CN109006823B - Application of 2-aryl substituted pyrrole compound in oncomelania killing drug - Google Patents
Application of 2-aryl substituted pyrrole compound in oncomelania killing drug Download PDFInfo
- Publication number
- CN109006823B CN109006823B CN201811054534.7A CN201811054534A CN109006823B CN 109006823 B CN109006823 B CN 109006823B CN 201811054534 A CN201811054534 A CN 201811054534A CN 109006823 B CN109006823 B CN 109006823B
- Authority
- CN
- China
- Prior art keywords
- aryl
- compound
- killing
- substituted pyrrole
- snail
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/36—Oxygen or sulfur atoms
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Plant Pathology (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Agronomy & Crop Science (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种2‑芳基取代吡咯类化合物在杀钉螺药物中的应用，属于血吸虫病防治技术领域。本发明具体提供2‑芳基取代吡咯类化合物的化学结构及其制备方法，并以2‑芳基取代吡咯类化合物活性成分制备成杀螺剂，杀螺剂形态为悬浮剂、乳剂、微乳剂，应用于钉螺杀灭。所述2‑芳基取代吡咯类化合物作为杀螺剂活性成分时，浸杀的使用量为0.1mg/L‑10.00mg/L，浸杀时间为24h‑72h；喷洒的使用量为1g/m2‑10g/m2，作用时间为3d‑7d。通过实验证实，2‑芳基取代吡咯类化合物对钉螺有杀灭活性，且对水生生物的毒性低于现有杀螺药物氯硝柳胺，可以制备成杀螺制剂应用于血吸虫病防治领域。The invention relates to the application of a 2-aryl-substituted pyrrole compound in a snail-killing drug, and belongs to the technical field of schistosomiasis prevention and control. The present invention specifically provides the chemical structure of 2-aryl-substituted pyrrole compounds and a preparation method thereof, and prepares a molluscicide by using the active ingredient of the 2-aryl-substituted pyrrole compound, and the molluscicide is in the form of a suspension, an emulsion, and a microemulsion. , used in snail killing. When the 2-aryl-substituted pyrrole compound is used as the active ingredient of the molluscicide, the usage amount of immersion and killing is 0.1mg/L-10.00mg/L, and the immersion and killing time is 24h-72h; the usage amount of spraying is 1g/m 2 ‑10g/m 2 , the action time is 3d‑7d. Experiments have confirmed that the 2-aryl substituted pyrrole compounds have killing activity on snails, and the toxicity to aquatic organisms is lower than that of the existing snailicide niclosamide, which can be prepared into a snailicide and applied in the field of schistosomiasis control.
Description
Technical Field
The invention relates to an application of a 2-aryl substituted pyrrole compound in the preparation of oncomelania killing drugs, belonging to the technical field of schistosomiasis control.
Background
Schistosome, also known as Schistosoma, belongs to the phylum platyphylla and mainly refers to all species classified in 19 genera of the same genus under the genus Schistosoma. The 6 main people capable of parasitizing human beings have three types, which are respectively popular in the middle east, Asia and south America, have wide distribution range and are the main three types of schistosomes capable of infecting human beings; the other three types are limited to the North Africa, Malaysia and Mei Gong river basin, and are mostly animal strains (zophilic strains), so the influence on people is small. The schistosoma japonicum growth process has to pass through the parasitic stage in the freshwater snail body to have the ability to infect other hosts, but after the schistosoma japonicum is parasitic, the venous blood vessels in the host body are selected for colonization, the symptoms caused by the schistosoma japonicum are different in expression, and the symptoms are all called schistosomiasis (or schistosomiasis), and are published in one of six tropical medical diseases by the world health organization.
The damage of schistosomiasis to human and livestock is most serious by taking the damage of worm eggs; the worm egg is deposited on the tissues of the liver, the intestinal wall and the like of a host to form worm egg granuloma, and finally hepatosplenomegaly, intestinal wall fibrosis, cirrhosis and ascites are caused; if children are infected with schistosoma repeatedly, development disorder, intelligence decline and reproductive function are caused, schistosomiasis 'dwarfism' is formed, and labor force is lost. The Japanese blood fluke is popular in China and is named after Japanese because of being discovered in Japan for the first time. The schistosoma japonicum miracidium can live for 2-3 days in water, and the miracidium is mainly parasitized in oncomelania and escapes after being developed into mother miracidium, daughter miracidium and cercaria in the oncomelania; after the livestock and the human being contact with the epidemic water containing the cercaria, the cercaria can invade through the skin; cercaria is removed to become a juvenile insect, which migrates in the host body and fails to reach the portal vein system during the migration development process, and the juvenile insect dies because it fails to develop into an adult. Once they reach the portal vein system, they colonize and develop into adults, which do not move throughout life.
Researches find that Oncomelania hupensis is the only intermediate host of Schistosoma japonicum, and the killing of Oncomelania hupensis is one of the important measures for preventing and controlling the epidemic of schistosomiasis japonica. The main molluscicidal methods are biological, physical and medicinal molluscicidal, while medicinal molluscicidal remains the primary method of oncomelania control. The major molluscicides in the market at present comprise sodium pentachlorophenolate, bromoacetamide, nicotinanilide, quick lime, trichlorfon, hexachloro cyclohexane, urea, naphthalene and niclosamide (comprising 50% niclosamide ethanolamine salt wettable powder, 4% niclosamide ethanolamine salt powder and 25% niclosamide suspending agent) serving as active ingredients, metaldehyde molluscicides (comprising cochine IV, molluscicide, Mida, Midarly, Rongbao, Rongya and the like), plant molluscicides (comprising saponin molluscicides, alkaloid plant molluscicides, flavone or isoflavone plant molluscicides) and the like. The molluscicide has certain defects while killing oncomelania, for example, sodium pentachlorophenolate is sensitive to light, the molluscicidal effect is reduced after the sodium pentachlorophenolate is absorbed by soil, the molluscicidal agent has serious harm to aquatic animals and plants such as human, livestock, fish and the like, the environmental pollution is serious, poisoning and death accidents of drug application personnel occur more than once in use, and the sodium pentachlorophenolate has teratogenic, carcinogenic and mutagenic effects, so the molluscicidal agent is forbidden to be applied to field molluscicidal. Niclosamide has low toxicity to human and livestock, does not stimulate skin, has strong toxicity to fishes, and can cause a great amount of death of the fishes at an effective molluscicidal concentration. Bromoacetamide has strong molluscicidal action, low toxicity to fish, good water solubility, easy use, deliquescence, instability to heat, acid and alkali, and dermatitis. Nicotinanilide has low solubility in water, has the phenomenon of climbing oncomelania when being soaked and killed, has poor killing effect on snail eggs, is high in price and low in yield, so that large-area popularization and application are limited to a certain extent. Other chemical molluscacide comprises quicklime, trichlorfon, hexachlorocyclohexane, urea, naphthalene and the like, but cannot be popularized and used due to high toxicity or strong irritation to human skin and the like. The plant molluscacide has the advantages of low toxicity, easy degradation and the like, but is mainly used for killing a plurality of aquatic snails distributed in Europe, Africa and America, the research on the killing effect of the aquatic and amphibious oncomelania in Asia regions such as China is less, the molluscacide has slow efficacy, the extraction cost of the active ingredients of the molluscacide is higher, and the fresh plant water extract is easy to cause environmental pollution. Therefore, the molluscicide with good molluscicide effect, less pollution and low price is developed, and has wide application prospect and great market value.
Disclosure of Invention
In view of the above-mentioned disadvantages of molluscicides of the prior art, it is an object of the present invention to provide the use of 2-aryl-substituted pyrroles for the preparation of molluscicides, characterized in that said 2-aryl-substituted pyrroles have the following structure of formula I:
wherein R is1Selected from the group consisting of hydrogen, methyl, ethyl, propyl, hydroxy, cyano, nitro, propargyl, hydroxyethyl, acetyl, iodopropargyl, methoxymethyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, methyl, ethyl, propyl, isopropyl,
ar is selected from phenyl, halogen substituted phenyl, methyl substituted phenyl, trifluoromethyl substituted phenyl, nitro substituted phenyl, hydroxy substituted phenyl, methoxy substituted phenyl,
R3Selected from hydrogen, cyano, nitro, acetyl, trifluoromethylthioether, trifluoromethylsulfone, ethoxycarbonyl or carboxanilido;
R4selected from hydrogen, fluoro, chloro, bromo, methyl, formyl, C1-C6 alkyl, thienyl or
R5Selected from hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, -C3F7、-C2F5A trifluoromethylthioether group, a trifluoromethylsulfone group;
and the hydrate or salt of the compound which is acceptable in the agricultural pharmacy.
Preferably, the 2-aryl substituted pyrrole compound has the structure of formula II:
wherein R is2One or more selected from H, halogen, methyl, trifluoromethyl, nitro, hydroxyl and methoxyl;
R1、R3、R4、R5as defined in claim 1;
and the hydrate or salt of the compound which is acceptable in the agricultural pharmacy.
Preferably, theThe 2-aryl substituted pyrrole compound has a structure shown in a formula III:
wherein R'2One selected from H, halogen, methyl, trifluoromethyl, nitro, hydroxyl and methoxyl;
R1、R3、R4、R5as defined in claim 1;
and the hydrate or salt of the compound which is acceptable in the agricultural pharmacy.
