CN109651183A - A kind of novel amide pyrethroids class chemical modification object and its preparation method and application - Google Patents

A kind of novel amide pyrethroids class chemical modification object and its preparation method and application Download PDF

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CN109651183A
CN109651183A CN201910049647.6A CN201910049647A CN109651183A CN 109651183 A CN109651183 A CN 109651183A CN 201910049647 A CN201910049647 A CN 201910049647A CN 109651183 A CN109651183 A CN 109651183A
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chemical modification
amide
modification object
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novel
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赵肃清
张炳杰
冯冬燕
方颖林
吴可
凌华英
谭绮婷
陈燕婷
杨洋
赵佳伟
马焯霖
洪为谦
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Guangdong University of Technology
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07C233/59—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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    • C07C233/60—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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Abstract

The invention discloses a kind of novel amide pyrethroids class chemical modification objects and its preparation method and application.Shown in the following formula (I) of structural formula of the novel amide pyrethroids class chemical modification object:, wherein R is to contain monosubstituted or polysubstituted aromatic ring class group.The present invention mainly by transfluthrin two end position chlorine atoms and ester group carry out modification transformation, will two end position chlorine atom be substituted for two bromine atoms, above-mentioned ester group is substituted for the structure of amide groups simultaneously, ring class replaces the substitution of predominantly aryl rings simultaneously, forms the novel chrysanthemum acidamide derivant structure containing dibromo substitution and amide based structures of a series of new.These novel chrysanthemum acidamide derivatives all have larva and adult mosquito certain desinsection effect exterminating mosquito, and it can be improved metabolic stability and reduce the toxicity of environment, and it can effectively solve existing pyrethroid insecticides drug resistance serious problem outstanding, with excellent transformation potential, have a extensive future.

Description

A kind of novel amide pyrethroids class chemical modification object and its preparation method and application
Technical field
The invention belongs to the technical field of pesticide of Medicine small molecule structural modification.More particularly, to a kind of novel amide Pyrethroids class chemical modification object and its preparation method and application.
Background technique
The female adult mosquito sucked blood is to propagate dengue fever, malaria, yellow fever, filariasis, Japanese Type-B encephalitis etc. up to 80 The intermediate host of the pathogen of a variety of diseases.The hot temperature and moist humidity of summer is that the breeding of mosquito and haunting provides Suitable condition.Entire summer or even part autumn are all the time that mosquito breeds and haunts, and the habit of mosquito just gives people Daily life bring greatly harm and influence, especially for aedes albopictus, also referred to as Asia tiger line, have very strong Vitality and cold tolerance and vitality, and breed that spread speed is fast, be the Common Mosquitoes kind in Southeast Asia and China.Based on this, Desinsection mosquito eradication and mosquito repellent keep away mosquito be prevention and control mosquito vection disease important measures, therefore effectively insecticide or Mosquito-repellent seems very necessary for daily life and work.It also more needs to drug resistance mosquito at present Insecticide or repellant can show good effect it is also desirable to small for the toxic of human body or animal, very To almost without harmfulness, environment especially aquatile is not poisoned or polluted.
Pyrethroid insecticides are the insecticide of a kind of biomimetic type synthesis, such as etrafluorine ethofenprox, can be used for mosquito The prevention and treatment of worm harm, and have many advantages, such as high specificity, insecticidal activity height and the small preventing and controlling field in mosquito of toxic In be widely used.Pyrethroid coumpound is initially to study chrysanthemum at United Kingdom National Research And Development Corp (NRDC) Extract be found when there are natural insecticidal properties.The research team has synthesized the pyrethroid stable to light first Compound, and chrysanthemum extract property before is unstable, just loses insecticidal activity after light-exposed.The pyrethroid of early stage synthesis The racemic mixture that ester type compound is made of many isomers is not to all have insecticidal activity.Tradition Viewpoint thinks, pyrethroid insecticides have bioactivity, low environment and the food residue degree, relatively of broad-spectrum high efficacy Low mammalian toxicity.But more and more research discovery pyrethroids can interfere the normal function of organism, to the mankind Sizable threat is caused with the health of animal.Some researches show that being exposed in the environment containing pyrethroid for a long time can be to people The health of body especially children has an adverse effect.And as some traditional pyrethroid insectides are long-term a large amount of single Use, the pests such as mosquitos and flies produce apparent drug resistance for pesticide, it is therefore desirable to a kind of high-efficiency low-toxicity type new type structure Pesticide compound.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the defect of the above-mentioned prior art and deficiencies, provide a kind of novel amide Pyrethroids class chemical modification object is high-efficiency low-toxicity type new type disinsection immunomodulator compounds.
It is a further object to provide a kind of preparation methods of novel amide pyrethroids class chemical modification object.
It is also another object of the present invention to provide above-mentioned novel amide pyrethroids class chemical modification object or use above method system Amide pyrethroids class chemical modification object as or application in terms of preparing insecticide.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
A kind of novel amide pyrethroids class chemical modification object, shown in structural formula such as following formula (I):
Wherein, R is to contain monosubstituted or polysubstituted aromatic ring class group.
Further, in preferred embodiments of the present invention, the aromatic ring class group is containing phenyl ring and/or thiphene ring Aromatic ring class group, or be the aromatic ring class group containing furan nucleus.
