Bromofuranone C-30 sustained release agent
The specific investigation steps are as follows: 1.0g of the bromofuranone C-30 slow release agent (prepared in example 2, the drug loading rate is 44%) and 0.44g of the bromofuranone C-30 are respectively filled into a sealed transparent glass bottle, the sealed transparent glass bottle is heated in a baking oven at 100 ℃ for 10min, red gas appears in the bromofuranone C-30 bottle, and no red gas is generated in the slow release agent bottle; experiments prove that the bromofuranone C-30 is easy to decompose at high temperature to generate simple substance bromine, and the bromofuranone C-30 slow release agent provided by the invention can resist high temperature treatment and is suitable for granulating feed.
EXAMPLE 8 stability of Bromofuranone C-30 sustained Release agent
The specific investigation steps are as follows: 1.0g of the bromofuranone C-30 slow release agent (prepared in example 2, drug loading rate is 44%) and 0.44g of bromofuranone C-30 are respectively filled into a sealed transparent glass bottle, and the sealed transparent glass bottle is placed for 30 days at room temperature, wherein red substances appear in the bromofuranone C-30 bottle, and no red substances appear in the slow release agent bottle; experiments prove that the sustained release agent has strong stability and is not easy to decompose in the process of storage.
EXAMPLE 8 sustained release of Bromofuranone C-30 sustained release agent
The specific investigation steps are as follows: in the basic feed, 10 mug/g of bromofuranone C-30 and 22.7 mug/g of sustained release agent (prepared in example 2, drug loading rate 44%) are respectively added, february-age zebra fish is raised for 14 days, and the toxicity is removed by vibrio parahaemolyticus ZB-1, and the death rate is calculated. As shown in figure 5, the death rate of the slow-release agent group zebra fish is always lower than that of the bromofuranone C-30 group within 72 hours of toxin counteracting, and the slow-release agent has low release rate in the stomach of animals, can be released continuously in the intestinal tract, and has long action time which can reach 72 hours.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.

Claims (10)

1. The preparation method of the bromofuranone C-30 comprises the following steps:
s1, carrying out bromination reaction on levulinic acid and liquid bromine in the presence of a catalyst and a solvent to obtain 3, 5-dibromo-4-oxo-pentanoic acid;
s2, carrying out a ring closure reaction on the 3, 5-dibromo-4-oxo-pentanoic acid in the presence of a dehydrating agent to obtain the bromofuranone C-30.
2. The method for preparing bromofuranone C-30 according to claim 1, which is characterized in that: in the step S1, the catalyst is selected from one or more of hydrogen bromide acetic acid solution, hydrogen bromide water solution and dilute hydrochloric acid;
the solvent is selected from one or more of dichloromethane, chloroform and petroleum ether;
the molar ratio of levulinic acid to catalyst is 1: (0.01-0.05);
the molar ratio of levulinic acid to liquid bromine is 1: (0.9 to 1.1);
the reaction conditions of the bromination reaction are as follows:
the temperature is 30-80 ℃;
the time is 50-120 min.
3. The method for preparing bromofuranone C-30 according to claim 1 or 2, characterized in that: in the step S2, the dehydrating agent is selected from one or more of concentrated sulfuric acid, phosphorus pentoxide, calcium chloride and magnesium sulfate;
the molar ratio of the 3, 5-dibromo-4-oxopentanoic acid to the dehydrating agent is 1: (2-40);
the reaction conditions of the ring closure reaction are as follows:
the temperature is 80-150 ℃;
the time is 10-50 min.
4. A bromofuranone C-30 sustained release agent, which comprises the following components: the core material and the packing material are coated on the outer surface of the core material;
the core material consists of nano silicon dioxide and bromofuranone C-30 embedded in the pores of the nano silicon dioxide;
the packing material is made of palm wax.
5. The sustained release preparation of bromofuranone C-30 according to claim 4, which is characterized in that: the mass fraction of the bromofuranone C-30 in the bromofuranone C-30 sustained release agent is 40% -44%.
6. The method for preparing the bromofuranone C-30 sustained release agent according to claim 4 or 5, comprising the following steps:
(1) Dissolving the bromofuranone C-30 in a solvent to prepare a saturated solution, and adding the nano silicon dioxide to prepare a core material;
(2) And adding the palm wax solution into the core material to prepare the bromofuranone C-30 slow release agent.
7. The method for preparing the sustained release preparation of bromofuranone C-30 according to claim 6, which is characterized in that: in the step (1), the solvent is selected from one or more of ethyl acetate, dichloromethane and petroleum ether;
the particle size of the nano silicon dioxide is 30-500 nm;
the addition amount of the nano silicon dioxide is 20-80% of the mass of the bromofuranone C-30.
8. The method for preparing the sustained release preparation of bromofuranone C-30 according to claim 6 or 7, which is characterized in that: in the step (2), the mass fraction of the palm wax in the palm wax solution is 0.5-1.25%;
the addition amount of the palm wax solution is 10-100% of the mass of the nano silicon dioxide.
9. Use of a sustained release formulation of bromofuranone C-30 as claimed in claim 4 or 5 as a bacterial quorum sensing inhibitor in feed for livestock, poultry and aquatic animals.
10. The use according to claim 9, characterized in that: the aquatic animal is one of zebra fish, tilapia, carp, micropterus salmoides and prawns;
the addition amount of the bromofuranone C-30 slow release agent is 0.00001-2.27 kg/t of feed.
CN202310126915.6A 2023-02-08 2023-02-08 Bromofuranone C-30 sustained release agent and preparation method and application thereof Pending CN116253703A (en)

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