Preferably, the 2-aryl substituted pyrrole compound has the following structure:
and the hydrate or salt of the compound which is acceptable in the agricultural pharmacy.
In addition, the invention also provides the 2-aryl substituted pyrrole compound as an active ingredient for preparing the molluscicide, and the molluscicide is selected from suspending agents, emulsions and microemulsions.
Preferably, when the 2-aryl substituted pyrrole compound is used as the molluscicide active ingredient, the soaking and killing amount is0.10mg/L to 10.00mg/L, and the soaking and killing time is 24h to 72 h; the amount of the spraying agent is 1g/m2-10g/m2The action time of the spraying is 3d-7 d.
Preferably, the 2-aryl substituted pyrrole compound is applied to the preparation of oncomelania killing medicines, and is characterized in that: the molluscicide also comprises one or more excipients acceptable in formulation.
Preferably, the adjuvant includes a diluent, a filler, a binder, a wetting agent, an absorption enhancer, a surfactant, an adsorption carrier and a lubricant, which are conventional in the field of pharmaceutical formulation.
In addition, the invention also provides a method for using the 2-aryl substituted pyrrole compound in oncomelania killing, which is characterized in that the 2-aryl substituted pyrrole compound is applied to the oncomelania-producing land.
Further, the application method of the molluscacide comprises the steps that the using amount of the molluscacide in an immersion method is 0.1-10.00 mg/L, and the immersion time is 24-72 hours; the amount of the spraying method is 1g/m2-10g/m2The action time is 3d-7d, and the use temperature is 10-40 ℃.
In another aspect of the present invention, there is provided an agricultural composition comprising (a) a compound according to any one of the above or an agriculturally pharmaceutically acceptable salt thereof; and (b) an agriculturally pharmaceutically acceptable carrier or excipient.
Preferably, said agricultural composition, said component (a) is present in said agricultural composition in an amount of 0.0001% to 99.99%, preferably 0.001% to 99.9% by weight.
Preferably, the agricultural composition has a content of the component (a) in the agricultural composition of 0.01-99% by weight.
Preferably, the agricultural composition further comprises other molluscicides; such other molluscicides are commercially available.
Preferably, the other molluscicides are selected from the group consisting of: niclosamide, Rongbao, Rongya, tea tree seed and other commercial plant molluscicides.
The agriculturally pharmaceutically acceptable salts may include inorganic salts, organic acid salts, basic amino acids, or salts of acidic amino acids. Inorganic acid salts in the present invention include, for example: hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, or phosphoric acid. Organic acids in the present invention include, for example: lactic acid, formic acid, acetic acid (i.e., acetic acid), trifluoroacetic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Acidic amino acids include, for example: glycine, aspartic acid, or glutamic acid.
The term "active substance according to the invention" or "active compound according to the invention" means a compound according to the invention or an agriculturally pharmaceutically acceptable salt thereof.
The active substances according to the invention can be prepared in a customary manner to give pesticide compositions. The active compounds can be formulated in conventional preparations such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols and the like.
These formulations can be produced by known methods, for example by mixing the active compounds with extenders which are liquid or liquefied gases or solid diluents or carriers, and optionally surfactants, i.e. emulsifiers and/or dispersants and/or foam formers. Organic solvents may also be used as adjuvants, for example when water is used as extender.
When a liquid solvent is used as the diluent or carrier, it is basically suitable, for example: aromatic hydrocarbons such as xylene, toluene or alkylnaphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzene, vinyl chloride or dichloromethane; aliphatic hydrocarbons, such as cyclohexane or paraffins, for example mineral oil fractions; alcohols, such as ethanol or ethylene glycol and their ethers and lipids; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; or less commonly polar solvents such as dimethylformamide and dimethylsulfoxide, and water.
By a diluent or carrier for liquefied gases is meant a liquid which will become gaseous at ambient temperature and pressure, for example aerosol propellants such as halogenated hydrocarbons as well as butane, propane, nitrogen and carbon dioxide. Solid carriers can be prepared from ground natural minerals, such as kaolin, clay, talc, quartz, attapulgite, montmorillonite or kieselguhr, and ground synthetic minerals, such as highly dispersed silicic acid, alumina and silicates. Solid carriers for granules are ground and classified natural marble, such as calcite, marble, pumice, sepiolite and dolomite, as well as synthetic granules of inorganic and organic meals, and granules of organic materials, such as sawdust, coconut shells, corn cobs and tobacco stalks, etc.
Nonionic and anionic emulsifiers can be used as emulsifiers and/or foam formers. Such as polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, such as alkylaryl polyethylene glycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates and albumin hydrolysates.
Dispersants include, for example, lignin sulfite waste liquor and methyl cellulose. Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions, for example gum arabic, polyvinyl alcohol and polyvinyl acetate, can be used in the formulations.
Colorants such as inorganic dyes, e.g., iron oxide, cobalt oxide and prussian blue; organic dyes, such as organic dyes, e.g., azo dyes or metallotitanyl cyanine dyes; and with trace nutrients such as salts of iron, manganese, boron, copper, cobalt, aluminum, and zinc, and the like.
The synthetic route of the 2-aryl pyrrole disclosed by the invention is selected from the following groups without limitation:
(1)
the halogenated aromatic compound reacts with boronic acid pinacol ester to generate aromatic pinacol ester, and then is subjected to SUZUKI coupling with the halogenated pyrrole compound to generate the 2-aryl substituted pyrrole compound.
(2)
Aryl boronic acids are directly SUZUKI coupled with halopyrrole compounds to produce 2-aryl substituted pyrrole compounds.
(3)
Firstly, a mixture of formic acid and acetic anhydride is used for carrying out N-formylation reaction on alpha-p-chlorophenyl glycine, the alpha-p-chlorophenyl glycine is converted into a corresponding N-formyl derivative, and further the alpha-p-chlorophenyl glycine and the 2-chloropropene nitrile carry out 1, 3-dipolar addition reaction in the presence of the acetic anhydride to generate a corresponding N-formyl derivative; further carrying out a1, 3-dipolar addition reaction with 2-chloroacrylonitrile in the presence of acetic anhydride to produce arylpyrrole carbonitrile as a main product.
After formation of the arylpyrrole carbonitrile, further derivatization may be carried out by other substitution reactions, such as Vilsmeier formylation of the arylpyrrole carbonitrile in excess DMF to give the corresponding 5-formylarylpyrrole carbonitrile.
(4)
Firstly, taking a as a raw material, and oxidizing by potassium bisulfate to prepare a compound b; b is taken as a raw material, and a compound c is prepared by ring-opening reaction under the alkaline condition; and finally, preparing a compound d by using the c as a raw material through anhydride catalysis.
(5)
Various 2- (2-nitrophenyl) pyrrole compounds (formula VII) are synthesized through the similar nucleophilic aryl substitution reaction of an o-halonitrobenzene compound (formula VI) and a pyrrole compound (formula V) under the alkaline condition.
The examples of the present invention only list a few typical synthetic methods of 2-arylpyrrole compounds, and other compounds in the present invention can be obtained by the conventional technical means in the field or directly obtained by commercial methods by referring to the above synthetic steps or synthetic methods of other 2-arylpyrrole compounds disclosed in the prior art.
As mentioned above, the present invention provides 2-aryl substituted pyrrolesThe application of the medicine in oncomelania killing has the following beneficial effects: (1) the synthetic method is simple, the raw materials are easy to obtain, and the source is wide; (2) low toxicity, especially low toxicity to aquatic organisms, and is suitable for being used in aquaculture areas and water-deficient mountain areas; (3) high efficiency, 1.0-10.00 mg/L or 1g/m2-10g/m2Within the concentration range, the fluke killing composition can be used for preparing a drug for killing oncomelania, and effectively kills oncomelania, thereby controlling the occurrence and propagation of schistosome.
Detailed Description
The following examples are given to illustrate the synthesis and efficacy of the compounds of the present invention, and the present invention is further illustrated by the following examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
Synthesis of Compound 5
(1) Synthesis of triisopropylpyrrole
200mL of LTHF is weighed into a 1000mL three-necked bottle, the temperature is reduced to 0 ℃, 12.0g (0.500mol) of sodium hydride is slowly added, the stirring is carried out for 10min, 17.0g (0.253mol) of pyrrole is dropwise added into the suspension, the temperature is controlled to 0 ℃, the stirring is carried out for 1.5h, then 13.7g (0.259mol) of triisopropyl chlorosilane is slowly dropwise added, the stirring is carried out for 2h, ice water is added, the extraction solution is extracted by ethyl acetate, and the extraction solution is dried by anhydrous sodium sulfate, filtered and concentrated to obtain 51.7g of oily matter.
(2) Synthesis of 3-formaldehyde-1H-pyrrole
Preparation of Vilsmeier reagent: weighing 3.9g (0.876mol) of DMF in a three-neck flask, cooling to 0 ℃, weighing 89.6g (0.584mol) of phosphorus oxychloride, slowly dripping into DMF, controlling the temperature to be 5 ℃ and stirring for 1.5h after the addition is finished.
