CN106957246B - Halogeno-benzene aminated compounds and its preparation method and application - Google Patents
Halogeno-benzene aminated compounds and its preparation method and application Download PDFInfo
- Publication number
- CN106957246B CN106957246B CN201710241033.9A CN201710241033A CN106957246B CN 106957246 B CN106957246 B CN 106957246B CN 201710241033 A CN201710241033 A CN 201710241033A CN 106957246 B CN106957246 B CN 106957246B
- Authority
- CN
- China
- Prior art keywords
- benzene
- halogeno
- aminated compounds
- chlorine
- cyano
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- 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
-
- 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
- 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
-
- 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
- A01N37/34—Nitriles
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- 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
- C07C211/57—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Abstract
The present invention relates to a kind of preparation method and applications of halogeno-benzene aminated compounds, belong to field of pharmaceutical chemistry technology.The general structure of the compound is as shown in the formula (I),, formula (I)；The present invention utilizes raw material simple and easy to get: polyhalo benzene-like compounds (II) and aminated compounds (III) the halogeno-benzene aminated compounds (I) of room temperature reaction synthesis with antibacterial, anti-insect activity in non-protonic solvent.The features such as synthetic route that the invention preparation method has is short, simple process, efficiently, and easy to operate, reaction condition is mild, does not need heating and anhydrous condition, does not need metal catalytic, and yield is high, and production cost is low, highly beneficial industrial production.Halogeno-benzene aminated compounds of the present invention has good antibacterial and insecticidal activity, and application prospect is significant.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to a kind of halogeno-benzene aminated compounds and preparation method thereof and
Using.
Background technique
Halide-containing plays highly important role in drug, has 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 quotient
The drug of product includes galanthamine hydrobromide (Galanthamine Hydrobromide), 2,3,4,6- tetrachloro isophthalic diformazan
Nitrile (trade name: Bravo), Norfloxacin (Norfloxacin) etc. contain halogen atom.Aniline compound answering in drug
With extremely extensively, common phenyl amines drug has treatment canker sore, acute laryngopharyngitis and the benzene assistant card as local anesthetic
Cause, local anaesthesia medication procaine hydrochloride, analgesic-antipyretic paracetamol, the local anaesthesia of external ophthalmologic operation are preferred
Drug bupivacaine hydrochloride injection.
There are the document and patent report of aniline or halogeno-benzene amine 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 halogenated virtue of N-
The chiral amino acid esters compound and preparation method and application that base replaces.
Since the research of the antibacterial of halogeno-benzene amine, desinsection is also seldom.Therefore it is short to establish a kind of synthetic route, technique letter
Single, efficient, the reaction time is short, and reaction condition is mild, does not need high temperature and anhydrous condition, does not need metal catalytic, and yield is high, raw
Synthetic route synthesizing halogen amino benzenes compounds at low cost are produced as agricultural bacteriocide and insecticidal materials with highly important
Meaning.Halogeno-benzene aminated compounds of the present invention has good antibacterial and anti-insect activity, and application prospect is significant.
Summary of the invention
It is an object of the present invention to solve the deficiency of the existing technology and provide a kind of preparation sides of halogeno-benzene aminated 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 invention is as follows:
Halogeno-benzene aminated compounds, shown in the structure of the compound such as formula (I):
Formula (I)；
In formula (I), R is cyano, nitro or hydrogen；
R1For fluorine, chlorine or hydrogen；
R2For cyano, nitro or hydrogen；
X is fluorine, chlorine or hydrogen；
Y is fluorine, chlorine or hydrogen；
R' is cyclopenta, cyclohexyl, substituted cyclohexyl, adamantyl, replaces adamantyl or 1- methyl-1-adamantane-
1- ylmethyl；
R " is hydrogen atom or unsubstituted.
The present invention also provides the preparation methods of above-mentioned halogeno-benzene aminated compounds, include 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 alkalinity or neutral environment, stirring carries out nucleophilic substitution, TLC tracking, wait react at a temperature of 10-60 DEG C
Water quenching on the rocks is gone out after after complete, dry later by product purification, obtains the halogeno-benzene aminated compounds of the formula (I) structure；
In formula (II), R is cyano, nitro or hydrogen；R1For fluorine, chlorine or hydrogen；R2For cyano, nitro or hydrogen；X be fluorine, chlorine or
Hydrogen；Y is fluorine, chlorine or hydrogen；
In formula (III), R' is cyclopenta, cyclohexyl, substituted cyclohexyl, adamantyl, replaces adamantyl, 1- methyl-
1- adamantane -1- ylmethyl or 1,2,3,4- tetrahydroisoquinoline -2- base；R " is hydrogen atom or unsubstituted.
It is further preferred that the aminated compounds of the polyhalo benzene-like compounds of formula (II) structure and formula (III) structure
Molar ratio be 1:1~1:2.
It is further preferred that the reaction time is 5min-4h.
It is further preferred that the alkali is K2CO3, the aminated compounds of formula (III) structure and the molar ratio of alkali are
1:1~2:1.
It is further preferred that the non-protonic solvent be acetonitrile or Isosorbide-5-Nitrae-dioxane, formula (II) structure it is more
Halogenated benzene-like compounds mole are 1mmol:15~25mL with the volume ratio of non-protonic solvent；The drying means is true
It is dry under sky drying, natural drying or infrared lamp.
It is further preferred that the purification process is that organic solvent and saturated common salt are added first into reactant
Water is extracted, organic phase anhydrous Na2SO4Or anhydrous MgSO4It is dry, the organic phase after drying is concentrated to dryness later,
Concentrate obtains the halogeno-benzene amine pure compounds as shown in formula (I) through column chromatography for separation or recrystallization.
It is further preferred that the organic solvent that the extraction uses is ethyl acetate or methylene chloride；
The petroleum ether and ethyl acetate that the eluant, eluent that the column chromatography for separation uses is 10:1~20:1 for volume ratio
Mixed solvent；
The mixed solvent or volume ratio of ethyl acetate and petroleum ether that the recrystallization is 1:10~1:20 with volume ratio
For the acetone of 1:10~1:20 and the mixed solvent of petroleum ether.
Application the present invention also provides above-mentioned halogeno-benzene aminated compounds as preparation antibacterials, may be preferably used for preparing
Anti- sickle-like bacteria drug, anti-Phytophthora nicotianae Breda cancer drug, anti-musae drug.
The present invention additionally provides above-mentioned halogeno-benzene aminated compounds as the application for preparing insecticidal materials, may be preferably used for making
Standby anti-artemia drug.
