CN109721554A - A kind of 4- amino-quinazoline compound and its preparation method and application - Google Patents
A kind of 4- amino-quinazoline compound and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of 4- amino-quinazoline compounds and its preparation method and application.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 quinazoline ditosylate salt chemical combination of the substitution of methylene containing aromatic rings
Object and the preparation method and application thereof.
Background technique
In recent years, bacterial diseases of plants (such as bacterial blight of rice and citrus bacterial canker disease) occurs simultaneously on a large scale in China
Prevalence, main economic corps diseases show the spies such as occurrence frequency height, serious extent, occurrence scope are wide, prevention and control difficulty is big
Point, this often results in heavy losses to Chinese national economy, particularly agricultural production, existing commercial antimicrobial agent (such as Yekuzuo,
Thiodiazole-copper can kill) it is active not efficient enough, it is badly in need of the efficiently anti-reactive compound for planting disease bacterium of discovery, creates on this basis
The green novel pesticide of independent intellectual property right is produced, provides drug candidate for bacterial diseases of crops prevention and control.
Quinazoline compound becomes researcher's research because having extensive bioactivity in antibacterium and anticancer aspect
One of hot spot, meanwhile, the compound containing furan structure also shows extensive bioactivity in terms of pesticide.In order to find height
Antibacterial active compounds are imitated, the present invention is based on quinazoline structure, it would be possible to improve the alkyl of target compound bioactivity
Chain and furyl are introduced into this system, synthesize a series of quinazoline compounds containing alkyl and furyl, investigate its biology
Activity provides important scientific basic for the research and development and initiative of novel pesticide.
The bioactivity research progress of quinazoline compounds is as follows:
2010, [Mani, the C.P. such as Mani；Yakaiah,T.；Gayatri,G.；Pranay,K.K.；Narsaiah,
B.；Murthy,U.S.；Raghu,R.R.A.Click chemistry:studies on the synthesis of novel
fluorous tagged triazol-4-yl substituted quinazoline derivatives and their
biological evaluation--theoretical and experimental
Validation [J] .Eur.J.Med.Chem., 2010,45,78-84.] draw on 2 of quinazolinone respectively
A phenyl and trifluoromethyl are entered, a Terminal Acetylenes have been introduced on 3, while also passing through the method for click chemistry on 4
The fluoric ether of different length is connected on quinazoline parent, a series of chemical combination containing different length alkane have been derived
Object.Biological activity test the result shows that, good biology is shown to Candida albicans, S. cervisiae, black-koji mould etc.
Activity.
2013, [Wang, the X. such as Wang；Li,P.；Li,Z.N.；Yin,J.He,M.；Xue,W.；Chen,Z.W.；
Song,B.A.Synthesis and Bioact-ivity Evaluation of Novel Arylimines Containing
a 3-Aminoethyl-2-[(p-trifluoromethoxy)anilino]-4(3H)-quinazolinone Moiety[J]
.J.Agric.Food.Chem., 2013,61,9575-9582.] report a series of quinoline azoles woods classes containing aromatic imine structure
Derivative, biological activity test the result shows that, such compound shows excellent water resistant rice bacterial leaf spot pathogenic bacteria activity.
2014, [the Van H.K. such as Van；Burda,S.F.,R.；Shaw,L.N.；Manetsch,R.,
Antibacterial activity of a series of N2,N4-disubstituted quinazoline-2,4-
Diamines [J] .J.Med.Chem., 2014,57,3075-3093] a series of N2 are reported, N4- quinazoline compounds are raw
Object active testing the result shows that, such compound have good antibacterial activity, structure-activity relationship (SAR) is research shows that in N2 and N4
It is above disubstituted to be conducive to improve antibacterial activity, wherein compound 11a, 11b, 11c are to staphylococcus aureus (S.aureus)
MIC value is respectively 0.37,0.67 and 0.73 μM.
