CN109627206A - One kind has the preparation method and application of the carbazyl Isopropanolamine derivatives of chiral centre - Google Patents
One kind has the preparation method and application of the carbazyl Isopropanolamine derivatives of chiral centre Download PDFInfo
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- CN109627206A CN109627206A CN201910028609.2A CN201910028609A CN109627206A CN 109627206 A CN109627206 A CN 109627206A CN 201910028609 A CN201910028609 A CN 201910028609A CN 109627206 A CN109627206 A CN 109627206A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
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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
- A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
- A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to the preparation method and application of a kind of carbazyl Isopropanolamine derivatives with chiral centre.The compound has the structure as shown in general formula (I):
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, especially a kind of carbazyl isopropanol amine with chiral centre
Close object and the preparation method and application thereof.
Background technique
In recent years, vegetative bacteria and fungi drastically influence the yield and quality of global crops, bring to peasant huge
Huge economic loss.For example, rice leaf spot bacteria (Xanthomonas oryzaepv.Oryzae) is rod-shaped gram-negative
Property bacterium, which can make the blade of rice withered, it brings at least underproduction of 10-50% to the country of Rice Cropping every year.This
Outside, citrus processing (Xanthomonas axonopodis pv.Citri) will lead to citrus and rot, in the world shadow
Ring the yield of citrus.In agricultural production process, due to the long-time service of traditional medicament, so that phytopathogen generates it
Certain resistance.Therefore, new and effective, less toxic, safe environment friendly agricultural is formulated to have a very important significance.
According to the literature, carbazole derivates illustrate broad-spectrum biological activity, such as；Antibacterial, antimycotic, desinsection, weeding
And coordinate plant growth, antitumor, anti-inflammatory etc..According to the previous work of this seminar, carbazole compound shows preferably anti-
Phytopathogen activity.
In order to find the reactive compound of efficient sterilizing, the present invention is using carbazole as female ring, by a series of substituted-amino structures
Through isopropanol chain link into carbazole structure, a series of carbazyl isopropanol aminated compounds of structure novels is synthesized, is tested
Its bioactivity provides important scientific basic for the research and development and initiative of novel pesticide.
The bioactivity research progress of carbazole derivates is as follows:
[Wang, the P.Y. such as Wang in 2017；Fang,H.S.；Shao,W.B.；Zhou,J.；Chen,Z.；Song,B.A.；
Yang,S.Synthesis and biological evaluation of pyridinium-functionalized
carbazole derivatives as promising antibacterial
Agents.Bioorg.Med.Chem.Lett., 2017,27,4294-4297] synthesize a series of N- substituted pyridines salt carbazoles
Derivative tests target compound to the activity of Xoo, Xac and tobacco ralstonia solanacearum using nephelometry, the results showed that partization
Object is closed to the minimum EC of three kinds of bacteriums50Respectively 0.4,0.3,0.3mg/L.
[Clausen, the J.D. such as Clausen in 2017；Kjellerup,L.；Cohrt,K.O.；Hansen,J.B.；
Dalbybrown,W.；Winther,A.M.L.Elucidation of antimicrobial activity and
mechanism of action by n-substituted carbazole derivatives.Bioorg.Med.Chem.L
Ett., 2017,27,4564-4570] synthesized it is a series of using carbazyl isopropanolamine as the compound of precursor structure, wherein changing
Object 5 is closed to the H of saccharomycete, Candida albicans+The Ca of-ATPase and mammalian cell2+-ATPase、Na+,K+- ATPase performance
Higher inhibiting effect out, IC50Value is respectively 2.0,1.1,0.3 and 1.0 μM.
[Pattanashetty, the S.H. such as Pattanashetty in 2018；Hosamani,K.M.；Shettar,A.K.；
Shafeeulla,R.M.Design,Synthesis and Computational Studies of Novel Carbazole
N-phenylacetamide Hybrids as Potent Antibacterial,Anti-inflammatory,and
Antioxidant Agents.J.Heterocyclic Chem., 2018,55,1765-1774] design synthesized a series of N-
The carbazole derivates that phenyl-acetamides replace, and test its external anti-Staphylococcus aureus, bacillus subtilis, large intestine bar
Bacterium and pseudomonas aeruginosa, the results showed that, MIC value is respectively 0.5,0.25,0.25,1 μ g/mL, is better than comparison medicament cyclopropyl
Sha Xing.