Compared with prior art, the present invention has the advantages that:
The present invention utilizes raw material simple and easy to get: the halogenated benzene-like compounds of formula (II) structure and the amine of formula (III) structure
Class compound under the conditions of temperature (10~60 DEG C), is stirred in non-protonic solvent, TLC tracking, to fully reacting
Afterwards, reactant is purified, dry the target compound with antibacterial and anti-insect activity, i.e. halogeno-benzene aminated compounds (I).
Preparation method of the present invention has synthetic route short (only single step reaction), and easy to operate, reaction condition is mild, does not need
High temperature (10~60 DEG C) and anhydrous condition do not need metal catalytic, and yield is high (up to 89%~98%), and production cost is low to wait spies
Point, highly beneficial industrial production.Halogeno-benzene aminated compounds produced by the present invention has good antibacterial and insecticidal activity, application
Prospect is significant.
Antibacterial activity is carried out to three kinds of agriculture bacterium (sickle-like bacteria, anthrax-bacilus, Phytophthora nicotianae Breda) using the compounds of this invention to grind
Study carefully (table 2~4).Result of study shows that 3~4,7~9,14 pairs three kinds of invented compound agriculture bacterium can be effectively suppressed.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 three kinds of sickle-like bacteria, anthrax-bacilus and Phytophthora nicotianae Breda bacterium
When 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 invented change
It closes 3~4,6,12~14 pairs of artemias of object effectively to inhibit, to artemia half lethal concentration (LD50) be respectively 0.440,1.353,
0.455,1.426,0.230,0.223mg/mL are superior to positive control imidacloprid (3.62mg/mL).
Detailed description of the invention
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 nuclear magnetic resonance spectroscopy of compound 14.
Fig. 4 is the carbon-13 nmr spectra of compound 14.
Specific embodiment
Below 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 range.In the examples where no specific technique or condition is specified, described technology or conditions according to the literature in the art
Or it is carried out according to product description.Production firm person is not specified in agents useful for same, instrument etc., is that can be obtained by purchase
Conventional products.
Raw material of the present invention can be prepared by the well known method of this field or be obtained by commercial product.
The conventional method of the synthesis of halogeno-benzene aminated 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 halogeno-benzene aminated compounds of the 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 alkalinity or neutral environment, stirring carries out nucleophilic substitution, TLC tracking, wait react at a temperature of 10-60 DEG C
Water quenching on the rocks is gone out after after complete, dry later by product purification, obtains the halogeno-benzene aminated compounds of the formula (I) structure；
In formula (II), R is cyano, nitro or hydrogen；R1For fluorine, chlorine or hydrogen；R2For cyano, nitro or hydrogen；X be fluorine, chlorine or
Hydrogen；Y is fluorine, chlorine or hydrogen；
In formula (III), R' is cyclopenta, cyclohexyl, substituted cyclohexyl, adamantyl, replaces adamantyl, 1- methyl-
1- adamantane -1- ylmethyl or 1,2,3,4- tetrahydroisoquinoline -2- base；R " is hydrogen atom or unsubstituted.
The molar ratio of the aminated compounds of the polyhalo benzene-like compounds and formula (III) structure of formula (II) structure be 1:1~
1:2。
Reaction time is 5min-4h.
Alkali is not required, and if you need to use alkali, the alkali is K2CO3, the amine of formula (III) structure and the molar ratio of alkali
For 1:1~2:1.
The non-protonic solvent is acetonitrile or Isosorbide-5-Nitrae-dioxane, molten on the basis of polyhalo benzene-like compounds 1mmol
The dosage (15~25mL) of agent；The drying means is dry under vacuum drying, natural drying or infrared lamp.
The purification process is that organic solvent is added first into reactant to be extracted with saturated salt solution, organic phase
Use anhydrous Na2SO4Or anhydrous MgSO4It is dry, the organic phase after drying is concentrated to dryness later, concentrate is through column chromatography point
From or recrystallization, obtain the halogeno-benzene amine pure compounds as shown in formula (I).
The organic solvent that the extraction uses is ethyl acetate or methylene chloride；
The petroleum ether and ethyl acetate that the eluant, eluent that the column chromatography for separation uses is 10:1~20:1 for volume ratio
Mixed solvent；
The mixed solvent or volume ratio of ethyl acetate and petroleum ether that the recrystallization is 1:10~1:20 with volume ratio
For the acetone of 1:10~1:20 and the mixed solvent of petroleum ether.
According to known methods, formula (III) compound is well known to the compound of formula (II), is commercially available or can be according to public affairs
The method preparation 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 in sterilizing and is cooled to 45 DEG C~50 DEG C
5mL medical fluid is added in 45mLPDA culture medium, shakes up and band medicine culture base plane is made in the culture dish of two diameter 9cm of injection.Often
Medicament presses sequence of the low concentration to high concentration, 4 repetitions of every processing.After culture medium solidification, in every culture dish center, inoculation is straight
Diameter is the tomato early blight bacterium fungus block of 0.6cm, is placed in 25 DEG C of incubator and cultivates.Wait compare ware bacterium colony it is long to close to ware side when,
Culture dish is taken out, each processing colony diameter is measured, each amount 1 time, is averaged in length and breadth, calculates the percentage for inhibiting bacterium colony growth
Rate.
Anti- artemia the determination of activity: (research of Wang Xinghong Podophyllum emodi var chinense class plant endogenesis epiphyte: the Kunming [D]: Yunnan University's life
Scientific institute, 2006.)
1. artemia hatch: in beaker be added 500mL artificial seawater (NaCl 28.150g, KCl 0.670g,
MgCl2·6H2O 5.510g, MgSO4·7H2O 6.920g, CaCl2·2H2O 1.450g adds deionized water constant volume to arrive
1000mL uses NaHCO3Adjusting pH value is 8.0), 30 DEG C to be heated on electric furnace.A little artemia eggs is added, is put into water-bath,
30 DEG C of hatchings for 24 hours, it is spare to isolate the vigorous artemia of energy with separatory funnel.
2. sample treatment: weighing 4mg sample, DMSO dissolution is added, (DMSO content is no more than 10%) trains in 96 hole cells
The artificial seawater that 50 μ L medical fluids and 100 μ L are added in every hole in plate is supported, 50 seawater of the μ L with artemia, every hole artemia number 4~7 are added
Tail, being diluted to concentration is 1mg/mL.Artificial seawater and same amount of DMSO, 30 DEG C of cultures are added in control group.It is stronger to activity
Medical fluid manually measures medical fluid after seawater is diluted to different multiples, each sample repeats 3 holes.