Further, in preferred embodiments of the present invention, R F, Cl ,-CH3O、-CF3,-CN or-OCF3。
Further, in preferred embodiments of the present invention, the aromatic ring class group is
The present invention mainly by transfluthrin two end position chlorine atoms and ester group carry out modification transformation, i.e., by two The chlorine atom of a end position is substituted for two bromine atoms, while above-mentioned ester group being substituted for the structure of amide groups, while ring class takes For the substitution of predominantly aryl rings, a variety of substituent groups such as halogen atom, methyl, methoxyl group, trifluoromethoxy are had in aryl rings Group forms the novel chrysanthemum acidamide derivant structure containing dibromo substitution and amide based structures of a series of new.These are novel Chrysanthemum acidamide derivant structure can be improved metabolic stability and reduce the toxicity of environment, and have good kill for larva Worm effect, while the novel chrysanthemum acidamide derivative in part also has certain desinsection effect exterminating mosquito to adult mosquito, this class formation has Excellent transformation potential.
The invention further relates to a kind of preparation methods of novel amide pyrethroids class chemical modification object, comprising the following steps:
S1. in protective gas atmosphere, super dry dichloromethane solvent is added into dibromo chrysanthemic acid and stirs at room temperature After mixing dissolution, ethanedioly chloride is added, after stirring 30~35min at room temperature, n,N-Dimethylformamide is added, in room temperature Stirring is lower to react 0.8~1h；
S2. product is dried under vacuum conditions, and super dry dichloromethane solvent is added in protective gas atmosphere, in room Under the conditions of temperature after stirring and dissolving, anhydrous pyridine is added, after being stirred to react 25~30min, adds cyclic annular benzylamine, be esterified anti- Answer 2~3h；
S3. crude product is obtained by washing extraction drying after completion of the reaction, then is purified by silica gel column chromatography, can obtained To novel amide pyrethroids class chemical modification object.
Further, in preferred embodiments of the present invention, in step S1, the substance of the dibromo chrysanthemic acid and ethanedioly chloride The ratio between amount be 1:2~3.
Further, in preferred embodiments of the present invention, in step S2, the amount of the substance of dibromo chrysanthemic acid and anhydrous pyridine The ratio between be 1:2~3；The ratio between dibromo chrysanthemic acid and the amount of substance of cyclic annular benzylamine are 1:1~2.
Further, in preferred embodiments of the present invention, it is described ring-type benzylamine be selected from benzene methanamine, 4- cyano benzene methanamine, 3,5- difluorobenzylamine, to trifluoromethyl benzylamine, 4-Methoxybenzylamine, 2- (trifluoromethoxy) benzylamine, fluoro- 4 emilium tosylate of 3-, 4- Phenoxybenzylamine, o-chlorine benzylamine, chlorobenzylamine, to chlorobenzylamine, adjacent fluorin benzyl amine, fluorin benzyl amine, 4-Fluorobenzylamine, O-methoxy benzylamine Or meta-methoxy benzylamine.
Further, in preferred embodiments of the present invention, the additional amount of the n,N-Dimethylformamide is 0.1mL.
Further, in preferred embodiments of the present invention, the protective gas is nitrogen.
Above-mentioned novel amide pyrethroids class chemical modification object or the novel amide pyrethroids class being prepared using the above method Learn modifier as or prepare application in insecticide, also within protection model of the invention.
Novel amide pyrethroids class chemical modification object of the present invention is preparing anti-mosquito, mosquito repellent, prevention and/or control malaria It has a good application prospect in drug in terms of the diseases such as disease, encephalitis B, yellow fever, malaria and filariasis.In addition, described Novel amide pyrethroids class chemical modification object can also be applied in pesticide chemicals and/or daily hygiene.
Further, in preferred embodiments of the present invention, the insecticide is anti-mosquito or culicifuge.
Further, in preferred embodiments of the present invention, the mosquito in the mosquito eradication or culicifuge is aedes albopictus And/or Culex quinquefasciatus.
Compared with prior art, the invention has the following advantages:
(1) present invention is chemically modified the structure of transfluthrin, obtains a series of new chrysanthemum amide chemical modification Object, these new compounds show certain insecticidal activity, and can be improved metabolic stability and reduce the toxicity of environment, It can be widely applied in the field application of desinsection mosquito eradication, new safe and efficient, stable compound provided for desinsection, effectively Solve drug resistance problems.
(2) present invention has reaction process simple, and reaction step is few, and the yield of synthesis is higher, and reaction time is short, repeated The advantages such as good, have a good application prospect and wide development space in pesticide field.
Detailed description of the invention
Fig. 1 is desinsection mosquito eradication kinetic test result of the analyte derivative object to female adult mosquito of the embodiment of the present invention 6.
Fig. 2 is the oxidation stability of chrysanthemum amide derivatives and transfluthrin.
Specific embodiment
Further illustrate the present invention below in conjunction with specific embodiment, but embodiment the present invention is not done it is any type of It limits.Unless otherwise specified, the conventional means that technological means used in embodiment is well known to those skilled in the art.Unless It illustrates, reagent that the present invention uses, method and apparatus is the art conventional reagents, method and apparatus.
Unless stated otherwise, following embodiment agents useful for same and material are commercially available.
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-01) of embodiment 1
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-01), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding the benzene methanamine 143mg (1.342mmol) of doubling dose, in room temperature under nitrogen Under protective condition, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=4:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-01, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 8:1) obtain compound DCA-CONH-01, colorless and transparent thick liquid, Rf=0.55 (solvent: petroleum ether: ethyl acetate= 4:1), yield: 69%.