Liu et al. [Liu, L, X. in 2015；Wang,X.Q.；Zhou,B.；Yang,L.J.；Li,Y.；Zhang,H.B.；
Yang,X.D.Synthesis and antitumor activity of novel N-substituted carbazole
Imidazolium salt derivatives.Sci.Rep.-UK, 2015,5,13101-13120] design synthesis is a series of new
The carbazole imidazolium derivative that replaces of N-, and measured by MTS and have studied their cell toxicants to human tumour cell line
Activity.Wherein compound 8 is to HL-60, and SMMC-7721, MCF-7 and SW480 cell line is with higher selectivity, IC50Value is
0.51-2.48μM。
[Zhang, the Y. such as Zhang in 2018；Tangadanchu,V.K.R.；Cheng,Y.；Yang,R.G.；Lin,
J.M.；Zhou,C.H.Potential antimicrobial isopropanol-conjugated carbazole azoles
as dual targeting inhibitors of enterococcus faecalis.ACS Med.Chem.Lett.,
2018,9,244-249] it using isopropanolamine is connection chain containing carbazole-azole compounds that design, which has synthesized a series of, tests it
To the activity of excrement enterobacteria, the results showed that compound 10 is active (MIC=2 μ g/mL) with higher.
Summary of the invention
An object of the present invention provides a kind of carbazyl isopropanol aminated compounds with chiral centre or it is vertical
Body isomers or its salt or its solvate.
Another object of the present invention is providing preparation above compound or its stereoisomer or its salt or its solvation
Midbody compound of object and preparation method thereof.
Further object of the present invention contains above compound or its stereoisomer or its salt there is provided one kind or its is molten
The composition of agent compound.
Further object of the present invention there is provided above compound or its stereoisomer or its salt or its solvate,
Or the purposes of the composition.
There is provided utilize above compound or its stereoisomer or its salt or its solvation for another object of the present invention
Object or the method for the composition for preventing and controlling agricultural pest.
To achieve the above object, present invention employs following technical proposals:
A kind of carbazyl isopropanolamine compound with chiral centre or its stereoisomer or its salt or its solvation
Object, the compound have the structure as shown in general formula (I):
Wherein,
R1And R4It is identical or different, it is independent to be selected from hydrogen, deuterium, halogen, amino, hydroxyl, C1-10Alkyl, C1-10Alkoxy,
C2-10One or more of alkenyl, acetyl group, propiono or bytyry；
R3Selected from hydrogen or deuterium；* R configuration, S configuration or raceme carbon are indicated；
R2Selected from any substituted or unsubstituted C1-10Alkyl, amino, any substituted or unsubstituted alkenyl, any substitution
Or unsubstituted C1-10Alkoxy, any substituted or unsubstituted C6-10It is naphthenic base, any substituted or unsubstituted aryl, any
One or more of substituted or unsubstituted heteroaryl.