3. observation counts: after sample-adding culture 8h, counting dead individuals number and total individual number, anti-artemia respectively with bitubular anatomical lens
Activity is indicated with corrected mortality.
Survival rate=8h living individuals number/total individual number × 100%
Corrected mortality=(control group survival rate-processing group survival rate)/control group survival rate × 100%
Square R that regress analysis method everywhere calculates the regression equation of each medicament, related coefficient is calculated with Spss software2,
(R is directly just the related coefficient of dependent variable independent variable in a linear equation, polynary, is coefficient of multiple correlation R2It is exactly phase relation
Several squares), LD50Deng the size of relatively two medicament virulence.
The present invention is described in detail below with reference to part specific embodiment.These embodiments are merely to illustrate the present invention,
Rather than it limits the scope of the invention.Preparation method in embodiment is only preferred embodiment, but the invention is not limited to excellent
Select preparation method.
Embodiment 1: synthesis 4- (cyclohexylamino) -2,5,6- trifluoro 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, ice water is added immediately to be quenched.Reaction solution is extracted with methylene chloride, organic layer is taken, then uses anhydrous Na2SO4It is done
It is dry, it will be evaporated by dry liquid concentration, object be evaporated to concentration later and carries out column chromatography, what the pillar layer separation used
Solvent is mixed solvent=20:1 of petrol ether/ethyl acetate, and vacuum drying product obtains white solid, 4- (cyclohexylamino) -2,
5,6- trifluoro isophthalodinitriles (compound 1), yield 88%.Fusing point: 108.5-111.6 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 600 instrument of Bruker AM): δ=1.24-2.18 (m, 10H, CH2),4.34–
4.40(m,1H,CH),5.61(s,1H,NH)；
Carbon-13 nmr spectra (deuterated chloroform, 600 instrument of Bruker AM): 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: the synthesis chloro- 4- of 5- (cyclohexyl amido) -2,6- difluoro isophthalodinitrile (compound 2)
Chloro- 2, the 6- fluorine isophthalodinitrile (1mmol, 216mg) of 5- is 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, ice water is added immediately to be quenched.Reaction solution is extracted with ethyl acetate, takes organic layer, then with anhydrous MgSO4It is done
It is dry, object is evaporated to concentration after being evaporated by dry liquid concentration and carries out column chromatography, what the pillar layer separation used
Solvent is mixed solvent=12:1 of petrol ether/ethyl acetate, obtains white solid, spontaneously dries product and obtains white solid, product
The chloro- 4- of 5- (cyclohexyl amido) -2,6- difluoro isophthalodinitrile (compound 2), yield 93%.Fusing point: 96.1-97.2 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): δ=1.23-2.15 (m, 10H, CH2),4.29–
4.36(m,1H,CH),5.65(s,1H,NH)；
Carbon-13 nmr spectra (deuterated chloroform, 500 instrument of Bruker AM): 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: the synthesis chloro- 6- of 2,4,5- tri- ((cyclo-hexylamine) isophthalodinitrile (compound 3)
2,4,5,6- termil (1mol, 266mg) is added in 25 milliliters of round-bottomed flasks, 1,4- dioxy is added
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, and cyclohexylamine (1mmol, 98mg) is added afterwards, after reacting 15min, ice water
It is quenched, reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4It is dried, it will be by drying
Liquid concentration is evaporated, and is evaporated object to concentration later and is carried out column chromatography, the solvent that the pillar layer separation uses is petroleum ether/second
Mixed solvent=20:1 of acetoacetic ester obtains white solid, obtains product, 2,4,5- tri- chloro- 6- ((hexamethylenes after drying under infrared lamp
Base amine) isophthalodinitrile (compound 3).Yield 92%, fusing point: 108.5-111.6 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 600 instrument of Bruker AM): δ=1.24-2.18 (m, 10H, CH2),4.34–
4.40(m,1H,CH),5.61(s,1H,NH)；
Carbon-13 nmr spectra (deuterated chloroform, 600 instrument of Bruker AM): 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: the synthesis chloro- 6- of 2,4,5- tri- (((2R) -2- methyl cyclohexane amido) amine) isophthalodinitrile (compound 4)
2,4,5,6- termil (1mol, 266mg) is added in 25 milliliters of round-bottomed flasks, 1,4- dioxy is added
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, rear that 2- methyl cyclohexylamine (1mmol, 113mg) is added, and react 15min
Afterwards, ice water is quenched, and is extracted with ethyl acetate to reaction solution, takes organic layer, then use anhydrous Na2SO4It is dried, it will be through
It crosses dry liquid concentration to be evaporated, object is evaporated to concentration later and is recrystallized, recrystallization solvent for use is petroleum ether/acetone
Mixed solvent=20:1, obtains white solid, dry products under infrared lamp, and it is chloro- to obtain product 2,4,5- tri- after dry under infrared lamp
6- (((2R) -2- methyl cyclohexane amido) amine) isophthalodinitrile (compound 4).Yield: 98%, fusing point: 132.7-133.9 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: the synthesis fluoro- 6- of 2,4,5- tri- ((4- methyl cyclohexane amido) amine isophthalodinitrile (compound 5)
2,4,5,6- tetrafluoro isophthalodinitrile (1mol, 200mg) is added in 25 milliliters of round-bottomed flasks, 1,4- dioxy is added
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, rear that 2- methyl cyclohexylamine (1mmol, 113mg) is added, and react 15min
Afterwards, ice water is quenched, and is extracted with ethyl acetate to reaction solution, takes organic layer, then use anhydrous Na2SO4It is dried, it will be through
Cross dry liquid concentration to be evaporated, object be evaporated to concentration later and carries out column chromatography, the solvent that the pillar layer separation uses for
Mixed solvent=20:1 of petrol ether/ethyl acetate, obtains white solid, dry products under infrared lamp, it is dry under infrared lamp after
To product, 2,4,5- tri- fluoro- 6- ((4- methyl cyclohexane amido) amine isophthalodinitriles (compound 5).Yield: 96%, fusing point:
101.3-102.1℃。
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: the synthesis fluoro- 6- of the chloro- 2,4- bis- of 5- ((4- methylcyclohexyl) amine) isophthalodinitrile (compound 6)
The chloro- 2,4,6- trifluoro isophthalodinitrile (1mol, 216mg) of 5- is added in 25 milliliters of round-bottomed flasks, 1,4- bis- is added
Six ring solvent (15mL) of oxygen, carries out magnetic agitation at 20 DEG C, rear that 2- methyl cyclohexylamine (1mmol, 113mg) is added, reaction
After 15min, ice water is quenched, and is extracted with ethyl acetate to reaction solution, is taken organic layer, then use anhydrous Na2SO4It is dried,
