CN104710323B - Salicylamide ester type compound and its preparation and use with ovicidal trait - Google Patents
Salicylamide ester type compound and its preparation and use with ovicidal trait Download PDFInfo
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- CN104710323B CN104710323B CN201310676706.5A CN201310676706A CN104710323B CN 104710323 B CN104710323 B CN 104710323B CN 201310676706 A CN201310676706 A CN 201310676706A CN 104710323 B CN104710323 B CN 104710323B
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- 0 C*CCOc(cc(cc1)[N+]([O-])=O)c1NC(c(cc(cc1)Cl)c1OCC=C)=O Chemical compound C*CCOc(cc(cc1)[N+]([O-])=O)c1NC(c(cc(cc1)Cl)c1OCC=C)=O 0.000 description 2
- RZNHSEZOLFEFGB-UHFFFAOYSA-N COc(cccc1)c1C(Cl)=O Chemical compound COc(cccc1)c1C(Cl)=O RZNHSEZOLFEFGB-UHFFFAOYSA-N 0.000 description 1
- RUQIUASLAXJZIE-UHFFFAOYSA-N COc1cc(C(Cl)=O)ccc1 Chemical compound COc1cc(C(Cl)=O)ccc1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 1
- QIKYZXDTTPVVAC-UHFFFAOYSA-N NC(c(cc1)ccc1N)=O Chemical compound NC(c(cc1)ccc1N)=O QIKYZXDTTPVVAC-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention relates to salicylamide ester type compound with ovicidal trait and its preparation method and application.Specifically, the invention discloses the compound with structure shown in formula A, the compound to have significant killing effect to its communication media, has excellent prevention effect and low to the toxicity of non-target organism fish to parasitic disease.
Description
Technical field
The invention belongs to chemical medicine.A kind of in particular it relates to salicylamide ester with ovicidal trait
Class compound and its preparation method and application.
Technical background
The amount reproduction of snail usually has serious harm, such as water is reduced quickly, and planktonic organism quantity is significantly
Decline.Simultaneously as spiral shell consumes dissolved oxygen in water, the growth of fry kind is influenced.In another example some snails are pathogen carrier,
If lamnaeid is the vector of fluke and double caves fluke of living in caves, lake spiral shell is the vector of Asymphylodora, and oncomelania is blood fluke
The unique intermediate host of cercaria.The oncomelania of people and livestock contact with blood fluke cercaria can infect snail fever, China at present by
Blood fluke threatens population to be up to 60,000,000, number of the infected 370,000.Therefore, the cercaria killed oncomelania or killed in oncomelania becomes
Prevention and an effective measures of control schistosomiasis.
In addition, after the Pomacea canaliculata as angiostrongylus cantonensis communication media introduced China from 1981, due to its individual
Greatly, feeding habits are wide, adaptable, growth and breeding is fast, yield is high, have cultivate and be spread in rapidly river and lake and field all over China,
The various growth that can destroy cereal crops, vegetables and aquatic crops of its heavy and food species, it has also become Guangdong, Guangxi,
The harmful animal on the ground such as Fujian, Yunnan, Zhejiang, Shanghai, Jiangsu.In addition, Pomacea canaliculata or a kind of parasitic disease of infecting both domestic animals and human
Intermediate host, easily bring health problem to surrounding resident.
So far, chemotherapy is still to control using snail as one of main means of parasitic disease of medium.Such as chlorine
Nitre willow amine is to kill the highest one kind of oncomelania activity at present to kill spiral shell medicine, has significant cercaricidal activity, and world health group concurrently
That knits that (WHO) uniquely recommend kills spiral shell medicine.But the shortcomings that niclosamidum, is it is also obvious that i.e. to non-target organism especially
Toxicity in fish is high, and which has limited its use.At present, the research to such compound mainly changes the formulation of niclosamidum
Into such as niclosamidum suspending agent.These can solve the problems, such as that its is deliquescent, but cannot fundamentally solve it to fish
The problem of class toxicity.
Therefore, researching and developing new efficient, the less toxic spiral shell medicine that kills becomes this area technical problem urgently to be resolved hurrily.
The content of the invention
It is an object of the present invention to provide a kind of new efficient, less toxic molluscacide.
Another object of the present invention is to provide protection for snail fever Susceptible population, protects it from bilharzial harm.
The first aspect of the present invention, which provides, a kind of has the compound of structure shown in formula A or its is pharmaceutically acceptable
Salt：
In formula：R1And R2It is each independently H, unsubstituted or substituted phenyl；Or R1、R2It is common with adjacent nitrogen-atoms
Form unsubstituted or substituted five-ring heterocycles or unsubstituted or substituted hexa-member heterocycle；The five-ring heterocycles or hexa-member heterocycle are only
Also contain oxygen atom and/or sulphur atom containing nitrogen-atoms or in addition to nitrogen-atoms；
R3For unsubstituted or substituted benzoyl, unsubstituted or substituted C1-6Alkyl unsubstituted or substituted contains
One or more heteroatomic quinary heteroaryl acyl groups or six membered heteroaryl acyl group in nitrogen, oxygen and sulphur；
Wherein, it is described substituted to refer to be substituted by one or more substituents selected from the group below：Halogen, nitro, hydroxyl
Base, cyano group, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy, C3-6Cycloalkyl.
In another preference, the compound is compound of formula I or Formula II compound：
In various, R3It is as defined above.