Preferably, R1And R4It is identical or different, it is independent selected from hydrogen, deuterium, halogen, amino, hydroxyl, methyl, ethyl, propyl,
One in butyl, amyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, acetyl group, propiono or bytyry or
It is multiple；
It is highly preferred that R1And R4It is identical or different, it is independent to be selected from hydrogen, deuterium, halogen, amino, hydroxyl, methyl, ethyl, third
One or more of base, methoxyl group, ethyoxyl, propoxyl group, acetyl group or propiono；
Preferably, R2Selected from hydrogen, deuterium, C1-5Alkyl, C1-5It is alkoxy, substituted or unsubstituted amino, substituted or unsubstituted
C6-C15Aryl, substituted or unsubstituted C6-C10Heteroaryl or C6-C10One or more of heterocycle, wherein the substitution
Refer to by one or more of methyl, ethyl, methoxyl group, ethyoxyl, amino, hydroxyl, halogen, nitro, trifluoromethyl
Replace；
It is highly preferred that R2Selected from hydrogen, deuterium, methyl, ethyl, n-propyl, Zhong Bingji, isopropyl, acrylic, allyl, fourth
Alkenyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, amino, methylamino, ethylamino, dimethylamino, lignocaine, propyl ammonia
Base, dipropyl amino, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyridyl group, substitution or
Unsubstituted thienyl, substituted or unsubstituted furyl, wherein the substitution is referred to by methyl, ethyl, methoxyl group, second
Oxygroup, amino, hydroxyl, halogen, nitro, one or more in trifluoromethyl replace；
Most preferably, R2Selected from methyl, ethyl, n-propyl, Zhong Bingji, isopropyl, acrylic, allyl, methoxyl group, second
Oxygroup, propoxyl group, amino, methylamino, ethylamino, chlorphenyl, fluorophenyl, bromophenyl, dichlorophenyl, difluorophenyl, dibromobenzene
Base, aminomethyl phenyl, trifluoromethyl, aminophenyl, hydroxy phenyl, nitrobenzophenone, 3,5-dimethylphenyl, di-trifluoromethyl benzene
Base, diamino-phenyl, dihydroxy phenyl, dinitrophenyl, 2- chlorobenzyl, 3- chlorobenzyl, 4- chlorobenzyl, 2- luorobenzyl, 3- fluorine
Benzyl, 4- luorobenzyl, 2- bromobenzyl, 3- bromobenzyl, 4- bromobenzyl, 2- trifluoromethyl benzyl, 3- trifluoromethyl benzyl, 4- trifluoro
Methylbenzyl, 2- methylbenzyl, 3- methylbenzyl, 4- methylbenzyl, pyridyl group, 3- picoline -2- methylene, 4- methyl pyrrole
Pyridine -2- methylene, 5- picoline -2- methylene, furans, 2- methylfuran, 3- methylfuran, thiophene, 2- methylthiophene, 3-
Methylthiophene.
A kind of carbazyl isopropanolamine compound with chiral centre or its stereoisomer or its salt or its
Solvate is chosen in particular from following compounds:
The present invention also provides a kind of midbody compounds for preparing logical formula (I) compound, with following formula (II) chemical combination
Shown in object:
Wherein, R1And R4As shown above；Preferably, following particular compounds are selected from:
The present invention also provides the carbazyl isopropanolamine compound with chiral centre or its stereoisomer or
The preparation method of its salt or its solvate comprising following step: formula (II) compound and R2-NH2Reaction generates formula (I)
The step of closing object；
Most preferably, include the following steps:
The present invention also provides a kind of composition, contain the compound or its stereoisomer or its salt or its
Solvate, and agriculturally available auxiliary agent or fungicide, insecticide or herbicide；Preferably, the dosage form of the composition
Selected from missible oil (EC), pulvis (DP), wettable powder (WP), granule (GR), aqua (AS), suspending agent (SC), ultra-low volume
Spray (ULV), soluble powder (SP), microcapsule formulations (MC), fumicants (FU), aqueous emulsion (EW), water-dispersible granules (WG).
The compound or its stereoisomer or its salt or its solvate or the composition can be used for preventing
Control agricultural pest, it is preferable that the agricultural pest is vegetative bacteria or fungal disease；It is highly preferred that the agricultural
Pest and disease damage is plant leaf blight and plant canker；Most preferably, the agricultural pest is that rice leaf spot bacteria, cucumber are white
Leaf spoting bacteria, konjaku leaf spot bacteria, citrus processing, grape ulcer bacterium, bacterial canker of tomato, Prospect on Kiwifruit Bacterial Canker
Bacterium, apple ulcer bacteria, botrytis cinerea pers, capsicum wilt bacterium, Sclerotinia sclerotiorum, fusarium graminearum, potato evening
Epidemic disease bacterium, blueberry pine root fungus and dragon fruit anthrax bacteria.
The present invention also provides it is a kind of prevent and treat agricultural pest method, make the compound or its stereoisomer,
Or its salt or its solvate or the composition act on nuisance or its living environment；Preferably, the agriculture disease pest
Evil is vegetative bacteria or fungal disease；It is highly preferred that the agricultural pest is rice leaf spot bacteria, cucumber bacterial leaf spot
Germ, konjaku leaf spot bacteria, citrus processing, grape ulcer bacterium, bacterial canker of tomato, Prospect on Kiwifruit Bacterial Canker bacterium, apple
Fruit ulcer bacteria, botrytis cinerea pers, capsicum wilt bacterium, Sclerotinia sclerotiorum, fusarium graminearum, the late blight of potato
Bacterium, blueberry pine root fungus and dragon fruit anthrax bacteria.