It will be evaporated by dry liquid concentration, object be evaporated to concentration later and carries out column chromatography, the pillar layer separation uses molten
Agent is mixed solvent=20:1 of petrol ether/ethyl acetate, obtains white solid, dry products under infrared lamp, dry under infrared lamp
After obtain the fluoro- 6- of the chloro- 2,4- bis- of product 5- ((4- methylcyclohexyl) amine) isophthalodinitrile (compound 6).Yield: 98%, it melts
Point: 94.9-96.1 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, 500 instrument of Bruker AM): 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, 500 instrument of Bruker AM): 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: the synthesis chloro- 6- of 2,4,5- tri- ((4- methylcyclohexyl) amine) isophthalodinitrile (compound 7)
2,4,5,6- termil (1mol, 266mg) is added in 25 milliliters of round-bottomed flasks, 1,4- dioxy is added
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, rear that 4- methyl cyclohexane (1mmol, 113mg) is added, and react 15min
Afterwards, ice water is quenched, and is extracted with ethyl acetate to reaction solution, takes organic layer, then use anhydrous Na2SO4It is dried, it will be through
Cross dry liquid concentration to be evaporated, object be evaporated to concentration later and carries out column chromatography, the solvent that the pillar layer separation uses for
Mixed solvent=20:1 of petrol ether/ethyl acetate, obtains white solid, dry products under infrared lamp, it is dry under infrared lamp after
To the chloro- 6- of product 2,4,5- tri- ((4- methylcyclohexyl) amine) isophthalodinitrile (compound 7).Yield: 97%, fusing point:
151.9-152.4℃。
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: the synthesis fluoro- 4- of the chloro- 2,6- bis- of 5- ((cyclohexyl methyl) amine) isophthalodinitrile (compound 8)
The chloro- 2,4,6- trifluoro isophthalodinitrile (1mol, 216mg) of 5- is added in 25 milliliters of round-bottomed flasks, 1,4- bis- is added
Six ring solvent (15mL) of oxygen, carries out magnetic agitation at 20 DEG C, and cyclohexyl methylamine (1mmol, 112mg) is added afterwards, reacts 10min
Afterwards, ice water is quenched, and is extracted with ethyl acetate to reaction solution, takes organic layer, then use anhydrous Na2SO4It is dried, it will be through
Cross dry liquid concentration to be evaporated, object be evaporated to concentration later and carries out column chromatography, the solvent that the pillar layer separation uses for
Mixed solvent=20:1 of petrol ether/ethyl acetate, obtains white solid, dry products under infrared lamp, it is dry under infrared lamp after
To product, 5- chloro-2,6-difluoro -4- ((cyclohexyl methyl) amine) isophthalodinitrile (compound 8).Yield: 92%, fusing point:
152.4-155.8℃。
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 600 instrument of Bruker AM): 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 (deuterated chloroform, 600 instrument of Bruker AM): 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: the synthesis chloro- 6- of 2,4,5- tri- (cyclohexyl methylamine base) isophthalodinitrile (compound 9)
2,4,5,6- termil (1mol, 266mg) is added in 25 milliliters of round-bottomed flasks, 1,4- dioxy is added
Six ring solvents (15mL), carry out magnetic agitation at 25 DEG C, and cyclohexyl methylamine (1mmol, 112mg) is added afterwards, after reacting 5min, ice
Water quenching is gone out, and is extracted with ethyl acetate to reaction solution, is taken organic layer, then use anhydrous Na2SO4It is dried, drying will be passed through
Liquid concentration be evaporated, object is evaporated to concentration later and is recrystallized, the solvent that the recrystallization uses is petroleum ether/acetic acid
Mixed solvent=10:1 of ethyl ester, obtains white solid, dry products under infrared lamp, between 2,4,5- tri- chloro- 6- (cyclohexyl methylamine base)
Benzene dicarbonitrile (compound 9).Yield: 92%, fusing point: 158.4-158.8 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 600 instrument of Bruker AM): 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 (deuterated chloroform, 600 instrument of Bruker AM): 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: the synthesis chloro- 2,6- bis- of 5- fluoro- 4- (cyclopentamine base) isophthalodinitrile (compound 10)
The chloro- 2,6- difluoro isophthalodinitrile (1mmol, 216mg) of 5- is added in 25 milliliters of round-bottomed flasks, 1,4- bis- is added
Six ring solvent (15mL) of oxygen, carries out magnetic agitation at 10 DEG C, and cyclopentamine (1mmol, 140mg) is added afterwards, after reacting 10min,
Ice water is added immediately to be quenched, 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, object be evaporated to concentration later and carries out column chromatography, the pillar layer separation uses molten
Agent is mixed solvent=20:1 of petrol ether/ethyl acetate, obtains white solid, dry products obtain white solid, 5- under infrared lamp
Chloro-2,6-difluoro -4- (cyclopentamine base) isophthalodinitrile (compound 10), yield 94%.Fusing point: 82.1-83.9 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 600 instrument of Bruker AM): 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 (deuterated chloroform, 600 instrument of Bruker AM): 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: the synthesis chloro- 6- of 2,4,5- tri- (cyclopentamine base) isophthalodinitrile (compound 11)
2,4,5,6- termil (1mol, 266mg) is added in 25 milliliters of round-bottomed flasks, 1,4- dioxy is added
Six ring solvents (15mL), carry out magnetic agitation at 20 DEG C, and cyclopentamine (2mmol, 170mg) is added afterwards, after reacting 5min, ice water
It is quenched, reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4It is dried, it will be by drying
Liquid concentration is evaporated, and is evaporated object to concentration later and is carried out column chromatography, the solvent that the pillar layer separation uses is petroleum ether/second
Mixed solvent=20:1 of acetoacetic ester, obtains white solid, dry products under infrared lamp, between 2,4,5- tri- chloro- 6- (cyclopentamine base)
Benzene dicarbonitrile (compound 11).Yield: 85%, fusing point: 142.0-143.6 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 600 instrument of Bruker AM): 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 (deuterated chloroform, 600 instrument of Bruker AM): 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: the synthesis fluoro- 4- of 2,5,6- tri- (- 2 (1H)-yl of bis- isoquinolin of 3,4-) isophthalodinitrile (compound 12)
Plus, Isosorbide-5-Nitrae-two is added in 2,4,5,6- tetrafluoro isophthalodinitriles (1.0mmol, 200mg) in 25 milliliters of round-bottomed flasks
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 reaction, after reacting 13min, ice 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 by dry liquid concentration, concentration is evaporated later
Object carries out column chromatography, and the solvent that the pillar layer separation uses obtains yellow for mixed solvent=10:1 of petrol ether/ethyl acetate