In another preference, R3For unsubstituted or substituted benzoyl or unsubstituted or substituted C1-6Alkyl.
In another preference, the C1-6Alkyl is C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-6Cycloalkyl.
The preparation method of compound described in first aspect, including step are provided in second aspect of the present invention：
(1) in atent solvent, in the presence of a catalyst, formula III compound and formula C compounds are reacted, from
And obtain formula B compounds；
(2) in atent solvent, in the presence of alkaline reagent, by formula B compounds and R3- Cl is reacted, so as to obtain
Formula A compounds；
In various, R1、R2、R3It is as defined above.
In another preference, in step (1), the atent solvent is selected from the group：Water, acetone, toluene, dichloromethane
Alkane, acetonitrile, ethanol；It is preferred that be toluene, dichloromethane.
In another preference, in step (1), the catalyst is selected from the group：PCl3, thionyl chloride.
In another preference, in step (2), the atent solvent is selected from the group：Water, acetone, toluene, dichloromethane
Alkane, acetonitrile, ethanol；It is preferred that be toluene, dichloromethane.
In another preference, in step (2), the alkaline reagent is selected from the group：Piperidines, DBU, DMAP, three second
Amine, diisopropylethylamine, pyridine or substituted pyridine.
In another preference, the formula C compounds are：
A kind of agriculturally useful compositions are provided in third aspect present invention, include the change (a) as described in the first aspect of the invention
Compound or its pharmaceutically acceptable salt；And acceptable carrier or excipient in (b) Pesticide Science.
In another preference, weight content of the component (a) in the agriculturally useful compositions is 0.0001%-99.99
%；It is preferred that it is 0.001%-99.9%；More preferably, it is 0.01%-99%.
In another preference, the agriculturally useful compositions also include other molluscacides；Other molluscacides are commercially available can
.
In another preference, other molluscacides are selected from the group：Niclosamidum, Rong Bao, flourish bud, Seed of Camellia Sinensis and its
Its commercially available plant molluscicide.
Fourth aspect present invention provides compound described in first aspect present invention or the group as described in third aspect present invention
The purposes of compound, for preventing parasite or killing the communication media of parasite；Or it is used to prepare prevention parasite or kills and post
The medicine of infested communication media.
In another preference, the parasite includes：Nematode, tapeworm, fluke.
In another preference, the communication media of the parasite includes：Oncomelania, Pomacea canaliculata, snail.
Fifth aspect present invention provides a kind of Verminosis prevention method, by compound described in first aspect present invention
Or agriculturally useful compositions described in third aspect present invention put on the communication media of parasite or the ring by the communication media disaster
Border (such as soil, waters).
In another preference, the application concentration of the compound or the agriculturally useful compositions is 0.02-5mg/L；Preferably
Ground, is 0.01-1mg/L；More preferably, it is 0.1-0.5mg/L.
It is to be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment)
It can be combined with each other between each technical characteristic of body description, so as to form new or preferable technical solution.As space is limited,
Not repeated them here.
Brief description of the drawings
Fig. 1 shows that compound is to the toxicity of fish made from the embodiment 4 of various concentrations.
Embodiment
The present inventor is by long-term and in-depth study, it was found that a kind of structure is novel to kill spiral shell medicine, it has spiral shell work of going out
Property and kill cercaria activity and significantly improve and to the very low advantage of toxicity of non-target organism.On this basis, inventor completes
The present invention.
Group definition
As used herein, term " C1-6Alkyl that alkyl " refers to have 1-6 carbon atom, alkenyl, alkynyl, cycloalkyl,
Cycloalkenyl group, aryl etc. be only carbon containing, hydrogen saturation or unsaturated group.Preferably alkyl, cycloalkyl, alkenyl or alkynyl.
As used herein, term " C1-6Alkyl " refers to the straight or branched alkyl with 1-6 carbon atom, such as methyl,
Ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group or similar group.
As used herein, term " C2-6Alkenyl " refers to the alkenyl of the straight or branched with 2-6 carbon atom, such as ethene
Base, pi-allyl, 1- acrylic, isopropenyl, 1- cyclobutenyls, 2- cyclobutenyls or similar group.
As used herein, term " C2-6Alkynyl " refers to the alkynyl with the straight or branched of 2-6 carbon atom, such as second
Alkynyl, propinyl etc..
As used herein, term " C3-6Cycloalkyl " cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or suberyl etc..
Term " C1-6Alkoxy " refers to the straight or branched alkoxyl with 1-6 carbon atom, such as methoxyl group, ethoxy
Base, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy or similar group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.Term " halo " refers to by identical or different one or more above-mentioned
The group of halogen atom substitution, such as trifluoromethyl, pentafluoroethyl group or similar group.
Term " quinary heteroaryl or six membered heteroaryl " refers to is selected from heteroatomic the five of nitrogen, oxygen or sulphur containing one or more
First or hexa-atomic heteroaryl, such as pyridine radicals, pyrrole radicals, furyl, thienyl, pyrazolyl, imidazole radicals, oxazolyl, Yi Evil
Azoles, thiazolyl, pyridazinyl, pyrimidine radicals, pyrazinyl etc..Term " quinary heteroaryl acyl group or six membered heteroaryl acyl group " refers to five
Unit's heteroaryl or the carbonyl of six membered heteroaryl substitution（Quinary heteroaryl-(C=O)-or six membered heteroaryl-(C=O)-）.