Weighing a proper amount of dichloromethane to completely dissolve the prepared Vilsmeier reagent, cooling to 0 ℃, diluting the oily substance obtained in the previous step, slowly dripping the diluted oily substance, stirring for 2 hours after the addition is finished, filtering, washing a filter cake with dichloromethane for 1 time, dissolving the filter cake in 100g of water, adjusting the pH value to be 9 by using 30% sodium hydroxide at room temperature, extracting with ethyl acetate, drying, carrying out suction filtration and concentration on an extract liquid to obtain 21.0g of oily substance, recrystallizing to obtain 17.2g of white solid, wherein the yield is 71.9%, the purity is 98.3%, and m.p.60-61 ℃;1H NMR(CDCl3)，δ：6.68～6.70(m，1H)，6.83～6.85(m，1H)，7.44～7.46(m，1H)，9.09(br，1H)，9.81(s，1H)。
(3) synthesis of 5-bromopyrrole-3-carbaldehyde
Weighing 15.0g (0.158mol) of 3-aldehyde-1-H-pyrrole and 200.0g of ethyl acetate in a three-necked bottle, stirring and cooling to-10 ℃, slowly adding 29.0g (0.163mol) of NBS solid, stirring and reacting for 30min after adding, adding 100g of sodium thiosulfate saturated solution, stirring for 30min, extracting with dichloromethane, washing an extract liquid with saline, drying with anhydrous sodium sulfate, carrying out suction filtration and concentration to obtain an oily substance, and eluting the oily substance with column chromatography v (ethyl acetate) to v (n-hexane) to 1: 10 to obtain 16.7g of gray solid 5-bromopyrrole-3-formaldehyde with the yield of 69.3%, the purity of 99.1% and the m.p.125-128 ℃; 1HNMR (CDCl3), δ: 6.65-6.67 (m, 1H), 7.38-7.40 (m, 1H), 8.80(brs, 1H), 9.71(s, 1H).
(4) Synthesis of 5- (2-fluorophenyl) pyrrole-3-carbaldehyde
Respectively weighing 15.0g (0.086mol) of 5-bromopyrrole-3-formaldehyde, 19.0g (0.136mol) of 2-fluorobenzeneboronic acid and 15.0g of potassium carbonate into a four-neck flask, adding 100g of DMF (dimethyl formamide) and 40g of water, adding a catalytic amount of palladium tetrakis (triphenylphosphine) in a nitrogen environment, heating to 105 ℃, reacting for 20 hours, cooling to room temperature after the reaction is finished, adding water for dilution, extracting with ethyl acetate, drying, filtering, concentrating and recrystallizing an extract liquor to obtain 13.5g of gray solid 1, wherein the yield is 82.8%, the purity is 99.94%, and m.p.130-131 ℃;1H NMR(CDCl3)，δ：7.07～7.28(m，4H)，7.52～7.54(m，1H)，7.61～7.67(m，1H)，9.49(brs，1H)，9.86(s，1H)。
example 2
Synthesis of Compound 7
(1) 2-phenyl aziridine synthesis:
dissolving 10.4g (100mmol) of styrene in 80mL of carbon tetrachloride, dissolving 16g (200mmol) of liquid bromine in 60mL of carbon tetrachloride, keeping the styrene solution at 15-20 ℃ in an ice-water bath, slowly dripping the liquid bromine solution into the styrene solution, stirring for 2h, washing with water, drying, and carrying out reduced pressure rotary evaporation to obtain a white solid (1).
The white solid (1) was dissolved in 140mL of DMSO, 9.8g (150mmol) of sodium azide was added under nitrogen, and the mixture was stirred at room temperature overnight. Then 4mL of an aqueous solution containing 4g of sodium hydroxide was added to the mixture and stirring was continued for 24 h. The reaction product was poured into 400mL of a 2% (wt%) sodium bicarbonate solution, extracted with dichloromethane, and the organic layer was washed repeatedly with water, dried, and rotary evaporated to give a dark red oil. Separating with silica gel column (petroleum ether as solvent) to obtain pale yellow oily substance (2).
Dissolving the light yellow oily substance (2) in 200mL of toluene, heating and refluxing for 4-6 h, stopping the reaction, and performing rotary evaporation to obtain 8.35g of red brown liquid 2-phenyl aziridine, wherein the total yield is 71%, and the red brown liquid 2-phenyl aziridine is directly used for synthesizing 2-phenyl-4-thiophene pyrrole without purification.
(2) Synthesis of 2-phenyl-4-thiophenepyrrole
3.8g (30mmol) of 2-acetylthiophene liquid and 1.2g of NaH (30mmol) with a mass fraction of 60% were added to 30mL of DMSO under ice bath conditions. 3.4g of the intermediate 2-phenyl-4-thiophenepyrrole (30mmol) prepared was added dropwise with constant stirring, and the color of the reaction liquid rapidly changed to purple. After the reaction was continued for 6 hours with stirring at room temperature, the mixture was poured into 500mL of ice water. Suction filtration was carried out, and the precipitated solid was washed with water for 3 times and then vacuum-dried. The obtained crude solid was subjected to silica gel column chromatography using a mixed solvent of methylene chloride/petroleum ether (1: 1, V/V) as an eluent to give 5.52g of a white solid in 82% yield. 1H NMR (400MHz, CDCl 3): δ 8.32(s, 1H), 7.56(d, 2H, J ═ 8.0Hz), 7.35(t, 2H, J ═ 8.0Hz), 7.22 to 7.19(m, 2H), 7.10 to 7.08(m, 2H), 7.05 to 7.03(m, 1H), 6.72 to 6.70(m, 1H).
Example 3
Synthesis of Compound 12
Firstly, a mixture of formic acid and acetic anhydride is used for carrying out N-formylation reaction on alpha-p-chlorophenyl glycine, the alpha-p-chlorophenyl glycine is converted into a corresponding N-formyl derivative, and further the alpha-p-chlorophenyl glycine and the 2-chloropropene nitrile carry out 1, 3-dipolar addition reaction in the presence of the acetic anhydride to generate a corresponding N-formyl derivative; further carrying out 1, 3-dipolar addition reaction with 2-chloroacrylonitrile in the presence of acetic anhydride to generate aryl pyrrole nitrile 12 as a main product, wherein the total yield of the two steps is 73.6 percent, the product is light yellow solid powder, and the melting point is 161-;1H NMR δ(in acetone-D6)：6.59(t，J＝2.7Hz，1H)，7.05(t，J＝2.8Hz，1H)，7.55(d，J＝8.5Hz，2H，Ar-H)，7.84(d，J＝8.3Hz，2H，Ar-H)，11.30(bs，1H，N-H)。
example 4
Synthesis of Compound 18
(1) Synthesis of 4- (p-chlorophenyl) -2-trifluoromethyl-3-oxazol-5-one
50g (0.025mol) of p-chlorophenylglycine was placed in a 250ml four-necked flask equipped with a stirrer, reflux condenser and thermometer, 42.7g (0.0375mol) of trifluoroacetic acid was slowly added thereto, and appropriate amounts of triethylammonium chloride and phosphorus trichloride were added thereto, followed by heating to 65 ℃ and holding for 5 hours, cooling to room temperature, and distillation under reduced pressure gave 4- (p-chlorophenyl) -2-trifluoromethyl-3-oxazol-5-one (intermediate) in a yield of 95.2%.
(2) Synthesis of 2- (p-chlorophenyl) -5-fluoromethylpyrrole-3-carbonitrile
Adding 7.1g (0.025mol) of the intermediate into a flask, adding 5.3g (0.06mol) of 2-chloroacrylonitrile, dropwise adding a quantitative catalyst, refluxing for 2-2.5 h after adding, cooling to room temperature, adding a proper amount of cold water, filtering a solid product to obtain a crude product, recrystallizing with dichloromethane, and drying to obtain a white solid; the yield is 86.1%; the melting point is 239-241 ℃.
Example 5
Synthesis of Compound 33
Preparation of 2- (p-chlorophenyl) -4, 5-bis (trifluoromethyl) pyrrole-3-carbonitrile: 4- (p-chlorophenyl) -2- (trifluoromethyl) -2-oxazolin-5-one (2.0g, 7.59mmol) and 2-bromo-4, 4, 4-trifluorobutenenitrile (0.81g, 4.05mmol) were dissolved in acetonitrile (10 ml). To the resulting yellow solution was added triethylamine (0.45g, 4.46mmol) dropwise while cooling the reaction flask in a water bath. After stirring overnight at 25 deg.C, the reaction mixture was poured into water, the aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed successively with water, 5% sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow solid which was chromatographed on silica gel and eluted with hexane/ethyl acetate (3: 1) to give the title compound (1.26g, mp 208 deg.C) as yellow crystals.