2014, [Patel, the A.B. such as Patel；Chikhalia,K.H.；Kumari,P.Synthesis and
biological evaluation of novel quinazoline derivatives obtained by Suzuki C–C
Coupling [J] .Med.Chem.Res., 2014,23,2338-2346.] pass through Suzuki C-C coupling method for benzene
Be coupled on 2 of quinazoline, derived a series of (sulphur) urea quinazoline derivatives, biological activity test the results show that
Compound shows good activity, and the MIC value of their anti-mycobacterias is optimal to reach 12.50 μ g/mL (comparison medicaments
Pyrazinamide pyrazinamide is 6.25 μ g/mL).
2017, [Jiang, Z.Y.Hong, the W.D. such as Jiang；Cui,X.P.；Gao,H.G.；Wu,P.P.；Chen,
Y.S.,Synthesis and structure-activity relationship of N4-benzylamine-N2-
isopropyl-quinazoline-2,4-diamines derivatives as potential antibacterial
Agents [J] .RSC.Advances., 2017,7,52227-52237.] synthesize series of quinazoline class diamines substituted compound
Object, through structure effect research filter out 8 compounds for having preferable antibacterial activity, bioactivity the result shows that, compound 12 is to large intestine
The MIC of bacillus (E.coli), staphylococcus aureus (S.aureus) and staphylococcus epidermis (S.epidermidis) is 3.9 μ
G/mL, the MIC to methicillin-resistant gold-coloured staphylococci (MRSA) are 7.8 μ g/mL.Better than comparison medicament vancomycin (31.2 μ
g/mL)。
Summary of the invention
An object of the present invention provide a kind of 4- amino-quinazoline compound or its stereoisomer 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 4- amino-quinazoline compound or its stereoisomer or its salt or its solvate, compound tool
Just like structure shown in general formula (I):
Wherein
X is N or S atom；
R1Selected from hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, it is any replace or
Unsubstituted alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted naphthenic base, hydroxyl, amino, halogen
One or more of element, sulfydryl, phosphino-, any substituted or unsubstituted aryl, any substituted or unsubstituted heteroaryl；
R2Selected from hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, it is any replace or
Unsubstituted alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted naphthenic base, hydroxyl, any substitution
Or one or more of unsubstituted aryl, any substituted or unsubstituted heteroaryl；
R3Selected from hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, it is any replace or
Unsubstituted alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted naphthenic base, hydroxyl, amino, halogen
One or more of element, sulfydryl, phosphino-, any substituted or unsubstituted aryl, any substituted or unsubstituted heteroaryl；
Preferably, R1In hydrogen, deuterium, alkyl, alkoxy, hydroxyl, amino, halogen, sulfydryl, phosphino-, aryl, heteroaryl
One or more；It is highly preferred that R1Selected from hydrogen, deuterium, C1-C6Alkyl, C1-C6Alkoxy, hydroxyl, amino, F, Cl, Br, sulfydryl,
Phosphino-, C6-C15Aryl, C6-C10One or more of heteroaryl；Most preferably, R1Selected from hydrogen, deuterium, methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, methoxyl group, ethyoxyl, the third oxygen
Base, butoxy, hydroxyl, amino, F, Cl, Br, phenyl, benzyl, naphthalene, phenanthryl, pyridyl group, thienyl, one in furyl
Or it is multiple；
Preferably, R2Selected from hydrogen, deuterium, alkyl, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
One or more of base；It is highly preferred that R2Selected from hydrogen, deuterium, C1-C6Alkyl, C1-C6Alkoxy, substituted or unsubstituted C6-C15
Aryl, substituted or unsubstituted C6-C10One or more of heteroaryl, wherein described substituted refers to by C1-C6Alkyl,
C1-C6Alkoxy, amino, hydroxyl, halogen replace；Most preferably, R2Selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, just
Butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, benzene
Base, chlorphenyl, bromophenyl, fluorophenyl, tolyl, amine phenyl, hydroxyphenyl, benzyl, adjacent luorobenzyl, luorobenzyl, to luorobenzyl,