" five-ring heterocycles or the hexa-member heterocycle " of the present invention can comprise only nitrogen-atoms, can also be in addition to containing nitrogen-atoms
Also contain aerobic and/or sulphur, such as morpholinyl, piperidyl, piperazinyl, pyrrolidinyl etc..
Heretofore described " substituted " refers to be substituted by one or more conventional substituents, is selected from down
Group：Halogen, nitro, hydroxyl, cyano group, C1-6Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Alkoxy, C3-6Cycloalkyl.
The preparation method of the compounds of this invention
Compound can be made by following method shown in general formula A of the present invention, but the condition of this method, such as be reacted
Thing, solvent, alkali, the amount of compound used therefor, reaction temperature, reaction required time etc. are not limited to following explanation.Chemical combination of the present invention
Various synthetic methods describing in the present specification or known in the art can also optionally be combined and easily made by thing
, such combination can readily be carried out by those skilled in the art in the invention.
In the specific embodiment of the invention, the synthetic method of compound of Formula I is as follows：
(1-1) is in certain temperature（Such as 0-130 DEG C, it is preferred that 60-80 DEG C) under, in atent solvent (such as toluene),
Under the catalysis of catalyst (such as phosphorus trichloride), III compound of formula and IV compound of formula are subjected to reaction a period of time（As 3-24 is small
When, it is preferred that when 4-8 is small）, obtain Formula IV compound；And
(2-1) is in certain temperature（Such as 0-130 DEG C, it is preferred that 15-40 DEG C) under, at atent solvent (such as dichloromethane)
In, in the presence of alkaline reagent (such as triethylamine), by Formula IV compound and contain R3- Cl carries out reaction a period of time（Such as 3-
24 it is small when, it is preferred that when 4-8 is small）, obtain compounds of formula I；
In the other embodiments of the present invention, the synthetic method of Compounds of formula II is as follows：
(1-2) is in certain temperature（Such as 0-130 DEG C, it is preferred that 60-80 DEG C) under, in atent solvent (such as toluene),
Under the catalysis of catalyst (such as phosphorus trichloride), III compound of formula and Formula V compound are subjected to reaction a period of time（As 3-24 is small
When, it is preferred that when 4-8 is small）, obtain Formula VII compound；And
(2-2) is in certain temperature（Such as 0-130 DEG C, it is preferred that 15-40 DEG C) under, at atent solvent (such as dichloromethane)
In, in the presence of alkaline reagent (such as triethylamine), by Formula VII compound and contain R3- Cl carries out reaction a period of time（Such as 3-
24 it is small when, it is preferred that when 4-8 is small）, obtain compounds of formula II.
The Antiparasitic Activity of active material of the present invention
Term " active material of the invention " or " reactive compound of the invention " refer to formula A compounds.This hair
Bright active material can efficiently control and eliminate parasite and its communication media etc., it has significant killing parasite
Communication media activity and Antiparasitic Activity.
The example of parasite includes but not limited to：
Fluke (trematode)：Such as middle clonorchis sinensis (Clonorchis sinensis), fasciolopsis buski
(Fasciolopsis buski), Fasciola hepatica (Fasciola hepatica), paragonimus (Paragonimiasis),
Schistosoma japonicum (Schistosoma japonicum), Schistosoma haematobium (S. haematobium), Schistosoma mansoni
(S.mansoni), blood fluke (S.intercalatum), river bank public affairs blood fluke (S.mekongi), Malaysia blood fluke are interleave
(S.malayensis)。
Tapeworm (tapeworm)：Such as Spirometra mansoni (Spirometra mansoni), fish tapeworm
(Diphyllobothrium latum), chain band tapeworm (Taenia solium), taeniarhynchus saginate (Taenia
Saginata), Taenia saginata asiatica (Taenia saginata asiatica), Hymenolepis nana (Hymenolepis
Nana), rat tapeworm (Hymenolepis diminuta), Echinococcus granulosus (Echinococcus
Granulosus), Echinococcus multilocularis (Echinococcus multilocularis), diphlidium caninum (Dipylidium
caninum)。
Nematode (nematode)：Such as ascaris lumbricoides (Ascaris lumbricoides), angiostrongylus cantonensis
(Angios trongylus cantonensis), ascaris trichiurus (Trichuris trichiura), compacted shape live gutstring
Worm (Enterobius vermicularis), Ancylostoma duodenale (Ancylostoma duodenale), America Ban Kou
Nematode (Necator americanus), strongyloides intestinalis (Strongy loides stercoralis), trichina(Trichinella spiralis)
(Trichinella spiralis), wuchereria bancrofti (Wuchereria bancrofti), cloth Shandong, Malaysia nematode
(Brugia malayi)。
The example of the communication media of parasite includes but not limited to：Spiral shell：As oncomelania (Oncomelania hupensis),
Pomacea canaliculata (Pomacea canaliculata), snail（snail）.
" anti-parasite medicine " of the present invention or " anti-parasite medicament " are mentioned above all with preventing
The general designation of the material of parasite and communication media effect.
The present invention reactive compound especially to fluke such as：Schistosoma japonicum, tapeworm (such as Echinococcus granulosus and more rooms
Echinococcus), oncomelania and other effects significantly.