Example 6
Synthesis of Compound 34
(1) Preparation of 2-p-chlorophenyl-1-methyl-5-trifluoromethyl-2-pyrrole-3-carbonitrile (2)
In a CaCl with a reflux condenser tube and no water2A250 mL three-necked flask with a drying tube and a constant pressure dropping funnel was charged with 4.0g (14mmol) of the compound (1) and 200mL of CCl4Heating to reflux, 1mL (19mmol) of Br was added dropwise from a constant pressure dropping funnel2And 50mL CCl4The solution of the composition;after dripping, the mixture is kept warm and reacted for 2 hours, and after cooling to room temperature, the reaction solution is added with 10 percent Na2S2O3Washing with water to neutrality; anhydrous Na2SO4Drying; removing CCl by evaporation4White solid is obtained, and the product 2.9g is obtained by ethanol recrystallization, with the yield of 72.7 percent. Melting point: 115 to 228 ℃.1H NMR(CDCl3)δ：3.65(s，3H，CH3)，6.96(s，1H，H4)，7.36～7.51(dd，4H，ArH)。
(2) Preparation of 4-bromo-2-p-chlorophenyl-1-methyl-5-trifluoromethylpyrrole-3-carbonitrile (34)
In a CaCl with a reflux condenser tube and no water2A250 mL three-necked flask equipped with a drying tube and a dropping funnel having a constant pressure was charged with 3.43g (12.1mmol) of Compound (2), 0.7g of iron powder and 70mL of CCl41.3mL (24.4mmol) of Br was added dropwise from a constant pressure dropping funnel with stirring at room temperature2And 20mL CCl4The solution of the composition; after dripping, reacting for 2h under heat preservation, and then heating and refluxing for 5 h; cooling to room temperature and then carrying out suction filtration; CCl for filter cake4Washing, filtering, and using 10% Na for filtrate2S2O3Washing with water to neutral, anhydrous Na2SO4Drying; removing CCl by evaporation4Yellow solid is obtained, and the product 3.1g is obtained by ethanol recrystallization, with the yield of 70.6 percent. Melting point: 120 to 122 ℃. 1H NMR (CDCl)3)δ：3.65(s，3H，CH3)，7136～7.51(dd，4H，ArH)。
Example 7
Synthesis of Compound 52
Vilsmeier formylation of the arylpyrrole nitrile 12 in excess DMF gave the corresponding 5-formylarylpyrrole nitrile 52 in a yield of 81.4% as an off-white solid powder having a melting point of 209-210 ℃,1HNMR δ(in DMSO-D6)：7.58(d，J＝2.3Hz，1H，pyrrole-H)，7.60(d，J＝8.8Hz，2H，Ar-H)，7.89(d，J＝8.7Hz，2H，Ar-H)，9.58(s，1H，CHO)，13.4(bs，1H，N-H)。
example 8
Synthesis of Compound 58
(1) Preparation of ethyl 2-hydroxyimino-3-oxobutanoate
Putting ethyl acetoacetate and glacial acetic acid into a three-neck flask, controlling the temperature at 0-5 ℃, dropwise adding a sodium nitrite solution under stirring, reacting for 2 hours after dropwise adding, and then standing for a period of time to remove a solvent to obtain a yellow oily liquid.
(2) Preparation of 4-methyl-2-phenyl-5-ethoxycarbonylpyrrole
Adding acetophenone, glacial acetic acid and anhydrous sodium acetate into a three-neck flask in sequence, controlling the temperature to be 75-85 ℃, dropwise adding ethyl 2-hydroxyimine-3-oxobutyrate while stirring, simultaneously adding zinc powder in batches, and carrying out reflux reaction for 1h at 100-105 ℃ after dropwise adding. After the reaction is finished, cooling to 70 ℃, pouring into ice water, standing for 20min, evaporating water and acetophenone, dissolving the obtained crude product by using chloroform, performing column chromatography by using eluent with the volume ratio of chloroform to ethyl acetate being 3: 1, and separating out the final product target compound.
Example 9
Synthesis of Compound 93
Adding 35g of 4-bromo-2- (4-chlorophenyl) -5-trifluoromethylpyrrole-3-carbonitrile, 9g of sodium hydroxide and 200ml of cyclohexanone into a three-necked flask, stirring for 20 minutes, dropwise adding 20g of chloromethyl chloroethyl ether, heating to 40 ℃, reacting at the temperature for 3 hours, sampling, monitoring, completely reacting, cooling to room temperature, adding 200ml of water, adjusting the pH to 5 with 10% diluted hydrochloric acid, layering, desolventizing, adding 150ml of 80% methanol, and recrystallizing to obtain the compound 93.
Example 10
Synthesis of Compound 107, Compound 108 and Compound 109
(1) Preparation of 2- (4-chlorophenyl) -3-cyano-5-pentafluoroethylpyrrole
47g4- (4-chlorophenyl) -2, 5-dihydro-5-oxo-2-pentafluoroethyl
A mixture of oxazole, 131.1g of 2-chloropropene extract and 750ml of nitromethane was refluxed for 22 hours and then cooled to about 5 ℃ and the precipitated solid was filtered off and washed with a small amount of cold dichloromethane. The mother liquor can be separated again if necessary to give the title compound, m.p. 223.5-224 ℃.
(2) 4-bromo-2- (4-chlorophenyl) -3-cyano-5-pentafluoroethylpyrrole
20g of 2- (4-chlorophenyl) -3-cyano-5-pentafluoroethylpyrrole and 12.8g of sodium acetate were added to 400mL of acetic acid. The mixture was stirred for 15 minutes (a clear solution formed), then 100ml of aldehydic acid containing 49.8 g of bromine was added dropwise to the above solution at room temperature over one hour, stirred at room temperature for 2 hours, poured into 2 l of 10% sodium bisulfite solution and filtered. The colorless crystals obtained are washed with water and dried at 50 ℃ under vacuum. The title compound was obtained. Its melting point 213-215 deg.C (decomposition).
(3) 4-bromo-2- (4-chlorophenyl) -3-cyano-1-ethoxymethyl-5-pentafluoroethylpyrrole
5g 4-bromo-2- (4-chlorophenyl) -3-cyano-5-pentafluoroethylpyrrole are dissolved in 50mL dry tetrahydrofuran and the above solution is treated with 2.7g potassium tert-butoxide at room temperature. 2.7g of chloromethyl ethyl ether was added dropwise thereto. After the reaction mixture was stirred for 22 hours, 400mL of water was added and extracted three times with ether. The combined organic phases were washed with NaCl solution, dried over Na2SO4, evaporated in vacuo and the resulting yellow crystals were recrystallized from 10ml of hexane. The title compound is obtained with a melting point of 69-70.5 ℃.
Compounds 108 and 109 can be prepared by following similar procedures and conditions as described above, with the substitution of the starting materials, wherein the melting point of compound 108 is 79-80 ℃ and the melting point of compound 109 is 199-201 ℃.
Example 11
Synthesis of Compound 110, Compound 111, and Compound 112
The compound a and bromine are used as raw materials, dibromo-substitution is carried out on the raw materials to obtain a compound 110, and then the compound 110 and the compound 112 are sequentially oxidized under the action of m-chloroperbenzoic acid. Compound 111: 1H-NMR (CDCl3) delta: 1.10(3H, t), 3.40(2H, dq), 5.32(1H, d), 5.55(1H, d), 7.45 (4H); compound 112: 1H-NMR (CDCl3) delta: 1.15(3H, t), 3.42(2H, q), 5.40(2H, s), 7.42(2H, d), 7.52(2H, d).
Example 12
Synthesis of Compound 114
(1) Preparation of ethyl 3- (4-chloro-phenylamino) -3-phenylacrylate (2)
0.68g (4m mol) of p-toluenesulfonic acid, 7.68g (40m mol) of ethyl 3-phenyl-3-oxopropionate and 5.10g (40m mol) of p-chloroaniline were dissolved in a three-necked cyclohexane flask containing 200mL, the mixture was heated under reflux for 24 hours, the solvent in the reaction mixture was evaporated to dryness to obtain an oily substance, 50mL of dichloromethane was used to dissolve the oily substance and the oily substance was filtered, the filtrate was vacuum distilled and then vacuum concentrated to obtain a solid, the crude product was recrystallized with n-hexane to obtain 3.30g in total, the yield was 29.5%, the melting point was 111-: 10.22(br, 1H, N H); 7.24-7.36 (m, 5H, ArH); 6.74-6.80 m, 2H, ArH); 6.61-6.64(s, 2H, A rH); 4.98(s, 1H, C-CH); 4.17-4.24(m, 2H, CH 2); 1.30-1.34(m, 3H, CH). MS, m/z: 291(M + H).
(2) Preparation of 3-methyl-1-nitrobutene
Dissolving 6.10g (85mmol) of isopropanal and 5.16g (85mmol) of nitromethane in a three-necked flask filled with 25mL of methanol, cooling to 0 ℃ under ice bath conditions, then dropwise adding 5mL (50%) of sodium hydroxide aqueous solution into the solution, after dropwise adding, raising the temperature of a reaction system to room temperature, continuing stirring for reaction for 1H, adding 30mL of distilled water and 10mL (6mol/L) of hydrochloric acid solution, stirring for 15min, extracting the obtained solution with dichloromethane (20mL multiplied by 3), combining organic phases, drying with anhydrous magnesium sulfate, removing the solvent after reduced pressure distillation to obtain a crude product, separating the crude product by column chromatography to obtain 3.2g of yellow liquid with the yield of 43%, and the nuclear magnetic hydrogen spectrum H NMR (CDCl3, 400MHz) and the yield of delta 7.11-7.19 (m, 1H); 6.84-6.91 (d, 1H, J ═ 2.81 Hz); 2.49 to 2.61(m, 1H); 1.01-1.09 (d, 6H, J ═ 3.2Hz, 2 CH).