2, result
(1) compound DCA-CONH-01, shown in molecular structural formula such as formula (1):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.39-7.31 (m, 2H), 7.28 (td, J=6.6,3.5Hz, 3H), 6.98 (d, J=8.8Hz, 1H), 6.16-5.65 (m, 1H), 4.42 (dt, J=5.7,2.8Hz, 2H), 1.88 (t, J=8.6Hz, 1H), 1.55 (dt, J=8.5, 1.7Hz, 1H), 1.31 (d, J=1.3Hz, 3H), 1.22 (s, 3H)13C NMR(101MHz,CDCl3)δ169.49,138.40, 134.50,128.87,127.95,127.94,127.66,88.43,43.84,35.14,33.98,28.82,26.66,15.40。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-02) of embodiment 2
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-02), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding the 4- cyano benzene methanamine 177mg (1.342mmol) of doubling dose, in room Under the conditions of warm nitrogen protection, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=4:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-02, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 8:1) obtain compound DCA-CONH-02, colourless light yellow viscous liquid, Rf=0.28 (solvent: petroleum ether: ethyl acetate =4:1), yield: 61%.
2, result
(1) compound DCA-CONH-02, shown in molecular structural formula such as formula (2):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.66-7.54 (m, 2H), 7.36 (d, J=8.1Hz, 2H), 6.90 (d, J=8.7Hz, 1H), 6.08 (t, J=5.8Hz, 1H), 4.55-4.40 (m, 2H), 1.91 (t, J=8.6Hz, 1H), 1.30 (s, 3H), 1.23 (s, 3H)13C NMR (101MHz,CDCl3)δ169.84,144.14,134.19,132.61,128.22,118.83,111.35,88.83,43.26, 35.30,33.81,28.79,26.89,15.34。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-03) of embodiment 3
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-03), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding 3, the 5- difluorobenzylamine 192mg (1.342mmol) of doubling dose, in room Under the conditions of warm nitrogen protection, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=4:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-03, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= Compound DCA-CONH-03 8:1) is obtained: colourless viscous liquid, Rf=0.46 (solvent: petroleum ether: ethyl acetate=4: 1), yield: 70%.
2, result
(1) compound DCA-CONH-03, shown in molecular structural formula such as formula (3):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 6.92 (d, J=8.7Hz, 1H), 6.78 (h, J=4.5Hz, 2H), 6.70 (tt, J=8.9,2.4Hz, 1H), 6.02 (t, J=6.1Hz, 1H), 4.39 (qd, J=15.4,6.0Hz, 2H), 1.91 (t, J=8.6Hz, 1H), 1.30 (s, 3H),1.23(s,3H).13C NMR(101MHz,CDCl3)δ169.67,164.41,161.94,142.46,134.03, 110.20,102.84,88.68,42.82,42.80,35.18,33.71,28.66,26.77,15.21。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-04) of embodiment 4
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-04), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and be stirred to react 30min, be eventually adding doubling dose to trifluoromethyl benzylamine 235mg (1.342mmol), Under room temperature under nitrogen protective condition, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=12:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-04, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 8:1) obtain compound DCA-CONH-04, colourless viscous liquid, Rf=0.38 (solvent: petroleum ether: ethyl acetate=12: 1), yield: 65%.
2, result
(1) compound DCA-CONH-04, shown in molecular structural formula such as formula (4):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz,CDCl3)δ 7.60,7.58,7.38,7.36,7.26,6.94,6.92,6.03,6.01,6.00,4.48,4.46,2.03,1.92,1.90, 1.88,1.63,1.60,1.57,1.31,1.25,1.23,1.20,0.88,0.86.13C NMR(101MHz,CDCl3)δ 169.73,142.63,134.29,129.91,127.97,125.80,124.22,88.76,43.26,35.26,33.90, 28.80,26.81,15.37。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-05) of embodiment 5
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-05), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding the 4-Methoxybenzylamine 184mg (1.342mmol) of doubling dose, in room Under the conditions of warm nitrogen protection, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-05, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 15:1) obtain compound DCA-CONH-05, colourless viscous liquid, Rf=0.45 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 62%.
2, result
(1) compound DCA-CONH-05, shown in molecular structural formula such as formula (5):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.24-7.14 (m, 2H), 6.98 (d, J=8.8Hz, 1H), 6.90-6.83 (m, 2H), 5.79 (d, J= 5.9Hz, 1H), 4.35 (d, J=5.5Hz, 2H), 3.80 (s, 3H), 1.86 (t, J=8.6Hz, 1H), 1.53 (d, J=8.5Hz, 1H),1.31(s,3H),1.21(s,3H).13C NMR(101MHz,CDCl3)δ169.23,159.06,134.40,130.37, 129.20,114.14,88.25,55.33,43.20,34.99,33.89,28.70,26.50,15.28。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-06) of embodiment 6
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-06), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) product of previous step reaction activation in the round-bottomed flask after reaction 1h is done in vacuum revolving evaporimeter revolving It is dry, and reduce outside air as far as possible in operation and enter in round-bottomed flask, protection gas then is done with nitrogen, is added super dry Dichloromethane solvent is placed on blender after stirring and dissolving at room temperature, is subsequently added into the anhydrous pyridine of doubling dose 0.109mL (1.342mmol), and it is stirred to react 30min, it is eventually adding 2- (trifluoromethoxy) the benzylamine 256mg of doubling dose (1.342mmol) is stirred to react 2h under room temperature under nitrogen protective condition；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-06, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 32:1) obtain compound DCA-CONH-06, colourless viscous liquid, Rf=0.40 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 60%.