Containing the molluscacide composition of active material of the present invention and the transformation of its formulation
Molluscacide composition can be made in the active material of the present invention in a conventional way.These reactive compounds can be done
Into conventional preparation, such as solution, emulsion, supensoid agent, pulvis, foaming agent, paste, granule.
These preparations can use known method to produce, for example, reactive compound is mixed with expanding agent, these expand agent
Be exactly liquid or liquefied gas or solid diluent or carrier, and can arbitrarily select surfactant i.e. emulsifying agent and/or
Dispersant and/or formation of foam agent.Such as when making expansion agent with water, organic solvent also is used as auxiliary agent.
It is substantially suitable when making diluent or carrier with liquid flux, such as：Arene, such as dimethylbenzene, first
Benzene or alkylnaphthalene；The fragrance of chlorination or the fat hydrocarbon of chlorination, such as chlorobenzene, vinyl chloride or dichloromethane；Fat hydrocarbon, example
Such as hexamethylene or paraffin, such as mineral oil fractions；Alcohols, such as ethanol or ethylene glycol and their ether and lipid；Ketone,
Such as acetone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) or cyclohexanone；Or the polar solvent being of little use, such as dimethylformamide and two
Methyl sulfoxide, Yi Jishui.
The diluent or carrier of liquefied gas is said, referring at normal temperatures and pressures will be molten as the liquid of gas, such as gas
Glue propellant, such as the hydro carbons and butane of halogenation, propane, nitrogen and carbon dioxide.
Solid carrier can use the natural mineral matter of grinding, such as kaolin, clay, talcum, quartz, atlapulgite, illiteracy to take off
Soil or diatomite, and the mineral matter of grinding synthesis, such as the silicic acid of high degree of dispersion, aluminium oxide and silicate.For consolidating for particle
Body carrier is pulverizing and classification natural to accuse stone, such as calcite, marble, float stone, sepiolite and dolomite, Yi Jiwu
Particle of machine and the particle of organic coarse powder synthesis, and organic material such as wood sawdust, cocoanut shell, maize cob and tobacco stems etc..
The non-ionic and emulsification of anion row can be used as emulsifying agent and/or formation of foam agent.Such as polyoxyethylene-fat
Fat esters of gallic acid, polyoxyethylene-fatty alcohol ethers, such as alkaryl polyethylene glycol ethers, alkyl sulfonates, alkyl sulfate
Class, aryl sulfonic acid esters and albumin hydrolysate.Dispersant includes, such as lignin sulfite waste liquor and methyl fibre
Dimension element.
Can use adhesive in the formulation, for example, carboxymethyl cellulose and with the natural of powder, granule or emulsion form and
The polymer of synthesis, such as Arabic gum, polyvinyl alcohol and polyvinyl acetate.
Colouring agent such as inorganic dyestuff can be used, such as iron oxide, cobalt oxide and Prussian blue；Organic dyestuff, if any engine dyeing
Material, such as azo dyes or metal phthalcyanine；With with trace nutritional agent, such as iron, the violent, salt of boron, copper, cobalt, aluminum and zinc.
The molluscacide composition usually contains 0.001-99.99 weight %, preferably 0.01-99.9 weight %, more preferably
The reactive compound of the invention of 0.05-90 weight %.
A kind of mixture can be made with other reactive compounds and be present in their business for these reactive compounds of the present invention
In product preparation or from use formulation prepared by these preparations.
These other reactive compounds can be commercially available other molluscacides, such as niclosamidum, Rong Bao,
Flourish bud, Seed of Camellia Sinensis and other commercially available plant molluscicides etc..Wherein, snail killing agent flourish precious and that honor bud is two kinds of formulations, Rong Bao
For solid, main component nitrolim, flourish bud is liquid, content 25%, main component cyanamide.
These other reactive compounds can also be insecticide, close bait, fungicide, acaricide, nematicide, is killed true
Microbial inoculum, growth control agent etc..Insecticide includes, such as phosphoric acid ester, carbamates, cinerins, chlorinated hydrocarbons,
Benzoyl area kind, neires toxin and the material produced by microorganism, such as avermectin.
In addition, a kind of mixture can also be made with synergist and be present in their business for these reactive compounds of the present invention
Into from use formulation prepared by these preparations in product preparation.Synergist is the compound for improving reactive compound effect, due to
Reactive compound itself is active, can need not also add synergist.
It is made from commercial preparation and can be changed using the concentration of the reactive compound in formulation in wide scope.Use
The concentration of reactive compound in formulation can be from 0.0000001-100% (g/v), preferably between 0.0001 and 1%.
The invention mainly comprises advantages below：
(1) a kind of novel compound of structure with excellent activity against snails and preparation method thereof is provided.
(2) a kind of composition comprising above-claimed cpd is additionally provided to be used to prevent parasitic disease or kill parasite
Communication media.