(3) Preparation of 1- (4-chloro-phenylamino) -4-isopropyl-2-phenylpyrrole-3-carboxylic acid ethyl ester (3)
Under the protection of nitrogen, 2.85 g of 3-methyl-1-nitrobutene and 1.15g of compound 2 were dissolved in a three-necked flask containing 50mL of anhydrous ethanol, the mixture was heated to 65 ℃ and kept at the temperature for reaction for 3d, ethanol was removed after reduced pressure distillation to obtain a crude product, which was separated by column chromatography to obtain 0.68g of yellow solid compound 3 in 19% yield, melting point 123-: 6.89-7.24 m, 9H, Ar-H); 6.65(s, 1H, C H-C); 4.05 to 4.12(m, 2H, C H2); 3.45 to 3.49(m, 1H, CH); 1.27 to 1.30(d, 6H, J ═ 1.2Hz, 2 CH); 1.04-1.08(m, 3H, CH).
(4) Preparation of 1- (4-chlorophenylamino) -4-isopropyl-2-phenylpyrrole-3-carboxylic acid (4)
Adding 0.8g (10mmol) of solid compound 3, 1.8g (45.6mmol) of sodium hydroxide, 50mL of methanol and 5mL of water into a100 mL flask, directly heating and refluxing for 24H, evaporating the solvent, adding 100mL of distilled water, adjusting the pH to 1-2 with dilute hydrochloric acid to generate a large amount of white precipitate, standing and filtering to obtain 0.7g of white solid 4, wherein the yield is 90%, the melting point is 139-143 ℃, and the nuclear magnetic hydrogen spectrum H NMR (DMSO, 400MHz), delta: 11.7(br, 1H, COOH); 7.08-7.20 (m, 9H, Ar-H); 6.84(s, 1H, CH-C); 3.57(m, 1H, CH); 1.11 to 1.20(d, 6H, J ═ 3.6Hz, 2 CH).
(5) Preparation of Compound 114
Dissolving 0.2g (0.6mmol) of compound 4 in 5mL of anhydrous dichloromethane, dropwise adding the mixture into a10 mL round-bottom flask containing 0.2g (1.8mmol) of oxalyl chloride, keeping the ice salt bath at 0-5 ℃ all the time during dropwise adding, heating the reaction system to room temperature after dropwise adding, continuously stirring for reaction for 3 hours, transferring the reaction solution to a constant-pressure funnel after the reaction is finished, dropwise adding the reaction solution into a 50mL round-bottom flask containing 0.075g (08mmol) of aniline, 1mL of N, N-diisopropylethylamine and 10mL of anhydrous dichloromethane, keeping the ice bath at 0-5 ℃ all the time during dropwise adding, continuously stirring for reaction for 12 hours, removing the solvent by reduced pressure distillation, adding 50mL (5%) of dilute hydrochloric acid, extracting the aqueous phase with ethyl acetate (20mL multiplied by 3), combining the organic phases, drying with anhydrous sodium sulfate, filtering to remove the solvent to obtain a crude product, the crude product was separated by column chromatography ((petroleum ether): V (ethyl acetate): 20: 1) to give 0.15g of compound 5 as a white solid in 51% yield, melting point 167-171 ℃, and nuclear magnetic hydrogen spectrum 1H NMR (DMSO, 400M Hz), δ: 9.71(s, 1H, NH); 7.47-7.50 (d, 2H, ArH); 7.10-7.24 (m, 11H, ArH); 6.94-7.01 (m, 1H, ArH); 6.88(s, 1H, CH-C); 3.04-3.10(m, 1H, CH); 1.20 to 1.23(d, 6H, J ═ 1.21Hz, 2 CH).
Example 13
Synthesis of Compound 131 (Chlorfenapyr)
(1) Synthesis of 2-p-chlorophenyl-4-bromo-5- (trifluoromethyl) pyrrole-3-carbonitrile
6.8g (0.025mol) of 2-p-chlorophenyl-5- (trifluoromethyl) pyrrole-3-carbonitrile (i.e., compound 18) was dissolved in 30mL of carbon tetrachloride, 5.8g (0.036mL) of bromine was slowly added thereto at room temperature, and after dropping, the reaction was refluxed for 6 hours until completion. The solvent was removed in vacuo and the residue was washed with water and sodium metabisulphite and filtered to give 7.9g of a yellow solid in 90% yield. Recrystallizing by using a mixed solvent of n-hexane and ethyl acetate to obtain a white solid with a melting point: 246-249 ℃. IR (cm-1): 3218, 3046, 2235, 1604, 1588, 1466, 1207, 1183, 1110, 976, 827; 1H NMR (DMSO, 400MHz) delta: 13.74(s, 1H), 7.81(d, J ═ 8.4Hz, 2H), 7.66(d, J ═ 8.4Hz, 2H); 13C NMR (DMSO, 100MHz) delta: 95.00, 101.59(q, J ═ 3.3Hz), 114.57, 119.37(q, J ═ 39Hz), 120.16(q, J ═ 267Hz), 126.8, 129.25, 129.38, 135.09, 140.7.
(2) Synthesis of target Compound 131
A solution of 7g (0.02mol) of 2-p-chlorophenyl-4-bromo-5- (trifluoromethyl) pyrrole-3-carbonitrile in 20mL of tetrahydrofuran was slowly dropped into 25mL of tetrahydrofuran containing 0.72g (0.03mol) of sodium hydride, and the mixture was stirred at room temperature for 30min, followed by dropping 2.8g (0.03mol) of chloromethyl ethyl ether and slowly refluxing with heating for 5 hours. Cooling, filtering, removing the solvent, recrystallizing the residue with n-hexane/L ethyl acetate to obtain 7.4g of white solid, wherein the yield is 90%, and the melting point is as follows: 93-94 ℃. IR (cm-1): 2983, 2898, 2231, 1598, 1545, 1482, 1438, 1171, 1125, 1097, 1055, 1031, 832; 1H NMR (CDCl3, 400MHz) delta: 7.54(d, J ═ 8.6Hz, 2H), 7.47(d, J ═ 8.6Hz, 2H), 5.19(s, 2H), 3.39(q, J ═ 7.0Hz, 2H), 1.17(t, J ═ 7.0Hz, 3H); 13C NMR (CDCl3, 100MHz) delta: 14.68, 64.57, 75.41, 99.18, 103.57(q, J-3 Hz), 113.39, 120.05(q, J-269 Hz), 120.63(q, J-39 Hz), 125.26, 129.62, 131.20, 137.27, 144.27.
In addition, compound 131 can also be prepared by the following method: 35g of 4-bromo-2- (4-chlorophenyl) -5-trifluoromethylpyrrole-3-carbonitrile, 8g of sodium hydroxide and 200ml of methyl isobutyl methyl ketone were added to a three-necked flask, stirred for 20 minutes, 20g of chloromethyl ethyl ether was added dropwise, the temperature was raised to 60 ℃ and the reaction was carried out at this temperature for 2 hours, sampling was carried out and monitoring was carried out until the reaction was complete, 200ml of water was added thereto, the pH was adjusted to less than 7 with 10% dilute hydrochloric acid, and then the mixture was layered, desolventized and dried to obtain 45.0 g of compound 131. The content is 90 percent, and the yield is 99 percent. To the desolventized material, 150ml of 80% t-butanol was added and recrystallized to obtain 38 g of 98% compound 131.
Compound 131 can also be obtained by the following method:
(1) synthesis of intermediate 4- (p-chlorophenyl) -2-trifluoromethyl-3-oxazoline-5-ketone body
To a 250mL round bottom flask was added 50mL acetonitrile, 5.0g p-chlorophenylglycine (0.025mol, 1.0eq) was added, the mixture was stirred magnetically, and 2.9mL trifluoroacetic acid (0.0375mol, 1.5eq) was added dropwise over about 5 min. After the mixture is uniformly mixed, 3.5mL (0.025mol, 1.0eq) of catalyst triethylamine is slowly dropped, and 2.4mL (0.0275mol, 1.1eq) of phosphorus trichloride is slowly dropped, and the dropping is finished within 0.5 h. Finally, the temperature is raised to 65 ℃ and the reaction is maintained for 4 h. After the reaction is completed, cooling to room temperature, performing rotary evaporation concentration, and adding a proper amount of toluene for spin drying. This gave the product as a yellow viscous oil, intermediate 1- (4- (p-chlorophenyl) -2-trifluoromethyl-3-oxazolin-5-one).