2, result
(1) compound DCA-CONH-06, shown in molecular structural formula such as formula (6):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.42 (dd, J=7.3,2.1Hz, 1H), 7.37-7.26 (m, 3H), 6.96 (d, J=8.8Hz, 1H), 5.97 (t, J=6.1Hz, 1H), 4.58-4.46 (m, 2H), 1.90 (t, J=8.6Hz, 1H), 1.58 (d, J=8.5Hz, 1H), 1.31(s,3H),1.24(s,3H).13C NMR(101MHz,CDCl3)δ169.47,147.32,134.22,130.88, 130.27,128.97,127.20,120.65,120.55,88.44,38.18,35.06,33.74,28.65,26.61,15.17。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-07) of embodiment 7
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-07), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) product of previous step reaction activation in the round-bottomed flask after reaction 1h is done in vacuum revolving evaporimeter revolving It is dry, and reduce outside air as far as possible in operation and enter in round-bottomed flask, protection gas then is done with nitrogen, is added super dry Dichloromethane solvent is placed on blender after stirring and dissolving at room temperature, is subsequently added into the anhydrous pyridine of doubling dose 0.109mL (1.342mmol), and it is stirred to react 30min, it is eventually adding the fluoro- 4 emilium tosylate 208mg of 3- of doubling dose (1.342mmol) is stirred to react 2h under room temperature under nitrogen protective condition；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-07, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 10:1) obtain compound DCA-CONH-07, colourless viscous liquid, Rf=0.45 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 66%.
2, result
(1) compound DCA-CONH-07, shown in molecular structural formula such as formula (7):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.06-6.82 (m, 4H), 5.92 (t, J=5.6Hz, 1H), 4.40-4.26 (m, 2H), 3.87 (s, 3H), 1.87 (t, J=8.6Hz, 1H), 1.55 (d, J=8.6Hz, 1H), 1.30 (s, 3H), 1.21 (s, 3H)13C NMR(101MHz, CDCl3)δ169.52,152.50,147.11,134.40,131.54,12.65,115.69,113.71,88.53,56.49, 42.94,42.92,35.18,33.93,28.80,26.70,15.37。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-08) of embodiment 8
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-08), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) product of previous step reaction activation in the round-bottomed flask after reaction 1h is done in vacuum revolving evaporimeter revolving It is dry, and reduce outside air as far as possible in operation and enter in round-bottomed flask, protection gas then is done with nitrogen, is added super dry Dichloromethane solvent is placed on blender after stirring and dissolving at room temperature, is subsequently added into the anhydrous pyridine of doubling dose 0.109mL (1.342mmol), and it is stirred to react 30min, it is eventually adding the 4- Phenoxybenzylamine 267mg of doubling dose (1.342mmol) is stirred to react 2h under room temperature under nitrogen protective condition；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-08, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 10:1) obtain compound DCA-CONH-08, colourless viscous liquid, Rf=0.48 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 58%.
2, result
(1) compound DCA-CONH-08, shown in molecular structural formula such as formula (8):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.40-7.33 (m, 2H), 7.28 (d, J=8.8Hz, 2H), 7.17-7.10 (m, 1H), 7.07-6.94 (m, 5H), 5.84 (s, 1H), 4.43 (d, J=5.6Hz, 2H), 1.91 (t, J=8.6Hz, 1H), 1.34 (s, 3H), 1.25 (s, 3H).13C NMR(101MHz,CDCl3)δ169.44,157.24,156.87,134.45,133.23,129.92,129.45, 123.51,119.21,119.03,88.51,43.30,35.17,34.02,28.84,26.69,15.42。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-09) of embodiment 9
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-09), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding the o-chlorine benzylamine 190mg (1.342mmol) of doubling dose, in room temperature nitrogen Under the conditions of gas shielded, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-09, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 16:1) obtain compound DCA-CONH-09, colourless viscous liquid, Rf=0.45 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 71%.
2, result
(1) compound DCA-CONH-09, shown in molecular structural formula such as formula (9):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.39 (dt, J=7.0,1.9Hz, 2H), 7.30-7.26 (m, 1H), 7.26-7.22 (m, 1H), 6.95 (d, J=8.7Hz, 1H), 6.02 (d, J=6.1Hz, 1H), 4.54 (d, J=6.0Hz, 2H), 1.89 (t, J=8.6Hz, 1H), 1.58(s,1H),1.30(s,3H),1.24(s,3H).13C NMR(101MHz,CDCl3)δ169.47,135.85,134.40, 133.78,130.35,129.68,129.10,127.30,88.57,41.69,35.13,33.94,28.80,26.67,15.39。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-10) of embodiment 10
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-10), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding chlorobenzylamine 190mg (1.342mmol) between doubling dose, in room temperature nitrogen Under the conditions of gas shielded, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-10, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 16:1) obtain compound DCA-CONH-10, colourless viscous liquid, Rf=0.45 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 69%.
2, result
(1) compound DCA-CONH-10, shown in molecular structural formula such as formula (10):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.32-7.26 (m, 3H), 7.17 (dt, J=6.4,2.1Hz, 1H), 6.97 (d, J=8.7Hz, 1H), 5.96 (t, J=6.0Hz, 1H), 4.49-4.35 (m, 2H), 1.92 (t, J=8.6Hz, 1H), 1.60 (d, J=8.4Hz, 1H), 1.33(s,3H),1.25(s,3H).13C NMR(101MHz,CDCl3)δ169.63,140.54,134.68,134.32, 130.14,127.88,127.79,125.94,88.65,43.21,35.24,33.93,28.81,26.79,15.37。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-11) of embodiment 11
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-11), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and be stirred to react 30min, be eventually adding doubling dose to chlorobenzylamine 190mg (1.342mmol), in room temperature nitrogen Under the conditions of gas shielded, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-11, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 16:1) obtain compound DCA-CONH-11, colourless viscous liquid, Rf=0.46 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 72%.