With reference to specific embodiment, the present invention is further explained.It is to be understood that these embodiments are merely to illustrate this hair
It is bright rather than limit the scope of the invention.The experimental method of actual conditions is not specified in the following example, usually according to routine
Condition, or according to the condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
The preparation method (I) of embodiment (I) salicylamide compound, applied to compound 1-11：
At ambient temperature, compound a (10mmol) and compound b (10mmol) are added in toluene (40mL), added
PCl is added dropwise after heat of solution3(about 1ml), is heated to flowing back, reaction 14 it is small when after steam solvent, residue is washed three times with hot water
Recrystallize in ethanol afterwards, obtain white solid c (2.58g, yield 80%), mp232.9-233.4 DEG C, LC-MS:[M+1]+
323.04,1H-NMR(CD3Cl):δ(ppm)11.02(s,1H,NH),10.78(s, 1H,OH),8.45(d,1H,PhH),7.76
(d,1H,PhH),7.63-7.59(m,1H,PhH),7.47(d, 1H,PhH),7.26(s,1H,PhH),7.02-6.99(m,1H,
PhH),7.02-6.99(m,1H,PhH), 6.72(d,1H,PhH),3.75(s,3H,OCH3);13C-NMR(100MHz,
CD3Cl):δ(ppm)163.34, 155.14,148.26,142.91,134.76,133.30,130.63,124.82,120.16,
118.99, 118.74,117.53,105.33,56.58.。
Compound c (2mmol) is added in 10ml dichloromethane, triethylamine (0.5ml) is added, is dripped under condition of ice bath
Add R-Cl (2mmol), room temperature reaction 6 as a child adds 10ml saturations K2CO3Solution, continues stirring 30 minutes, uses dichloromethane
Extraction 3 times, extract is merged, the residue after revolving recrystallizes in ethanol, obtains compound d.
Embodiment 1
According to the method for embodiment (I), R-Cl is usedPrepare compound 1.
Example 1：Yellow solid, yield 81%, m.p.193.8-195.4 DEG C, LC-MS:[M+1]+444.75, 1H-NMR
(400MHz,CD3Cl)δ:9.15(s,1H,NH),8.59(d,1H,PhH),8.22(dd, 2H,PhH),7.96(d,1H,PhH),
7.88(d,1H,PhH),7.68(s,1H,PhH),7.61-7.57 (m,1H,PhH),7.31-7.21(m,3H,PhH),3.72
(s,3H,OCH3);13C-NMR(100MHz, CD3Cl):δ(ppm)170.14,168.53,167.14,152.87,151.65,
148.49,138.25, 138.18,138.09,137.70,137.03,135.36,134.31,130.03,129.59,
124.13, 122.28,121.22,121.00,110.24,61.07.
Embodiment 2
According to the method for embodiment (I), R-Cl is usedPrepare compound 2.
Example 2：Yellow solid, yield 84%;LC-MS:[M+1]+462.84;m.p.166.3-167.9 ℃.1H-NMR
(400MHz,CD3Cl):δ(ppm)8.81(s,1H,NH),8.62(d,1H,PhH), 8.14-8.12(m,1H,PhH),7.94-
7.89(m,2H,PhH),7.69(d,J=2.4Hz,1H,PhH), 7.57(dd,1H,PhH),7.27-7.25(m,1H,PhH),
7.02-6.94(m,2H,PhH),3.77 (s,3H,OCH3).13C-NMR(100MHz,CD3Cl):δ(ppm)165.30,
162.37,147.86, 146.47,143.81,135.06,134.96,133.45,133.03,132.80,130.52,
129.63, 125.11,119.27,117.88,112.65,112.62,112.43,112.40,105.89,105.64,
105.41,56.32.
Embodiment 3
According to the method for embodiment (I), R-Cl is usedPrepare compound 3.
Example 3：Brown solid, yield 75%, m.p.162.3-163.6 DEG C, LC-MS:[M+1]+506.74；1H-NMR
(400MHz,CD3Cl):δ(ppm)8.87(s,1H,NH),8.64(d,1H,PhH), 8.06-8.03(m,2H,PhH),7.97
(d,1H,PhH),7.90(dd,1H,PhH),7.68-7.65 (m,3H,PhH),7.56(dd,1H,PhH),7.25(d,1H,
PhH),3.69(s,3H,OCH3). 13C-NMR(100MHz,CD3Cl):δ(ppm)165.20,162.30,147.72,146.80,
143.77, 133.41,133.08,132.46,132.08,130.69,129.45,127.45,125.10,119.19,
117.91,105.40,56.25.
Embodiment 4
According to the method for embodiment (I), R-Cl is usedPrepare compound 4.
Example 4：Brown solid, yield 92%;LC-MS:[M+1]+456.81;m.p.162.1-163.3 ℃.1H-NMR
(400MHz,CD3Cl):δ(ppm)9.1(s,1H,NH),8.66(d,1H,PhH), 8.13(dd,2H,PhH),8.03(d,1H,
PhH),7.88(dd,1H,PhH),7.60(d,1H,PhH), 7.52(dd,1H,PhH),7.24-7.13(m,1H,PhH),
6.99-6.96(m,2H,PhH),3.88 (s,3H,OCH3),3.55(s,3H,OCH3).13C-NMR(100MHz,CD3Cl):δ
(ppm)164.91, 164.47,162.30,147.81,147.18,143.66,133.61,133.08,133.00,132.37,
131.14,129.04,128.15,125.17,120.64,119.25,117.84,114.36,105.27, 56.10,55.89.
Embodiment 5
According to the method for embodiment (I), R-Cl is usedPrepare compound 5.
Example 5：Brown solid, yield 46%, m.p.209.5-210.1 DEG C, LC-MS:[M+1]+471.80；1H-
NMR(CD3Cl):δ(ppm)8.65(s,1H,NH),8.58(d,1H,PhH),7.91-7.87(m,2H, PhH),7.71(s,1H,
PhH),7.61(dd,1H,PhH),7.28(t,2H,PhH),3.86(s,3H, OCH3).13C-NMR:δ(ppm)164.88,
162.33,147.75,146.68,143.55,133.48, 133.12,132.49,132.18,130.72,129.85,
127.67,125.83,119.24,117.78, 105.26,56.25.