(2) Synthesis of intermediate 2- (p-chlorophenyl) -5- (trifluoromethyl) -pyrrole-3-carbonitrile
The 250mL round bottom flask used in the first step was used directly in the next step and 50mL acetonitrile was added, with an amount of intermediate 1 of about 5.3g (0.02mol, 1.0 eq). After stirring at room temperature, 3.5g (0.04mol, 2.0eq) of 2-chloroacrylonitrile was added. 7.2mL (0.05mol, 2.5eq) of a quantitative catalyst triethylamine was added dropwise at a rate of 6-7 min/mL. After the dropwise addition, refluxing is carried out for 1h at about 78 ℃. After the reaction is completed, cooling to room temperature, adding a proper amount of cold water into the reaction solution, precipitating a light yellow solid, and performing suction filtration under reduced pressure to obtain a product, namely an intermediate 2- (2- (p-chlorophenyl) -5- (trifluoromethyl) -pyrrole-3-nitrile), and recrystallizing the product by using ethanol. Drying at about 50 ℃ in a vacuum drying oven for the next reaction. The total yield of the first step and the second step is up to 93.5 percent. Intermediate 2 melting point 234-238 deg.C; 1H NMR (400MHz, DMSO) delta (ppm) delta: 13.43(s, 1H), 7.83(d, J ═ 8.6Hz, 2H), 7.67(d, J ═ 8.7Hz, 2H), 7.32(d, J ═ 0.9Hz, 1H); 13C NMR (100MHz, DMSO). delta. (ppm)140.5, 134.4, 129.3, 128.70, 127.4, 120.9, 116.1, 114.9, 90.0.
(3) Synthesis of intermediate 4-bromo-2- (p-chlorophenyl) -5- (trifluoromethyl) -pyrrole-3-carbonitrile
75.0mL of acetic acid was placed in a 250mL two-necked flask, 25.4g of intermediate (0.020mol, 1.0eq) was added thereto, the mixture was magnetically stirred until uniform, and 1.97g of anhydrous sodium acetate (0.024mol, 1.2eq) was added thereto and dissolved completely, followed by slow heating to 90.0 ℃ and stirring for 10 min. 20.0mL of an acetic acid solution of elemental bromine (6.4g, 0.040mol, 2.0eq) was added dropwise at a constant temperature of 90.0 ℃ at a rate adjusted depending on the presence or absence of orange-red bromine vapor in the condenser tube. After the dropwise addition, stirring is continued for 30min, then the temperature is raised to 110.0 ℃, and the reaction is maintained for 3.0 h. After the reaction is completed, the system is cooled to room temperature, the same amount of ice water is added, a large amount of white solid is separated out, and the product, namely the intermediate 3- (4-bromo-2- (p-chlorophenyl) -5- (trifluoromethyl) -pyrrole-3-nitrile, can be obtained after decompression and suction filtration. After drying, 1H NMR (400MHz, DMSO) δ (ppm) δ for intermediate 3 in yields of up to 92.7% was achieved: 13.76(s, 1H), 7.81(d, J ═ 8.6Hz, 2H), 7.67(d, J ═ 8.6Hz, 2H); 13C NMR (100MHz, DMSO). delta. (ppm)140.4, 134.9, 129.2, 129.0, 126.6, 121.3, 119.3, 118.9, 114.4, 101.5, 94.8.
(4) Synthesis of target product 4-bromo-2- (p-chlorophenyl) -1-ethoxymethyl-5- (trifluoromethyl) -pyrrole-3-carbonitrile
50mL of toluene was added to a 250mL round-bottom flask, 35.2g of intermediate (0.015mol, 1.0eq) was added, and after dissolving by magnetic stirring, 3.12g of diethoxymethane (0.030mol, 2.0eq) was added, and the mixture was mixed well and slowly heated to 97.0 ℃. 0.8mL (0.015mol, 1.0eq) of phosphorus trichloride was slowly added dropwise at constant temperature, and the reaction was carried out for more than 0.5h under stirring and refluxing. 1.05mL (0.030mol, 2.0eq) of triethylamine was slowly added dropwise, and the reaction was continued at a constant temperature of 97.0 ℃ for 5 hours. After the reaction is completed, the system is cooled to room temperature, ice water is added, the mixture is vigorously stirred and then extracted by toluene, and the organic phase is dried in a spinning mode to obtain a yellow solid, namely the target product of the chlorfenapyr- (4-bromo-2- (p-chlorophenyl) -1-ethoxymethyl-5- (trifluoromethyl) -pyrrole-3-carbonitrile), wherein the yield is about 92.3 percent after the drying. The melting point is 93-94 ℃;
example 14
Synthesis of Compound 132
(1)2- (4-chlorophenyl) -3-cyano-4, 5-dihydro-1-methyl-5-pentafluoroethylpyrrole
A mixture of 15g of N-carboxy-4-chlorophenyl-methyl-N-pentafluoroethylcarboxylamine, 100ML of acetonitrile, 4.2ML of acrylonitrile, 11g of acetic acid and 15 drops of triethylamine was heated under reflux for 5.5 hours and then evaporated to dryness. The residue was purified by column chromatography to give the title compound, m.p. 113-116 ℃.
(2) 4-chloro-2- (4-chlorophenyl) -3-cyano-1-methyl-5-pentafluoroethylpyrrole
A saturated solution of N, N-dimethylformamide containing 12g of N-chlorosuccinimide was added over a period of 30 minutes to a mixture of 10g of 2- (4-chlorophenyl) -3-atmosphere-4, 5-dihydro-1-methyl-5-pentafluoroethylpyrrole and 10ml of LN, N-dimethylformamide. The reaction mixture was heated to 100 ℃ for 30 minutes and then poured into 1 liter of water with stirring. The oily precipitate was dissolved in ethyl acetate, washed several times with water, dried and evaporated to dryness. The residue was recrystallized from ethyl acetate/hexane to give the title compound, m.p. 120 ℃.
Example 15
Synthesis of Compound 133
(1) Synthesis of potassium 3- (4-chlorophenyl) oxirane-2-carboxylate (Compound 133b)
Dissolving 4-chlorocinnamic acid 133a (9.15g, 0.05mol) in acetone, sequentially adding 15g of sodium bicarbonate (0.178mol) and 75ml of water, adding 20g of potassium hydrogen persulfate (0.132mol), stirring, reacting at 28 ℃ for 4 hours, filtering, adjusting the solution to acidity, extracting with ethyl acetate, spinning, and drying to obtain about 6.8g of a product 133 b;
(2) synthesis of potassium 3- ((carboxymethyl) amino) -3- (4-chlorophenyl) -2-hydroxypropionate (Compound 133c)
Dissolving compound 133b (7.5g, 0.038mol) and glycine (2.9g, 0.038mol) in 15% KOH solution, adjusting the pH to alkaline, refluxing for 2.5 hours, cooling to room temperature, extracting with dichloromethane, collecting the aqueous layer, spin-drying, recrystallizing with 98% ethanol, filtering, and drying to obtain about 8.5g of compound 133 c;
(3) synthesis of 1-acetyl-5-phenyl- (4-chloro) -1H-pyrrol-3-yl acetate (Compound 133)
Compound 133c (5g, 0.014mol) was dissolved in 15ml of pyridine, 20ml of acetic anhydride was added, the reaction was carried out at 75 to 100 ℃ for 5 hours, the mixture was cooled to room temperature, 100ml of ethyl acetate and 100ml of water were added, liquid separation was carried out, the ester layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was dried by spinning, and recrystallization from anhydrous ethanol, followed by collection and drying, whereby about 3.9g of Compound 133 was obtained.
Example 16
Preparation of Compound 134
(1) Synthesis of potassium 3- (4-fluorophenyl) oxirane-2-carboxylate (Compound 134b)
4-fluorocinnamic acid (134a) (10g, 0.06mol) was dissolved in acetone, followed by addition of 30g of sodium bicarbonate (0.354mol) and 100ml of water, addition of 30g of potassium hydrogen persulfate (0.197mol)/120ml, stirring, reaction at 30 ℃ for 2 hours, filtration, adjustment of the solution to acidity, extraction with ethyl acetate, spin-drying and drying to give about 7.2g of compound 134 b.
(2) Synthesis of potassium 3- ((carboxymethyl) amino) -3- (4-fluorophenyl) -2-hydroxypropionate (Compound 134c)
Compound 134b (11.9g, 0.065mol) and glycine (4.8g, 0.064mol) were dissolved in 15% KOH solution and PH adjusted to basic, then reacted at reflux for 2 hours, cooled to room temperature, extracted with dichloromethane, the aqueous layer collected was spun dry, recrystallized with 95% ethanol, filtered, and dried to give about 9.6g of compound 134 c.
(3) Synthesis of 1-acetyl-5- (4-fluorophenyl) -1H-pyrrol-3-yl acetate (Compound 134)
Compound 134c (5g, 0.015mol) was dissolved in 15ml of pyridine, 20ml of acetic anhydride was added, and the reaction was carried out at 80 to 100 ℃
After 5 hours, the mixture was cooled to room temperature, 100ml of ethyl acetate and 100ml of water were added, liquid separation was performed, the ester layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was dried by spinning, and the mixture was recrystallized from anhydrous ethanol, collected, and dried to obtain about 2.8g of compound 134.