The present invention also provides the methods for protecting the plants from agricultural pest infringement, make plant and the chemical combination
Object or the method and step of its stereoisomer or its salt or its solvate or the composition contact.
The term " alkyl " used herein be include the branch and linear saturation alkyl with given number carbon atom.Such as
“C1-10Alkyl " (or alkylidene) purpose is C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl.In addition, such as " C1-6Alkane
Base " indicates the alkyl with 1 to 6 carbon atoms.Alkyl can be to be non-substituted or substitution, so that its one or more hydrogen atom quilt
Other chemical groups replace.The embodiment of alkyl includes but is not limited to methyl (Me), ethyl (Et), propyl (such as n-propyl and different
Propyl), butyl (such as normal-butyl, isobutyl group, tert-butyl), amyl (such as n-pentyl, isopentyl, neopentyl) and the like.And
It further include its all isomerism in addition to including n-hexyl, n-heptyl, n-octyl and when mentioning hexyl, heptyl, octyl
Body.
" alkenyl " is hydrocarbon both including straight or branched structure, and there is one or more to appear in any stable point in chain
Carbon-to-carbon double bond.Such as " C2-6Alkenyl " (or alkenylene) purpose be include C2, C3, C4, C5 and C6 alkenyl.The example packet of alkenyl
Include but be not limited to vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyl, 3- cyclobutenyl, 2- pentenyl, 3- pentenyl, 4- amylene
Base, 2- hexenyl, 3- hexenyl, 4- hexenyl, 5- hexenyl, 2- methyl -2- acrylic, 4- methyl-3-pentenyl and its class
Like object.
The term " substituted " used herein refers to any one or more hydrogen atoms on specified atom or group
Replaced with the specified group of selection, on condition that being no more than the general chemical valence of specified atom.If without other explanation, substituent group
It names to division center.For example, it is to be understood that when (naphthenic base) alkyl is possible substituent group, the substituent group to centre junction
The tie point of structure is in moieties.Ring double bond used herein is formed at two double bond (such as C closed between annular atom
=C, C=N or N=N).When mentioning substitution, when especially polysubstituted, refer to that multiple substituent groups are each in specified group
Replace on a position, as dichlorophenyl refers to 1,2- dichlorophenyl, 1,3- dichlorophenyl and Isosorbide-5-Nitrae-dichlorophenyl.
The combination of substituent group and/or variable is allowed, and only generates stable compound or useful synthesis when these are combined
Intermediate.When stable compound or rock-steady structure implies that the compound is separated with useful purity from reaction mixture
Be it is sufficiently stable, therewith prepare form effective therapeutic reagent.Preferably, the compound does not include N- halogen, S at present
(O)2H or S (O) H base.
Term " aryl " is referred in monocycle or Bicyclic alkyl that loop section has 6 to 12 carbon atoms, such as phenyl
And naphthalene, it each can be substituted.
Term " halogen " or " halogen atom " refer to chlorine, bromine, fluorine and iodine.
Term " heteroaryl " refer to replace and non-substituted fragrant 5 or 6 unit monocycle group, 9- or 10- membered bicyclic group, and
11 to 14 membered tricyclic groups have at least one hetero atom (O, S or N) at least one ring, described excellent containing heteroatomic ring
Choosing has 1,2 or 3 hetero atom in O, S and N.Each ring containing heteroatomic heteroaryl can contain one or two oxygen or
Sulphur atom and/or by 1 to 4 nitrogen-atoms, on condition that heteroatomic sum is 4 or less in each ring, and each ring has extremely
A few carbon atom.Carbon atom can only be contained by completing bicyclic and three cyclic groups fused rings, and can be saturation, fractional saturation or
It is unsaturated.Nitrogen and sulphur atom can be optionally oxidized and nitrogen-atoms can be optionally quaternized.Bicyclic or tricyclic heteroaryl must wrap
At least one full aromatic rings is included, the other fused rings of nitrogen can be armaticity or nonaromatic.Heteroaryl can be in any of any ring
Using being connected on nitrogen or carbon atom.When chemical valence allows, if other rings are naphthenic base or heterocycle, in addition optionally with
=O (oxygen) replaces.