Embodiment 6
According to the method for embodiment (I), R-Cl is usedPrepare compound 6.
Example 6：Yellow solid, yield 91%;m.p.177.3-178.5℃;LC-MS:[M+1]+458.82. 1H-NMR
(400MHz,CD3Cl):δ(ppm)9.10(s,1H,NH),8.67(d,1H,PhH), 8.10-8.05(m,3H,PhH),7.89
(dd,1H,PhH),7.62(d,1H,PhH),7.55(dd, 1H,PhH),7.34-7.23(m,3H,PhH),3.55(s,3H,
OCH3),2.47(s,3H,CH3).13C-NMR (100MHz,CD3Cl):δ(ppm)164.86,162.24,147.79,147.09,
145.94,143.66, 133.57,133.10,132.46,131.16,130.82,129.79,129.06,125.74,
125.15, 119.25,117.84,105.25,56.01,22.09.
Embodiment 7
According to the method for embodiment (I), R-Cl is usedPrepare compound 7.
Example 7：Brown solid, yield 64%;m.p.167.2-168.6℃;LC-MS:[M+1]+460.50. 1H-NMR
(400MHz,CD3Cl):δ(ppm)8.88(s,1H,NH),8.61(d,1H,PhH), 8.14-8.12(m,2H,PhH),7.97
(d,1H,PhH),7.90(dd,1H,PhH),7.66(d,1H, PhH),7.56(dd,1H,PhH),7.52-7.26(m,2H,
PhH),7.26-7.24(m,1H,PhH), 3.69(s,3H,OCH3).13C-NMR(100MHz,CD3Cl):δ(ppm)164.09,
162.30,147.72, 146.82,143.75,141.41,133.41,133.08,132.70,132.02,130.70,
129.46, 129.43,127.00,125.10,119.20,117.90,105.38,56.25.
Embodiment 8
According to the method for embodiment (I), R-Cl is usedPrepare compound 8.
Example 8：Yellow solid, yield 74%;m.p.180.6-181.8℃;LC-MS:[M+1]+432.82. 1H-NMR
(CD3Cl):δ(ppm)8.99(s,1H,NH),8.68(d,1H,PhH),8.03-8.00(m, 2H,PhH),7.92(dd,1H,
PhH),7.74(d,1H,PhH),7.67(d,1H,PhH),7.55(dd, 1H,thiophene-H),7.27(d,1H,
thiophene-H),7.26-7.20(m,1H,thiophene-H), 3.70(s,3H,OCH3).13C-NMR:δ(ppm)
162.26,147.85,146.53,143.73,136.02, 135.18,133.54,133.05,132.68,130.98,
129.28,128.64,125.04,119.27, 117.88,105.33,56.19.
Embodiment 9
According to the method for embodiment (I), R-Cl is usedPrepare compound 9.
Example 9：Yellow solid, yield 52%;m.p.230.4-231.5℃;LC-MS:[M+1]+451.79. 1H-NMR
(CD3Cl):δ(ppm)8.68(s,1H,NH),8.60(d,1H,PhH),8.29(d,2H,PhH), 7.92-7.88(m,2H,
PhH),7.82(d,2H,PhH),7.71(d,1H,PhH),7.60(dd,1H, PhH),7.26(d,1H,PhH),3.83(s,3H,
OCH3).13C-NMR:δ(ppm)163.40,162.28, 147.34,147.30,146.98,143.89,134.56,133.41,
133.21,132.46,132.58, 130.78,129.21,128.31,127.45,125.22,119.87,117.78,
105.40,56.23.
Embodiment 10
According to the method for embodiment (I), R-Cl is usedPrepare compound 10.
Example 10：Yellow solid, yield 44%;m.p.182.0-183.3℃;[M+1]+376.93. 1H-NMR(CD3Cl):
δ(ppm)10.66(s,1H,NH),8.81(d,1H,PhH),8.25(d,1H,PhH), 7.96(dd,1H,PhH),7.77(d,
1H,PhH),7.44(dd,1H,PhH),6.98(d,1H,PhH), 6.21-6.12(m,1H,=CH),5.52-5.43(m,2H,
CH2=),4.01(s,3H,OCH3).13C-NMR: δ(ppm)164.50,162.54,155.20,148.18,143.36,
134.58,133.57,132.60, 132.09,127.53,123.22,119.86,119.46,118.04,114.66,
105.43,71.22, 59.48.
Embodiment 11
According to the method for embodiment (I), R-Cl is usedPrepare compound 11.