Example 17
Synthesis of Compound 135
(1) Synthesis of potassium 3- (3-chlorophenyl) oxirane-2-carboxylate (Compound 135b)
Dissolving 3-chlorocinnamic acid 135a (20g, 0.1mol) in acetone, sequentially adding 84g of sodium bicarbonate (1mol) and 120ml of water, adding 98.5g of potassium hydrogen persulfate (0.65mol)/426ml, stirring, reacting at 28 ℃ for 2.5 hours, filtering, adjusting the solution to acidity, filtering, washing with water, and drying to obtain about 16g of a compound 135 b;
(2) synthesis of potassium 3- ((carboxymethyl) amino) -3- (3-chlorophenyl) -2-hydroxypropionate (Compound 135c)
Dissolving the compound 135b serving as a raw material (7.2g, 0.036mol) and glycine (2.6g, 0.035mol) by using a 15% KOH solution, adjusting the pH of the system to be alkaline, carrying out reflux reaction for 3.5 hours, cooling to room temperature, extracting by using dichloromethane, collecting a water layer, carrying out spin drying, recrystallizing by using 98% ethanol, and drying to obtain about 5.1 g of a compound 135 c;
(3) synthesis of 1-acetyl-5-phenyl- (3-chloro) -1H-pyrrol-3-yl acetate (Compound 5)
Compound 135c (5g, 0.014mol) was dissolved in 30ml of pyridine, 40ml of acetic anhydride was added, reaction was carried out at 80-100 ℃ for 5 hours, cooling was carried out to room temperature, 120ml of ethyl acetate and 120ml of water were added, liquid separation was carried out, the ester layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was dried by spinning, recrystallization from anhydrous ethanol was carried out, and collection and drying were carried out to obtain about 3.2g of compound 135.
Example 18
Preparation of Compound 136
A mixture of pyrrole (0.54g, 8.0mmol), 2-iodonitrobenzene (0.50g, 2.0mmol), Cs2CO3(1.30g, 4mmol) and acetonitrile (30mL) was stirred at reflux under nitrogen. After the completion of the reaction by TLC, the system was cooled to room temperature, and the solid in the system was removed by filtration to collect the filtrate. The filtrate was evaporated under reduced pressure to remove the solvent, and then eluted by flash column chromatography [ silica gel, PE (petroleum ether)/DCM (dichloromethane) ], and concentrated under reduced pressure to give 0.25g of 2- (2-nitrophenyl) pyrrole as a yellow solid (yield 66%). mp: 13C NMR at 40-41 ℃: δ 147.8, 132.2, 130.4, 126.9, 126.7, 126.0, 124.1, 120.4, 110.5, 109.8. Elemental analysis: for C10H8N2O 2: c, 63.82; h, 4.28; n, 14.89. mount: c, 63.87; h, 4.23: n, 14.83.
Example 19
Preparation of Compound 137
The preparation was carried out as described in the previous example, by reacting N-methylpyrrole with 2-bromonitrobenzene to give the product 2- (2-nitrophenyl) -N-methylpyrrole in a yield of 70%. mp: 26-28 ℃ (PE/EA). 13C NM: δ 149.7, 133.2, 132.2, 128.6, 128.1, 127.7, 123.9, 123.5, 109.4, 107.9, 34.1. Elemental analysis: for C11H10N2O 2: c, 65.34; h, 4.98; n, 13.85. Found: c, 65.60; h, 4.93; n, 13.81.
Example 20
Preparation of Compound 138
The preparation method is the same as the previous example, and the N-phenylpyrrole reacts with 2-bromonitrobenzene to obtain the product 2- (2-nitrophenyl) N-phenylpyrrole, wherein the yield is 80%. mp: 104 ℃ and 105 ℃ (PE/EA). 13C NMR: δ 149.0, 139.3, 132.8, 132.1, 129.1, 128.0, 127.8, 126.7, 125.1, 124.3, 123.9, 111.7, 109.6. Elemental analysis: for C16H12N2O 2: c, 72.72; h, 4.58; n, 10.60. mount: c, 72.77; h, 4.56; n, 10.61.
Example 21
Preparation of the suspending agent
Weighing 10kg of the compound 131, 2kg of alkylphenol polyoxyethylene ether phosphate serving as a dispersant, 1kg of wetting agent modified alkyl sodium sulfate, 1kg of alkylphenol polyoxyethylene ether, 0.2kg of an organosilane defoaming agent, 3kg of white carbon black serving as a thickening agent, 0.2kg of xanthan gum, 4kg of propylene glycol serving as an antifreezing agent and water which are added to 100 kg. Dispersing the raw medicine, the dispersing agent, the wetting agent, the stabilizer, the defoaming agent and the white carbon black at a high speed, grinding to 2-5 mu m, adding xanthan gum and the antifreezing agent, and shearing and dispersing uniformly to obtain the suspending agent.
Example 22
Preparation of microemulsions
Weighing 2g of the compound 131, dissolving the compound with 7g of xylene and 17g of ethyl acetate, adding 18g of mixed emulsifier of benzyl phenol polyoxyethylene polyoxypropylene ether and calcium dodecyl benzene sulfonate, 1g of azone and 1g of ethylene glycol, adding 1g of sodium lauryl sulfate, heating to 40-50 ℃, stirring to dissolve, adding 60g of metered water, stirring strongly and uniformly, maintaining for 15-20 minutes, and then recovering to room temperature to obtain 100g of the microemulsion of the compound 131.
Example 23
Preparation of emulsions
Putting 17g of ethyl acetate and 23g of acetone into a reactor, uniformly mixing, adding 20g of the compound 131, and continuously stirring until the compound 131 is completely dissolved, so as to prepare an oil solution for later use; putting 26g of water into a reactor, adding a mixed emulsifier of benzyl phenol polyoxyethylene polyoxypropylene ether and a phenethyl phenol polyoxyethylene ether formaldehyde condensate, polyvinyl alcohol, propylene glycol and a defoaming agent, continuously stirring until all the substances are completely dissolved to form uniform liquid, and preparing an auxiliary agent composite water aqua for later use; and (3) placing the assistant composite aqueous solution obtained in the previous step into a container provided with a shearing machine, adding the oil agent obtained in the previous step under high-speed stirring, controlling the rotating speed to be 1000 rpm, and stirring for 60 minutes to obtain milky opaque liquid, thereby obtaining the emulsion in the embodiment.
Example 24
Preparation of the suspending agent
Weighing 1 part of compound 91, 8 parts of metaldehyde, 10 parts of sodium lignosulfonate, 10 parts of alkylphenol polyoxyethylene, 10 parts of xanthan gum and 61 parts of water, mixing, adding into a ball milling tank, grinding for 1 hour on a planetary ball mill at 500r/min to ensure that the particle size is less than 5 microns, and thus obtaining the compound suspending agent of the embodiment.
Example 25
Preparation of microemulsions
Sequentially adding 20g of the compound 91, 80g of absolute ethyl alcohol, 80g of n-butyl alcohol, 100g of DBS-Ca and 10100g of NP into a 1000ml three-necked bottle with a stirrer under high-speed stirring, uniformly mixing, adding 620g of deionized water, uniformly mixing, stirring at a high speed at 50-60 ℃ to form a homogeneous transparent liquid, cooling to room temperature, and filtering to obtain the microemulsion of the embodiment.
Example 26
Preparation of the suspending agent
Weighing 1 part of compound 112, 8 parts of metaldehyde, 10 parts of sodium lignosulfonate, 10 parts of alkylphenol polyoxyethylene, 10 parts of xanthan gum and 61 parts of water, mixing, adding into a ball milling tank, grinding for 1 hour on a planetary ball mill at 500r/min to ensure that the particle size is less than 5 microns, and thus obtaining the compound suspending agent of the embodiment.
Example 27
Preparation of microemulsions
Sequentially adding 20g of compound 112, 80g of absolute ethyl alcohol, 80g of n-butyl alcohol, 100g of DBS-Ca and 10100g of NP into a 1000ml three-necked bottle with a stirrer under high-speed stirring, uniformly mixing, adding 620g of deionized water, uniformly mixing, stirring at a high speed at 50-60 ℃ to form a homogeneous transparent liquid, cooling to room temperature, and filtering to obtain the microemulsion of the embodiment.
Example 28
Efficacy and toxicity test
(1) Taking Oncomelania hupensis as a test object, and testing by adopting a soaking method
The operation process is as follows: each sample (any of the compounds of examples 1-20, including compounds 5, 7, 12, 18, 33, 34, 52, 58, 93, 107, 108, 109, 110, 111, 112, 114, 131, 132, 133, 134, 135, 136, 137, 138) was accurately weighed, dissolved in 0.2mL of dimethyl sulfoxide (DMSO), and diluted to two solutions of 0.1mg/L and 0.5mg/L with dechlorinated tap water. 30 oncomelania snails are placed in each beaker, 100 milliliters of the prepared liquid medicine is poured into each beaker, a plastic gauze is covered on each beaker to prevent the oncomelania snails from climbing up the liquid level, the beakers filled with the liquid medicine and the oncomelania snails are placed in an incubator at the constant temperature of 25 ℃, the humidity is kept at 60 percent and the illumination is sufficient, the liquid medicine is poured out after being respectively soaked and killed for 24 hours, the beakers are washed for 3 times by clear water, 15 milliliters of dechlorinated tap water is added for resuscitation for 1 hour, resuscitation is carried out for 24 hours again, and the oncomelania activity is determined by knocking after 24 hours. Each sample was replicated 3 times.
Comparison was performed with 0.1mg/L, 0.5mg/L niclosamide (positive control) and clear water containing 0.1mg/L, 0.5mL/L DMSO (blank control). The number of deaths of oncomelania was counted and the mortality (%) was calculated (see table 1).
Mortality (%) - (number of blank control live snails-number of treated live snails)/number of blank control live snails × 100%.