Adjacent bromobenzyl, bromobenzyl, to bromobenzyl, o-chlorobenzyl, chlorobenzyl, p-chlorobenzyl, naphthalene, phenanthryl, pyridyl group, adjacent fluorine pyrrole
Piperidinyl, fluorine pyridyl group, adjacent bromopyridine base, bromopyridine base, adjacent chloropyridine base, m-chloro pyridyl group, adjacent fluorine thienyl, fluorine thiophene
Pheno base, adjacent fluorine furyl, fluorine furyl, adjacent bromothiophene base, bromothiophene base, adjacent bromine furyl, bromine furyl, adjacent diuril
Pheno base, m-chloro thienyl, adjacent chlorine furyl, m-chloro furyl, adjacent hydroxybenzyl, hydroxybenzyl, to hydroxybenzyl, adjacent amino
Benzyl, aminobenzyl, aminobenzyl, adjacent methylbenzyl, methylbenzyl, to methylbenzyl, adjacent pyridone, hydroxyl
Pyridyl group, to hydroxy-pyridyl, adjacent aminothiophene base, aminothiophene base, adjacent hydroxyfuryl, hydroxyfuryl, adjacent first
One or more of base furyl, methylfuran base；
Preferably, R3Selected from hydrogen, deuterium, alkyl, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
One or more of base；It is highly preferred that R3Selected from hydrogen, deuterium, C1-C6Alkyl, C1-C6Alkoxy, substituted or unsubstituted C6-C15
Aryl, substituted or unsubstituted C6-C10One or more of heteroaryl, wherein described substituted refers to by C1-C6Alkyl,
C1-C6Alkoxy, amino, hydroxyl, halogen replace；Most preferably, R3Selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, just
Butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, benzene
Base, chlorphenyl, bromophenyl, fluorophenyl, tolyl, amine phenyl, hydroxyphenyl, benzyl, adjacent luorobenzyl, luorobenzyl, to luorobenzyl,
Adjacent bromobenzyl, bromobenzyl, to bromobenzyl, o-chlorobenzyl, chlorobenzyl, p-chlorobenzyl, naphthalene, phenanthryl, pyridyl group, adjacent fluorine pyrrole
Piperidinyl, fluorine pyridyl group, adjacent bromopyridine base, bromopyridine base, adjacent chloropyridine base, m-chloro pyridyl group, adjacent fluorine thienyl, fluorine thiophene
Pheno base, adjacent fluorine furyl, fluorine furyl, adjacent bromothiophene base, bromothiophene base, adjacent bromine furyl, bromine furyl, adjacent diuril
Pheno base, m-chloro thienyl, adjacent chlorine furyl, m-chloro furyl, adjacent hydroxybenzyl, hydroxybenzyl, to hydroxybenzyl, adjacent amino
Benzyl, aminobenzyl, aminobenzyl, adjacent methylbenzyl, methylbenzyl, to methylbenzyl, adjacent pyridone, hydroxyl
Pyridyl group, to hydroxy-pyridyl, adjacent aminothiophene base, aminothiophene base, adjacent hydroxyfuryl, hydroxyfuryl, adjacent first
One or more of base furyl, methylfuran base.
Most preferably, the compound is selected from following particular compounds:
A kind of intermediate preparing compound described in claim 1 or its stereoisomer or its salt or its solvate
Compound, as follows:
Wherein R1And R3As described above.
Preferably, the preparation method of the compound or its stereoisomer or its salt or its solvate, further includes:
CompoundThe step of compound shown in general formula (I) is generated in the presence of halides.
Preferably, the preparation method further include:It is generated in the presence of replacing amine
The step of, wherein R1And R3As described in weighing.
It is highly preferred that the preparation method further includes following specific steps:
Wherein R1、R2And R3As described above.
A kind of composition contains the compound or its stereoisomer or its salt or its solvate, and agricultural
Upper available auxiliary agent or fungicide, insecticide or herbicide；
Preferably, the dosage form of the composition is selected from missible oil (EC), pulvis (DP), wettable powder (WP), granule
(GR), aqua (AS), suspending agent (SC), ultra-low volume spray agent (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 bacterial blight of rice, the white leaf of cucumber
Blight, tobacco bacterial wilt, konjaku bacterial leaf-blight, citrus ulcer, grape ulcer, canker of tomato, Prospect on Kiwifruit Bacterial Canker, apple
Fruit canker, gray mold of cucumber, capsicum wilt, sclerotinia sclerotiorum, wheat scab, the late blight of potato, blueberry root-rot.