2, result
(1) compound DCA-CONH-11, shown in molecular structural formula such as formula (11):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.31 (d, J=8.3Hz, 2H), 7.20 (d, J=8.1Hz, 2H), 6.94 (d, J=8.8Hz, 1H), 5.86 (t, J=5.8Hz, 1H), 4.39 (d, J=5.7Hz, 2H), 1.89 (t, J=8.6Hz, 1H), 1.31 (s, 3H), 1.22 (s,3H).13C NMR(101MHz,CDCl3)δ169.41,136.88,134.21,133.32,129.10,128.86,88.50, 42.98,35.07,33.82,28.68,26.61,15.25。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-12) of embodiment 12
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-12), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding the adjacent fluorin benzyl amine 168mg (1.342mmol) of doubling dose, in room temperature nitrogen Under the conditions of gas shielded, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-12, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 16:1) obtain compound DCA-CONH-12, colourless viscous liquid, Rf=0.42 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 67%.
2, result
(1) compound DCA-CONH-12, shown in molecular structural formula such as formula (12):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.34 (td, J=7.6,1.8Hz, 1H), 7.31-7.26 (m, 1H), 7.14 (td, J=7.5,1.2Hz, 1H), 7.07 (ddd, J=9.6,8.2,1.2Hz, 1H), 6.96 (d, J=8.7Hz, 1H), 5.96 (t, J=5.9Hz, 1H), 4.50 (d, J=5.9Hz, 2H), 1.89 (t, J=8.6Hz, 1H), 1.57 (d, J=8.5Hz, 1H), 1.30 (s, 3H), 1.23 (s,3H).13C NMR(101MHz,CDCl3)δ169.49,161.19,134.41,130.42,129.46,125.41,124.51, 115.54,88.51,37.78,37.74,35.13,33.93,28.80,26.67,15.36。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-13) of embodiment 13
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-13), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding fluorin benzyl amine 168mg (1.342mmol) between doubling dose, in room temperature nitrogen Under the conditions of gas shielded, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-13, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 16:1) obtain compound DCA-CONH-13, colourless viscous liquid, Rf=0.42 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 65%.
2, result
(1) compound DCA-CONH-13, shown in molecular structural formula such as formula (13):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.35-7.24 (m, 1H), 7.08-7.00 (m, 1H), 7.01-6.89 (m, 3H), 5.95 (d, J= 6.1Hz 1H), 4.49-4.33 (m, 2H), 1.89 (t, J=8.6Hz, 1H), 1.57 (d, J=8.5Hz, 1H), 1.31 (s, 3H), 1.23(s,4H).13C NMR(101MHz,CDCl3)δ169.62,163.12,141.07,134.34,130.38,123.32, 114.69,114.47,88.61,43.25,35.22,33.92,28.81,26.77,15.37。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-14) of embodiment 14
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-14), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding the 4-Fluorobenzylamine 168mg (1.342mmol) of doubling dose, in room temperature nitrogen Under the conditions of gas shielded, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-14, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 16:1) obtain compound DCA-CONH-14, colourless viscous liquid, Rf=0.42 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 68%.
2, result
(1) compound DCA-CONH-14, shown in molecular structural formula such as formula (14):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.28 (d, J=6.1Hz, 1H), 7.25 (d, J=5.5Hz, 1H), 7.08-7.01 (m, 2H), 6.97 (d, J=8.8Hz, 1H), 5.89 (s, 1H), 4.41 (d, J=5.6Hz, 2H), 1.90 (t, J=8.6Hz, 1H), 1.33 (s, 3H), 1.24(s,3H).13C NMR(101MHz,CDCl3)δ169.50,162.32,134.40,134.26,129.59,115.71, 88.57,43.10,35.17,33.96,28.82,26.71,15.39。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-15) of embodiment 15
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-15), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding the O-methoxy benzylamine 184mg (1.342mmol) of doubling dose, in room Under the conditions of warm nitrogen protection, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-15, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 15:1) obtain compound DCA-CONH-15, colourless viscous liquid, Rf=0.46 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 65%.
2, result
(1) compound DCA-CONH-15, shown in molecular structural formula such as formula (15):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.29 (d, J=8.2Hz, 1H), 7.26 (s, 1H), 7.00-6.86 (m, 3H), 6.05 (d, J=6.1Hz, 1H), 4.43 (d, J=5.8Hz, 2H), 3.88 (s, 3H), 1.84 (t, J=8.7Hz, 1H), 1.53 (d, J=8.5Hz, 1H), 1.29(s,3H),1.21(s,3H).13C NMR(101MHz,CDCl3)δ169.12,157.72,134.68,129.99, 129.05,126.43,120.87,110.48,88.15,55.50,39.57,34.98,34.16,28.84,26.47,15.42。
The preparation of the novel chrysanthemum amide chemical modification object (DCA-CONH-16) of embodiment 16
1, the preparation of novel chrysanthemum amide chemical modification object (DCA-CONH-16), comprising the following steps:
(1) dibromo chrysanthemic acid of 200mg (0.671mmol) is weighed first in the round-bottomed flask of 50mL, in nitrogen protection Under the conditions of, with syringe measure the super dry anhydrous methylene chloride of 15mL in flask and stirring make it completely dissolved after, then plus Enter ethanedioly chloride 0.171mL (2.014mmol), the stir about 30min of triplication, is then added 0.1mL's with the syringe of 1mL Anhydrous grade n,N-Dimethylformamide (DMF), reaction can generate a large amount of bubble, then react 1h at room temperature；
(2) it will react in the round-bottomed flask after 1h and react the product of activation in vacuum revolving evaporimeter revolving drying, and Outside air is reduced in operating process as far as possible to enter in round-bottomed flask, then does protection gas with nitrogen, super dry dichloromethane is added Alkane solvents are placed on blender after stirring and dissolving at room temperature, are subsequently added into the anhydrous pyridine 0.109mL of doubling dose (1.342mmol), and it is stirred to react 30min, it is eventually adding the meta-methoxy benzylamine 184mg (1.342mmol) of doubling dose, in room Under the conditions of warm nitrogen protection, it is stirred to react 2h；
(3) reaction end (solvent: petroleum ether: ethyl acetate=8:1) is detected with TLC, it is dry etc. by washing extraction Step obtains the crude product of compound DCA-CONH-16, by silica gel column chromatography purifying (eluant, eluent: petroleum ether: ethyl acetate= 15:1) obtain compound DCA-CONH-16, colourless viscous liquid, Rf=0.48 (solvent: petroleum ether: ethyl acetate=8: 1), yield: 70%.