Exemplary monocyclic heteroaryl includes pyrrole radicals, pyrazolyl, pyrazolinyl, imidazole radicals, oxazolyl, isoxazolyl, thiophene
Oxazolyl, thiadiazolyl group, furyl, thienyl, oxadiazoles base, pyridyl group, pyrazinyl, pyrimidine radicals, pyridazinyl, triazine radical and its class
Like object.
Exemplary bicyclic heteroaryl include indyl, benzothiazolyl, benzodioxole base, benzoxazolyl,
Benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl, benzofuranyl, indolizine base, benzo furan
It mutters base, chromone base, cumarin base, benzofuranyl, cinnoline base, quinoxalinyl, indazolyl, pyrrolopyridinyl, fluorinated pyridine
Base, dihydro-iso indolyl, tetrahydric quinoline group and the like.
If the compound of the present invention is interpreted as including free state and its salt without other explanations.Term " salt " indicate with
Inorganic and/or organic bronsted lowry acids and bases bronsted lowry forms acid and/or basic salt.In addition, " salt may include amphoteric ion (inner salt) to term, such as work as
Compound of formula I contains basic moiety such as amine or pyridine or imidazole ring and acid segment such as carboxylic acid.It is pharmaceutically acceptable (i.e. non-
It is toxicity, physiologically acceptable) salt is preferred, such as acceptable metal and amine salt, wherein cation does not have notable contribution
The bioactivity of toxicity or salt.However, other salt can be useful, isolated or purified step is such as used during the preparation process, because
This is also contained in the scope of the invention.
Preferably, C1-C10Alkyl refers to methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, the last of the ten Heavenly stems
Base and its isomer；C1-C10Alkoxy refer to methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, hexyloxy,
Heptan oxygroup, octyloxy, nonyl epoxide, decyloxy and its isomer；C2-C5Alkenyl refer to vinyl, acrylic, allyl,
Cyclobutenyl, pentenyl and its isomer.
When mentioning substituent group, as alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, naphthenic base, hydroxyl,
When amino, sulfydryl, phosphino- or these substituent groups are specifically some specific alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl
When base, alkoxy, naphthenic base, hydroxyl, amino, sulfydryl, phosphino-, one to three above-mentioned substituent group is referred to.Such as aminomethyl phenyl
Refer to one to three methyl substituted phenyl.
By using above-mentioned technical proposal, the present invention is connection chain by isopropanol, will be improved based on carbazole
The substituted-amino of target compound bioactivity is introduced into this system, synthesizes a series of carbazyl isopropanol aminated compounds,
And find that the compound has good inhibiting effect to infective pathogen bacterium, for pathogenetic bacteria such as rice leaf spot bacteria
(Xanthomonas oryzae pv.oryzae, Xoo), citrus processing (Xanthomonas axonopodis
Pv.citri, Xac) and kiwi berry bacterial canker bacterium (Pseudomonas syingae pv.Actinidiae, PSA) etc.]
Good inhibitory effect is all had, provides important scientific basic for the research and development and initiative of novel pesticide.
Embodiment
Below by embodiment, the invention will be further described.It should be understood that the method for the embodiment of the present invention
It is only used for illustrating the present invention, rather than limiting the invention, to preparation side of the invention under concept thereof of the invention
The simple modifications of method belong to the scope of protection of present invention.All raw materials and solvent used in embodiment are commercially available production
Product.
Embodiment 1: the preparation of intermediate (R) -3,6- di-t-butyl -9- (2- methyl oxidation ethylene) -9H- carbazole
By 3,6- di-t-butyl carbazole (29.9mmol) and potassium hydroxide (35.9mmol) in 100mL round-bottomed flask, to
30mL DMF stirring is wherein added, stops reaction, extraction, column after R- epoxychloropropane (35.9mmol) reaction 8h is added under ice bath
It chromatographs (eluant, eluent PE:EA=30:1), obtains white solid, yield 54.5%.