A method of prevention and treatment agricultural pest comprising make the compound or its stereoisomer or its salt or
Its solvate or the composition act on nuisance or its living environment；Preferably, the agricultural pest is plant
Bacillary or fungal disease；It is highly preferred that the agricultural pest is that bacterial blight of rice, cucumber bacterial leaf-blight, konjaku are white
It is leaf blight, citrus ulcer, grape ulcer, canker of tomato, Prospect on Kiwifruit Bacterial Canker, apple canker, gray mold of cucumber, peppery
Green pepper wilt disease, sclerotinia sclerotiorum, wheat scab, the late blight of potato, blueberry root-rot.
Method for protecting the plants from agricultural pest infringement comprising wherein make plant and the compound or
Its stereoisomer or the method and step of 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.
" 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.
" alkynyl " is hydrocarbon both including straight or branched structure, and there is one or more to appear in any stable point in chain
Three key of carbon-to-carbon.Such as " C2-6Alkynyl " (or alkynylene) purpose be include C2, C3, C4, C5 and C6 alkynyl；Such as acetenyl, third
Alkynyl, butynyl, pentynyl, hexin base and the like.
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).
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 " naphthenic base " refers to naphthenic base, including mono-, double-or polycyclic system.C3-7The purpose of naphthenic base be include C3,
C4, C5, C6 and C7 naphthenic base.Examples of cycloalkyl includes but is not limited to cyclopropyl, goes back butyl, cyclopenta, cyclohexyl, norborny
And the like." carbocyclic ring " used herein or " carbocyclic ring is remaining " refers to any stablizing 3,4,5,6 or 7- unit monocycle or bicyclic
Or the first double or tricyclic of 7,8,9,10,11,12 or 13-, it can be saturation, part unsaturation, insatiable hunger and/or armaticity.These carbon
Ring example includes but is not limited to cyclopropyl, cyclobutyl, cyclobutane base, cyclopenta, pentenyl, cyclohexyl, cyclohexenyl group, cycloheptyl
Base, cycloheptenyl, adamantyl, cyclooctyl, cyclo-octene base, cyclo-octadiene, [3.3.0] double-octane, [4.3.0] bicyclic nonyl
Alkane, [4.4.0] bicyclic decane, [2.2.2] double-octane, fluorenyl, phenyl, naphthalene, indanyl, adamantyl, anthryl and tetrahydro
Naphthalene (tetralin).As described above, bridged ring is also contained in the definition of carbocyclic ring (such as [2.2.2] double-octane).If not other
Illustrate, preferred carbocyclic ring is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl and phenyl.When use term " carbocyclic ring ", it is therefore an objective to wrap
Include " aryl ".There is bridged ring when one or more carbon atoms connect two non-carbon atoms that close on.Preferred bridge is one or two
Carbon atom.It is bicyclic to be pointed out that bridge always converts monocycle to.When ring is bridging, the substituent group of ring is existed on bridge.
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 " halogenated alkyl " refers to the substitution alkyl with one or more halogenic substituents.Such as " halogenated alkyl "
Including single, double and trifluoromethyl；Even if in halogenated alkyl it is halogenated by clearly be fluorine, chlorine, bromine, iodine, again refer to have one
A or multiple fluorine, chlorine, bromine, iodine substituent group substitution alkyl.
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.The salt of compound of formula I can be formed such as compound of formula I and a certain amount of acid or alkali, such as
Amount, in medium as salt wherein is precipitable or its it is water-borne in, then carry out lyophilization.
It is alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, naphthenic base, hydroxyl, ammonia when mentioning substituent group
When base, sulfydryl, phosphino- or these substituent groups be specifically some specific alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl,
When alkoxy, naphthenic base, hydroxyl, amino, sulfydryl, phosphino-, one to three above-mentioned substituent group is referred to.As aminomethyl phenyl refers to
It is one to three methyl substituted phenyl.
By using above-mentioned technical proposal, the present invention will improve target chemical combination based on quinazoline compounds
The alkyl and furans methylamino of microbic activity are introduced into this system, synthesize a series of quinoline azoles containing alkyl and furylamine base
Quinoline class compound, 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) etc.] all have good inhibitory effect, for novel pesticide research and development and initiative provide it is important
Scientific basic.
