CN113264878B - Preparation method of compound for treating drug-resistant microbial bacteria in animal husbandry - Google Patents
Preparation method of compound for treating drug-resistant microbial bacteria in animal husbandry Download PDFInfo
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- CN113264878B CN113264878B CN202110096536.8A CN202110096536A CN113264878B CN 113264878 B CN113264878 B CN 113264878B CN 202110096536 A CN202110096536 A CN 202110096536A CN 113264878 B CN113264878 B CN 113264878B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a preparation method of a compound for treating drug-resistant microbial bacteria in animal husbandry, which comprises the following steps: preparing a sodium ethoxide solution by using metal sodium and absolute ethyl alcohol, adding diethyl phthalate by using benzene as a solvent, dropwise adding an acetone solution, pouring the solution into a single-mouth bottle, adding distilled water with the same volume, and adding a proper amount of a 5% hydrochloric acid solution; dehydrochlorination of p-bromophenylhydrazine hydrochloride with proper amount of 10% sodium oxide solution, adding the compound from step S1 into one-mouth bottle, washing with ethanol as solvent and small amount of anhydrous ethanol for 2-3 times; adding norfloxacin and potassium carbonate into a round-bottom flask, adding acetonitrile as a solvent, recrystallizing, drying and carrying out other post-treatments to obtain a white needle-shaped compound. Is helpful for solving the clinical treatment problems of increasingly serious drug resistance, stubborn pathogenic microorganisms, newly appeared harmful microorganisms and the like.
Description
Technical Field
The invention relates to the field of microorganisms, in particular to a preparation method of a compound for treating drug-resistant microorganisms in animal husbandry.
Background
Since fleming discovered penicillin, the use of antibiotics in large doses or abuse of antibiotics, not only caused the resistance and cross-resistance of escherichia coli to antibacterial drugs due to the selection pressure of antibiotics, but also laboratory studies showed that antibiotic treatment could cause the release of pathogenic bacteria and prolong the disease of animals. For a long time, the application of conventional antibacterial drugs for the purpose of treating, preventing diseases, promoting growth, etc., the development and spread of resistance to bacteria is a very important factor. The increasing of the resistance of E.coli, which is caused by the inappropriate use of antibiotics under the pressure of specific resistance selection by bacteria, poses a direct threat to human health when multiple E.coli resistance interferes with the effectiveness of antibiotics, and an indirect threat to human health when E.coli resistance is transmitted to other human pathogens (Adrienne and Paton, 1998). Coli multidrug resistance has increased and has become an important health safety issue.
According to the reports of the literature, the drug resistance rate of the pathogenic bacteria to penicillin antibacterial drugs is more than 70%, and the drug resistance rate to most quinolone drugs is more than 50%. The generation of drug resistance has the direct consequence of seriously influencing the clinical curative effect and increasing the treatment cost; and the clinical application period of the new medicine is shortened, and the cost of development and research make internal disorder or usurp of the new medicine is increased. According to the WHO report, over 1700 million people die from various infectious diseases on average every year in the world, and the wide spread of bacterial drug-resistant strains and the emergence of multiple drug-resistant strains are one of the main reasons.
Bacterial resistance refers to the resistance of bacteria to antibacterial agents, including inherent resistance and acquired resistance. Inherent drug resistance refers to the congenital insensitivity of bacteria to some antibacterial drugs, which is determined by the biological characteristics of the bacteria per se, so that the bacteria harm the health of livestock and people, the drug resistance refers to acquired drug resistance, namely, the acquired drug resistance of the bacteria is the state characteristic that the bacteria spontaneously changes from an originally sensitive state to a resistant state, the change is not necessarily connected with the biological characteristics of the bacteria per se, and is the generation reason of mutant drug-resistant pathogenic bacteria which are acquired from the next day and obtain new genes and genes from the sources, genetic materials determine the biological characteristics, the restriction of drug-resistant genes is one of important reasons for the drug resistance of the microorganisms to the antibiotics, the acquired drug resistance of the microorganisms is the focus of attention in the research field, and the acquired modes are divided into two types, namely, the mutation of the genes in the microorganisms per se; the other is that the drug-resistant genes of other strains are transferred in a certain way and enter into the recipient bacteria, so that the recipient bacteria can obtain the drug resistance of certain antibacterial drugs. The severity of the problem faced by us is mostly that the resistant strains are of many kinds and grow very fast. The main reason is that not only some drug-resistant genes are delivered to the next generation by bacterial reproduction, but also some drug-resistant factors can be transferred horizontally in the natural environment. Bacteria carrying drug-resistant factors can be rapidly spread among animals, plants, microorganisms and people.
