CN106957246A - Halo amino benzenes compounds and its preparation method and application - Google Patents
Halo amino benzenes compounds and its preparation method and application Download PDFInfo
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- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
- A01N33/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds
- A01N33/18—Nitro compounds
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
- A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
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- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/10—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
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- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
- C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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- C07C211/57—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton
- C07C211/61—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton with at least one of the condensed ring systems formed by three or more rings
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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Abstract
The present invention relates to a kind of preparation method and applications of halo amino benzenes compounds, belong to field of pharmaceutical chemistry technology.The general structure of the compound such as formula（I）It is shown,, formula（I）；The present invention utilizes raw material simple and easy to get：Polyhalo benzene-like compounds（II）With aminated compounds（III）Room temperature reaction synthesis has antibacterial, the halo amino benzenes compounds of anti-insect activity in non-protonic solvent（I）.The synthetic route that the invention preparation method has is short, and technique is simple, efficient, and easy to operate, reaction condition is gentle, it is not necessary to which heating and anhydrous condition, it is not necessary to metal catalytic, yield are high, the low feature of production cost, highly beneficial industrial production.Halo amino benzenes compounds of the present invention have good antibacterial and insecticidal activity, and application prospect is notable.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of halo amino benzenes compounds and preparation method thereof and
Using.
Background technology
Halide-containing plays highly important role in medicine, with rich and varied bioactivity, is such as used for
Antibacterial, antitumor, analgesia, anti-inflammation drugs, antiviral drugs, treatment myasthenia gravis, poliomyelitis sequelae etc..Such as business
The medicine of product includes galanthamine hydrobromide (Galanthamine Hydrobromide), 2,3,4,6- tetrachloro isophthalic diformazans
Nitrile (trade name：Bravo), Norfloxacin (Norfloxacin) etc. contain halogen atom.Aniline compound answering in medicine
With extremely extensively, common phenyl amines medicine has treatment canker sore, acute laryngopharyngitis and the benzene as local anesthetic to help and block
Cause, local anaesthesia medication procaine hydrochloride, analgesic-antipyretic paracetamol, the local anaesthesia first choice of external ophthalmologic operation
Medicine bupivacaine hydrochloride injection.
There are the document and patent report of aniline or halo phenyl amines both at home and abroad at present, such as：
CN201310166649.6 (Zhang Wei, Zhao Jiao) discloses a kind of combination sterilization composition of fluorine-containing azoles bacterium aniline.
CN201210411413.X (Zhu Hailiang, Xiao Zhuping, Zhang Fei, Yang Yushun) discloses a kind of furan prepared by metronidazole
Ketone amino benzenes derivates and its preparation method of muttering and the application in antibacterials.
CN201610458462.7 (Yan Shengjiao, Lin Jun, Zhu Dandan, Kong Lingbin, Wang Xinghong) discloses a kind of N- halos virtue
Chiral amino acid esters compound of base substitution and preparation method and application.
Because the research of the antibacterial of halo phenyl amines, desinsection is also seldom.Therefore a kind of synthetic route is set up short, technique letter
Single, efficient, the reaction time is short, and reaction condition is gentle, it is not necessary to high temperature and anhydrous condition, it is not necessary to metal catalytic, and yield is high, raw
The synthetic route synthesizing halogen amino benzenes compounds of production low cost have highly important as agricultural bacteriocide and insecticidal materials
Meaning.Halo amino benzenes compounds of the present invention have good antibacterial and anti-insect activity, and application prospect is notable.
The content of the invention
The invention aims to solve the deficiencies in the prior art, there is provided a kind of preparation side of halo amino benzenes compounds
Method and application, such compound have good antibacterial and insecticidal activity, great application prospect.
To achieve the above object, the technical solution adopted by the present invention is as follows：
Halo amino benzenes compounds, shown in the structure such as formula (I) of the compound：
Formula (I)；
In formula (I), R is cyano group, nitro or hydrogen；
R1For fluorine, chlorine or hydrogen；
R2For cyano group, nitro or hydrogen；
X is fluorine, chlorine or hydrogen；
Y is fluorine, chlorine or hydrogen；
R' is cyclopenta, cyclohexyl, substituted cyclohexyl, adamantyl, substitution adamantyl or 1- methyl isophthalic acid-adamantane-
1- ylmethyls；
R " is hydrogen atom or unsubstituted.
The present invention also provides the preparation method of above-mentioned halo amino benzenes compounds, comprises the following steps：
It is molten in aprotic by the aminated compounds of the polyhalo benzene-like compounds of formula (II) structure and formula (III) structure
In agent, in alkalescence or neutral environment, stirring carries out nucleophilic substitution at a temperature of 10-60 DEG C, and TLC tracking, question response is complete
Water quenching on the rocks is gone out after after complete, afterwards by product purification, is dried, is obtained the halo amino benzenes compounds of the formula (I) structure；
In formula (II), R is cyano group, nitro or hydrogen；R1For fluorine, chlorine or hydrogen；R2For cyano group, nitro or hydrogen；X be fluorine, chlorine or
Hydrogen；Y is fluorine, chlorine or hydrogen；
In formula (III), R' be cyclopenta, cyclohexyl, substituted cyclohexyl, adamantyl, substitution adamantyl, 1- methyl-
1- adamantane -1- ylmethyls or 1,2,3,4- tetrahydroisoquinoline -2- bases；R " is hydrogen atom or unsubstituted.
It is further preferred that the polyhalo benzene-like compounds of formula (II) structure and the aminated compounds of formula (III) structure
Mol ratio be 1:1~1:2.
It is further preferred that the reaction time is 5min-4h.
It is further preferred that described alkali is K2CO3, the aminated compounds of formula (III) structure and the mol ratio of alkali are
1:1~2:1.
It is further preferred that described non-protonic solvent be acetonitrile or Isosorbide-5-Nitrae-dioxane, formula (II) structure it is many
Halo benzene-like compounds mole are 1mmol with the volume ratio of non-protonic solvent：15~25mL；Described drying means is true
Dried under sky drying, natural drying or infrared lamp.
It is further preferred that described purification process is that organic solvent and saturated common salt are added first into reactant
Water is extracted, organic phase anhydrous Na2SO4Or anhydrous MgSO4Dry, dried organic phase is concentrated under reduced pressure into afterwards it is dry,
Concentrate obtains the halo amino benzenes compounds sterling as shown in formula (I) through column chromatography for separation or recrystallization.
It is further preferred that the organic solvent that described extraction is used is ethyl acetate or dichloromethane；
The eluant, eluent that described column chromatography for separation is used is 10 for volume ratio:1~20:1 petroleum ether and ethyl acetate
Mixed solvent；
Described recrystallization volume ratio is 1:10~1:20 ethyl acetate and the mixed solvent of petroleum ether, or volume ratio
For 1:10~1:20 acetone and the mixed solvent of petroleum ether.
The present invention also provides application of the above-mentioned halo amino benzenes compounds as antibacterials are prepared, and may be preferably used for preparing
Anti- sickle-like bacteria medicine, anti-Phytophthora nicotianae Breda cancer drug, anti-musae medicine.
The present invention additionally provides above-mentioned halo amino benzenes compounds as the application for preparing insecticidal materials, system may be preferably used for
Standby anti-artemia medicine.
Compared with prior art, its advantage is the present invention：
The present invention utilizes raw material simple and easy to get：The halo benzene-like compounds of formula (II) structure and the amine of formula (III) structure
Class compound, in non-protonic solvent, under the conditions of temperature (10~60 DEG C), is stirred, and TLC tracking, question response is complete
Afterwards, reactant is purified, dry target compound that must be with antibacterial and anti-insect activity, i.e. halo amino benzenes compounds (I).