2, result
(1) compound DCA-CONH-16, shown in molecular structural formula such as formula (16):
(2) pass through nuclear magnetic resonance1HNMR、13C NMR analysis etc. carries out Structural Identification.1H NMR(400MHz, Chloroform-d) δ 7.28 (td, J=4.2,1.7Hz, 1H), 7.01 (d, J=8.8Hz, 1H), 6.92-6.79 (m, 3H), 5.96 (t, J=5.9Hz, 1H), 4.42 (dd, J=5.7,1.7Hz, 2H), 3.83 (s, 3H), 1.91 (t, J=8.6Hz, 1H), 1.59 (d, J=8.5Hz, 1H), 1.35 (s, 3H), 1.25 (s, 3H)13C NMR(101MHz,CDCl3)δ169.50,160.01, 140.03,134.48,129.87,120.10,113.36,113.21,88.37,55.37,43.76,35.17,33.97, 28.81,26.69,15.37。
17 larva desinsection mosquito eradication active testing of embodiment
Aedes albopictus children mosquito (Aedes has been carried out using 24 well plate methods come compound of the measuring method to embodiment 1~16 Albopictus larva) insecticidal activity test.
The test of larva half lethal concentration: this experiment carries out novel chrysanthemum amide and its chemical modification object by sterile 24 orifice plate To the active testing of Aedes Albopictus Larva half lethal concentration.
Experiment obtains the sample after being diluted of 12 gradients using acetone (Aceton) solvent using doubling dilution first Product compound, 985 μ L are then added into each orifice plate with liquid-transfering gun goes chlorine water and the food solns (fish of 13mg/mL of 5 μ L Powdered food solution), and the larva (5~10) of 5 or more 1 ages is added into each orifice plate.It is added into each orifice plate The sample compound of 8 concentration gradients of 10 μ L, each sample concentration is in parallel in triplicate；It is placed on 26~28 DEG C of room temperature condition After lower culture for 24 hours, the death rate or lethality of each orifice plate are recorded.And all novel chrysanthemum amide derivatives are counted to 1 age The semilethal rate LC of phase larva50Value, statistical result see the table below 1.
The novel chrysanthemum amide derivatives of table 1 test the killing activity of 1 instar larvae of mosquito
Note: every group of experiment is repeated 3 times, and data indicate average value (n=3) ± standard deviation in table.LC50It is dense for median lethal Degree.Mosquito selection is the aedes albopictus of sensitive strain, and it is 01~No. 16 that compound number, which can simplify,.The adult mosquito of blank group is dead Rate controls within 5%.
Carry out measuring method by using 24 well plate methods and aedes albopictus children mosquito (Aedes has been carried out to embodiment 1~16 Albopictus larva) insecticidal activity test result illustrate that novel dibromo chrysanthemum amide structure of the invention is for white There is the larva of line yellow-fever mosquito killing effect, especially 06,09 and 15 3 group of derivative of embodiment to show to larva with excellent Insecticidal activity, i.e., the structure of the part ortho position substitution in novel dibromo chrysanthemum amide phenyl ring there is height to have Aedes Albopictus Larva The insecticidal effect of effect.
18 adult mosquito desinsection mosquito eradication active testing of embodiment
Using CDC bottle bioassay experiment to the compound of embodiment 6,9,15 carried out aedes albopictus female at The insecticidal activity of mosquito (Aedes albopictus female adult mosquito) is tested.Novel thiol pyrethroids derivative pair The insecticidal activity experiment test of female adult mosquito and result are as shown in table 2 below.Table 3 indicates two positive group Biphenthrins and phenyl tetrafluoride Pyrethroids tests the insecticidal activity of female adult mosquito.
The active testing of female adult mosquito: carrying out in female adult mosquito experiment, by it is all go out pupas after adult mosquito with 10% syrup With dechlorination Aquaponic 3~5 days or so, it is then blood sucking using female adult mosquito and then isolate female mosquito.Adult mosquito experiment uses Standard CD C bottle bioassay (contact method), experiment are obtained using acetone (Aceton) solvent using doubling dilution first Sample compound after to being diluted of 10 gradients, then each sample compound does high, normal, basic 3 groups of different concentration, each Concentration is repeated 3 times in parallel, and the sample solution of 1mL is added into each favour bottle, is uniformly coated on the inner bottle of entire favour bottle On wall, placement is protected from light dry 2~3h in ventilating and cooling place or so, after it is completely dried, is added 15~25 into each favour bottle Only or above female adult mosquito, every the The dead quantity of 15 minutes record mosquitoes, and it is derivative finally to count novel thiol pyrethroids Object is shown in Table 2 and table 3 to the lethality in different time periods of female adult mosquito 30min, 60min and 120min etc. 3, statistical result.
The novel chrysanthemum amide derivatives of table 2 test female adult mosquito using CDC bottle bioassay
Note: every group of experiment is repeated 3 times, and data indicate average value (n=3) ± standard deviation in table.μ g/bottle indicates every Additional amount in a favour bottle.Then 06,09 and No. 15 sample 1600,200 and 12.5 high, normal, basic three different concentration and system are taken Count out the lethality of respective concentration and corresponding time point.