Therefore, the development of antibacterial drugs with novel structures and unique action mechanisms has very important significance for killing or inhibiting the growth of broad-spectrum drug-resistant bacteria. The method is an optimal method for quickly finding out the small molecular weight head compounds aiming at the drug-resistant strains by methods such as high-throughput screening and the like, and carrying out structure optimization to obtain lead compounds, and further obtain drug candidates and final finished drugs.
Disclosure of Invention
One of the objects of the present invention is to provide a method for the preparation of a compound for the treatment of drug-resistant microbial bacteria in animal husbandry.
In order to realize the purpose, the invention adopts the following technical scheme:
a method for preparing a compound for treating drug-resistant microorganisms in animal husbandry, comprising the steps of:
s1, preparing a sodium ethoxide solution by using 2mmol of metal sodium and 2mmol of absolute ethyl alcohol, adding the sodium ethoxide solution into a three-neck flask, using 80mL of benzene as a solvent, then adding 2mmol of diethyl phthalate, stirring, dropwise adding 2.5mmol of an acetone solution, heating and refluxing, monitoring a reaction by TCL, cooling to room temperature after the reaction is finished, pouring the mixture into a 100mL single-neck bottle, performing rotary evaporation until a yellow oily substance is generated, adding equal volume of distilled water, standing and layering to obtain a yellow mixed solution, adding a proper amount of 5% hydrochloric acid solution, standing until a large amount of yellow flocculent solids are generated, performing suction filtration, washing and drying to obtain yellow solids, wherein the yellow solids are directly used in the next step without further purification;
s2, dehydrochlorinating p-bromophenylhydrazine hydrochloride with an appropriate amount of 10% sodium oxyhydroxide solution, then adding about 3mmol of the compound prepared in step S1 into a single-neck bottle, controlling the temperature at 25 ℃ with 20mL of ethanol as a solvent, monitoring the reaction by TLC, completing the reaction, suction-filtering, washing 2-3 times with a small amount of absolute ethanol, drying, and recrystallizing (ethyl acetate: petroleum ether ═ 1: 2);
s3, norfloxacin 0.5mmol and potassium carbonate 0.7mmol were charged in a round-bottom flask, 50mL of acetonitrile was added as a solvent, and after stirring at 50 ℃ for 1 hour, the compound of example 2 (0.55mmol) was added. TLC monitored the reaction to completion. Concentrating, recrystallizing (ethyl acetate: petroleum ether: 1:2), drying, and performing other post-treatments to obtain the white needle-shaped compound.
The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C1-6Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
"alkenyl" is a hydrocarbon group that includes both straight and branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. E.g. "C2-6Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.
"alkynyl" is intended to include both straight and branched chain hydrocarbons having one or more carbon-carbon triple bonds at any stable point in the chain. E.g. "C2-6Alkynyl "(or alkynylene) is intended to include C2, C3, C4, C5, and C6 alkynyl; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.
The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N).
Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O)2H or S (O) H group.
The term "cycloalkyl" refers to cycloalkyl groups, including mono-, bi-or polycyclic ring systems. C3-7Cycloalkyl groups are intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocycle" or "carbocycle residue" refers to any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bi-or tricyclic ring which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, pentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0]Bicyclo-octane, [4.3.0]Bicyclo nonane, [4.4.0]Bicyclo decane, [2.2.2]Bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As mentioned above, bridged rings are also included in carbocyclic rings (e.g. [2.2.2 ]]Bicyclooctane). Preferred carbocycles, if not otherwise stated, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connects two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is pointed out that the bridge always converts a single ring into a double ring. When the rings are bridged, substituents of the rings are also present on the bridge.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.
The term "halogen" or "halogen atom" refers to chlorine, bromine, fluorine and iodine.
The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, said heteroatom containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted with ═ O (oxygen), as valency permits.
Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, isoindolinyl, tetrahydroquinolinyl, and the like.
The compounds of the invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (internal salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention. Salts of the compounds of formula I may be formed, for example, by combining a compound of formula I with an amount of acid or base, for example, in equal amounts, in a vehicle, for example, in which the salt precipitates or in which it is present in an aqueous vehicle, and then lyophilizing.
Examples
The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All starting materials and solvents used in the examples are commercially available analytical products.