Color solid, dry products obtain white solid, 4- (- 2 (1H)-yl of 3,4- bis- isoquinolin) -2,5,6- trifluoro isophthalic two under infrared lamp
Formonitrile HCN (compound 12), yield 88%.Fusing point: 117.0-117.6 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: the synthesis chloro- 4- of 5- (- 2 (1H)-yl of bis- isoquinolin of 3,4-) -2,6- difluoro isophthalodinitrile (compound
13)
5- chloro-2,6-difluoro isophthalodinitrile (1.0mmol, 216mg) is added in 25 milliliters of round-bottomed flasks, Isosorbide-5-Nitrae-is added
Under dioxane solvent (15mL) magnetic agitation, then raw material 1,2,3,4- tetrahydroisoquinolines (1.5mmol, 199mg) slowly drip
Add.24 DEG C of reaction after 18min, ice water is added immediately and is quenched.Reaction solution is extracted with ethyl acetate, takes organic layer, then
Use anhydrous Na2SO4It is dried, will be evaporated by dry liquid concentration, object is evaporated to concentration later and is recrystallized, it is described
The solvent that uses of recrystallization obtain yellow solid for petroleum ether/acetone mixed solvent=10:1, dry products obtain under infrared lamp
White solid, the chloro- 4- of 5- (- 2 (1H)-yl of 3,4- bis- isoquinolin) -2,6- difluoro isophthalodinitrile (compound 13), yield
88%.Fusing point: 127.0-127.3 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: the synthesis chloro- 6- of 2,5,6- tri- (- 2 (1H)-yl of bis- isoquinolin of 3,4-) 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, 1,2,3,4- tetrahydroisoquinolines (2mmol, 266mg) are added at 30 DEG C, react 10min
Afterwards, ice water is added immediately to be quenched, reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4It is done
It is dry, will be evaporated by dry liquid concentration, object is evaporated to concentration later and is recrystallized, the recrystallization use solvent for
Mixed solvent=20:1 of petrol ether/ethyl acetate obtains yellow solid, and dry products obtain yellow solid under infrared lamp, and 2,5,6-
Three chloro- 6- (- 2 (1H)-yl of 3,4- bis- isoquinolin) isophthalodinitriles (compound 14), yield 93%, fusing point: 180.6-181.2
℃。
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 600 instrument of Bruker AM): 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 (deuterated chloroform, 600 instrument of Bruker AM): 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: the synthesis fluoro- 4- of 2,5,6- tri- (((3s, 5s, 7s)-adamantane -1- base) amine) isophthalodinitrile (chemical combination
Object 15)
2,4,5,6- tetrafluoro isophthalodinitrile (1mmol, 200mg) is added in 50 milliliters of round-bottomed flasks, acetonitrile solvent is added
(25mL) carries out magnetic agitation at 30 DEG C, and amantadine (1mmol, 151mg) is added afterwards, after reacting 60min, is added immediately
Ice water is quenched, and is extracted with ethyl acetate to reaction solution, takes organic layer, then use anhydrous Na2SO4It is dried, it will be through overdrying
Dry liquid concentration is evaporated, and is evaporated object to concentration later and is recrystallized, and the recrystallization uses solvent for petroleum ether/acetic acid
Mixed solvent=15:1 of ethyl ester obtains white solid, and dry products obtain white solid, 2,5,6- tri- fluoro- 4- under infrared lamp
(((3s, 5s, 7s)-adamantane -1- base) amine) isophthalodinitrile (compound 15), yield 92%.Fusing point: 150.0-150.6 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, 600 instrument of Bruker AM): 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, 600 instrument of Bruker AM): 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: the synthesis fluoro- 4- of the chloro- 2,6- bis- of 5- (((3s, 5s, 7s)-adamantane -1- base) amine) isophthalodinitrile
(compound 16)
It is molten that chloro- 2,6- difluoro isophthalodinitrile (1mmol, 216mg) the addition acetonitrile of 5- is added in 25 milliliters of round-bottomed flasks
Agent (20mL), carries out magnetic agitation at 15 DEG C, afterwards be added amantadine (2mmol, 302mg), react 25min after, immediately plus
Enter ice water to be quenched, reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4It is dried, will pass through
Dry liquid concentration is evaporated, and is evaporated object to concentration later and is carried out column chromatography, the solvent that the pillar layer separation uses is stone
Mixed solvent=15:1 of oily ether/ethyl acetate obtains white solid, and dry products obtain white solid, 5- chloro- 2,6- under infrared lamp
Two fluoro- 4- (((3s, 5s, 7s)-adamantane -1- base) amine) isophthalodinitriles (compound 16), yield 93%.Fusing point: 123.0-
124.6℃。
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, 600 instrument of Bruker AM): 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, 600 instrument of Bruker AM): 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: the synthesis chloro- 4- of 2,5,6- tri- (((3s, 5s, 7s)-adamantane -1- base) amine) isophthalodinitrile (chemical combination
Object 17)
2,4,5,6- termil (1mmol, 266mg) is added in 25 milliliters of round-bottomed flasks, acetonitrile solvent is added
(20mL) carries out magnetic agitation at 50 DEG C, is added amantadine (2mmol, 302mg), and K is added2CO3(1mmol,138mg)
Afterwards, after reacting 3h, ice water is added immediately and is quenched, reaction solution is extracted with ethyl acetate, takes organic layer, then with anhydrous
Na2SO4It is dried, will be evaporated by dry liquid concentration, object is evaporated to concentration later and carries out column chromatography, the column color
The solvent that spectrum separation uses obtains white solid, dry products under infrared lamp for mixed solvent=20:1 of petrol ether/ethyl acetate
Obtain white solid, 2,5,6- tri- chloro- 4- (((3s, 5s, 7s)-adamantane -1- base) amine) isophthalodinitriles (compound 17), yield
91%.Fusing point: 210.0-210.6 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, 600 instrument of Bruker AM): 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, 600 instrument of Bruker AM): 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: the synthesis fluoro- 4- of 2,5,6- tri- ((1- ((3r, 5r, 7r)-amantadine -1- base) ethyl) amine) isophthalic
Dimethoxy nitrile (compound 18)
2,4,5,6- tetrafluoro isophthalodinitrile (1mol, 200mg) is added in 25 milliliters of round-bottomed flasks, acetonitrile solvent is added
(20mL) carries out magnetic agitation at 30 DEG C, and 4- ((1- ((3r, 5r, 7r)-adamantane amido -1- base) ethyl) amine is added afterwards
(1mmol, 179mg) extracts reaction solution with ethyl acetate, takes organic layer, then use anhydrous Na after reacting 30min2SO4
It is dried, will be evaporated by dry liquid concentration, object is evaporated to concentration later and carries out column chromatography, the pillar layer separation
The solvent used obtains white solid for mixed solvent=20:1 of petrol ether/ethyl acetate, dry products under infrared lamp, and 2,5,
The fluoro- 4- of 6- tri- ((1- ((3r, 5r, 7r)-amantadine -1- base) ethyl) amine) isophthalodinitrile (compound 18), yield 92%.