The positive group of table 3 tests the CDC bottle bioassay of aedes albopictus female adult mosquito
Note: every group of experiment is repeated 3 times, and data indicate average value (n=3) ± standard deviation in table.μ g/bottle indicates every Additional amount in a favour bottle.Then Biphenthrin and transfluthrin is taken to take 1600,12.5 and 1.56 μ g/ as a control group The high, normal, basic three different concentration of bottle and the lethality for counting respective concentration and corresponding time point.
Aedes albopictus female adult mosquito (Aedes has been carried out by using CDC bottle bioassay experiment Albopictus female adult mosquito) insecticidal activity test and result illustrate, the novel chrysanthemum amide of the present invention Under the conditions of a certain concentration, still there is killing activity to female adult mosquito, and over time, the effect of desinsection also by It is cumulative to add.Although still there are also a certain distance compared with two positive controls.But such derivant structure has structure letter Single, it is convenient easy to synthesize, the advantages such as synthesis cost is cheap.
The experiment of 19 adult mosquito desinsection mosquito eradication kinetic test of embodiment
According to 18 adult mosquito desinsection mosquito eradication active testing of embodiment as a result, choosing the sample of the best embodiment 6 of effect exterminating mosquito Product derivative carries out dynamic experiment test, all operating methods and embodiment 18 with the compound of 6 various concentration gradients It is identical, survival/The dead quantity of female adult mosquito inside favour bottle is surveyed at interval of 15min, and finally make corresponding time point Lethality, follow-on test 120min.And by calculating and counting, the curve of the death rate of female adult mosquito at any time is drawn out such as Shown in Fig. 1.
It is as shown in Figure 1 to female adult mosquito desinsection mosquito eradication kinetic test experimental result to obtain No. 06 derivative.It can by Fig. 1 Know, such novel chrysanthemum amide DCA-CONH-06 sample has excellent desinsection mosquito eradication activity to female adult mosquito, and with sample The increase of concentration, insecticidal activity gradually increase.In addition over time, under conditions of same concentration, female adult mosquito it is dead The rate of dying is also to gradually increase, and is shown over time, and novel chrysanthemum amide derivatives of the invention are to female adult mosquito Desinsection mosquito eradication activity is enhancing.
The test of 20 metabolic stability of embodiment
1, oxidation of drug stability approach
Any DCA-CONH-06 number chosen in thiol synthesis pyrethroids derivative is a, and chooses transfluthrin It is b as standard control group #；20mg is respectively weighed, is dissolved in the methanol solvate of 2mL, stirring 15min dissolves it sufficiently； Then the oxydol H of 200 μ L 30% is respectively taken with liquid-transfering gun2O2, and start, 60min after stopping meter primary every 15min timing When, it is c that blank control group is dissolved in the methanol solvate of 2mL number with DCA-CONH-06, and stirring and dissolving.With TLC detectionization Close object stability (solvent: petroleum ether: ethyl acetate=8:1), then will number a, b and c three groups of tests sample into The stability contrast of row TLC detection compound.
2, result
Experiment discovery, as shown in Fig. 2, when sample is dissolved in 2mL methanol, when the hydrogen peroxide of 200 μ L is added, chrysanthemum amide DCA- CONH-06, transfluthrin control group generates micro white bubble, but after 15min hydrogen peroxide oxidation, works as use When TLC plate contact plate (solvent: petroleum ether: ethyl acetate=8:1), it is only that blank control group c group, which is held essentially constant, which not to be become, One point is Rf=0.40；And the DCA-CONH-06 of a group does not change substantially, with blank control group a group basic one It causes, illustrates that chrysanthemum amide stability is very good；B group point plate sample, which has raw material point also, other impure points, illustrates phenyl tetrafluoride chrysanthemum Ester control group is by hydrogen peroxide partial oxidation；Measurement is primary again after 60min, and the oxidation of transfluthrin is more, occurs apparent White bubble, when (solvent: petroleum ether: ethyl acetate=8:1) measures when using TLC plate contact plate, original point becomes Fuzzy, impure point becomes apparent, and illustrates that transfluthrin is largely oxidized.
For synthesis, the oxidation stability of transfluthrin will be weaker than chrysanthemum amide chemical modification object of the invention；Root simultaneously According in embodiment 17 and embodiment 18 anti-mosquito activity in it can be concluded that, chrysanthemum amide in larva insecticidal activity equally have it is excellent Insecticidal activity, but it is poor for the insecticidal activity of adult mosquito.This may have inevitable relationship, chrysanthemum amide with the structure of compound Polarity is bigger than transfluthrin polarity, leads to occur weaker situation in the insecticidal activity to adult mosquito, but still for larva Show good killing activity.
21 cytotoxicity Pretreatment Test of embodiment
1, detection method for cytotoxicity of gas-liquid
Cell (selecting human liver cancer cell model HepG2) is inoculated into the cell density of 3000 cells/every hole, 80 μ L In 96 orifice plates.After inoculation 24 hours, (sample concentration is equal for 20 μ L transfluthrins of addition and DCA-CONH-06 compound solution For 100 μ g/mL).The test cell activity after compound handles 48h.Staurosporicae (MCE) is used as the inside in plate Control group after incubation, the MTT (5mg/mL, Yeasen) in 10 holes μ L/ is added into each hole of cell plates, by cell plates 37 DEG C be incubated for 4h.Discard the supernatant of cell liquid plate, and to the aerial DMSO that 120 holes μ L/ are added of each of cell plates.Shake orifice plate 10min, with Envision (PekinElmer), absorbing wavelength is that 570nm is measured OD value.