Example 1:
preparing a sodium ethoxide solution by using 2mmol of metal sodium and 2mmol of absolute ethyl alcohol, adding the sodium ethoxide solution into a three-neck flask, using 80mL of benzene as a solvent, then adding 2mmol of diethyl phthalate, stirring, dropwise adding 2.5mmol of acetone solution, heating and refluxing, monitoring the reaction by TCL, cooling to room temperature after the reaction is finished, pouring the mixture into a 100mL single-neck bottle, performing rotary evaporation until yellow oily substances are generated, adding distilled water with the same volume, standing and layering to obtain yellow mixed liquid, adding a proper amount of 5% hydrochloric acid solution, standing until a large amount of yellow flocculent solids are generated, performing suction filtration, washing and drying to obtain yellow solids, wherein the yield is 69%. The reaction mixture was used in the next step without further purification.
Example 2:
after dehydrochlorination of p-bromophenylhydrazine hydrochloride with an appropriate amount of 10% sodium oxyhydroxide solution, about 3mmol of the compound prepared in example 1 was added to a single-necked flask, 20mL of ethanol was used as a solvent, the temperature was controlled at 25 ℃, the reaction was monitored by TLC, the reaction was completed, suction filtered, washed with a small amount of absolute ethanol 2 to 3 times, dried, oven-dried, and recrystallized (ethyl acetate: petroleum ether ═ 1:2) at a yield of 75%.
Example 3:
norfloxacin 0.5mmol and potassium carbonate 0.7mmol were added to a round-bottomed flask, 50mL of acetonitrile was added as a solvent, and after stirring at 50 ℃ for 1 hour, the compound of example 2 (0.55mmol) was added. TLC monitored the reaction to completion. After concentration, recrystallization (ethyl acetate: petroleum ether: 1:2), drying and the like, the white needle-like compound was obtained with a yield of 66.1%.
1H NMR(400MHz,d6-DMSO)δ14.93(bs,1H,COOH),9.02(s,1H,H),8.98(s,1H,NH),8.01(d,1H,CH),7.59～7.71(m,4H,benzene-CH),6.72～6.74(m,4H,benzene-CH),6.04(d,1H,CH),4.62(m,2H,CH2),3.9(s,1H,NH),3.30～3.57(m,8H,CH2),2.26(s,3H,CH3),1.46(t,3H,CH3).
The following compounds were prepared by substituting the corresponding starting materials with similar reaction procedures and conditions as in the above examples.
Example 4:
1H NMR(400MHz,d6-DMSO)δ14.92(bs,1H,COOH),9.20(s,1H,H),8.97(s,1H,NH),7.60～7.72(m,4H,benzene-CH),7.37(s,1H,pyridine-CH),6.71～6.75(m,4H,benzene-CH),4.13(m,2H,CH2),3.89(s,1H,NH),3.28～3.57(m,8H,CH2),2.25(s,3H,CH3),1.29(t,3H,CH3).
example 5:
1H NMR(400MHz,d6-DMSO)δ14.99(bs,1H,COOH),8.91(s,1H,NH),8.66(s,1H,H),8.01(s,1H,benzene-CH),7.63～7.75(m,4H,benzene-CH),6.70～6.76(m,4H,benzene-CH),6.04(d,1H,benzene-CH),4.12(m,1H,CH),3.93(s,1H,NH),3.23～3.55(m,8H,CH2),2.28(s,3H,CH3),1.33(m,4H,CH2).
example 6:
1H NMR(400MHz,d6-DMSO)δ14.91(bs,1H,COOH),8.94(s,1H,NH),8.61(s,1H,H),7.89(s,1H,benzene-CH),7.60～7.76(m,4H,benzene-CH),6.59～6.80(m,4H,benzene-CH),4.57(s,1H,NH),4.10(m,1H,CH),3.90(s,1H,NH),3.15～3.42(m,4H,CH2),2.72(m,1H,CH),2.23(s,3H,CH3),1.91(m,2H,CH2),1.31(m,4H,CH2).
example 7: antimicrobial activity
The Minimal Inhibitory Concentration (MIC) of the compounds prepared in examples 3 to 6 against gram-positive bacteria (methicillin-resistant Staphylococcus aureus, enterococcus faecalis, Staphylococcus aureus ATCC29213, and Staphylococcus aureus ATCC 25923) was measured by a 96-well microdilution method in accordance with Clinical and Laboratory Standards Institute (CLSI) established by the Association for Clinical and Laboratory Standards, and the compounds to be tested were dissolved in a small amount of dimethyl sulfoxide, diluted with water to a 1.28mg/mL solution, diluted with a culture medium to 256. mu.g/mL, cultured at 35 ℃ for 24 hours, and after the plate was sufficiently shaken on a shaker, MIC was measured at a wavelength of 490nm, as shown in the results Table (MIC,. mu.g/mL).