Embodiment 2: target compound 1- (9H- carbazyl -9- base) -3- ((2- chlorobenzyl) amino) -2- hydroxypropanol
Preparation
9- (2- methyl oxidation ethylene) -9H- carbazole (0.90mmol), potassium carbonate (0.90mmol) are added to dissolved with 2- chlorine
In the 5mL aqueous isopropanol of benzylamine (1.80mmol), 60 DEG C reaction 6 hours after stop reaction, precipitation, column chromatograph (eluant, eluent
CH2Cl2:CH3OH=200:1 white solid, yield 74.7%) are obtained.
With the preparation step of similar embodiment 1/2, other compounds are prepared using corresponding raw material.The carbazyl of synthesis is different
The structure and nuclear magnetic resonance spectroscopy and carbon modal data of propyl alcohol amine structure class compound are as shown in table 1, and physico-chemical property is as shown in table 2.
The nuclear magnetic resonance spectroscopy and carbon modal data of 1 part of compounds of table
The physicochemical property of 2 partial target compound of table
Pharmacological Examples 1:
Using nephelometry test target compound to the inhibiting rate of phytopathogen, subjects are rice leaf spot bacteria
(Xoo), citrus processing (Xac) and kiwi berry bacterial canker bacterium (PSA).DMSO dissolution is used as blank in the medium
Control.Rice leaf spot bacteria (bacterial blight of rice opportunistic pathogen is in M210 solid medium) is put into NB culture medium, 28 DEG C,
Shaken cultivation is spare to logarithmic growth phase in 180rpm constant-temperature table；Citrus processing (on M210 solid medium) is put
Into NB culture medium, shaken cultivation is spare to logarithmic growth phase in 28 DEG C, 180rpm constant-temperature table；Kiwi berry bacterial is burst
Ulcer germ (on M210 solid medium) is put into NB culture medium, in 28 DEG C, 180rpm constant-temperature table shaken cultivation to pair
Number growth period is spare.Medicament (compound) is configured to the toxic NB fluid nutrient medium of various concentration (example: 100,50 μ g/mL)
5mL is added in test tube, is separately added into 40 μ L and is contained the NB fluid nutrient medium for planting sick bacterium, shakes in 28-30 DEG C, 180rpm constant temperature
It is vibrated in bed, bacterial blight of rice opportunistic pathogen culture 48h, citrus processing culture 36h, the training of kiwi berry bacterial canker bacterium
Support 36h.The bacterium solution of each concentration is measured into OD on spectrophotometer595Value, and in addition measure the toxic sterile of corresponding concentration
The OD of NB fluid nutrient medium595Value.
The embodiment of the present invention, which is aided with, illustrates technical solution of the present invention, but the content of embodiment is not limited thereto, part
Target compound experimental result is as shown in table 3,4 and 5.
Inhibitory activity of 3 compound of class containing carbazole structure of table to rice leaf spot bacteria
Inhibitory activity of 4 compound of class containing carbazole structure of table to citrus processing
Inhibitory activity of 5 compound of class containing carbazole structure of table to kiwi berry bacterial canker bacterium
From table 3,4 and 5 as can be seen that in isolated test, target compound 1-12,13-25 is to bacterial blight of rice
Bacterium shows higher bioactivity, EC50Value is in 0.902-23.5 μ g/mL；Target compound 1-12,16-25 is to c itrus canker
Germ shows higher bioactivity, EC50Value is in 0.993-30.5 μ g/mL；Target compound 1-5,7-9,11-13 is to macaque
Peach bacterial canker germ shows higher bioactivity, EC50Value is in 0.603-32.0 μ g/mL.Wherein, compound 1-5 and
7-9 shows higher inhibitory activity to three kinds of bacteriums, can be used for preparing anti-plant pathogenic pathogenetic bacteria pesticide.