TABLE 1 results of molluscicidal Activity of the Compounds of examples 1-20
(2) Laboratory experiment of spraying effect
Taking pollution-free soil, drying in the sun, breaking, and sieving with a 20-mesh sieve to obtain fine soil. 500g of fine soil is weighed and poured into an enamel tray (20 multiplied by 25cm) to prepare a mud tray with the thickness of 1-2 cm, 125ml of dechlorinated tap water is added after the mud tray is paved, and the water content is about 25 percent. Adding 100 oncomelania snails, and adding 1.0g/m of effective dose of active ingredients of the compound2Uniformly spraying with water consumption of 1L/m2. Meanwhile, setting a blank control niclosamide control, taking out the experimental mud tray after 5d, picking up all oncomelania in the tray, washing with clear water, and identifying the death number and survival number of the oncomelania by a knocking method after 48h of breeding recovery.
TABLE 2 laboratory dusting molluscicidal Effect of the suspension
(3) Study on acute toxicity of aquatic organisms
And (3) testing the fish species: zebra fish, 18 mm in length and 0.3 + -0.1 g in weight.
The test process comprises the following steps: the concentrations of effective drugs (compounds of any of examples 1-20, including compounds 5, 7, 12, 18, 33, 34, 52, 58, 93, 107, 108, 109, 110, 111, 112, 114, 131, 132, 133, 134, 135, 136, 137, 138) were 0.01mg/L, 0.05mg/L, 0.20mg/L, 0.50mg/L, 2mg/L, 20mg/L, 40mg/L, 60mg/L, 80mg/L, respectively, for 9 groups.
The domestication is carried out for 7 days in the continuously aerated diluted water before the test, and the water quality condition and the lighting condition during the domestication are consistent with the conditions during the test. Feeding is stopped 24h before the test, the death rate during the domestication period is not more than 10%, the water temperature is kept at 23 +/-1 ℃ during the test, the dissolved oxygen content in the test is higher than 60% of the air saturation value, the pH value is 7.0 +/-0.2, the test period is 48h, the poisoning symptoms and the death rate of the tested fish are observed and recorded at any time within 3 to 6h after the test is started, and the poisoning symptoms and the death rate of the tested fish under different concentrations are observed and recorded within 12h, 24h, 36h and 48h after the test is started. The dead fish is judged by tapping the tail part of the fish with glass, and the dead fish is determined if no reaction occurs.
The toxicity results of the compounds prepared in examples 1-20 on fish are shown in Table 3.
LC50 value determination of 48 hour toxicity to Zebra fish for compounds in Table 3 example
The results show that: (1) the compound has obvious molluscacidal effect, and the molluscacidal effect of most compounds reaches more than 50% under the concentration of 0.1mg/L and reaches more than 90% under the concentration of 0.5 mg/L; (2) the LC50 values of the compound of the invention in 48h are all more than 10mg/L, while the LC50 value of niclosamide in 48h is only 0.067mg/L, and the niclosamide is applied for 1 hour at the concentration of 0.2mg/L, which leads to almost all the death of fish. It can be seen that the compounds of the present invention have very low toxicity to fish. Therefore, the niclosamide compound is safe to aquatic organisms and is expected to be further researched and developed into a safe and effective niclosamide substitute medicament.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811054534.7A CN109006823B (en) | 2018-09-11 | 2018-09-11 | Application of 2-aryl substituted pyrrole compound in oncomelania killing drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811054534.7A CN109006823B (en) | 2018-09-11 | 2018-09-11 | Application of 2-aryl substituted pyrrole compound in oncomelania killing drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109006823A CN109006823A (en) | 2018-12-18 |
| CN109006823B true CN109006823B (en) | 2021-05-07 |
Family
ID=64621310
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811054534.7A Expired - Fee Related CN109006823B (en) | 2018-09-11 | 2018-09-11 | Application of 2-aryl substituted pyrrole compound in oncomelania killing drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109006823B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110218170A (en) * | 2019-07-03 | 2019-09-10 | 山东潍坊双星农药有限公司 | A kind of mixed catalyst catalyzes and synthesizes the production technology of capillary |
| CN110612984B (en) * | 2019-10-16 | 2021-11-05 | 江苏省血吸虫病防治研究所 | Application of Cyclopropimide in Snail Killing Drugs |
| CN115536568B (en) * | 2021-06-30 | 2024-05-17 | 湖南化工研究院有限公司 | Method for continuously synthesizing chlorfenapyr |
| CN116239551B (en) * | 2022-12-05 | 2024-07-26 | 湖北大学 | Furanylurea compound with molluscicidal activity and preparation and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4929634A (en) * | 1987-10-23 | 1990-05-29 | American Cyanamid Company | Method of and bait compositions for controlling mollusks |
| CN1056491A (en) * | 1990-05-11 | 1991-11-27 | 美国氰胺公司 | As desinsection, kill the useful New N-acylated aryl pyrrolines of mite, nematicide, invertebrate poison |
| CN1086211A (en) * | 1992-10-27 | 1994-05-04 | 美国氰胺公司 | N-pyrrole derivative insecticide, miticide and mollusk kill agent |
| CN1086212A (en) * | 1992-10-27 | 1994-05-04 | 美国氰胺公司 | N-aminoalkylcarbonyloxinsecticidale azole pesticides, miticide and invertebrate poison |
| CN1087082A (en) * | 1992-10-27 | 1994-05-25 | 美国氰胺公司 | N-substituted carbonyloxyalkylpyrrinsecticidal insecticidal, miticide and invertebrate poison |
| CN1106798A (en) * | 1993-12-29 | 1995-08-16 | 美国氰胺公司 | Alkoxymethylation of pyrroles |
-
2018
- 2018-09-11 CN CN201811054534.7A patent/CN109006823B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4929634A (en) * | 1987-10-23 | 1990-05-29 | American Cyanamid Company | Method of and bait compositions for controlling mollusks |
| CN1056491A (en) * | 1990-05-11 | 1991-11-27 | 美国氰胺公司 | As desinsection, kill the useful New N-acylated aryl pyrrolines of mite, nematicide, invertebrate poison |
| CN1086211A (en) * | 1992-10-27 | 1994-05-04 | 美国氰胺公司 | N-pyrrole derivative insecticide, miticide and mollusk kill agent |
| CN1086212A (en) * | 1992-10-27 | 1994-05-04 | 美国氰胺公司 | N-aminoalkylcarbonyloxinsecticidale azole pesticides, miticide and invertebrate poison |
| CN1087082A (en) * | 1992-10-27 | 1994-05-25 | 美国氰胺公司 | N-substituted carbonyloxyalkylpyrrinsecticidal insecticidal, miticide and invertebrate poison |
| CN1106798A (en) * | 1993-12-29 | 1995-08-16 | 美国氰胺公司 | Alkoxymethylation of pyrroles |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109006823A (en) | 2018-12-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109006823B (en) | Application of 2-aryl substituted pyrrole compound in oncomelania killing drug | |
| CN102459235B (en) | Pyrazinylpyrazole | |
| CN109006824B (en) | Application of 2-aryl substituted pyrrole compound in medicament for killing amphioxus | |
| CN109169668B (en) | Application of 2-aryl substituted pyrrole compound in drug for killing vesicular snails | |
| JPH04305579A (en) | Milbemycin ether derivative | |
| KR20100113598A (en) | Insecticidal arylpyrrolines | |
| CN102186816A (en) | Insecticidal arylpyrrolidine | |
| ES2400574T3 (en) | Pyridyl-triazolopyrimidine derivative or its salt, pesticide that contains it and its production procedure | |
| CN115724772B (en) | Compound with urea structure, and preparation and application thereof | |
| CN115925576B (en) | Bisamide compound containing sevoflurane isopropyl, and preparation method and application thereof | |
| MX2012011857A (en) | Process for the preparation of pyrrolines from gamma-nitroketones. use of the gamma-nitroketones as pesticidal agents. | |
| JP2013510080A (en) | Insecticidal arylpyrroline compounds | |
| JP2012062267A (en) | Pesticidal pyrroline n-oxide derivative | |
| CN114853748A (en) | Trifluoromethyl-containing isoxazoline derivative, and preparation method and application thereof | |
| JP2020536933A (en) | Uses of pyridineurea compounds with snail-killing activity | |
| CN107266511B (en) | A novel compound of 5-oxime ester B2a structure and its preparation method and application | |
| CN101528761A (en) | Avermectin derivatives | |
| CN104710323B (en) | Salicylamide ester type compound and its preparation and use with ovicidal trait | |
| JP2002527437A (en) | 2-hetaryl-3,4-dihydro-2H-pyrrole derivatives | |
| CN116969954B (en) | Tricyclic fused heterocyclic compounds containing lactam and application thereof | |
| KR910008476B1 (en) | Process for fungicidal pyridazines | |
| CN113200976A (en) | 3-aryl azabicyclo derivatives, preparation thereof and nematicidal application thereof | |
| CN114409664A (en) | Spiro-heterocyclic tetrahydropyran compound and preparation method and application thereof | |
| CN117534677B (en) | Imine-containing tricyclic fused heterocyclic compound and application thereof | |
| WO2019086009A1 (en) | Nitrogen-containing fused tricyclic compound and use thereof as agroforestry insecticide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210507 |