Example 8: susceptibility testing
The K-B paper method detects the drug sensitivity of the strain. The drug sensitivity test is carried out according to a Kirby-Bauer paper sheet agar diffusion method recommended by a clinical laboratory, and the specific method is as follows:
1) picking single colony from a common nutrient agar medium plate, inoculating the colony in 5mL LB culture medium, and culturing at 37 ℃ for 16-18 h;
2) the turbidity of the broth was corrected to 0.5 McLeod units with sterile physiological saline (and the broth was applied within 15 min);
3) dipping the corrected bacteria liquid by using a sterile cotton swab, rotating the sterile cotton swab on the wall of the test tube, extruding redundant liquid, coating the liquid on the surface of an LB culture medium flat plate, rotating the flat plate for 60 degrees each time, coating the liquid for 3 times to ensure that the whole flat plate is uniformly coated, and finally coating the edge of agar by using the cotton swab;
4) placing the flat plate in room temperature environment for 3-5min, clamping the drug sensitive paper sheets with sterile sharp-pointed forceps, sticking the paper sheets on the surface of the flat plate, slightly pressing the paper sheets to make the paper sheets flat, wherein the distance between the paper sheets is not less than 24mm, and the distance between the center of the paper sheet and the edge of the flat dish is not less than 15 mm;
5) turning the flat plate of the drug sensitive test paper to the bottom upwards, culturing at 37 deg.C for 16-18h, and measuring the diameter (mm) of the antibacterial ring with vernier caliper.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (1)
1. A method for preparing a compound for treating drug-resistant microorganisms in animal husbandry, comprising the steps of:
s1, preparing a sodium ethoxide solution by using 2mmol of metal sodium and 2mmol of absolute ethyl alcohol, adding the sodium ethoxide solution into a three-neck flask, using 80mL of benzene as a solvent, then adding 2mmol of diethyl phthalate, stirring, dropwise adding 2.5mmol of an acetone solution, heating and refluxing, monitoring a reaction by TCL, cooling to room temperature after the reaction is finished, pouring the mixture into a 100mL single-neck bottle, performing rotary evaporation until a yellow oily substance is generated, adding equal volume of distilled water, standing and layering to obtain a yellow mixed solution, adding a proper amount of 5% hydrochloric acid solution, standing until a large amount of yellow flocculent solids are generated, performing suction filtration, washing and drying to obtain yellow solids, wherein the yellow solids are directly used in the next step without further purification;
s2, removing hydrogen chloride from p-bromophenylhydrazine hydrochloride by using a proper amount of 10% sodium hydroxide solution, then adding 3mmol of the compound prepared in the step S1 into a single-mouth bottle, controlling the temperature at 25 ℃ by using 20mL of ethanol as a solvent, monitoring the reaction by TLC, completely reacting, filtering, washing for 2-3 times by using a small amount of absolute ethyl alcohol, drying, and recrystallizing according to the ratio of ethyl acetate to petroleum ether of 1: 2;
s3, adding 0.5mmol of norfloxacin and 0.7mmol of potassium carbonate into a round-bottom flask, adding 50mL of acetonitrile as a solvent, stirring at 50 ℃ for 1 hour, adding 0.55mmol of the compound in the step S2, monitoring by TLC until the reaction is finished, concentrating, recrystallizing according to the ratio of ethyl acetate to petroleum ether of 1:2, drying and the like, and then processing to obtain the white needle-shaped compound.
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| AU2010204269B2 (en) * | 2009-01-12 | 2015-05-07 | Intervet International B.V. | Pharmaceutical composition to protect an animal against a disorder arising from an infection with a bacterium that belongs to the group of nocardioform actinomycetes |
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| MX2011004759A (en) * | 2011-05-04 | 2012-11-21 | Senosiain S A De C V Lab | Novel antibiotic solid forms. |
| TWI606044B (en) * | 2011-08-31 | 2017-11-21 | 大塚製藥股份有限公司 | Quinolone compound |
| CN107721924B (en) * | 2017-11-10 | 2021-10-22 | 西南大学 | Gatifloxacin derivative and preparation method and application thereof |
| CN110407717B (en) * | 2018-04-27 | 2022-09-13 | 北京市环境保护科学研究院 | P-diethylamino salicylaldehyde modified fluorene fluorescent probe and preparation method thereof |
| CN108727332A (en) * | 2018-05-07 | 2018-11-02 | 王若 | A kind of propylene ties Ciprofloxacin-isatin hybrid and its preparation method and use |
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| CN108863964A (en) * | 2018-08-01 | 2018-11-23 | 西南大学 | Sulphonyl azole compounds of isopropanol bridging and its preparation method and application |
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| CN112939860A (en) | 2021-06-11 |
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