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.
The preparation of embodiment 1:5- chloro-quinazoline -4 (3H) -one
By the chloro- 2- aminobenzoic acid (87.0mmol) of 6- in 100mL round-bottomed flask, 30mL formamide is added thereto and stirs
It mixes, stops reaction after being heated to 145 DEG C of reaction 5h, be cooled to room temperature, filter, washing obtains pale solid, yield after drying
76.0%.
The preparation of bis- chloroquine quinoline azoles of embodiment 2:4,5-
By 5- chloro-quinazoline -4 (3H) -one (11.0mmol) in 100mL round-bottomed flask, 20mL toluene is added thereto and stirs
Dissolution is mixed, then the POCl of 5 equivalents is added to system3With the triethylamine of 2 equivalents, 120 DEG C of reflux are heated to, are stopped instead after reacting 5h
It answers, precipitation, with 100mLDCM dissolved solid, adjusts pH to 6-7 with ammonium hydroxide, be washed with water (30mL*3), column Chromatographic purification (PE:EA
=10:1), obtain white solid, yield 54.4%.
The preparation of the chloro- N- of embodiment 3:5- (furans -2- methylene) quinazoline -4- amine
5- chloro-quinazoline (5mmol) is added in 50mL round-bottomed flask, addition 20mL dry isopropyl stirring and dissolving, then plus
Enter the triethylamine of 1.5 equivalents and the 2- furylamine of 1.2 equivalents, stops reaction, precipitation, column chromatography (elution after 80 DEG C of reaction 1h
Agent PE:EA=15:1) obtain white solid, yield 76.9%.
The preparation of the chloro- N- of embodiment 4:5- (furans -2- methylene)-N- methylquinazolin -4- amine
By the chloro- N- of 5- (furans -2- methylene), quinazoline -4- amine (1.34mmol) is in 25mL round-bottomed flask, thereto
The dry DMF stirring and dissolving of 5mL is added, the NaH stirring 10min of 2 equivalents is added under condition of ice bath to system, then is added 2 to system
The iodomethane of equivalent stops reaction after reacting 1h under ice bath.System is transferred to 250mL separatory funnel with 80mL ethyl acetate
In, three times with the extraction of 15mL saturated ammonium chloride, merge organic phase, dry, concentration, column chromatographs (eluant, eluent DCM:MeOH=10:1)
Obtain yellow solid, yield 72.2%.
Corresponding raw material or substituent group are selected in the synthesis of other target compounds, are prepared referring to embodiment 1-4.
The structure and nuclear magnetic resonance spectroscopy and carbon of the quinazoline compounds containing alkyl and furylamine base of synthesis compose number
According to as shown in table 1, physico-chemical property is as shown in table 2.
The nuclear magnetic resonance spectroscopy and carbon modal data of 1 compound of table
The physicochemical property of 2 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) and citrus processing (Xac).DMSO dissolution is used as blank control in the medium.By rice leaf spot bacteria (rice
Bacterial leaf-blight opportunistic pathogen is in M210 solid medium) it is put into NB culture medium, shaken cultivation arrives in 28 DEG C, 180rpm constant-temperature table
Logarithmic growth phase is spare；Citrus processing (on M210 solid medium) is put into NB culture medium, in 28 DEG C, 180rpm
Shaken cultivation is spare to logarithmic growth phase in constant-temperature table.Medicament (compound) is configured to various concentration (example: 100,50,25 μ
G/mL toxic NB fluid nutrient medium 5mL) is added in test tube, is separately added into 40 μ L and is contained the NB Liquid Culture for planting sick bacterium
Base vibrates in 28-30 DEG C, 180rpm constant-temperature table, bacterial blight of rice opportunistic pathogen culture 36h, citrus processing culture
48h.The bacterium solution of each concentration is measured into OD on spectrophotometer595Value, and in addition measure the toxic sterile NB of corresponding concentration
The OD of fluid nutrient medium595Value.