Claims (9)
1. a kind of carbazyl isopropanolamine compound with chiral centre or its stereoisomer or its salt or its solvation
Object, it is characterised in that the compound has the structure as shown in general formula (I):
Wherein,
R1And R4It is identical or different, it is independent to be selected from hydrogen, deuterium, halogen, amino, hydroxyl, C1-10Alkyl, C1-10Alkoxy, C2-10Alkene
One or more of base, acetyl group, propiono or bytyry；
R3Selected from hydrogen or deuterium；* R configuration, S configuration or raceme carbon are indicated；
R2Selected from any substituted or unsubstituted C1-10Alkyl, any substituted or unsubstituted alkenyl, any replaces or not amino
Substituted C1-10Alkoxy, any substituted or unsubstituted C6-10Naphthenic base, any substituted or unsubstituted aryl, any substitution
Or one or more of unsubstituted heteroaryl.
2. a kind of carbazyl isopropanolamine compound or its alloisomerism with chiral centre according to claim 1
Body or its salt or its solvate, it is characterised in that:
Preferably, R1And R4It is identical or different, it is independent to be selected from hydrogen, deuterium, halogen, amino, hydroxyl, methyl, ethyl, propyl, fourth
One or more in base, amyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, amoxy, acetyl group, propiono or bytyry
It is a；It is highly preferred that R1And R4It is identical or different, it is independent to be selected from hydrogen, deuterium, halogen, amino, hydroxyl, methyl, ethyl, propyl, first
One or more of oxygroup, ethyoxyl, propoxyl group, acetyl group or propiono；
Preferably, R2Selected from hydrogen, deuterium, C1-5Alkyl, C1-5Alkoxy, substituted or unsubstituted amino, substituted or unsubstituted C6-
C15Aryl, substituted or unsubstituted C6-C10Heteroaryl or C6-C10One or more of heterocycle, wherein the substituted finger
It is to be replaced by the one or more in methyl, ethyl, methoxyl group, ethyoxyl, amino, hydroxyl, halogen, nitro, trifluoromethyl；More
Preferably, R2Selected from hydrogen, deuterium, methyl, ethyl, n-propyl, Zhong Bingji, isopropyl, acrylic, allyl, cyclobutenyl, methoxy
Base, ethyoxyl, propoxyl group, butoxy, amino, methylamino, ethylamino, dimethylamino, lignocaine, propylcarbamic, dipropyl ammonia
It is base, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyridyl group, substituted or unsubstituted
Thienyl, substituted or unsubstituted furyl, wherein the substitution is referred to by methyl, ethyl, methoxyl group, ethyoxyl, ammonia
Base, hydroxyl, halogen, nitro, one or more in trifluoromethyl replace；Most preferably, R2Selected from methyl, ethyl, n-propyl,
Zhong Bingji, isopropyl, acrylic, allyl, methoxyl group, ethyoxyl, propoxyl group, amino, methylamino, ethylamino, chlorphenyl, fluorine
Phenyl, bromophenyl, dichlorophenyl, difluorophenyl, dibromo phenyl, aminomethyl phenyl, trifluoromethyl, aminophenyl, hydroxy benzenes
Base, nitrobenzophenone, 3,5-dimethylphenyl, di-trifluoromethyl phenyl, diamino-phenyl, dihydroxy phenyl, dinitrophenyl, 2- chlorine
Benzyl, 3- chlorobenzyl, 4- chlorobenzyl, 2- luorobenzyl, 3- luorobenzyl, 4- luorobenzyl, 2- bromobenzyl, 3- bromobenzyl, 4- bromobenzyl,
2- trifluoromethyl benzyl, 3- trifluoromethyl benzyl, 4- trifluoromethyl benzyl, 2- methylbenzyl, 3- methylbenzyl, 4- methyl benzyl
Base, pyridyl group, 3- picoline -2- methylene, 4- picoline -2- methylene, 5- picoline -2- methylene, furans, 2-
Methylfuran, 3- methylfuran, thiophene, 2- methylthiophene, 3 methyl thiophene.