2, result
Experiment discovery, after dosing for 24 hours, which nearly all can normally grow in 96 orifice plates, and sample DCA-CONH-06 compound is smaller to the toxic of HepG2；Its cell survival can it is some higher, survival rate substantially 80% with On.Illustrate that amide pyrethroids class chemical modification object of the invention can reduce environmental toxicity, can be widely applied to desinsection mosquito eradication In the application of field, new safe and efficient, stable compound is provided for desinsection.
22 drug of embodiment tests preliminary experiment to aedes albopictus resistance activity
1, the drug resistance test method of mosquito
Biphenthrin processing: make (150 μ L) using the positive group Biphenthrin of 1mg/mL and act in 300ml aqueous solution The larva processing 15min or so (0.5mg/L) of 3 ages, then filters out larva, is put into and fresh goes in chlorine water to be trained It supports, the death rate 50%~60% or so, cultivated by the larva of remaining survival.To must turn out come female adult mosquito by using CDC bottle bioassay experiment has carried out aedes albopictus female adult mosquito (Aedes albopictus female adult Mosquito insecticidal activity test)；The female adult mosquito with Biphenthrin resistance is carried out using the method for embodiment 18 Test the drug resistance to drug.Selection Biphenthrin and sample sets DCA-CONH-06 chrysanthemum amide are tested, and simultaneous selection Concentration be 100 μ g/bottle concentration tested.
2, result
Found after test 120min, the lethality of chrysanthemum amide DCA-CONH-06 medicine group antagonism adult mosquito 25% or so, With certain death rate；However the Biphenthrin of same concentrations to the lethality of the female adult mosquito with anti-medicine 5% Within, the death rate is very low.Illustrate that chrysanthemum amide DCA-CONH-06 sample is turned out the drug resistance mosquito come to such and still had Certain insecticidal activity, but Biphenthrin has the drug resistance of height to the female adult mosquito of such anti-medicine.Illustrate of the invention Novel amide pyrethroids class chemical modification object can effectively solve the problems, such as existing pyrethroid insecticides drug resistance.
The preferred embodiment that the above specific embodiment is of the invention for ease of understanding and illustrates, but the invention is not limited to Above-described embodiment does not mean that the present invention must rely on above-described embodiment and could implement.Person of ordinary skill in the field It is the addition of equivalence replacement and auxiliary element to raw material selected by the present invention, specific it will be clearly understood that any improvement in the present invention The selection etc. of mode, all of which fall within the scope of protection and disclosure of the present invention.

Claims (10)

1. a kind of novel amide pyrethroids class chemical modification object, which is characterized in that shown in the following formula (I) of its structural formula:
,
Wherein, R is to contain monosubstituted or polysubstituted aromatic ring class group.
2. novel amide pyrethroids class chemical modification object according to claim 1, which is characterized in that the aromatic ring class group is Aromatic ring class group containing phenyl ring and/or thiphene ring, or be the aromatic ring class group containing furan nucleus.
3. novel amide pyrethroids class chemical modification object according to claim 1, which is characterized in that R F, Cl ,-CH3O、- CF3,-CN or-OCF3。
4. novel amide pyrethroids class chemical modification object according to claim 1, which is characterized in that the aromatic ring class group is
。
5. a kind of preparation method of novel amide pyrethroids class chemical modification object, which comprises the following steps:
S1. in protective gas atmosphere, super dry dichloromethane solvent is added into dibromo chrysanthemic acid, at room temperature, stirs molten Ethanedioly chloride is added in Xie Hou, after stirring 30~35 min at room temperature, n,N-Dimethylformamide is added, stirs in room temperature Mix 0.8~1 h of lower reaction；
S2. product is dried under vacuum conditions, and super dry dichloromethane solvent is added in protective gas atmosphere, in room temperature Under the conditions of after stirring and dissolving, anhydrous pyridine is added, after being stirred to react 25~30 min, adds cyclic annular benzylamine, be esterified anti- Answer 2~3 h；
S3. crude product is obtained by washing extraction drying after completion of the reaction, then is purified by silica gel column chromatography, can be obtained new Type amide pyrethroids class chemical modification object.
6. preparation method according to claim 5, which is characterized in that in step S1, the dibromo chrysanthemic acid and ethanedioly chloride The ratio between the amount of substance be 1:2~3.
7. preparation method according to claim 5, which is characterized in that in step S2, the object of dibromo chrysanthemic acid and anhydrous pyridine The ratio between amount of matter is 1:2~3；The ratio between dibromo chrysanthemic acid and the amount of substance of cyclic annular benzylamine are 1:1~2.
8. the Claims 1 to 4 any novel amide pyrethroids class chemical modification object or any side of claim 5~7 The novel amide pyrethroids class chemical modification object that method is prepared as or prepare application in insecticide.
9. application according to claim 8, which is characterized in that the insecticide is anti-mosquito or culicifuge.
10. application according to claim 9, which is characterized in that the mosquito in the mosquito eradication or culicifuge is aedes albopictus And/or Culex quinquefasciatus.
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Publication number Priority date Publication date Assignee Title
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Publication number Priority date Publication date Assignee Title
DE3317399A1 (en) * 1983-05-13 1984-01-19 Celamerck Gmbh & Co Kg, 6507 Ingelheim Insecticides
JPH05279511A (en) * 1992-03-31 1993-10-26 Sumitomo Chem Co Ltd Polymer stabilizer
WO2012150221A2 (en) * 2011-05-04 2012-11-08 Bayer Cropscience Ag Novel halogenated benzyl alcohol esters of cyclopropane carboxylic acid as pest control agents
CN104185620A (en) * 2012-03-13 2014-12-03 Redx药品有限公司 Agricultural chemicals
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