Example 11：Yellow solid, yield 35%;m.p.171.2-172.3℃;LC-MS:[M+1]+390.75. 1H-NMR
(CD3Cl):δ(ppm)9.15(s,1H,NH),8.73(d,1H,PhH),7.98-7.94(m,2H, PhH),7.79(d,1H,
PhH),7.49(dd,1H,PhH),7.16(d,1H,PhH),4.02(s,3H, OCH3),1.93-1.89(m,1H,CH),1.16-
1.02(m,4H,CH2-CH2).13C-NMR:δ(ppm) 164.50,162.33,147.79,146.80,143.77,133.41,
133.21,132.58,132.23, 131.00,129.45,128.09,128.45,125.10,119.19,117.91,
105.40,56.25,13.4, 10.09
The preparation method (II) of embodiment (II) salicylamide compound, applied to compound 12-24：
At ambient temperature, compound a (10mmol) and compound e (10mmol) are added in toluene (40mL), added
PCl is added dropwise after heat of solution3(about 1ml), is heated to flowing back, reaction 14 it is small when after steam solvent, residue is washed three times with hot water
Recrystallize in ethanol afterwards, obtain white solid f (2.18g, yield 90%), mp216.6-217.3 DEG C, LC-MS:[M+1]+
241.99。
Compound f (2mmol) is added in 10ml dichloromethane, triethylamine (0.5ml) is added, is dripped under condition of ice bath
Add R-Cl (2mmol), room temperature reaction 6 as a child adds 10ml saturations K2CO3Solution, continues stirring 30 minutes, uses dichloromethane
Extraction 3 times, extract is merged, the residue after revolving recrystallizes in ethanol, obtains compound g.
Embodiment 12
According to the method for embodiment (II), R-Cl is usedPrepare compound 12.
Example 12：White solid, yield 76%, fusing point：137.6-139.3℃.
Embodiment 13
According to the method for embodiment (II), R-Cl is usedPrepare compound 13.
Example 13：White solid, yield 65%, fusing point：142.4-143.0℃.
Embodiment 14
According to the method for embodiment (II), R-Cl is usedPrepare compound 14.
Example 14：Yellow solid, yield 85%, fusing point：111.7-112.5℃.
Embodiment 15
According to the method for embodiment (II), R-Cl is usedPrepare compound 15.
Example 15：White solid, yield 83%, fusing point：159.0-159.9℃.
Embodiment 16
According to the method for embodiment (II), R-Cl is usedPrepare compound 16.
Example 16：White solid, yield 35%, fusing point：129.4-130.6℃.
Embodiment 17
According to the method for embodiment (II), R-Cl is usedPrepare compound 17.
Example 17：White solid, yield 64%, fusing point：173.7-175.0℃.
Embodiment 18
According to the method for embodiment (II), R-Cl is usedPrepare compound 18.
Example 18：White solid, yield 82%, fusing point：132.2-133.5℃.
Embodiment 19
According to the method for embodiment (II), R-Cl is usedPrepare compound 19.
Example 19：White solid, yield 90%, fusing point：94.7-96.3℃.
Embodiment 20
According to the method for embodiment (II), R-Cl is usedPrepare compound 20.
Example 20：White solid, yield 83%, fusing point：115.6-117.5℃.
Embodiment 21
According to the method for embodiment (II), R-Cl is usedPrepare compound 21.
Example 21：Brown solid, yield 92%, fusing point：149.6-151.1℃.
Embodiment 22
According to the method for embodiment (II), R-Cl is usedPrepare compound 22.
Example 22：White solid, yield 94%, fusing point：90.6-91.5℃.
Embodiment 23
According to the method for embodiment (II), R-Cl is usedPrepare compound 23.
Example 23：Yellow solid, yield 88%, fusing point：175.4-176.2℃.
Embodiment 24
According to the method for embodiment (II), R-Cl is usedPrepare compound 24.
Example 24：Yellow solid, yield 95%, fusing point：167.9-169.0℃.
Embodiment（III）The ovicidal trait test of the compounds of this invention and the toxotest to fish
(1)：To the ovicidal trait of oncomelania
With oncomelania (Oncomelania hupensis) for test object, tested using infusion method.
Operating process：The various samples of precise（Any compound in embodiment 1-24）, with 0.2mL N, N- dimethyl
Formyl amine solvent, is diluted to the liquid of 0.2mg/L with dechlorination tap water.30 oncomelanias are put into every beaker, respectively
The liquid of 100 milliliters of above-mentioned configurations is poured into, covering plastic gauze climbs up liquid level to prevent non-magnetic shim spiral shell on beaker, and medicine is housed by above-mentioned
The beaker of liquid and oncomelania is placed under 25 DEG C of constant temperatures, and humidity is maintained at 60%, and in the sufficient incubator of illumination, leaching respectively is killed
Liquid is removed after 24,48h, is washed 3 times with clear water, 15mL dechlorination tap water recoveries 1h, 24h recovery 1h again are added, in 24h
It is active with decision oncomelania is tapped afterwards.3 repetitions are set per a sample.
With the clear water (blank pair of 0.2mg/L niclosamidums (positive control) and the N,N-dimethylformamide containing 0.2mL/L
According to) compare.
The death toll of oncomelania is counted, and calculates the death rate (%) (the result is shown in Tables 1 and 2).
The death rate (%)=(control spiral shell number living-processing work spiral shell number)/control spiral shell number × 100% living
(2)：Research to fish acute toxicity
Tested material：Any compounds of embodiment 1-24, experimental concentration are respectively 0mg/L, 20mg/L, 40mg/L, 60mg/
L、80mg/L、100mg/L。
Test fingerling：Zebra fish, body length 20 scholar 1mm, 0.3 scholar 0.1g of weight.
Experiment process：Raised and train before experiment in the dilution water of continuous aeration 7 days, condition of water quality when raising and train and illumination bar
It is consistent when part is with testing.24h stops feeding before experiment, and the death rate during raising and train is no more than 10%, water temperature during experiment
Constant dissolved oxygen content should be higher than that the 60% of saturation of the air value in experiment in 1 DEG C of 23 scholar, and pH value is 7.0 scholars 0.2, the test period
For 96h, the interior poisoning symptom and the death rate observed at any time and record tested fish when 3 to 6 is small after on-test, its after 24h,
48h, 72h, 96h are observed and are recorded the poisoning symptom and the death rate of tested fish under various concentrations.The criterion of dead fish is to use glass
Glass touches the afterbody of fish, does not react as death.
Using method of linear interpolation, per cent death loss of the compound in 96h made from embodiment 4 is drawn to tested material
The curve (as shown in Figure 1) of concentration, so as to draw the LC of 96h50Value, is handled with clear water and makees blank control.According to said method draw it
The LC of its compound 96h50Value.
Compound is shown in Tables 1 and 2 to the toxicity data of fish made from embodiment 1-24.
Table 1. leads to the ovicidal trait of formula (I) compound and the toxicity to fish
Table 2. leads to the ovicidal trait of formula (II) compound and the toxicity to fish
The result shows that：
1）The spiral shell effect of going out of the compounds of this invention is very excellent, and the killing effect of majority of compounds 200ppm reaches
100%.
2）The LC of the compounds of this invention 96h50Value is all higher than 10mg/L, and the LC of niclosamidum 96h50Only 0.1 mg/L,
And niclosamidum under 0.2mg/L concentration apply 1 it is small when cause fish almost all death.As it can be seen that the compounds of this invention
It is very low to the toxicity of fish.Therefore, it is very safe to environment.
Embodiment（IV）The preparation for killing spiral shell worm agent composition containing the compounds of this invention
First, the preparation of molluscacide aqueous solution：
Precise reactive compound（The compound of any preparations of embodiment 1-24）, with 0.2mL N, N- dimethyl methyls
Acid amides dissolves, and is diluted to dechlorination tap water to the liquid of 0.5mg/L.
2nd, go out the preparation of spiral shell granule：
Precise reactive compound（The compound of any preparations of embodiment 1-24）, using appropriate filler material therewith
Mixing；It can make filler material with dry sandy soil or chemical fertilizer during dilution）Stir evenly by a certain percentage.
All references mentioned in the present invention is incorporated herein by reference, just as each document coverlet
Solely it is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, people in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Fixed scope.
Claims (16)
1. a kind of have the compound of structure shown in Formulas I or its pharmaceutically acceptable salt：
In formula：R3For to methoxybenzoyl base.
2. the preparation method of compound as claimed in claim 1, it is characterised in that including step：
(1) in atent solvent, in the presence of a catalyst, formula III compound and formula C compounds are reacted, so that
To formula B compounds；
(2) in atent solvent, in the presence of alkaline reagent, by formula B compounds and R3- Cl is reacted, so as to obtain formula Aization
Compound；
In various, R1For H, R2For 2- methoxyl group -4- nitrobenzophenones, and R3For to methoxybenzoyl base.
3. preparation method as claimed in claim 2, it is characterised in that in step (1), the atent solvent is selected from the group：
Water, acetone, toluene, dichloromethane, acetonitrile, ethanol.
4. preparation method as claimed in claim 2, it is characterised in that in step (1), the atent solvent is toluene, two
Chloromethanes.
5. preparation method as claimed in claim 2, it is characterised in that in step (1), the catalyst is selected from the group：
PCl3, thionyl chloride.
6. preparation method as claimed in claim 2, it is characterised in that in step (2), the atent solvent is selected from the group：
Water, acetone, toluene, dichloromethane, acetonitrile, ethanol.
7. preparation method as claimed in claim 2, it is characterised in that in step (2), the atent solvent is toluene, two
Chloromethanes.
8. preparation method as claimed in claim 2, it is characterised in that in step (2), the alkaline reagent is selected from the group：
Piperidines, DBU, DMAP, triethylamine, diisopropylethylamine, pyridine or substituted pyridine.
A kind of 9. agriculturally useful compositions, it is characterised in that comprising (a) compound as claimed in claim 1 or its can pharmaceutically connect
The salt received；And acceptable carrier or excipient in (b) Pesticide Science.
10. agriculturally useful compositions as claimed in claim 9, it is characterised in that the component (a) is in the agriculturally useful compositions
Weight content is 0.0001%-99.99%.
11. agriculturally useful compositions as claimed in claim 9, it is characterised in that the component (a) is in the agriculturally useful compositions
Weight content is 0.001%-99.9%.
12. agriculturally useful compositions as claimed in claim 9, it is characterised in that the component (a) is in the agriculturally useful compositions
Weight content is 0.01%-99%.
13. agriculturally useful compositions as claimed in claim 9, it is characterised in that the agriculturally useful compositions also include other molluscacides；
Other molluscacides are commercially available.
14. agriculturally useful compositions as claimed in claim 9, it is characterised in that other molluscacides are selected from the group：Chlorine nitre willow
Amine, Rong Bao, flourish bud, Seed of Camellia Sinensis and other commercially available plant molluscicides.
15. the purposes of compound as claimed in claim 1 or composition as claimed in claim 9, it is characterised in that be used to prepare
Prevent parasite or kill the medicine of the communication media of parasite, wherein, the communication media of the parasite is oncomelania.
16. purposes as claimed in claim 15, it is characterised in that the parasite includes：Nematode, tapeworm, fluke.
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