3. a kind of carbazyl isopropanolamine compound or its alloisomerism with chiral centre according to claim 1
Body or its salt or its solvate are selected from following compounds:
4. a kind of midbody compound for preparing logical formula (I) compound, it is characterised in that shown in following formula (II) compound:
Wherein, R1And R4As shown in claim 1；
Preferably, following particular compounds are selected from:
5. a kind of carbazyl isopropanolamine compound with chiral centre described in claim 1 or its stereoisomer or
The preparation method of its salt or its solvate, it is characterised in that include the following steps: formula (II) compound and R2-NH2Reaction generates
The step of formula (I) compound；
Most preferably, include the following steps:
6. a kind of composition, it is characterised in that containing claim the 1-3 any compound or its stereoisomer or its
Salt or its solvate, and agriculturally available auxiliary agent or fungicide, insecticide or herbicide；Preferably, the composition
Dosage form be selected from missible oil (EC), pulvis (DP), wettable powder (WP), granule (GR), aqua (AS), suspending agent (SC), super
Low-gallonage spraying agent (ULV), soluble powder (SP), microcapsule formulations (MC), fumicants (FU), aqueous emulsion (EW), water dispersible grain
Agent (WG).
7. claim the 1-3 any compound or its stereoisomer or its salt or its solvate or claim
Purposes of the composition described in 6 in terms of preventing and treating agricultural pest, it is preferable that the agricultural pest is for vegetative bacteria or very
Fungal disease；It is highly preferred that the agricultural pest is plant leaf blight and plant canker；Most preferably, the agricultural disease
Insect pest is bacterial blight of rice, cucumber bacterial leaf-blight, konjaku bacterial leaf-blight, citrus bacterial canker disease, grape ulcer, tomato ulcer
Disease, Prospect on Kiwifruit Bacterial Canker, apple canker, gray mold of cucumber, capsicum wilt, sclerotinia sclerotiorum, wheat scab, potato
Late blight, blueberry root rot and dragon fruit anthracnose.
8. a kind of method for preventing and treating agricultural pest, it is characterised in that: make any compound of claim 1-3 or it is vertical
Body isomers or its salt or its solvate or composition as claimed in claim 6 act on nuisance or its living environment；
Preferably, the agricultural pest is vegetative bacteria or fungal disease；It is highly preferred that the agricultural pest is that rice is white
Leaf blight, cucumber bacterial leaf-blight, konjaku bacterial leaf-blight, citrus bacterial canker disease, grape ulcer, canker of tomato, Kiwi berry ulcer
Disease, apple canker, gray mold of cucumber, capsicum wilt, sclerotinia sclerotiorum, wheat scab, the late blight of potato, blueberry root
Maize ear rot and dragon fruit anthracnose.
9. the method for protecting the plants from agricultural pest infringement comprising wherein make plant and claim 1-3 any
The side of the compound or the contact of its stereoisomer or its salt or its solvate or composition as claimed in claim 6
Method step.
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| CN115594641A (en) * | 2022-12-12 | 2023-01-13 | 中国农业大学（Cn） | Compound containing benzyl 1,2,3-triazole structure and application of compound as bactericide |
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| CN110012907A (en) * | 2019-05-22 | 2019-07-16 | 浙江养生堂天然药物研究所有限公司 | The method that prevention and treatment pathogen infects plant |
| CN111170997A (en) * | 2019-12-31 | 2020-05-19 | 广州医科大学 | Carbazole compound and preparation method and application thereof |
| CN111454260A (en) * | 2020-05-25 | 2020-07-28 | 贵州大学 | 1, 2, 3, 4-tetrahydro- β -carboline compounds containing isopropanolamine substructure as well as preparation method and application thereof |
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| CN112624962A (en) * | 2021-01-15 | 2021-04-09 | 贵州大学 | Carbazolyl isopropanolamine derivatives with double chiral centers and preparation method and application thereof |
| CN113999222A (en) * | 2021-11-19 | 2022-02-01 | 贵州大学 | Adamantyl oxadiazole-containing compounds and preparation method and application thereof |
| CN113999222B (en) * | 2021-11-19 | 2023-06-27 | 贵州大学 | Adamantyl oxadiazole-containing compound and preparation method and application thereof |
| CN114751885A (en) * | 2022-03-22 | 2022-07-15 | 贵州大学 | Coumarin compound containing isopropanolamine structure and preparation method and application thereof |
| CN114751885B (en) * | 2022-03-22 | 2023-08-08 | 贵州大学 | Coumarin compound containing isopropanolamine structure and preparation method and application thereof |
| CN115594641A (en) * | 2022-12-12 | 2023-01-13 | 中国农业大学（Cn） | Compound containing benzyl 1,2,3-triazole structure and application of compound as bactericide |
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