Preparation method of the present invention has synthetic route short (only single step reaction), and easy to operate, reaction condition is gentle, it is not necessary to
High temperature (10~60 DEG C) and anhydrous condition, it is not necessary to metal catalytic, yield are high (up to 89%~98%), the low spy of production cost
Point, highly beneficial industrial production.Halo amino benzenes compounds produced by the present invention have good antibacterial and insecticidal activity, application
Prospect is notable.
Antibacterial activity is carried out using the compounds of this invention to three kinds of agriculture bacterium (sickle-like bacteria, anthrax-bacilus, Phytophthora nicotianae Breda) to grind
Study carefully (table 2~4).Result of study shows that agriculture bacterium can effectively suppress 3~4,7~9,14 pairs three kinds of the compound invented.Wherein
Compound Compound 9 for sickle-like bacteria, three kinds of bacterium of anthrax-bacilus and Phytophthora nicotianae Breda drug concentration be 6.25mg/L when, inhibiting rate
Respectively 93%, 95%, 90%；Compound 14 is in drug concentration for sickle-like bacteria, three kinds of bacterium of anthrax-bacilus and Phytophthora nicotianae Breda
During 6.25mg/L, inhibiting rate is respectively 92%, 93%, 88%；And compound 9 and 14 is for sickle-like bacteria, anthrax-bacilus and tobacco epidemic disease
The bactericidal effect of mould is superior to positive control Bravo.
The compound of the present invention carries out anti-insect activity research (table 5~6) to artemia.Result of study shows, the change invented
Compound 3~4,6,12~14 is effective to artemia to be suppressed, and it is to artemia half lethal concentration (LD50) be respectively 0.440,1.353,
0.455th, 1.426,0.230,0.223mg/mL, is superior to positive control imidacloprid (3.62mg/mL).
Brief description of the drawings
Fig. 1 is the high resolution mass spectrum of compound 8.
Fig. 2 is the high resolution mass spectrum of compound 9.
Fig. 3 is the proton nmr spectra of compound 14.
Fig. 4 is the carbon-13 nmr spectra of compound 14.
Embodiment
With reference to embodiment, the present invention is described in further detail.
It will be understood to those of skill in the art that the following example is merely to illustrate the present invention, and it should not be regarded as limiting this hair
Bright scope.In the examples where no specific technique or condition is specified, according to the technology or condition described by document in the art
Or carried out according to product description.The unreceipted production firm person such as agents useful for same, instrument, is what can be obtained by buying
Conventional products.
Raw material of the present invention can be prepared by the known method of this area or obtained by commercially available prod.
The conventional method of the synthesis of halo amino benzenes compounds of the invention explained further below, but halogeno-benzene of the present invention
The preparation method of aminated compounds is not limited to this.
The method for synthesizing the halo amino benzenes compounds of the present invention is as follows：
It is molten in aprotic by the aminated compounds of the polyhalo benzene-like compounds of formula (II) structure and formula (III) structure
In agent, in alkalescence or neutral environment, stirring carries out nucleophilic substitution at a temperature of 10-60 DEG C, and TLC tracking, question response is complete
Water quenching on the rocks is gone out after after complete, afterwards by product purification, is dried, is obtained the halo amino benzenes compounds of the formula (I) structure；
In formula (II), R is cyano group, nitro or hydrogen；R1For fluorine, chlorine or hydrogen；R2For cyano group, nitro or hydrogen；X be fluorine, chlorine or
Hydrogen；Y is fluorine, chlorine or hydrogen；
In formula (III), R' be cyclopenta, cyclohexyl, substituted cyclohexyl, adamantyl, substitution adamantyl, 1- methyl-
1- adamantane -1- ylmethyls or 1,2,3,4- tetrahydroisoquinoline -2- bases；R " is hydrogen atom or unsubstituted.
The polyhalo benzene-like compounds of formula (II) structure are 1 with the mol ratio of the aminated compounds of formula (III) structure:1~
1:2。
Reaction time is 5min-4h.
Alkali is not essential, and as that need to use alkali, described alkali is K2CO3, the amine of formula (III) structure and the mol ratio of alkali
For 1:1~2:1.
Described non-protonic solvent is acetonitrile or Isosorbide-5-Nitrae-dioxane, on the basis of polyhalo benzene-like compounds 1mmol, molten
The consumption (15~25mL) of agent；Described drying means is dry under vacuum drying, natural drying or infrared lamp.
Described purification process is to add organic solvent first into reactant to be extracted with saturated aqueous common salt, organic phase
Use anhydrous Na2SO4Or anhydrous MgSO4Dry, be afterwards concentrated under reduced pressure into dried organic phase dry, concentrate is through column chromatography point
From or recrystallization, obtain the halo amino benzenes compounds sterling as shown in formula (I).
The organic solvent that described extraction is used is ethyl acetate or dichloromethane；
The eluant, eluent that described column chromatography for separation is used is 10 for volume ratio:1~20:1 petroleum ether and ethyl acetate
Mixed solvent；
Described recrystallization volume ratio is 1:10~1:20 ethyl acetate and the mixed solvent of petroleum ether, or volume ratio
For 1:10~1:20 acetone and the mixed solvent of petroleum ether.
According to known methods, formula (III) compound is known to the compound of formula (II), is commercially available or can be according to public affairs
It is prepared by the method known.
Antibacterial test：Growth rate method (Yang Lijuan, Li Junfeng, Xu Rong, Lin Jun：Bravo and its three fluorine derivatives
To the Indoor antibacterial expression activitiy 2004,11,11-13 of tomato early blight bacterium):Melt and be cooled to 45 DEG C~50 DEG C sterilizing
5mL decoctions are added in 45mLPDA culture mediums, band medicine culture base plane is made in the culture dish for shaking up two diameter 9cm of injection.Often
Medicament often handles 4 repetitions by the order of low concentration to high concentration.It is straight in the inoculation of every culture dish center after after culture medium solidifying
Footpath is 0.6cm tomato early blight bacterium fungus block, is placed in 25 DEG C of incubator and cultivates.When ware bacterium colony length is compareed to close to ware side,
Culture dish is taken out, each processing colony diameter is measured, it is each in length and breadth to measure 1 time, average, calculate the percentage for suppressing colony growth
Rate.
Anti- artemia determination of activity：(the research of the red Podophyllum emodi var chinense class plant endogenesis epiphytes of Wang Xing：[D] Kunming：Yunnan University's life
Science institute, 2006.)
1. artemia is hatched：In beaker add 500mL artificial seawater (NaCl 28.150g, KCl 0.670g,
MgCl2·6H2O 5.510g, MgSO4·7H2O 6.920g, CaCl2·2H2O 1.450g, plus deionized water constant volume are arrived
1000mL, uses NaHCO3PH value is adjusted 8.0), 30 DEG C to be heated on electric furnace.A little artemia cysts is added, is put into water-bath,
30 DEG C of hatching 24h, the vigorous artemia of energy are isolated with separatory funnel standby.
2. sample treatment：4mg samples are weighed, DMSO dissolvings are added, (DMSO contents are no more than 10%) is in 96 hole cell trainings
Support and add 50 μ L decoctions and 100 μ L artificial seawater in plate per hole, add 50 seawater of the μ L with artemia, per hole artemia number 4~7
Tail, is diluted to concentration for 1mg/mL.Control group adds artificial seawater and same amount of DMSO, 30 DEG C of cultures.It is stronger to activity
Decoction, by decoction, manually seawater is diluted to measure after different multiples, and each sample repeats 3 holes.