EC50(median effective concentration) is to evaluate phytopathogen to the weight of compound responsive
Want index, while when being also to target compound study on mechanism, the important parameter of compound concentration setting.In concentration gradient
In experiment, suitable 5 concentration is set using doubling dilution, it is finally that inhibiting rate, medicament of the medicament to phytopathogen is dense
Degree is converted into logarithm, obtains virulence curve by SPSS software regression analysis, calculates EC50。
Using nephelometry test target compound to the median effective concentration EC of phytopathogen50, subjects are that rice is white
Leaf spoting bacteria (Xoo) and citrus processing (Xac).DMSO dissolution is used as blank control in the medium.By rice bacterial leaf spot
Germ (bacterial blight of rice opportunistic pathogen is in M210 solid medium) is put into NB culture medium, in 28 DEG C, 180rpm constant-temperature table
Shaken cultivation is spare to logarithmic growth phase；Citrus processing (on 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.Medicament (compound) is configured to various concentration
The toxic NB fluid nutrient medium 5mL of (example: 100,50,25,12.5,6.25 μ g/mL) is added in test tube, is separately added into 40 μ L and is contained
There is the NB fluid nutrient medium for planting sick bacterium, is vibrated in 28-30 DEG C, 180rpm constant-temperature table, the training of bacterial blight of rice opportunistic pathogen
Support 36h, citrus processing culture 48h.The bacterium solution of each concentration is measured into OD on spectrophotometer595Value, and in addition survey
Determine the OD of the toxic sterile NB fluid nutrient medium of corresponding concentration595Value.
Correct OD value=value of OD containing bacterium culture medium-aseptic culture medium OD value
Inhibiting rate %=[(control medium bacterium solution OD value-toxic culture medium OD value of correction after correction)/
Control medium bacterium solution OD value after correction] × 100
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, target
Compound experimental result is as shown in Tables 3 and 4.
Inhibitory activity of quinazoline compounds of the table 3 containing alkyl and furylamine base to plant pathogenetic bacteria
" NT " expression is not tested
EC of quinazoline compounds of the table 4 containing alkyl and furylamine base to plant pathogenetic bacteria50
From table 3 and 4 as can be seen that in isolated test, target compound is to plant pathogenic pathogen (the white leaf of such as rice
Blight bacterium and citrus processing) show preferable inhibitory activity.Wherein, compound 2,8~11,13~18,20~22,
24~27,30~33 under 50 μ g/mL concentration be respectively 98.8 to the inhibitory activity of rice leaf spot bacteria, 98.8,95.1,
90.1、73.4、100、98.3、100、99.6、98.5、97.6、99.4、95.2、99.1、98.5、97.2、98.9、99.5、
76.6,95.6,96.1 and 97.2%, compound 2,8,9,10,13,15~18,20,22,24~27 and 31~33 is in 25 μ g/mL
Under concentration to the inhibitory activity of rice leaf spot bacteria be 99.1,84.5,95.1,72.7,96.2,94.0,99.7,92.6,
89.1,79.9,80.2,72.7,54.1,96.6,97.0,95.4,86.5 and 96.1%；Compound 8~11,13~18,20,24
~27 and 30~33 under 100 μ g/mL concentration be respectively 99.7 to the inhibiting rate of citrus processing, 88.7,76.1,73.0,
97.4,99.9,99.5,88.2,99.4,99.1,94.5,99.3,98.6,99.2,99.9,79.3,91.5,97.7 and
98.0%, suppression of the compound 8~11,13~18,20,24~27 and 30~33 under 50 μ g/mL concentration to citrus processing
System activity be respectively 70.7,57.2,58.8,57.4,87.51,65.5,91.4,74.8,71.4,91.8,63.8,93.0,
83.3,99.4,69.1,62.4,88.6,70.5 and 74.0%.Further test result show compound 2,8~11,13~18,
20, the EC of 21,22,24~27,30~33 pairs of rice leaf spot bacterias50Respectively 9.77,14.1,7.03,21.6,31.0,
11.2、26.9、13.0、7.13、12.7、12.1、13.1、21.9、11.1、14.1、24.1、10.1、8.89、32.0、7.24、
8.75 and 7.44 μ g/mL, the EC of 8~11,13~17,18,20,24~27,30~33 pairs of citrus processings of compound50Respectively
For 19.9,41.7,49.6,73.0,16.2,36.3,13.5,18.6,17.9,15.6,24.8,10.3,39.0,16.7,23.6,
47.6,14.6,34.1,26.6 μ g/mL can be used for preparing anti-plant pathogenic pathogenetic bacteria pesticide.
Claims (9)
1. a kind of 4- amino-quinazoline compound or its stereoisomer or its salt or its solvate, it is characterised in that: should
Compound has the structure as shown in general formula (I):
Wherein
X is N or S atom；
R1Selected from hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, any substituted or unsubstituted
Alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted naphthenic base, hydroxyl, amino, halogen, sulfydryl,
One or more of phosphino-, any substituted or unsubstituted aryl, any substituted or unsubstituted heteroaryl；
R2Selected from hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, any substituted or unsubstituted
Alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted naphthenic base, hydroxyl, any replace or do not take
One or more of the aryl in generation, any substituted or unsubstituted heteroaryl；
R3Selected from hydrogen, deuterium, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, any substituted or unsubstituted
Alkynyl, any substituted or unsubstituted alkoxy, any substituted or unsubstituted naphthenic base, hydroxyl, amino, halogen, sulfydryl,
One or more of phosphino-, any substituted or unsubstituted aryl, any substituted or unsubstituted heteroaryl；
Preferably, R1One in hydrogen, deuterium, alkyl, alkoxy, hydroxyl, amino, halogen, sulfydryl, phosphino-, aryl, heteroaryl
It is a or multiple；It is highly preferred that R1Selected from hydrogen, deuterium, C1-C6Alkyl, C1-C6Alkoxy, hydroxyl, amino, F, Cl, Br, sulfydryl, phosphine
Base, C6-C15Aryl, C6-C10One or more of heteroaryl；Most preferably, R1Selected from hydrogen, deuterium, methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, methoxyl group, ethyoxyl, propoxyl group,
Butoxy, hydroxyl, amino, F, Cl, Br, phenyl, benzyl, naphthalene, phenanthryl, pyridyl group, thienyl, one or more in furyl
It is a；
Preferably, R2In hydrogen, deuterium, alkyl, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
It is one or more；It is highly preferred that R2Selected from hydrogen, deuterium, C1-C6Alkyl, C1-C6Alkoxy, substituted or unsubstituted C6-C15Aryl,
Substituted or unsubstituted C6-C10One or more of heteroaryl, wherein described substituted refers to by C1-C6Alkyl, C1-C6
Alkoxy, amino, hydroxyl, halogen replace；Most preferably, R2Selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, benzene
Base, chlorphenyl, bromophenyl, fluorophenyl, tolyl, amine phenyl, hydroxyphenyl, benzyl, adjacent luorobenzyl, luorobenzyl, to luorobenzyl,
Adjacent bromobenzyl, bromobenzyl, to bromobenzyl, o-chlorobenzyl, chlorobenzyl, p-chlorobenzyl, naphthalene, phenanthryl, pyridyl group, adjacent fluorine pyrrole
Piperidinyl, fluorine pyridyl group, adjacent bromopyridine base, bromopyridine base, adjacent chloropyridine base, m-chloro pyridyl group, adjacent fluorine thienyl, fluorine thiophene
Pheno base, adjacent fluorine furyl, fluorine furyl, adjacent bromothiophene base, bromothiophene base, adjacent bromine furyl, bromine furyl, adjacent diuril
Pheno base, m-chloro thienyl, adjacent chlorine furyl, m-chloro furyl, adjacent hydroxybenzyl, hydroxybenzyl, to hydroxybenzyl, adjacent amino
Benzyl, aminobenzyl, aminobenzyl, adjacent methylbenzyl, methylbenzyl, to methylbenzyl, adjacent pyridone, hydroxyl
Pyridyl group, to hydroxy-pyridyl, adjacent aminothiophene base, aminothiophene base, adjacent hydroxyfuryl, hydroxyfuryl, adjacent first
One or more of base furyl, methylfuran base；
Preferably, R3In hydrogen, deuterium, alkyl, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl
It is one or more；It is highly preferred that R3Selected from hydrogen, deuterium, C1-C6Alkyl, C1-C6Alkoxy, substituted or unsubstituted C6-C15Aryl,
Substituted or unsubstituted C6-C10One or more of heteroaryl, wherein described substituted refers to by C1-C6Alkyl, C1-C6
Alkoxy, amino, hydroxyl, halogen replace；Most preferably, R3Selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, methoxyl group, ethyoxyl, propoxyl group, butoxy, benzene
Base, chlorphenyl, bromophenyl, fluorophenyl, tolyl, amine phenyl, hydroxyphenyl, benzyl, adjacent luorobenzyl, luorobenzyl, to luorobenzyl,
Adjacent bromobenzyl, bromobenzyl, to bromobenzyl, o-chlorobenzyl, chlorobenzyl, p-chlorobenzyl, naphthalene, phenanthryl, pyridyl group, adjacent fluorine pyrrole
Piperidinyl, fluorine pyridyl group, adjacent bromopyridine base, bromopyridine base, adjacent chloropyridine base, m-chloro pyridyl group, adjacent fluorine thienyl, fluorine thiophene
Pheno base, adjacent fluorine furyl, fluorine furyl, adjacent bromothiophene base, bromothiophene base, adjacent bromine furyl, bromine furyl, adjacent diuril
Pheno base, m-chloro thienyl, adjacent chlorine furyl, m-chloro furyl, adjacent hydroxybenzyl, hydroxybenzyl, to hydroxybenzyl, adjacent amino
Benzyl, aminobenzyl, aminobenzyl, adjacent methylbenzyl, methylbenzyl, to methylbenzyl, adjacent pyridone, hydroxyl
Pyridyl group, to hydroxy-pyridyl, adjacent aminothiophene base, aminothiophene base, adjacent hydroxyfuryl, hydroxyfuryl, adjacent first
One or more of base furyl, methylfuran base；
Most preferably, the compound is selected from following particular compounds:
2. a kind of intermediate for preparing compound described in claim 1 or its stereoisomer or its salt or its solvate
Close object, it is characterised in that as follows:
Wherein R1And R3As described in claim 1.
3. the preparation method of compound described in claim 1 or its stereoisomer or its salt or its solvate, feature exist
In including: compoundThe step of compound shown in general formula (I) is generated in the presence of halides.
4. preparation method according to claim 3, it is characterised in that further include:
It is generated in the presence of replacing amineThe step of, wherein R1And R3As claim 1 institute
It states.
5. preparation method according to claim 3, it is characterised in that further include following specific steps:
Wherein R1、R2And R3As described in claim 1.
6. a kind of composition, it is characterised in that containing compound described in claim 1 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).
7. described in compound described in claim 1 or its stereoisomer or its salt or its solvate or claim 6
Purposes of the composition in terms of preventing and treating agricultural pest, it is preferable that the agricultural pest is vegetative bacteria or fungoid
Disease；It is highly preferred that the agricultural pest is plant leaf blight and plant canker；Most preferably, the agricultural pest
For bacterial blight of rice, cucumber bacterial leaf-blight, konjaku bacterial leaf-blight, citrus ulcer, grape ulcer, canker of tomato, Mi
Monkey peach canker, apple canker, gray mold of cucumber, capsicum wilt, sclerotinia sclerotiorum, wheat scab, potato late blight
Disease, blueberry root rot.
8. a kind of method for preventing and treating agricultural pest, it is characterised in that: make compound described in claim 1 or its alloisomerism
Body 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 be bacterial blight of rice,
Tobacco bacterial wilt, cucumber bacterial leaf-blight, konjaku bacterial leaf-blight, citrus ulcer, grape ulcer, canker of tomato, Kiwi berry
Canker, apple canker, gray mold of cucumber, capsicum wilt, sclerotinia sclerotiorum, wheat scab, the late blight of potato, indigo plant
Certain kind of berries root-rot.
9. for protect the plants from agricultural pest infringement method comprising wherein make plant with it is described in claim 1
Compound or the method step of its stereoisomer or its salt or its solvate or composition as claimed in claim 6 contact
Suddenly.
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