Fusing point: 132.3-133.3 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, 600 instrument of Bruker AM): 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, 600 instrument of Bruker AM): 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: the synthesis fluoro- 4- of the chloro- 2,6- bis- of 5- ((1- ((3r, 5r, 7r)-adamantane amido -1- base) ethyl) amine)
Isophthalodinitrile (compound 19)
The chloro- 2,6- difluoro isophthalodinitrile (1mol, 216mg) of 5- is added in 25 milliliters of round-bottomed flasks, acetonitrile solvent is added
(15mL) carries out magnetic agitation at 25 DEG C, and 4- ((1- ((3r, 5r, 7r)-amantadine -1- base) ethyl) amine) is added afterwards
(1mmol, 179mg) after reacting 40min, ice water is added immediately and is quenched, is extracted, is taken organic to reaction solution with ethyl acetate
Layer, then uses anhydrous Na2SO4It is dried, will be evaporated by dry liquid concentration, object is evaporated to concentration and is recrystallized (second
Acetoacetic ester: petroleum ether=1:15), white solid is obtained, dry products obtain white solid, 5- chloro-2,6-difluoro -4- under infrared lamp
((1- ((3r, 5r, 7r)-adamantane amido -1- base) ethyl) amine) isophthalodinitrile (compound 19), yield 93%.Fusing point:
141.4-143.2℃。
Nuclear magnetic resonance spectroscopy (deuterated dimethyl sulfoxide, 600 instrument of Bruker AM): 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, 600 instrument of Bruker AM): 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.
The chloro- 4- of embodiment 20:2,5,6- tri- ((change by (1- ((3r, 5r, 7r)-adamantane -1- base) amido) isophthalodinitrile
Close object 20)
2,4,5,6- termil (2mol, 532mg) is added in 50 milliliters of round-bottomed flasks, acetonitrile solvent is added
(25mL) carries out magnetic agitation at 60 DEG C, afterwards be added 4- (((3r, 5r, 7r)-adamantane -1- base) amine (2mmol, 302mg),
K2CO3(1mmol, 138mg) after reacting 4h, ice water is added immediately and is quenched, is extracted, is taken organic to reaction solution with ethyl acetate
Layer, then uses anhydrous Na2SO4It is dried, will be evaporated by dry liquid concentration, object is evaporated to concentration later and carries out column layer
Analysis, the solvent that the pillar layer separation uses obtains white solid for mixed solvent=20:1 of petrol ether/ethyl acetate, red
Dry products obtain white solid, 2,5,6- tri- chloro- 4- ((1- ((3r, 5r, 7r)-adamantane -1- base) amido) isophthalic two under outer lamp
Formonitrile HCN (compound 20), yield 92%.Fusing point: 230.0-231.4 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: the synthesis 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- difluoro isophthalodinitrile (1mol, 216mg) of 5- is added in 25 milliliters of round-bottomed flasks, acetonitrile solvent is added
(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),K2CO3(1mmol, 138mg) after reacting 2h, ice water is added immediately and is quenched, with ethyl acetate to reaction solution
It is extracted, takes organic layer, then use anhydrous Na2SO4It is dried, will be evaporated by dry liquid concentration, concentration is evaporated
Object is recrystallized (acetone: petroleum ether=1:15), obtains white solid, and dry products obtain white solid under infrared lamp, 5- chloro- 2,
The fluoro- 4- of 6- bis- ((1- ((1r, 3R, 5S, 7r) -3,5- dimethyladamantane amine -1- base) ethyl) amine) isophthalodinitrile (compound
21), yield 89%.Fusing point: 184.4-185.0 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: synthesis (3s, 5s, 7s)-N- (the fluoro- 5- nitrobenzophenone of 2,3- bis-) adamantane -1- amine (compound 22)
The fluoro- 5- nitrobenzene (1mol, 216mg) of 1,2,3- tri- is added in 25 milliliters of round-bottomed flasks, acetonitrile solvent is added
(15mL) carries out magnetic agitation at 40 DEG C, amantadine (2mmol, 336mg) is added afterwards, K2CO3(1.5mmol,207mg)。
After reacting 30min, ice water is quenched, and is extracted with ethyl acetate to reaction solution, takes organic layer, then use anhydrous Na2SO4It carries out
It is dry, it will be evaporated by dry liquid concentration, object be evaporated to concentration later and carries out column chromatography, the pillar layer separation uses
Solvent be petrol ether/ethyl acetate mixed solvent=20:1, obtain white solid, dry products under infrared lamp, (3s, 5s,
7s)-N- (the fluoro- 5- nitrobenzophenone of 2,3- bis-) adamantane -1- amine (compound 22).Yield: 96%, fusing point: 136.6-137.1
℃。
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: synthesis (3s, 5s, 7s)-N- (the fluoro- 3- nitrobenzophenone of 2,6- bis-) adamantane -1- amine (compound 23)
The fluoro- 3- nitrobenzene (1mol, 216mg) of 1,2,6- tri- is added in 25 milliliters of round-bottomed flasks, acetonitrile solvent is added
(15mL) carries out magnetic agitation at 40 DEG C, amantadine (2mmol, 336mg) is added afterwards, K2CO3(1mmol, 138mg), instead
After answering 30min, ice water is quenched, and is extracted with ethyl acetate to reaction solution, is taken organic layer, then use anhydrous Na2SO4It is done
It is dry, it will be evaporated by dry liquid concentration, object be evaporated to concentration later and carries out column chromatography, what the pillar layer separation used
Solvent is mixed solvent=20:1 of petrol ether/ethyl acetate, obtains white solid, dry products under infrared lamp, (3s, 5s, 7s)-
N- (the fluoro- 3- nitrobenzophenone of 2,6- bis-) adamantane -1- amine (compound 23).Yield: 94%, fusing point: 132.3-133.1 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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: the synthesis fluoro- 2- nitroaniline (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- methylbenzyl amine (1mmol, 121mg) is slowly added dropwise.25 DEG C of room temperature, reaction
After 7min, ice water is added immediately and is quenched.Reaction solution is extracted with ethyl acetate, organic layer is taken, then uses anhydrous Na2SO4Into
Row drying will be evaporated by dry liquid concentration, be evaporated object to concentration later and carry out column chromatography, the pillar layer separation be adopted
Solvent is petroleum ether/acetone mixed solvent=10:1, and dry products obtain yellow solid under infrared lamp, cyclohexyl -4 N-,
The fluoro- 2- nitroaniline (compound 24) of 5- bis-, yield 94%.Fusing point: 120.8-121.5 DEG C.