3. observation is counted：After sample-adding culture 8h, dead individuals number and total individual number, anti-artemia are counted respectively with bitubular anatomical lens
Activity is represented with corrected mortality.
Survival rate=8h living individuals number/total individual number × 100%
Corrected mortality=(control group survival rate-treatment group survival rate)/control group survival rate × 100%
With the regression equation of each medicament of Spss softwares calculating regress analysis method calculating everywhere, square R of coefficient correlation2,
(R is directly just the coefficient correlation of dependent variable independent variable in a linear equation, polynary, is coefficient of multiple correlation R2It is exactly phase relation
Several squares), LD50Etc. the size for comparing two medicament virulence.
The present invention is described in detail with reference to part specific embodiment.These embodiments are merely to illustrate the present invention,
Rather than limitation the scope of the present invention.Preparation scheme in embodiment is only preferred scheme, but the invention is not limited in excellent
Select preparation scheme.
Embodiment 1：Synthesize 4- (cyclohexylamino) -2,5,6- trifluoros isophthalodinitrile (compound 1)
2,4,5,6- termils (1mmol, 266mg) are added in 25 milliliters of round-bottomed flasks, Isosorbide-5-Nitrae-two is added
Under oxygen six ring solvent (20mL) magnetic agitation, then raw material cyclohexylamine (1mmol, 99mg) is slowly added dropwise.12 DEG C of reaction, 40min
Afterwards, frozen water is added immediately to be quenched.Reaction solution is extracted with dichloromethane, organic layer is taken, then uses anhydrous Na2SO4Done
It is dry, it will be evaporated by dry liquid concentration, be evaporated thing to concentration afterwards and carry out column chromatography, what described pillar layer separation was used
Solvent is mixed solvent=20 of petrol ether/ethyl acetate:1, vacuum drying product obtains white solid, 4- (cyclohexylamino) -2,
5,6- trifluoro isophthalodinitriles (compound 1), yield 88%.Fusing point：108.5-111.6℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=1.24-2.18 (m, 10H, CH2),4.34–
4.40(m,1H,CH),5.61(s,1H,NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 600):D=24.0,24.0,25.0,25.1,34.0,
53.3,94.6,102.9,113.2,114.2,119.4,139.3,142.4,148.5。
High resolution mass spectrum C14H12Cl3N3,[M-H]–, theoretical value 326.0024；Measured value, 326.0021.
Embodiment 2：Synthesize 5- chloro- 4- (cyclohexyl amido) -2,6- difluoros isophthalodinitrile (compound 2)
Chloro- 2, the 6- fluorine isophthalodinitriles (1mmol, 216mg) of 5- are added in 25 milliliters of round-bottomed flasks, Isosorbide-5-Nitrae-dioxy is added
Under six ring solvent (20mL) magnetic agitations, then raw material cyclohexylamine ((1mmol, 99mg)) is slowly added dropwise.25 DEG C of reaction, 15min
Afterwards, frozen water is added immediately to be quenched.Reaction solution is extracted with ethyl acetate, organic layer is taken, anhydrous MgSO is then used4Done
It is dry, thing is evaporated to concentration after being evaporated by dry liquid concentration and carries out column chromatography, what described pillar layer separation was used
Solvent is mixed solvent=12 of petrol ether/ethyl acetate:1, white solid is obtained, product is spontaneously dried and obtains white solid, product
The chloro- 4- of 5- (cyclohexyl amido) -2,6- difluoros isophthalodinitrile (compound 2), yield 93%.Fusing point：96.1-97.2℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=1.23-2.15 (m, 10H, CH2),4.29–
4.36(m,1H,CH),5.65(s,1H,NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=24.0,24.0,25.0,25.0,33.9,
53.0,80.8,81.6,104.1,108.0,111.3,148.7,160.0,165.9；
High resolution mass spectrum C14H12Cl3N3,[M-H]–, theoretical value 294.0615；Measured value, 294.0618.
Embodiment 3：Synthesize chloro- 6- ((cyclo-hexylamine) isophthalodinitriles (compound 3) of 2,4,5- tri-
2,4,5,6- termils (1mol, 266mg) are added in 25 milliliters of round-bottomed flasks and add 1,4- dioxies
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, add afterwards after cyclohexylamine (1mmol, 98mg), reaction 15min, frozen water
It is quenched, reaction solution is extracted with ethyl acetate, takes organic layer, then use anhydrous Na2SO4It is dried, by by drying
Liquid concentration is evaporated, and being evaporated thing to concentration afterwards carries out column chromatography, and the solvent that described pillar layer separation is used is petroleum ether/second
Mixed solvent=20 of acetoacetic ester:1, to obtain and obtain product, 2,4,5- tri- chloro- 6- ((hexamethylenes after being dried under white solid, infrared lamp
Base amine) isophthalodinitrile (compound 3).Yield 92%, fusing point：108.5-111.6℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=1.24-2.18 (m, 10H, CH2),4.34–
4.40(m,1H,CH),5.61(s,1H,NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=24.0,24.0,25.0,25.1,34.0,
53.3,94.6,102.9,113.2,114.2,119.4,139.3,142.4,148.5；
High resolution mass spectrum C14H12Cl3N3,[M-H]–, theoretical value 326.0024；Measured value, 326.0021.
Embodiment 4：Synthesize 2,4,5- tri- chloro- 6- (((2R) -2- methyl cyclohexanes amido) amine) isophthalodinitrile (compound 4)
2,4,5,6- termils (1mol, 266mg) are added in 25 milliliters of round-bottomed flasks and add 1,4- dioxies
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, rear to add 2- methyl cyclohexylamines (1mmol, 113mg), react 15min
Afterwards, frozen water is quenched, and reaction solution is extracted with ethyl acetate, is taken organic layer, is then used anhydrous Na2SO4It is dried, will be through
Cross dry liquid concentration to be evaporated, being evaporated thing to concentration afterwards recrystallizes, recrystallization solvent for use is petroleum ether/acetone
Mixed solvent=20:1, obtain after being dried under dry products under white solid, infrared lamp, infrared lamp that to obtain product 2,4,5- tri- chloro-
6- (((2R) -2- methyl cyclohexanes amido) amine) isophthalodinitrile (compound 4).Yield：98%, fusing point：132.7-133.9℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=0.95 (d, J=7.0Hz, 3H, CH3),
1.35-2.06(m,8H,CH2), 2.06-2.07 (m, 1H, CH), 4.60-4.64 (m, 1H, CH), 5.77 (d, J=9.0Hz, 1H,
NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=16.2,21.7,22.9,29.4,30.1,
34.1,55.0,94.8,103.0,112.4,115.0,119.7,139.4,142.4,149.0；
High resolution mass spectrum C15H14Cl3N3,[M-H]–, theoretical value 340.0181；Measured value, 340.0180.
Embodiment 5：Synthesize fluoro- 6- ((4- methyl cyclohexanes amido) the amine isophthalodinitriles (compound 5) of 2,4,5- tri-
2,4,5,6- tetrafluoros isophthalodinitrile (1mol, 200mg) is added in 25 milliliters of round-bottomed flasks and adds 1,4- dioxies
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, rear to add 2- methyl cyclohexylamines (1mmol, 113mg), react 15min
Afterwards, frozen water is quenched, and reaction solution is extracted with ethyl acetate, is taken organic layer, is then used anhydrous Na2SO4It is dried, will be through
Cross dry liquid concentration to be evaporated, be evaporated thing to concentration afterwards and carry out column chromatography, the solvent that described pillar layer separation is used for
Mixed solvent=20 of petrol ether/ethyl acetate:1, obtain and obtained after being dried under dry products under white solid, infrared lamp, infrared lamp
To product, 2,4,5- tri- fluoro- 6- ((4- methyl cyclohexanes amido) amine isophthalodinitriles (compound 5).Yield：96%, fusing point：
101.3-102.1℃。
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=0.94 (d, J=6.5Hz, 3H, CH3),
1.10-2.12(m,8H,CH2), 2.12-2.15 (m, 1H, CH), 4.02 (m, 1H, CH), 5.09 (d, J=3.5Hz, 1H, NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=21.8,31.6,33.0,33.0,34.2,
34.2,53.8,80.0,82.9,108.0,110.9,135.5,143.4,152.5,162.5；
High resolution mass spectrum C15H14F3N3,[M-H]-, theoretical value 292.1067；Measured value, 292.1063.
Embodiment 6：Synthesize the chloro- 2,4- bis- of 5- fluoro- 6- ((4- methylcyclohexyls) amine) isophthalodinitrile (compound 6)
The chloro- 2,4,6- trifluoros isophthalodinitriles (1mol, 216mg) of 5- are added in 25 milliliters of round-bottomed flasks and add 1,4- bis-
The ring solvent (15mL) of oxygen six, carries out magnetic agitation at 20 DEG C, rear to add 2- methyl cyclohexylamines (1mmol, 113mg), reaction
After 15min, frozen water is quenched, and reaction solution is extracted with ethyl acetate, is taken organic layer, is then used anhydrous Na2SO4It is dried,
It will be evaporated by dry liquid concentration, be evaporated thing to concentration afterwards and carry out column chromatography, it is molten that described pillar layer separation is used
Agent is mixed solvent=20 of petrol ether/ethyl acetate:1, obtain and dried under dry products under white solid, infrared lamp, infrared lamp
After obtain the fluoro- 6- of the chloro- 2,4- bis- of product 5- ((4- methylcyclohexyls) amine) isophthalodinitrile (compound 6).Yield：98%, melt
Point：94.9-96.1℃.
Proton nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 500):δ=0.88 (d, J=6.5Hz, 3H,
CH3),0.97-1.91(m,8H,CH2), 1.91-1.93 (m, 1H, CH), 4.09 (m, 1H, CH), 7.28 (d, J=8.5Hz, 1H,
NH)；
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 500):δ=22.5,31.5,33.0,33.0,
33.4,33.4,54.3,79.3,81.3,103.9,109.4,112.4,149.8,159.8,166.2；
High resolution mass spectrum C15H14ClF2N3,[M-H]-, theoretical value 308.0772；Measured value, 308.0770.
Embodiment 7：Synthesize 2,4,5- tri- chloro- 6- ((4- methylcyclohexyls) amine) isophthalodinitrile (compound 7)
2,4,5,6- termils (1mol, 266mg) are added in 25 milliliters of round-bottomed flasks and add 1,4- dioxies
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, rear to add 4- methyl cyclohexanes (1mmol, 113mg), react 15min
Afterwards, frozen water is quenched, and reaction solution is extracted with ethyl acetate, is taken organic layer, is then used anhydrous Na2SO4It is dried, will be through
Cross dry liquid concentration to be evaporated, be evaporated thing to concentration afterwards and carry out column chromatography, the solvent that described pillar layer separation is used for
Mixed solvent=20 of petrol ether/ethyl acetate:1, obtain and obtained after being dried under dry products under white solid, infrared lamp, infrared lamp
To the chloro- 6- of product 2,4,5- tri- ((4- methylcyclohexyls) amine) isophthalodinitrile (compound 7).Yield：97%, fusing point：
151.9-152.4℃。
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=0.94 (d, J=6.5Hz, 3H, CH3),
1.15-2.17(m,8H,CH2), 2.18-2.19 (m, 1H, CH), 4.29 (m, 1H, CH), 5.55 (d, J=8.0Hz, 1H, NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=21.9,31.0,32.9,32.9,34.3,
34.3,53.7,94.4,102.9,112.3,114.4,119.3,133.9,139.4,142.3,148.6；
High resolution mass spectrum C20H12ClF2N3,[M-H]-, theoretical value 366.0615；Measured value, 366.0617.
Embodiment 8：Synthesize the chloro- 2,6- bis- of 5- fluoro- 4- ((cyclohexyl methyl) amine) isophthalodinitrile (compound 8)
The chloro- 2,4,6- trifluoros isophthalodinitriles (1mol, 216mg) of 5- are added in 25 milliliters of round-bottomed flasks and add 1,4- bis-
The ring solvent (15mL) of oxygen six, carries out magnetic agitation at 20 DEG C, and cyclohexyl methylamine (1mmol, 112mg) is added afterwards, reacts 10min
Afterwards, frozen water is quenched, and reaction solution is extracted with ethyl acetate, is taken organic layer, is then used anhydrous Na2SO4It is dried, will be through
Cross dry liquid concentration to be evaporated, be evaporated thing to concentration afterwards and carry out column chromatography, the solvent that described pillar layer separation is used for
Mixed solvent=20 of petrol ether/ethyl acetate:1, obtain and obtained after being dried under dry products under white solid, infrared lamp, infrared lamp
To product, 5- chloro-2,6-difluoros -4- ((cyclohexyl methyl) amine) isophthalodinitrile (compound 8).Yield：92%, fusing point：
152.4-155.8℃。
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=0.93 (m, 2H, CH2),1.20(m,2H,
CH2),1.66(m,2H,CH2),1.75(m,5H,CH2),3.60(m,2H,CH2),7.81(s,4H,NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=25.8,25.8,26.4,37.8,37.8,
50.1,93.5,100.8,114.2,115.1,119.4,138.3,142.3,150.1；
As shown in figure 1, high resolution mass spectrum C15H13ClF2N3,[M-H]–, theoretical value 308.0761；Measured value, 308.0762.
Embodiment 9：Synthesize 2,4,5- tri- chloro- 6- (cyclohexyl methylamine base) isophthalodinitrile (compound 9)
2,4,5,6- termils (1mol, 266mg) are added in 25 milliliters of round-bottomed flasks and add 1,4- dioxies
Six ring solvents (15mL), carry out magnetic agitation at 25 DEG C, add afterwards after cyclohexyl methylamine (1mmol, 112mg), reaction 5min, ice
Water quenching is gone out, and reaction solution is extracted with ethyl acetate, is taken organic layer, is then used anhydrous Na2SO4It is dried, drying will be passed through
Liquid concentration be evaporated, concentration is evaporated by thing recrystallized afterwards, the solvent that described recrystallization is used is petroleum ether/acetic acid
Mixed solvent=10 of ethyl ester:1, obtain between dry products under white solid, infrared lamp, 2,4,5- tri- chloro- 6- (cyclohexyl methylamine base)
Benzene dicarbonitrile (compound 9).Yield：92%, fusing point：158.4-158.8℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=0.93 (m, 2H, CH2),1.20(m,2H,
CH2),1.66(m,2H,CH2),1.75(m,5H,CH2),3.60(m,2H,CH2),7.81(s,4H,NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=25.8,25.8,26.4,29.9,30.1,
38.5,49.7,79.1,80.4,103.8,109.3,112.4,150.3,159.7,166.3；
As shown in Fig. 2 high resolution mass spectrum C15H14Cl3N3,[M-H]–, theoretical value 340.0170；Measured value, 340.0170.
Embodiment 10：Synthesize the chloro- 2,6- bis- of 5- fluoro- 4- (cyclopentamine base) isophthalodinitrile (compound 10)
The chloro- 2,6- difluoros isophthalodinitriles (1mmol, 216mg) of 5- are added in 25 milliliters of round-bottomed flasks and add 1,4- bis-
The ring solvent (15mL) of oxygen six, carries out magnetic agitation at 10 DEG C, adds afterwards after cyclopentamine (1mmol, 140mg), reaction 10min,
Frozen water is added immediately to be quenched, and reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4It is dried,
It will be evaporated by dry liquid concentration, be evaporated thing to concentration afterwards and carry out column chromatography, it is molten that described pillar layer separation is used
Agent is mixed solvent=20 of petrol ether/ethyl acetate:1, obtain dry products under white solid, infrared lamp and obtain white solid, 5-
Chloro-2,6-difluoro -4- (cyclopentamine base) isophthalodinitrile (compound 10), yield 94%.Fusing point：82.1-83.9℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=1.61-2.25 (m, 8H, CH2),4.72–
4.76 (m, 1H, CH), 5.68 (d, J=6.5Hz, 1H, NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=23.8,23.9,35.1,35.2,56.0,
80.9,81.7,103.9,108.0,111.3,149.0,160.0,165.9；
High resolution mass spectrum C13H10ClF2N3,[M-H]–, theoretical value 280.0449；Measured value, 280.0448.
Embodiment 11：Synthesize 2,4,5- tri- chloro- 6- (cyclopentamine base) isophthalodinitrile (compound 11)
2,4,5,6- termils (1mol, 266mg) are added in 25 milliliters of round-bottomed flasks and add 1,4- dioxies
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, add afterwards after cyclopentamine (2mmol, 170mg), reaction 5min, frozen water
It is quenched, reaction solution is extracted with ethyl acetate, takes organic layer, then use anhydrous Na2SO4It is dried, by by drying
Liquid concentration is evaporated, and being evaporated thing to concentration afterwards carries out column chromatography, and the solvent that described pillar layer separation is used is petroleum ether/second
Mixed solvent=20 of acetoacetic ester:1, obtain between dry products under white solid, infrared lamp, 2,4,5- tri- chloro- 6- (cyclopentamine base)
Benzene dicarbonitrile (compound 11).Yield：85%, fusing point：142.0-143.6℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=1.68 (m, 8H, CH2),4.72–4.76(m,
1H, CH), 5.68 (d, J=6.5Hz, 1H, NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=23.8,23.9,35.1,35.2,56.0,
80.9,81.7,103.9,108.0,111.3,149.0,160.0,165.9；
High resolution mass spectrum C13H9Cl3N3,[M-H]–, theoretical value 311.9857；Measured value, 311.9858.
Embodiment 12：Synthesize 2,5,6- tri- fluoro- 4- ((the 1H)-yl of bis- isoquinolin of 3,4- -2) isophthalodinitrile (compound 12)
Add in 25 milliliters of round-bottomed flasks, 2,4,5,6- tetrafluoro isophthalodinitriles (1.0mmol, 200mg), add Isosorbide-5-Nitrae-two
Under oxygen six ring solvent (19mL) magnetic agitation, then raw material 1,2,3,4- tetrahydroisoquinolines (1.5mmol, 199mg) are slowly added dropwise.
Reaction is at 30 DEG C, TLC monitoring reactions, after reaction 13min, frozen water is added immediately and is quenched.Reaction solution is carried out with ethyl acetate
Extraction, takes organic layer, then uses anhydrous Na2SO4It is dried, will be evaporated, concentration is evaporated by dry liquid concentration afterwards
Thing carry out column chromatography, the solvent that described pillar layer separation is used for petrol ether/ethyl acetate mixed solvent=10:1 obtains yellow
Dry products obtain white solid, 4- ((the 1H)-yl of 3,4- bis- isoquinolin -2) -2,5,6- trifluoro isophthalic two under color solid, infrared lamp
Formonitrile HCN (compound 12), yield 88%.Fusing point：117.0-117.6℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=3.14 (t, J=6.0Hz, 2H, CH2),
3.89 (t, J=5.5Hz, 2H, CH2),4.83(s,2H,CH2),7.10–7.25(m,4H,ArH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=29.6,50.0,53.2,83.6,89.8,
107.6,111.3,126.7,127.3,129.3,131.9,133.2,133.6,139.0,147.3,153.8,162.3；
High Resolution Spectrum C17H10F3N3,[M-H]+, theoretical value 314.0900；Measured value, 314.0899.
Embodiment 13：Synthesize 5- chloro- 4- ((the 1H)-yl of bis- isoquinolin of 3,4- -2) -2,6- difluoro isophthalodinitrile (compounds
13)
The addition 5- chloro-2,6-difluoros isophthalodinitrile (1.0mmol, 216mg) in 25 milliliters of round-bottomed flasks, addition Isosorbide-5-Nitrae-
Under dioxane solvent (15mL) magnetic agitation, then raw material 1,2,3,4- tetrahydroisoquinolines (1.5mmol, 199mg) slowly drip
Plus.24 DEG C of reaction, after 18min, adds frozen water and is quenched immediately.Reaction solution is extracted with ethyl acetate, organic layer is taken, then
Use anhydrous Na2SO4It is dried, will be evaporated by dry liquid concentration, being evaporated thing to concentration afterwards recrystallizes, described
The solvent that uses of recrystallization for petroleum ether/acetone mixed solvent=10:1, which obtains dry products under yellow solid, infrared lamp, obtains
White solid, the chloro- 4- of 5- ((the 1H)-yl of 3,4- bis- isoquinolin -2) -2,6- difluoros isophthalodinitrile (compound 13), yield
88%.Fusing point：127.0-127.3℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=3.15 (t, J=5.5Hz, 2H, CH2),
3.88 (t, J=6.0Hz, 2H, CH2),4.79(s,2H,CH2),7.09–7.25(m,4H,ArH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=29.5,50.2,53.6,93.4,107.5,
111.0,126.1,126.6,127.3,129.2,132.1,132.9,156.0,160.6,162.7,163.4,165.6；
High Resolution Spectrum C17H10ClF2N3,[M-H]-, theoretical value 328.0459；Measured value, 328.0458.
Embodiment 14：Synthesize 2,5,6- tri- chloro- 6- ((the 1H)-yl of bis- isoquinolin of 3,4- -2) isophthalodinitrile (compound 14)
2,4,5,6- termils (1mmol, 200mg) are added in 25 milliliters of round-bottomed flasks, Isosorbide-5-Nitrae-two is added
Under oxygen six ring solvent (18mL) magnetic agitation, Jia 1 at 30 DEG C, 2,3,4- tetrahydroisoquinolines (2mmol, 266mg) react 10min
Afterwards, frozen water is added immediately to be quenched, reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4Done
It is dry, will be evaporated by dry liquid concentration, being evaporated thing to concentration afterwards recrystallizes, described recrystallization use solvent for
Mixed solvent=20 of petrol ether/ethyl acetate:1, obtain dry products under yellow solid, infrared lamp and obtain yellow solid, 2,5,6-
Three chloro- 6- ((the 1H)-yl of 3,4- bis- isoquinolin -2) isophthalodinitriles (compound 14), yield 93%, fusing point：180.6-181.2
℃。
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 600):3.10 (t, J=5.6Hz, 2H, CH2),3.81
(t, J=5.8Hz, 2H, CH2),4.69(s,2H,CH2), 7.07-7.25 (m, 4H, ArH), as shown in Figure 3；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 600):δ=29.6,50.1,53.1,53.6,109.0,
109.6,112.6,113.6,125.8,126.4,127.0,129.3,132.5,133.2 140.8,141.9,155.8, such as Fig. 4
It is shown；
High Resolution Spectrum C17H10Cl3N3,[M-H]-, theoretical value 363.9984；Measured value, 363.9976.
Embodiment 15：Synthesize 2,5,6- tri- fluoro- 4- (((3s, 5s, 7s)-adamantane -1- bases) amine) isophthalodinitrile (chemical combination
Thing 15)
2,4,5,6- tetrafluoros isophthalodinitrile (1mmol, 200mg) is added in 50 milliliters of round-bottomed flasks and adds acetonitrile solvent
(25mL), carries out magnetic agitation at 30 DEG C, adds after amantadine (1mmol, 151mg), reaction 60min, adds immediately afterwards
Frozen water is quenched, and reaction solution is extracted with ethyl acetate, is taken organic layer, is then used anhydrous Na2SO4It is dried, will be through overdrying
Dry liquid concentration is evaporated, and being evaporated thing to concentration afterwards recrystallizes, and described recrystallization uses solvent for petroleum ether/acetic acid
Mixed solvent=15 of ethyl ester:1, obtain dry products under white solid, infrared lamp and obtain white solid, 2,5,6- tri- fluoro- 4-
(((3s, 5s, 7s)-adamantane -1- bases) amine) isophthalodinitrile (compound 15), yield 92%.Fusing point：150.0-150.6℃.
Proton nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=1.64 (s, 6H, CH2),1.94(s,
6H,CH2),2.10(s,3H,CH),6.31(s,1H,NH)；
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=28.8,29.6,29.7,35.5,
35.5,35.8,42.8,42.8,42.8,55.4,82.0,89.6,109.1,112.0,137.7,143.8,154.2,161.9；
High Resolution Spectrum C18H16F3N3[M-H]–；Theoretical value 330.1224；Measured value, 330.1226.
Embodiment 16：Synthesize the chloro- 2,6- bis- of 5- fluoro- 4- (((3s, 5s, 7s)-adamantane -1- bases) amine) isophthalodinitrile
(compound 16)
Chloro- 2,6- difluoros isophthalodinitrile (1mmol, 216mg) the addition acetonitriles of 5- are added in 25 milliliters of round-bottomed flasks molten
Agent (20mL), carries out magnetic agitation at 15 DEG C, adds after amantadine (2mmol, 302mg), reaction 25min, adds immediately afterwards
Enter frozen water to be quenched, reaction solution is extracted with ethyl acetate, take organic layer, then use anhydrous Na2SO4It is dried, will passes through
Dry liquid concentration is evaporated, and being evaporated thing to concentration afterwards carries out column chromatography, and the solvent that described pillar layer separation is used is stone
Mixed solvent=15 of oily ether/ethyl acetate:1, obtain dry products under white solid, infrared lamp and obtain white solid, 5- chloro- 2,6-
Two fluoro- 4- (((3s, 5s, 7s)-adamantane -1- bases) amine) isophthalodinitriles (compound 16), yield 93%.Fusing point：123.0-
124.6℃。
Proton nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=1.64 (s, 6H, CH2),2.00(s,
6H,CH2),2.10(s,3H,CH),6.01(s,1H,NH)；
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=29.0,30.0,30.0,35.6,
35.8,35.9,36.0,42.9,43.5,58.7,83.7,89.1,109.1,109.9,114.5,151.3,160.3,165.2；
High Resolution Spectrum C18H16ClF2N3,[M-H]–；Theoretical value 346.0928；Measured value, 346.0927.
Embodiment 17：Synthesize 2,5,6- tri- chloro- 4- (((3s, 5s, 7s)-adamantane -1- bases) amine) isophthalodinitrile (chemical combination
Thing 17)
2,4,5,6- termils (1mmol, 266mg) are added in 25 milliliters of round-bottomed flasks and add acetonitrile solvent
(20mL), carries out magnetic agitation at 50 DEG C, adds amantadine (2mmol, 302mg), adds K2CO3(1mmol,138mg)
Afterwards, after reaction 3h, frozen water is added immediately and is quenched, reaction solution is extracted with ethyl acetate, organic layer is taken, then with anhydrous
Na2SO4It is dried, will be evaporated by dry liquid concentration, being evaporated thing to concentration afterwards carries out column chromatography, described post color
The spectrum solvent that uses of separation for petrol ether/ethyl acetate mixed solvent=20:1, obtain dry products under white solid, infrared lamp
Obtain white solid, 2,5,6- tri- chloro- 4- (((3s, 5s, 7s)-adamantane -1- bases) amine) isophthalodinitriles (compound 17), yield
91%.Fusing point：210.0-210.6℃.
Proton nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=1.62 (s, 6H, CH2),2.03(s,
6H,CH2),2.10(s,3H,CH),5.70(s,1H,NH)；
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=30.0,30.0,30.0,35.8,
35.8,35.8,43.3,43.3,43.3,60.0,105.9,107.1,113.8,116.8,127.4,139.6,140.4,
151.8；
High Resolution Spectrum C18H16F3N3,[M-H]–；Theoretical value 378.0337, measured value, 378.0338.
Embodiment 18：Synthesize 2,5,6- tri- fluoro- 4- ((1- ((3r, 5r, 7r)-amantadine -1- bases) ethyl) amine) isophthalic
Dimethoxy nitrile (compound 18)
2,4,5,6- tetrafluoros isophthalodinitrile (1mol, 200mg) is added in 25 milliliters of round-bottomed flasks and adds acetonitrile solvent
(20mL), carries out magnetic agitation at 30 DEG C, and 4- ((1- ((3r, 5r, 7r)-adamantane amido -1- bases) ethyl) amine is added afterwards
After (1mmol, 179mg), reaction 30min, reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4
It is dried, will be evaporated by dry liquid concentration, being evaporated thing to concentration afterwards carries out column chromatography, described pillar layer separation
The solvent used for petrol ether/ethyl acetate mixed solvent=20:1, obtain dry products under white solid, infrared lamp, 2,5,
The fluoro- 4- of 6- tri- ((1- ((3r, 5r, 7r)-amantadine -1- bases) ethyl) amine) isophthalodinitrile (compound 18), yield 92%.
Fusing point：132.3-133.3℃.
Proton nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=1.20 (d, J=6.7Hz, 3H,
CH3),1.48-1.67(m,12H,CH2), 1.96 (s, 3H, CH), 4.08 (q, J=6.7Hz, 1H, CH), 7.33 (d, J=
8.3Hz,1H,NH)；
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=14.7,28.1,28.2,36.9,
37.8,37.8,37.8,38.1,38.1,38.1,58.9,58.9,78.3,82.4,109.4,112.2,136.2,145.3,
151.8,163.3；
High Resolution Spectrum C20H20F3N3,[M-H]–Theoretical value 358.1537, measured value, 358.1547.
Embodiment 19：Synthesize the fluoro- 4- of the chloro- 2,6- bis- of 5- ((1- ((3r, 5r, 7r)-adamantane amido -1- bases) ethyl) amine)
Isophthalodinitrile (compound 19)
The chloro- 2,6- difluoros isophthalodinitriles (1mol, 216mg) of 5- are added in 25 milliliters of round-bottomed flasks and add acetonitrile solvent
(15mL), carries out magnetic agitation at 25 DEG C, and 4- ((1- ((3r, 5r, 7r)-amantadine -1- bases) ethyl) amine) is added afterwards
After (1mmol, 179mg), reaction 40min, frozen water is added immediately and is quenched, reaction solution is extracted with ethyl acetate, taken organic
Layer, then uses anhydrous Na2SO4It is dried, will be evaporated by dry liquid concentration, being evaporated thing to concentration is recrystallized (second
Acetoacetic ester：Petroleum ether=1:15) dry products under white solid, infrared lamp, are obtained and obtain white solid, 5- chloro-2,6-difluoros -4-
((1- ((3r, 5r, 7r)-adamantane amido -1- bases) ethyl) amine) isophthalodinitrile (compound 19), yield 93%.Fusing point：
141.4-143.2℃。
Proton nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=1.26 (d, J=6.7Hz, 3H,
CH3),1.48-1.68(m,12H,CH2), 1.97 (s, 3H, CH), 4.11 (q, J=6.7Hz, 1H, CH), 6.63 (d, J=
10.4Hz,1H,NH)；
Carbon-13 nmr spectra (deuterated dimethyl sulfoxide, the instrument of Bruker AM 600):δ=14.9,28.1,28.2,36.8,
37.8,37.8,37.8,38.1,38.1,38.1,60.1,60.1,80.3,82.5,104.4,109.3,112.2,151.0,
160.2,166.1；
High Resolution Spectrum C20H20ClF2N3,[M-H]–；Theoretical value 374.1241；Measured value, 374.1240.
Embodiment 20：The chloro- 4- of 2,5,6- tri- ((change by (1- ((3r, 5r, 7r)-adamantane -1- bases) amido) isophthalodinitrile
Compound 20)
2,4,5,6- termils (2mol, 532mg) are added in 50 milliliters of round-bottomed flasks and add acetonitrile solvent
(25mL), carries out magnetic agitation at 60 DEG C, afterwards add 4- (((3r, 5r, 7r)-adamantane -1- bases) amine (2mmol, 302mg),
K2CO3After (1mmol, 138mg), reaction 4h, frozen water is added immediately and is quenched, reaction solution is extracted with ethyl acetate, taken organic
Layer, then uses anhydrous Na2SO4It is dried, will be evaporated by dry liquid concentration, thing is evaporated to concentration afterwards carries out post layer
Analysis, the solvent that described pillar layer separation is used for petrol ether/ethyl acetate mixed solvent=20:1, white solid is obtained, it is red
Dry products obtain white solid, 2,5,6- tri- chloro- 4- ((1- ((3r, 5r, 7r)-adamantane -1- bases) amido) isophthalic two under outer lamp
Formonitrile HCN (compound 20), yield 92%.Fusing point：230.0-231.4℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=1.27 (d, J=6.5Hz, 3H, CH3),
1.54-1.77(m,12H,CH2), 2.06 (s, 3H, CH), 4.26 (q, J=6.5Hz, 1H, CH), 5.72 (d, J=g10.0Hz,
1H,NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=15.6,15.6,28.2,28.2,36.8,
38.3,38.3,38.3,38.3,59.7,59.7,94.5,102.7,111.5,114.2,115.7,119.4,133.9,139.5,
142.4,149.7；
High Resolution Spectrum C20H20F3N3,[M-H]–；Theoretical value 406.0650；Measured value, 406.0649.
Embodiment 21：Synthesize the fluoro- 4- of the chloro- 2,6- bis- of 5- ((1- ((1r, 3R, 5S, 7r) -3,5- dimethyladamantane amine -1-
Base) ethyl) amine) isophthalodinitrile (compound 21)
The chloro- 2,6- difluoros isophthalodinitriles (1mol, 216mg) of 5- are added in 25 milliliters of round-bottomed flasks and add acetonitrile solvent
(20mL), carries out magnetic agitation at 40 DEG C, and 4- ((1- ((1r, 3R, 5S, 7r) -3,5- dimethyladamantane amine is added afterwards
(1mmol,165mg),K2CO3After (1mmol, 138mg), reaction 2h, frozen water is added immediately and is quenched, with ethyl acetate to reaction solution
Extracted, take organic layer, then use anhydrous Na2SO4It is dried, will be evaporated by dry liquid concentration, concentration is evaporated
Thing is recrystallized (acetone：Petroleum ether=1:15) dry products under white solid, infrared lamp, are obtained and obtain white solid, 5- chloro- 2,
The fluoro- 4- of 6- bis- ((1- ((1r, 3R, 5S, 7r) -3,5- dimethyladamantane amine -1- bases) ethyl) amine) isophthalodinitrile (compound
21), yield 89%.Fusing point：184.4-185.0℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=0.82 (s, 6H, CH3),1.10-1.86(m,
12H,CH2),2.16(s,1H,CH),4.59(s,1H,NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=29.3,30.0,30.7,33.2,41.9,
42.1,42.1,49.3,49.9,50.1,59.9,85.6,113.0,113.0,114.7,148.9,166.6；
High Resolution Spectrum C20H20ClF2N3,[M-H]–；Theoretical value 374.1241；Measured value, 374.1240.
Embodiment 22：Synthesize (3s, 5s, 7s)-N- (the fluoro- 5- nitrobenzophenones of 2,3- bis-) adamantane -1- amine (compound 22)
The fluoro- 5- nitrobenzene (1mol, 216mg) of 1,2,3- tri- are added in 25 milliliters of round-bottomed flasks and add acetonitrile solvent
(15mL), carries out magnetic agitation at 40 DEG C, and amantadine (2mmol, 336mg), K are added afterwards2CO3(1.5mmol,207mg)。
React after 30min, frozen water is quenched, and reaction solution is extracted with ethyl acetate, is taken organic layer, is then used anhydrous Na2SO4Carry out
Dry, will be evaporated by dry liquid concentration, be evaporated thing to concentration afterwards and carry out column chromatography, described pillar layer separation is used
Solvent be petrol ether/ethyl acetate mixed solvent=20:1, dry products under white solid, infrared lamp are obtained, (3s, 5s,
7s)-N- (the fluoro- 5- nitrobenzophenones of 2,3- bis-) adamantane -1- amine (compound 22).Yield：96%, fusing point：136.6-137.1
℃。
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=1.57-1.84 (m, 12H, CH2),2.07
(s,3H,CH),3.99(s,1H,NH),7.70-7.71(m,2H,ArH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=29.9,29.9,29.9,36.0,36.0,
36.0,43.4,43.4,43.5,54.3,108.4,108.5,131.2,151.6；
High Resolution Spectrum C20H20ClF2N3,[M-H]–；Theoretical value 307.1264；Measured value, 307.1261；
Embodiment 23：Synthesize (3s, 5s, 7s)-N- (the fluoro- 3- nitrobenzophenones of 2,6- bis-) adamantane -1- amine (compound 23)
The fluoro- 3- nitrobenzene (1mol, 216mg) of 1,2,6- tri- are added in 25 milliliters of round-bottomed flasks and add acetonitrile solvent
(15mL), carries out magnetic agitation at 40 DEG C, and amantadine (2mmol, 336mg), K are added afterwards2CO3(1mmol, 138mg), instead
Answer after 30min, frozen water is quenched, reaction solution is extracted with ethyl acetate, take organic layer, then use anhydrous Na2SO4Done
It is dry, it will be evaporated by dry liquid concentration, be evaporated thing to concentration afterwards and carry out column chromatography, what described pillar layer separation was used
Solvent is mixed solvent=20 of petrol ether/ethyl acetate:1, dry products under white solid, infrared lamp are obtained, (3s, 5s, 7s)-
N- (the fluoro- 3- nitrobenzophenones of 2,6- bis-) adamantane -1- amine (compound 23).Yield：94%, fusing point：132.3-133.1℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=1.54-1.89 (m, 12H, CH2),2.06
(s,3H,CH),6.47-6.52(m,1H,ArH),7.60(s,1H,NH),7.88-7.91(m,1H,ArH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=29.9,29.9,29.9,36.0,36.0,
36.0,43.5,43.6,43.6,55.5,105.2,123.2,134.1,136.7,141.2,155.5；
High Resolution Spectrum C16H18F2N2O2,[M-H]+；Theoretical value 309.1409；Measured value, 309.1406.
Embodiment 24：Synthesize the fluoro- 2- nitroanilines (compound 24) of N- cyclohexyl -4,5- two
2,4,5- trifluoronitrobenzenes (2mmol, 350mg) are added in 25 milliliters of round-bottomed flasks, Isosorbide-5-Nitrae-dioxane is added
Under solvent (15mL) magnetic agitation, then raw material 4- methyl-benzyls amine (1mmol, 121mg) is slowly added dropwise.25 DEG C of room temperature, reaction
After 7min, frozen water is added immediately and is quenched.Reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4Enter
Row drying, will be evaporated by dry liquid concentration, and being evaporated thing to concentration afterwards carries out column chromatography, and described pillar layer separation is adopted
Solvent is mixed solvent=10 of petroleum ether/acetone:1, dry products obtain yellow solid under infrared lamp, N- cyclohexyl -4,
The fluoro- 2- nitroanilines (compound 24) of 5- bis-, yield 94%.Fusing point：120.8-121.5℃.
Proton nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=1.25-2.05 (m, 10H, CH2),3.39
(m,1H,CH),6.63(m,1H,ArH),8.03(m,1H,ArH),8.17(s,1H,NH)；
Carbon-13 nmr spectra (deuterochloroform, the instrument of Bruker AM 500):δ=24.4,25.4,25.5,32.5,32.5,
51.7,101.4,115.8,126.2,140.6,143.1,155.4；
High Resolution Spectrum C12H9F2N2O2,[M-H]+；Theoretical value 258.1130；Measured value, 258.1134.
Halo amino benzenes compounds structure synthesized by above is as shown in table 1：
The halo amino benzenes compounds structural formula of table 1
The antibacterial effect of Part II the compounds of this invention：
The compound of the present invention carries out antibacterial activity research to three kinds of agriculture bacterium (sickle-like bacteria, anthrax-bacilus, Phytophthora nicotianae Breda)
(table 2~4).Result of study shows that agriculture bacterium effectively suppresses 3~4,7~9,14 pairs three kinds of the compound invented.Wherein chemical combination
Compounds 9 are for sickle-like bacteria, anthrax-bacilus, and three kinds of bacterium of Phytophthora nicotianae Breda are when drug concentration is 6.25mg/L, inhibiting rate difference
For 93%, 95%, 90%；Compound 14 is in drug concentration for sickle-like bacteria, anthrax-bacilus, three kinds of bacterium of Phytophthora nicotianae Breda
During 6.25mg/L, inhibiting rate is respectively 92%, 93%, 88%；Compound 9 and 14 is for sickle-like bacteria, anthrax-bacilus, Phytophthora nicotianae Breda
Bactericidal effect be superior to positive control Bravo.
The compound of table 2 is to sickle-like bacteria screening active ingredients
The compound of table 3 is to anthrax-bacilus screening active ingredients
Note："-" is not test in form.
The compound of table 4 is to Phytophthora nicotianae Breda screening active ingredients
The insect resistant effect of Part III the compounds of this invention：
The compound of the present invention carries out anti-insect activity research (table 5~6) to artemia.Result of study shows, the change invented
Compound 3~4,6,12~14 is effective to artemia to be suppressed, and it is to artemia half lethal concentration (LD50) be respectively 0.440,1.353,
0.455th, 1.426,0.230,0.223mg/mL, is superior to positive control imidacloprid (3.62mg/mL).
The representation compound of table 5 is to artemia insecticidal activity equation of linear regression
Note：R2For square of coefficient correlation, (R is directly just the coefficient correlation of dependent variable independent variable in a linear equation,
It is polynary, it is multiple correlation coefficient, R2It is exactly square of coefficient correlation, R2Closer to 1, fitting degree is better, and correlation is also got over
It is high).
Half lethal concentration LD of the representation compound of table 6 to artemia50(mg/mL)
General principle, principal character and the advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the simply explanation described in above-described embodiment and specification is originally
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appending claims and its
Equivalent thereof.
Claims (10)
1. halo amino benzenes compounds, it is characterised in that shown in the structure of the compound such as formula (I)：
In formula (I), R is cyano group, nitro or hydrogen；
R1For fluorine, chlorine or hydrogen；
R2For cyano group, nitro or hydrogen；
X is fluorine, chlorine or hydrogen；
Y is fluorine, chlorine or hydrogen；
R' is cyclopenta, cyclohexyl, substituted cyclohexyl, adamantyl, substitution adamantyl, 1- methyl isophthalic acids-adamantane -1- Ji Jia
Base or 1,2,3,4- tetrahydroisoquinoline -2- bases；
R " is hydrogen atom or unsubstituted.
2. the preparation method of the halo amino benzenes compounds described in claim 1, it is characterised in that comprise the following steps：
By the polyhalo benzene-like compounds of formula (II) structure and the aminated compounds of formula (III) structure, in non-protonic solvent,
In alkaline or neutral environment, stirring carries out nucleophilic substitution at a temperature of 10-60 DEG C, and TLC tracking, question response is completely rear
Water quenching on the rocks is gone out, afterwards by product purification, is dried, is obtained the halo amino benzenes compounds of the formula (I) structure；
In formula (II), R is cyano group, nitro or hydrogen；R1For fluorine, chlorine or hydrogen；R2For cyano group, nitro or hydrogen；X is fluorine, chlorine or hydrogen；Y
For for fluorine, chlorine or hydrogen；
In formula (III), R' is cyclopenta, cyclohexyl, substituted cyclohexyl, adamantyl, substitution adamantyl, 1- methyl isophthalic acids-gold
Firm alkane -1- ylmethyls or 1,2,3,4- tetrahydroisoquinoline -2- bases；R " is hydrogen atom or unsubstituted.
3. the preparation method of halo amino benzenes compounds according to claim 2, it is characterised in that formula (II) structure it is many
Halo benzene-like compounds are 1 with the mol ratio of the aminated compounds of formula (III) structure:1~1:2.
4. the preparation method of halo amino benzenes compounds according to claim 2, it is characterised in that the reaction time is
5min-4h。
5. the preparation method of halo amino benzenes compounds according to claim 2, it is characterised in that described alkali is K2CO3,
The aminated compounds of formula (III) structure and the mol ratio of alkali are 1:1~2:1.
6. the preparation method of halo amino benzenes compounds according to claim 2, it is characterised in that described aprotic
Solvent is acetonitrile or Isosorbide-5-Nitrae-dioxane, the body mole with non-protonic solvent of the polyhalo benzene-like compounds of formula (II) structure
Product is than being 1mmol：15~25mL；Described drying means is dry under vacuum drying, natural drying or infrared lamp.
7. the preparation method of halo amino benzenes compounds according to claim 2, it is characterised in that described purification process
Extracted to add organic solvent first into reactant with saturated aqueous common salt, organic phase anhydrous Na2SO4Or anhydrous MgSO4
Dry, be afterwards concentrated under reduced pressure into dried organic phase dry, concentrate is obtained such as formula (I) through column chromatography for separation or recrystallization
Shown halo amino benzenes compounds sterling.
8. the preparation method of halo amino benzenes compounds according to claim 7, it is characterised in that described extraction is used
Organic solvent be ethyl acetate or dichloromethane；
The eluant, eluent that described column chromatography for separation is used is 10 for volume ratio:1~20:The mixing of 1 petroleum ether and ethyl acetate
Solvent；
Described recrystallization volume ratio is 1:10~1:20 ethyl acetate and the mixed solvent of petroleum ether, or volume ratio are 1:
10~1:20 acetone and the mixed solvent of petroleum ether.
9. the halo amino benzenes compounds described in claim 1 are used as the application for preparing antibacterials.
10. the halo amino benzenes compounds described in claim 1 are used as the application for preparing insecticidal materials.
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