Nuclear magnetic resonance spectroscopy (deuterated chloroform, 500 instrument of Bruker AM): 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 (deuterated chloroform, 500 instrument of Bruker AM): 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.
The above synthesized halogeno-benzene amine compound structure is as shown in table 1:
1 halogeno-benzene amine structural formula of compound of table
The antibacterial effect of second part 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 3~4,7~9,14 pairs three kinds of invented compound agriculture bacterium effectively inhibit.Wherein chemical combination
Compounds 9 are for sickle-like bacteria, and anthrax-bacilus, three kinds of bacterium of Phytophthora nicotianae Breda are when drug concentration is 6.25mg/L, inhibiting rate difference
It is 93%, 95%, 90%；Compound 14 is in drug concentration for sickle-like bacteria, anthrax-bacilus, three kinds of bacterium of Phytophthora nicotianae Breda
When 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.
2 compound of table is to sickle-like bacteria screening active ingredients
3 compound of table is to anthrax-bacilus screening active ingredients
Note: "-" is not test in table.
4 compound of table 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 invented change
It closes 3~4,6,12~14 pairs of artemias of object effectively to inhibit, to artemia half lethal concentration (LD50) be respectively 0.440,1.353,
0.455,1.426,0.230,0.223mg/mL are superior to positive control imidacloprid (3.62mg/mL).
5 representation compound of table is to artemia insecticidal activity equation of linear regression
Note: R2For square of related coefficient, (R is directly just the related coefficient of dependent variable independent variable in a linear equation,
It is polynary, it is multiple correlation coefficient, R2It is exactly square of related coefficient, R2Closer to 1, fitting degree is better, and correlation is also got over
It is high).
Half lethal concentration LD of 6 representation compound of table to artemia50(mg/mL)
The basic principles, main features and advantages of the present invention have 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 above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (10)
1. halogeno-benzene aminated compounds, which is characterized in that shown in the structure of the compound such as formula (I):
In formula (I), R is cyano or nitro；
R1For fluorine or chlorine；
R2For cyano or nitro；
X is fluorine or chlorine；
Y is fluorine or chlorine；
R' is cyclopenta, cyclohexyl, 4- methylcyclohexyl, adamantyl, 1- adamantyl ethyl or 1,2,3,4- Tetrahydroisoquinoli-
Quinoline -2- base；
R " is hydrogen atom or unsubstituted；
Wherein, when R is nitro, R2It is not cyano；
When R' is 4- methylcyclohexyl, R is cyano, R1For fluorine, R2For cyano, X is fluorine, and Y is that chlorine, R " are unsubstituted；
When R' is 1- adamantyl ethyl, R is cyano, R1For chlorine, R2For cyano, X is chlorine, and Y is that chlorine, R " are hydrogen atom.
2. the preparation method of halogeno-benzene aminated compounds described in claim 1, which comprises the steps of:
By the aminated compounds of the polyhalo benzene-like compounds of formula (II) structure and formula (III) structure, in non-protonic solvent,
Alkalinity or neutral environment in, at a temperature of 10-60 DEG C stirring carry out nucleophilic substitution, TLC tracking, after complete reaction plus
Ice water is quenched, dry later by product purification, obtains the halogeno-benzene aminated compounds of the formula (I) structure；
Wherein, R is cyano or nitro；
R1For fluorine or chlorine；
R2For cyano or nitro；
X is fluorine or chlorine；
Y is fluorine or chlorine；
R' is cyclopenta, cyclohexyl, 4- methylcyclohexyl, adamantyl, 1- adamantyl ethyl or 1,2,3,4- Tetrahydroisoquinoli-
Quinoline -2- base；
R " is hydrogen atom or unsubstituted；
Wherein, when R is nitro, R2It is not cyano；
When R' is 4- methylcyclohexyl, R is cyano, R1For fluorine, R2For cyano, X is fluorine, and Y is that chlorine, R " are unsubstituted；
When R' is 1- adamantyl ethyl, R is cyano, R1For chlorine, R2For cyano, X is chlorine, and Y is that chlorine, R " are hydrogen atom.
3. the preparation method of halogeno-benzene aminated compounds according to claim 2, which is characterized in that formula (II) structure it is more
The molar ratio of halogenated benzene-like compounds and the aminated compounds of formula (III) structure is 1:1~1:2.
4. the preparation method of halogeno-benzene aminated compounds according to claim 2, which is characterized in that the reaction time is
5min-4h。
5. the preparation method of halogeno-benzene aminated compounds according to claim 2, which is characterized in that the alkali is K2CO3,
The aminated compounds of formula (III) structure and the molar ratio of alkali are 1:1~2:1.
6. the preparation method of halogeno-benzene aminated compounds according to claim 2, which is characterized in that the 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；The drying means is dry under vacuum drying, natural drying or infrared lamp.
7. the preparation method of halogeno-benzene aminated compounds according to claim 2, which is characterized in that the purification process
It is extracted for organic solvent is added first into reactant with saturated salt solution, organic phase anhydrous Na2SO4Or anhydrous MgSO4
It is dry, the organic phase after drying is concentrated to dryness later, concentrate is obtained through column chromatography for separation or recrystallization such as formula (I)
Shown in halogeno-benzene amine pure compounds.
8. the preparation method of halogeno-benzene aminated compounds according to claim 7, which is characterized in that the extraction uses
Organic solvent be ethyl acetate or methylene chloride；
The mixing of petroleum ether and ethyl acetate that the eluant, eluent that the column chromatography for separation uses is 10:1~20:1 for volume ratio
Solvent；
The mixed solvent or volume ratio of ethyl acetate and petroleum ether that the recrystallization is 1:10~1:20 with volume ratio are 1:
The acetone of 10~1:20 and the mixed solvent of petroleum ether.
9. application of the halogeno-benzene aminated compounds described in claim 1 as preparation antibacterials.
10. halogeno-benzene aminated compounds described in claim 1 is as the application for preparing insecticidal materials.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710241033.9A CN106957246B (en) | 2017-04-13 | 2017-04-13 | Halogeno-benzene aminated compounds and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710241033.9A CN106957246B (en) | 2017-04-13 | 2017-04-13 | Halogeno-benzene aminated compounds and its preparation method and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106957246A CN106957246A (en) | 2017-07-18 |
| CN106957246B true CN106957246B (en) | 2019-06-25 |
Family
ID=59484388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710241033.9A Active CN106957246B (en) | 2017-04-13 | 2017-04-13 | Halogeno-benzene aminated compounds and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106957246B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US946862A (en) * | 1908-09-22 | 1910-01-18 | Butters Patent Vacuum Filter Company Inc | Filter for metallurgical and other purposes. |
| CN101132695A (en) * | 2005-02-19 | 2008-02-27 | 梅瑞尔有限公司 | Pesticidal substituted piperidines |
| WO2010097815A2 (en) * | 2009-02-27 | 2010-09-02 | Council Of Scientific & Industrial Research | A two component recyclable heterogeneous catalyst, process for preparation thereof and its use for preparation of amines |
| WO2012172043A1 (en) * | 2011-06-15 | 2012-12-20 | Laboratoire Biodim | Purine derivatives and their use as pharmaceuticals for prevention or treatment of bacterial infections |
| CN103467395A (en) * | 2013-07-04 | 2013-12-25 | 北京理工大学 | Solid-phase synthetic method of amantadine derivative |
-
2017
- 2017-04-13 CN CN201710241033.9A patent/CN106957246B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US946862A (en) * | 1908-09-22 | 1910-01-18 | Butters Patent Vacuum Filter Company Inc | Filter for metallurgical and other purposes. |
| CN101132695A (en) * | 2005-02-19 | 2008-02-27 | 梅瑞尔有限公司 | Pesticidal substituted piperidines |
| WO2010097815A2 (en) * | 2009-02-27 | 2010-09-02 | Council Of Scientific & Industrial Research | A two component recyclable heterogeneous catalyst, process for preparation thereof and its use for preparation of amines |
| WO2012172043A1 (en) * | 2011-06-15 | 2012-12-20 | Laboratoire Biodim | Purine derivatives and their use as pharmaceuticals for prevention or treatment of bacterial infections |
| CN103467395A (en) * | 2013-07-04 | 2013-12-25 | 北京理工大学 | Solid-phase synthetic method of amantadine derivative |
Non-Patent Citations (2)
| Title |
|---|
| Synthesis and Potent Antimicrobial Activities of Some Novel Retinoidal Monocationic Benzimidazoles;Zeynep Ates-Alagoz et al.;《Arch. Pharm. Chem. Life Sci.》;20161231;第339卷;74-80 |
| 金刚烷胺缩3,5-二溴水杨醛Schiff碱的合成、表征及抗菌活性研究;金旭东 等;《辽宁大学学报自然科学版》;20101231;第37卷(第4期);306-309 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106957246A (en) | 2017-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103214532B (en) | Avermectin B2a/2bAmido derivative, derivative salt and avermectin B2a/2bThe Preparation method and use of amido derivative salt | |
| CN103396396B (en) | Amido alkane acyl Clinafloxacin and application thereof | |
| CN108314679B (en) | Bactericide containing 1,3, 4-oxadiazole ring stilbene amide and preparation method and application thereof | |
| CN106957246B (en) | Halogeno-benzene aminated compounds and its preparation method and application | |
| CN110354113A (en) | A kind of borneol derivative antibacterial agent and the preparation method and application thereof | |
| CN108299255A (en) | Histone deacetylase 8 selective depressant and its preparation method and application | |
| CN112341402A (en) | Preparation method and application of pyrimidine compound capable of inhibiting bacteria in medical care process | |
| CN101638391A (en) | 2-[(substituted aminobenzene)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-3H-pyrimidyl-4-ketone derivative and preparation method and application thereof | |
| CN112771048A (en) | Inhibitors of influenza virus replication and intermediates and uses thereof | |
| CN106220558B (en) | N-4- pyridine acyl-dehydroabietylamine derivatives and its preparation method and application | |
| CN106967146A (en) | Oleanolic acid terazole derivatives and its production and use | |
| CN102993105A (en) | 1-methyl-2, 4-quinazoline diketone derivative and preparation method and application thereof | |
| CN102584670B (en) | Indole-3-formaldehyde shrinkage phenylenediamine bis-schiff base and preparation method thereof | |
| CN109232552B (en) | Piperidine thiazole derivative containing bisamide structure and preparation method and application thereof | |
| CN103275073B (en) | 2-(1,2,4-triazole-1-methyl)-2-(cumarone-5-base)-DOX and application thereof | |
| CN107311949B (en) | Sulfonamide-substituted aryl triazine compound and preparation method and application thereof | |
| CN106565744B (en) | The crystal form and preparation method thereof of PA-824 compound | |
| CN106431977B (en) | A kind of unsaturated oximido ethers compound and application thereof | |
| CN106565624B (en) | 9- azepine -1,11- undecalactone compound and its preparation and application containing substituent group | |
| CN106220559B (en) | N-3- pyridine acyl-dehydroabietylamine derivatives and its preparation method and application | |
| CN100358519C (en) | Medicine against fungus | |
| CN102659714B (en) | 5-aryl-1,2,3-thiadiazolyl-4-sulfhydrylacetamide derivatives, and preparation method and application thereof | |
| CN116768876A (en) | Dihydrobenzofuranyl-containing isoxazole compound and preparation method and application thereof | |
| CN112125838B (en) | Trifluoromethylated aniline compound and application thereof | |
| RU2479571C1 (en) | 4-(1-cyclohepta-2,4,6-trienyl)aniline and chloride thereof, exhibiting antimicrobial activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |