CN108822045B - Quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, preparation method and application - Google Patents
Quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
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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
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
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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
Abstract
The invention discloses a quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative, which is characterized in that: the general formula is as follows:
wherein R is1Is phenyl, substituted phenyl or substituted aromatic heterocyclic radical; r2Is phenyl, substituted phenyl or substituted aromatic heterocyclic radical; r3Is more than one hydrogen atom, methoxyl, nitryl, methyl, trifluoromethyl or halogen atom contained in 5, 6,7 or 8 position of quinazoline. The compound has higher treatment and protection effects on Cucumber Mosaic Virus (CMV) and Tobacco Mosaic Virus (TMV), shows higher plant virus resistance activity, and can be used for preparing plant virus resistance pesticides.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a preparation method of quinazoline-containing pentadiene ketoxime ether derivatives and application thereof in the aspect of plant virus resistance.
Background
Annual economic losses of crops caused by infection with plant viruses reach $ 6000 billion, and therefore, effective control and treatment of plant viral diseases are of great significance to the development of the whole agriculture. Among many plant viruses, tobacco mosaic has the characteristics of high incidence and difficulty in prevention and treatment, and is one of the most destructive plant viruses. However, all commercial plant antiviral agents to date have only 30-50% therapeutic activity against plant viruses at a concentration of 500. mu.g/mL, and the inhibition results are clearly unsatisfactory. Therefore, how to develop new, efficient and environmentally friendly plant antiviral agents remains a significant challenge to drug founders.
The natural product and the bionic pesticide thereof have the characteristics of environmental friendliness, unique action site and high selectivity, and play an increasingly important role in preventing and treating plant diseases. Curcumin, a polyphenol compound derived from turmeric, is widely used as a spice, a food preservative, monosodium glutamate and a dye. 1, 4-pentadiene ketone compound, as an important curcumin derivative, has gradually become one of the hot spots in the field of medicament creation because of having broad-spectrum biological activities such as insecticidal, bacteriostatic, plant virus resistant, anticancer, anti-inflammatory and antioxidant activities. In particular, related reports in recent years show that 1, 4-pentadiene-3-ketone compounds have extremely good anti-plant virus activity. Therefore, it is highly possible to obtain an organic active molecule having excellent anti-plant virus activity by modifying the structure of the compound as a precursor.
In 2011, Secrema et al (Secrema, Scheiwei, Luping, Ligustrum lucidum, Weizhou, synthesis of oxime ester-containing curcumin derivatives and antiviral activity [ J ]. synthetic chemistry, 2011,19(1):36-40.) adopt a bioactive factor splicing method to introduce an oxime ester structure into a framework of a mono-carbonyl curcumin derivative 1, 5-substituted phenyl-1, 4-pentadiene-3-ketone, synthesize a series of asymmetric 1, 5-disubstituted aryl-1, 4-pentadiene-3-ketoxime curcumin derivatives, and perform activity test on the derivatives against cucumber mosaic virus. The test result shows that: at the concentration of 500 mug/mL, the synthesized target compound has a certain inhibition effect on cucumber mosaic virus, but is lower than a control medicament ningnanmycin.
Luo et al (Luo, H.; Liu, J.; Jin, L.; Hu D.; Chen, Z.; Yang, S.; Wu, J.; Song, B. Synthesis and anti viral bioactivity of novel- (1E,4E) -1-aryl-5- (2- (quinazolin-4-yloxy) phenyl) -1,4-pentadien-3-one derivatives [ J.]Eur.J.Med.chem.,2013,63:662-669.) A series of (1E,4E) -1-aryl-5- (2- (4-oxoquinazolin) phenyl) -1,4-pentadien-3-one compounds were synthesized by introducing the quinazoline structure into the backbone of 1, 5-diaryl-1, 4-pentadien-3-one and tested for activity against tobacco mosaic virus and against cucumber mosaic virus. The test result shows that: the series of compounds have remarkable protective effect on tobacco mosaic virus, wherein some compounds have protective effect on EC of tobacco mosaic virus50The value is superior to that of the reference medicament ningnanmycin.
In 2014 Ma et al (Ma, J.; Li, P.; Li, X.; Shi, Q.; Wan, Z.; Hu, D.; Jin, L.; Song, B.Synthesis and antibiotic Bioactivity of Novel 3- ((2- ((1E,4E) -3-oxo-5-arylpenta-1,4-dien-1-yl) phenoxy) methyl) -4(3H) -quinazolinone Derivatives [ J ]. J.Agric.Food chem.,2014,62, 8928-pentadien 8934.) A series of quinazolinone-containing pentadienone compounds were synthesized and tested for their activity against TMV. The test result shows that: at a medicament concentration of 500 mug/mL, most of the synthesized compounds have certain in-vivo inhibition and cure effects on TMV. Some of the compounds have excellent effects on in vivo treatment, and the inhibition rate of the compounds is better than that of a control medicament, namely ningnanmycin.
2015 Chen et al (Chen, M.; Hu, D.; Li, X.; Yang, S.; Zhang, W.; Li, P.; Song, B. antibiotic activity and interaction mechanisms study of novel glucopyranoside derivatives [ J.)]Bioorg.med.chem.lett.,2015,25:3840-The virosome takes curcumin as a lead, adopts the active group splicing principle to introduce a natural active component pyranoside into a pentadienone structure, synthesizes a series of pentadienone compounds containing pyranoside, and adopts a half-leaf withered spot method and ribavirin as a contrast agent to test the anti-TMV passivation activity of a target compound. The test result shows that: the synthesized compounds have certain passivation activity on TMV, wherein the passivation effect of partial compounds is better, and the EC of the compounds50The values are all better than those of the control medicament ribavirin. Preliminary mechanistic studies indicate that: such compounds inactivate TMV coat protein primarily by binding it autonomously.
2015 Han et al (Han, Y.; Ding, Y.; Xie, D.; Hu D.; Li, P.; Li, X.; Xue, W.; Jin, L.; Song, B.design, synthesis and anti-viral activity of novel radiation compositions 1, 4-dependent-3-one formation [ J. ]]Eur.J.Med.chem.,2015,92:732-737.) rutin separated from Artemisia princeps is introduced into the framework of 1, 5-diaryl-1, 4-pentadiene-3-ketone, so as to synthesize a series of novel rutin compounds containing 1, 4-pentadiene-3-ketone structures in the molecules, and the novel rutin compounds are subjected to anti-TMV and anti-CMV activity tests. The test result shows that: at a drug concentration of 500. mu.g/mL, most of the synthesized compounds had some anti-TMV and anti-CMV activity. Among them, some compounds have the best anti-CMV therapeutic activity, and the EC thereof50The value is superior to that of the reference medicament ningnanmycin.
Long et al (Long, C.; Li, P.; Chen, M.; Dong, L.; Hu D.; Song, B. Synthesis, anti-tobaco molar virus and current molar virus activity, and 3D-QSAR student of novel 1, 4-heterocyclic-3-one derivative contact 4-thioquinoline molecule [ J.]Eur.J.Med.chem.,2015,102:639-647.) A series of pentadienones containing quinazoline thioether substitution in the molecule were synthesized by introducing thioquinazoline into the skeleton of 1, 5-diaryl-1, 4-pentadien-3-one, and tested for activity against TMV and CMV. The test result shows that: at a concentration of 500. mu.g/mL, the synthesized compound has certain anti-TMV and anti-CMV activities. Wherein the partial compound has excellent inhibition on TMV and CMV in treatment and protectionPreparation activity, EC thereof50The value is superior to that of the reference medicament ningnanmycin.
Gan et al (Gan, x.; Hu, d.; Li, p.; Wu, J.; Chen, x.; Xue, w.; Song, b. design, synthesis, anti-activity and needle-activity relationship of novel 1, 4-pentagon-3-one derivative connectivity 1,3, 4-oxo-azo-activity [ J.,]pest Manag.Sci.,2016,72: 534-. The test result shows that: the synthesized compound has better anti-TMV activity when the concentration of the medicament is 500 mu g/mL. Wherein the partially differentiated compound has excellent activity in the aspect of anti-TMV protective activity, and the EC thereof50The value is far better than that of the control medicament ribavirin.
Quinazolinone compounds, as an important heterocyclic compound, are hot spots in the field of medicament creation because of the structure in the variability and the broad-spectrum and high-efficiency biological activity. Recent studies have shown that: the compound has wider prospect in the aspect of resisting plant viruses.
A series of Schiff base compounds containing a 4(3H) -quinazolinone structure were designed and synthesized in 2007 Gao et al (Gao, X.; Cai, X.; Yan, K.; Song, B.; Gao, L.; Chen, Z. Synthesis and anti-viral bioactives of 2-phenyl-3- (substitated-benzalamino) -4(3H) -quinazolinone derivatives [ J ]. Molecules,2007,12: 2621-. The test result shows that: at a drug concentration of 500. mu.g/mL, most of the synthesized compounds had some in vivo inhibitory effect on TMV.
In 2014 Ma et al (Ma, J.; Li, P.; Li, X.; Shi, Q.; Wan, Z.; Hu, D.; Jin, L.; Song, B.Synthesis and antibiotic Bioactivity of Novel 3- ((2- ((1E,4E) -3-oxo-5-arylpenta-1,4-dien-1-yl) phenoxy) methyl) -4(3H) -quinazolinone Derivatives [ J ]. J.Agric.Food chem.,2014,62, 8928-pentadien 8934.) A series of quinazolinone-containing pentadienone compounds were synthesized and tested for their activity against TMV. The test result shows that: at a medicament concentration of 500 mug/mL, most of the synthesized compounds have certain in-vivo inhibition and cure effects on TMV. Wherein the partial compound has excellent effect on in-vivo treatment, and the inhibition rate of the partial compound is better than that of a control medicament, namely ningnanmycin.
In 2016 (Chen, M.; Li, P.; Hu, D.; Zeng, S.; Li, T.; Jin, L.; Xue, W.; Song, B. Synthesis, anti-viral activity, 3D-AR, and interaction mechanisms student of novel malonate derivative accompanying quinazolin-4(3H) -4-one motif [ J ]. bioorg.Med.Chem.Lett.,2016,26: 168-. The test result shows that: at a drug concentration of 500. mu.g/mL, most of the synthesized compounds had some inhibitory effect on CMV in vivo. Wherein the partial compound has excellent effect on in-vivo treatment, and the inhibition rate of the partial compound is better than that of a control medicament, namely ningnanmycin.
In conclusion, the 1, 4-pentadiene-3-ketone compound and the quinazolinone compound have certain research value in the aspect of plant virus resistance, but the currently created compound with antiviral activity does not exceed ningnanmycin in both the aspects of protection and treatment activity, and reports on the aspects of synthesis of the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether compound, plant virus resistance activity and antibacterial activity are not found.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the compounds have good control effect on plant viruses and plant pathogenic bacteria, and can be used as antiviral agents and agricultural bactericides.
The technical scheme of the invention is as follows: 1, 4-pentadiene-3-ketoxime ether derivative containing quinazoline has a general formula as shown in the following:
wherein R is1Is phenyl, substituted phenyl or substituted aromatic heterocyclic radical; r2Is phenyl, substituted phenyl or substituted aromatic heterocyclic radical; r3Is more than one hydrogen atom, methoxy, nitro, methyl, trifluoromethyl or halogen atom contained in 5, 6,7 or 8 position of quinazoline.
The substituted phenyl is characterized in that the ortho-position, the meta-position, the para-position or the two-position of the benzene ring contains more than one methoxyl group, nitryl group, methyl group, trifluoromethyl group or halogen atom.
The substituted aromatic heterocyclic group is furyl, pyridyl, thienyl, pyrrolyl, thiazolyl, 2-chloropyridyl or 2-chlorothiazolyl.
The preparation method of the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative comprises the following steps of preparing the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative by taking substituted 4-chloroquinazoline and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials:
the preparation method of the 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or the 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime comprises the following steps: (1) preparing 2- (hydroxyphenyl) -3-butene-2-one or 4- (hydroxyphenyl) -3-butene-2-one from acetone, salicylaldehyde or 4-hydroxybenzaldehyde under alkaline conditions:
(2) preparing 1-substituted aryl-5- (4-hydroxyphenyl) -1, 4-pentadiene-3-ketone or 1-substituted aryl-5- (2-hydroxyphenyl) -1, 4-pentadiene-3-ketone under alkaline conditions by using substituted aromatic aldehyde, 2- (hydroxyphenyl) -3-buten-2-ketone or 4- (hydroxyphenyl) -3-buten-2-ketone as raw materials:
(3) preparing 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadien-3-one or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadien-3-one by using substituted benzyl chloride, 1-substituted aryl-5- (4-hydroxyphenyl) -1,4-pentadien-3-one as raw materials:
(4) preparing 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime by taking hydroxylamine hydrochloride and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketone or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials:
the preparation method of the 4-chloroquinazoline containing the substituent comprises the following steps: preparing 4-chloroquinazoline containing substituent groups by using quinazolinone containing substituent groups and thionyl chloride as raw materials:
a quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative is used for preparing plant virus resistant pesticide for Cucumber Mosaic Virus (CMV) and Tobacco Mosaic Virus (TMV).
A quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative is used for preparing agricultural bactericides for citrus canker pathogen and rice bacterial leaf blight pathogen.
The invention has the beneficial effects that: the invention introduces a quinazoline structure with excellent activity into a pentadiene ketoxime ether structure, designs and synthesizes pentadiene ketoxime ether compounds containing quinazoline in a series of structures, and applies the synthesized 1, 4-pentadiene-3-ketoxime ether compounds containing quinazoline to the research of the aspect of plant virus resistance.
Detailed Description
General example:
(1) preparing 2- (hydroxyphenyl) -3-butene-2-one or 4- (hydroxyphenyl) -3-butene-2-one from acetone, salicylaldehyde or 4-hydroxybenzaldehyde under alkaline conditions:
(2) preparing 1-substituted aryl-5- (4-hydroxyphenyl) -1, 4-pentadiene-3-ketone or 1-substituted aryl-5- (2-hydroxyphenyl) -1, 4-pentadiene-3-ketone under alkaline conditions by using substituted aromatic aldehyde, 2- (hydroxyphenyl) -3-buten-2-ketone or 4- (hydroxyphenyl) -3-buten-2-ketone as raw materials:
(3) preparing 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadien-3-one or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadien-3-one by using substituted benzyl chloride, 1-substituted aryl-5- (4-hydroxyphenyl) -1,4-pentadien-3-one as raw materials:
(4) preparing 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime by taking hydroxylamine hydrochloride and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketone or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials:
(5) preparing 4-chloroquinazoline containing substituent groups by using quinazolinone containing substituent groups and thionyl chloride as raw materials:
(6) preparing the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives by using 4-chloroquinazoline containing substituent groups and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials:
specific examples are listed below by way of a list, see the following table:
example 1
Synthesis of (4-quinazolinyl) -1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (compound No. I)1) The method comprises the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
adding 4-hydroxybenzaldehyde (50mmol) into 60mL of acetone, stirring for about 15min, carrying out ice-bath on the reaction system for about 30min, adding about 100mL of 5% NaOH solution into the system, removing the ice-bath chamber after the dropwise addition is finished, and stirring at normal temperature for about 24 h. And after the reaction is finished, transferring the system into a 500mL beaker, adding a proper amount of ice water, adjusting the pH of the system to be about 5-6 by using a 5% dilute hydrochloric acid solution, separating out a large amount of yellow solid, pumping out the solid, and finally recrystallizing by using an ethanol/water system to obtain the yellow solid with the yield of 68%.
(2) Synthesis of 1- (2-pyridyl) -5- (4-hydroxyphenyl) -1, 4-pentadien-3-one:
adding 4- (hydroxyphenyl) -3-buten-2-one (24.7mmol), pyridine-2-formaldehyde (29.6mmol) and 50mL of ethanol into a 250mL three-neck flask, stirring for about 30min, adding 60mL of 5% NaOH solution into the system, removing the ice bath chamber after dropwise addition, and stirring at normal temperature for about 24 h. After the reaction is finished, transferring the system to a 500mL beaker, adding a proper amount of ice water, adjusting the pH of the system to be about 5-6 by using a 5% dilute hydrochloric acid solution, separating out a large amount of yellow solid, and extracting the solid to obtain the yellow solid with the yield of 82%.
(3) Synthesis of 1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
1- (2-pyridyl) -5- (4-hydroxyphenyl) -1, 4-pentadiene-3-one (9.95mmol), m-methylbenzyl chloride (11.94mmol), potassium carbonate (14.92mmol), potassium iodide (4.97mmol) and acetone (60mL) are sequentially added into a 100mL three-neck flask, after uniform stirring, heating and refluxing are carried out, after about 3-4 h, the reaction is finished, desolventization and column chromatography are carried out, so that a yellow solid is obtained, and the yield is 39%.
(4) Synthesis of 1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime:
1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one (8.44mmol), hydroxylamine hydrochloride (25.32mmol), pyridine (25mL) and ethanol (50mL) are sequentially added into a 100mL three-necked bottle, and after stirring at normal temperature for about 24 hours, a white solid is separated out in the system, and the solid is extracted and rinsed with ethanol to obtain the white solid with the yield of 60%.
(5) Synthesis of 4-chloroquinazoline:
and (3) sequentially adding quinazolinone (20.53mmol), 5 drops of DMF (dimethyl formamide), 1, 2-dichloroethane (15mL) and thionyl chloride (30mL) into a 100mL three-necked bottle, and after uniformly stirring, heating and refluxing for 1-2 h to finish the reaction. Recovering solvent, and vacuum distilling to obtain yellow solid. After dissolution with dichloromethane, the pH was adjusted to basic with saturated sodium carbonate solution. Separating liquid, washing with water for three times, collecting organic phase, drying, concentrating to obtain light yellow solid, and recrystallizing with petroleum ether. White crystals are obtained. The yield was 81%.
(6) Synthesis of (4-quinazolinyl) -1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
1- (4- (3-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime (1.28mmol), 4-chloroquinazoline (1.54mmol), potassium carbonate (2.56mmol) and acetonitrile (35mL) are sequentially added into a 50mL three-necked bottle, and after the mixture is uniformly stirred, the mixture is heated and refluxed for 3-4 h, and then the reaction is finished. The system is filtered when hot, the filtrate is dissolved, and then acetonitrile (35mL multiplied by 3) is used for recrystallization, so that white needle-shaped crystals are obtained, and the yield is 72%.
Example 2
Synthesis of (4-quinazolinyl) -1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (Compound No. I)2) The method comprises the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
as in step (1) of example 1.
(2) Synthesis of 1- (2-pyridyl) -5- (4-hydroxyphenyl) -1, 4-pentadien-3-one:
as in step (2) of example 1.
(3) Synthesis of 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (2-pyridyl) -5- (4-hydroxyphenyl) -1,4-pentadien-3-one and o-chlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 4-chloroquinazoline:
as in step (5) of example 1.
(6) Synthesis of (4-quinazolinyl) -1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime is used as the starting material.
Example 3
Synthesis of (4-quinazolinyl) -1- (4- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (Compound No. I)3) The method comprises the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
as in step (1) of example 1.
(2) Synthesis of 1- (2-pyridyl) -5- (4-hydroxyphenyl) -1, 4-pentadien-3-one:
as in step (2) of example 1.
(3) Synthesis of 1- (4- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (2-pyridyl) -5- (4-hydroxyphenyl) -1,4-pentadien-3-one and p-chlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (4- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (4- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 4-chloroquinazoline:
as in step (5) of example 1.
(6) Synthesis of (4-quinazolinyl) -1- (4- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure was as in step (6) of example 1, except that 1- (4- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime was used as a starting material.
Example 4
(4-quinazolinyl) -1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadieneSynthesis of (3-ketoxime ether) (Compound No. I)4) The method comprises the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
as in step (1) of example 1.
(2) Synthesis of 1- (2-pyridyl) -5- (4-hydroxyphenyl) -1, 4-pentadien-3-one:
as in step (2) of example 1.
(3) Synthesis of 1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 2, 4-dichlorobenzyl chloride and 1- (2-pyridyl) -5- (4-hydroxyphenyl) -1,4-pentadien-3-one are used as starting materials.
(4) Synthesis of 1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 4-chloroquinazoline:
as in step (5) of example 1.
(6) Synthesis of (4-quinazolinyl) -1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (4- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime is used as the starting material.
Example 5
Synthesis of (8-methyl-4-quinazolinyl) -1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (Compound No. I)5) The method comprises the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
as in step (1) of example 1.
(2) Synthesis of 1- (4-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
as in step (2) of example 1.
(3) Synthesis of 1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
as in step (3) of example 1.
(4) Synthesis of 1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime:
as in step (4) of example 1.
(5) Synthesis of 8-methyl-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 8-methylquinazolinone is used as the starting material.
(6) Synthesis of (8-methyl-4-quinazolinyl) -1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 8-methyl-4-chloroquinazoline are used as starting materials.
Example 6
Synthesis of (8-methyl-4-quinazolinyl) -1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether (Compound No. I)6) The method comprises the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
as in step (1) of example 1.
(2) Synthesis of 1- (4-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
as in step (2) of example 1.
(3) Synthesis of 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (4-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and o-chlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 8-methyl-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 8-methylquinazolinone is used as the starting material.
(6) Synthesis of (8-methyl-4-quinazolinyl) -1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 8-methyl-4-chloroquinazoline are used as starting materials.
Example 7
Synthesis of (6-chloro-4-quinazolinyl) -1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether (Compound No. I)7) The method comprises the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
as in step (1) of example 1.
(2) Synthesis of 1- (4-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
as in step (2) of example 1.
(3) Synthesis of 1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
as in step (3) of example 1.
(4) Synthesis of 1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime:
as in step (4) of example 1.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-quinazolinyl) -1- (4- (3-methylbenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 6-chloro-4-chloroquinazoline is used as the starting material.
Example 8
Synthesis of (6-chloro-4-quinazolinyl) -1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether (Compound No. I)8) The method comprises the following steps:
(1) synthesis of 4- (hydroxyphenyl) -3-buten-2-one:
as in step (1) of example 1.
(2) Synthesis of 1- (4-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
as in step (2) of example 1.
(3) Synthesis of 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that o-chlorobenzyl chloride is used as the starting material.
(4) Synthesis of 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-quinazolinyl) -1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (4- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
Example 9
Synthesis of (4-quinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (Compound No. I)9) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and o-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 4-chloroquinazoline:
as in step (5) of example 1.
(6) Synthesis of (4-quinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime is used as the starting material.
Example 10
Synthesis of (4-quinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (compound No. I)10) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and 2, 4-dichlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 4-chloroquinazoline:
as in step (5) of example 1.
(6) Synthesis of (4-quinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime is used as the starting material.
Example 11
Synthesis of (8-methyl-4-quinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether (Compound No. I)11) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and o-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 8-methyl-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 8-methyl-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (8-methyl-4-quinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 8-methyl-4-chloroquinazoline are used as starting materials.
Example 12
Synthesis of (8-methyl-4-quinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (compound number I)12) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and 2, 4-dichlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 8-methyl-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 8-methyl-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (8-methyl-4-quinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 8-methyl-4-chloroquinazoline are used as starting materials.
Example 13
Synthesis of (4-quinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (Compound No. I)13) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and p-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 4-chloroquinazoline:
as in step (5) of example 1.
(6) Synthesis of (4-quinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime is used as the starting material.
Example 14
Synthesis of (8-methyl-4-quinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether (Compound No. I)14) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and p-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesis of 8-methyl-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 8-methyl-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (8-methyl-4-quinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 8-methyl-4-chloroquinazoline are used as starting materials.
Example 15
Synthesis of (6-chloro-4-quinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether (Compound No. I)15) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and o-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloro-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-quinazolinyl) -1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
Example 16
Synthesis of (6-chloro-4-quinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-ketoxime ether (compound number I)16) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and 2, 4-dichlorobenzyl chloride are used as starting materials.
(4) Synthesis of 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloro-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-quinazolinyl) -1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2, 4-dichlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
Example 17
Synthesis of (6-chloro-4-quinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether (Compound No. I)17) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1, except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and p-chlorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadiene-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloro-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-quinazolinyl) -1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (4-chlorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
Example 18
(6-chloro-4-quinazolinyl) -1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-oneSynthesis of Oxime Ether (Compound No. I)18) The method comprises the following steps:
(1) synthesis of 2- (hydroxyphenyl) -3-buten-2-one:
the procedure is as in step (1) of example 1, except that salicylaldehyde is used as a starting material.
(2) Synthesis of 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure is as in step (2) of example 1, except that 2- (hydroxyphenyl) -3-buten-2-one is used as the starting material.
(3) Synthesis of 1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1, 4-pentadien-3-one:
the procedure was as in step (3) of example 1 except that 1- (2-hydroxyphenyl) -5- (2-pyridyl) -1,4-pentadien-3-one and o-fluorobenzyl chloride were used as starting materials.
(4) Synthesis of 1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime:
the procedure is as in step (4) of example 1, except that 1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one is used as the starting material.
(5) Synthesizing 6-chloro-4-chloroquinazoline:
the procedure is as in step (5) of example 1, except that 6-chloro-4-chloroquinazolinone is used as the starting material.
(6) Synthesis of (6-chloro-4-quinazolinyl) -1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime ether:
the procedure is as in step (6) of example 1, except that 1- (2- (2-fluorobenzyloxy) phenyl) -5- (2-pyridyl) -1,4-pentadien-3-one oxime and 6-chloro-4-chloroquinazoline are used as starting materials.
The physicochemical properties and mass spectrum data of the synthesized quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives are shown in Table 1, and the nuclear magnetic resonance hydrogen spectrum (C: (M))1H NMR) and carbon Spectroscopy (13C NMR) data are shown in tables 2 and 3.
TABLE 1 physicochemical Properties of the target Compounds
| Compound (I) | Yield (%) | Traits | Melting Point (. degree.C.) |
| I1 | 72 | White solid | 144-146 |
| I2 | 75 | White solid | 170-172 |
| I3 | 60 | White solid | 188-189 |
| I4 | 86 | White solid | 140-142 |
| I5 | 76 | White solid | 143-144 |
| I6 | 66 | White solid | 145-147 |
| I7 | 70 | White solid | 176-177 |
| I8 | 79 | White solid | 161-162 |
| I9 | 76 | White solid | 164-165 |
| I10 | 67 | White solid | 201-202 |
| I11 | 86 | White solid | 174-176 |
| I12 | 87 | White solid | 135-135 |
| I13 | 45 | White solid | 161-162 |
| I14 | 64 | White solid | 159-161 |
| I15 | 78 | White solid | 181-182 |
| I16 | 72 | White solid | 184-186 |
| I17 | 71 | White solid | 174-175 |
| I18 | 86 | White solid | 160-160 |
TABLE 2 NMR data on target Compounds
TABLE 3 NMR carbon spectral data of the target Compound
Anti-tobacco mosaic virus activity of the above target compound:
(1) test method
A. Purification of viruses
A Zhoxueping method (Zhou, X.P.; Xu, Z.X.; Xu, J.; Li, D.B.J.south Chin.Agric.Univ.1995,16,74-79.) is adopted, and the upper leaves of the host Nicotiana tabacum.L plant are selected and inoculated for more than 3 weeks, a TMV system infects, and are homogenized in a phosphate buffer solution, the double-layer gauze is filtered, the centrifugation is carried out at 8000g, the polyethylene glycol treatment is carried out for 2 times, the centrifugation is carried out again, the sediment is suspended by the phosphate buffer solution, and then the refined extraction liquid of the TMV is obtained. The whole experiment was carried out at 4 ℃. And measuring the absorbance value of the 260nm wavelength by using an ultraviolet spectrophotometer, and calculating the virus concentration according to a formula.
Concentration of virus (mg/mL) ═ A260X dilution times)/E0.1％ 1cm 260nm
Wherein E represents the extinction coefficient, i.e. the light absorption at a wavelength of 260nm for a suspension having a concentration of 0.1% (1mg/mL) at an optical path length of 1 cm. E of TMV0.1％ 1cm 260nmIs 5.0.
B. In vivo therapeutic effect of agents on TMV infection
In vivo treatment of infections with agents: selecting folium Xinliangye of 5-6 leaf stage with consistent growth, topping, spreading emery to the whole leaf, dipping virus juice (6 × 10) with a row pen-3mg/mL) whole leaf virus, air-dried naturally and washed with clear water. After the leaves are dry, lightly applying the medicament on the left half leaf by using a writing brush, applying a solvent with the concentration corresponding to the solvent on the right half leaf as a control, recording the number of the dead spots after 6-7 days, and calculating the inhibition rate according to the following formula.
C. In vivo protection of agents against TMV infection
In vivo protection of agents against TMV infection: selecting the heart-leaf tobacco with consistent growth and 5-6 leaf stage, topping, lightly applying the medicament on the left half leaf with a writing brush, and applying the solvent with the concentration corresponding to the solvent on the right half leaf as a control. Spreading emery powder to the whole leaf after 24 hr, and dipping virus juice (6 × 10) with a row pen-3mg/mL) of the whole leaf was inoculated with the virus, washed with clear water, and after 6-7 days, the number of dead spots was recorded, and the inhibition rate was calculated according to the following formula.
Wherein the average number of half-leaf dry spots without the application of the medicament and the average number of half-leaf dry spots with the application of the medicament are the average of three times of repetition of each group.
(2) Results of biological Activity test
TABLE 4 protective and therapeutic Activity of target Compounds against tobacco mosaic Virus
The therapeutic and protective activity of the target compounds I1-I18 against Tobacco Mosaic Virus (TMV) was tested at a test concentration of 500. mu.g/mL using the semi-leaf cumic plaque method with the commercial agent ningnanmycin as a control (see Table 4). The test results show that: most of the target compounds have good therapeutic and protective activity against TMV. Wherein, the target compound I3And I10Has better therapeutic effect on TMV, the inhibition rates of the TMV are respectively 55.5 percent and 62.5 percent, and the TMV is slightly better than ningnanmycin (52.9 percent). Target Compound I1Has better protection effect on TMV, and the inhibition rates of the TMV are respectively 70.6 percent and slightly better than that of ningnanmycin (64.8 percent). I is3、I11And I17The inhibition rates were 63.8, 61.0 and 60.1%. Near ningnanmycin (64.8%).
Antibacterial activity of the above target Compound
(1) Test method
The inhibition activity of a target compound on rice bacterial blight (X.oryzae) and citrus canker (X.citri) is tested by adopting a turbidity method, and the specific operation steps are as follows:
A. adding 1000mL of sterilized distilled water into a 2000mL beaker, sequentially adding 5.0g of peptone, 1.0g of yeast powder, 10.0g of glucose and 3.0g of beef extract under electromagnetic stirring, and after uniformly stirring, adjusting the pH value to be neutral (7.2 +/-0.2) by using a sodium hydroxide aqueous solution;
B. cleaning and sterilizing the test tubes, placing the test tubes on a test tube rack, transferring 4.0mL of the solution obtained in the first step (1) into each test tube by using a liquid transferring gun, adding a rubber plug, packaging every 6 test tubes, and sterilizing for 20min at 121 ℃ by using a sterilizing pot for later use;
C. weighing 0.00375-0.0042g of a sample of a compound to be detected in a centrifuge tube, dissolving 150 mu LDMSO, transferring 80 mu L and 40 mu L of the dissolved compound to the centrifuge tube which is numbered after sterilization, additionally adding 40 mu LDMSO to the centrifuge tube filled with 40 mu L of sample solution, respectively adding 4ml of Tween-20 into the centrifuge tube, simultaneously setting thiediazole copper or bismerthiazol as a contrast agent, and using DMSO as a blank contrast;
D. 1mL to 3 solutions in each centrifugal tube are transferred and contained in the second step (2) of pilot tube (operation before an alcohol lamp is carried out, other bacteria are prevented from being polluted);
E. taking a blank 96-well plate, measuring a blank OD value, excluding holes with OD values larger than 0.05, adding 200 mu L (4) of in-vitro solution into each available hole to measure the OD value and record, finally, inoculating 40 mu L of activated citrus canker pathogen (X.citri) or tobacco pseudomonas solanacearum or rice blight pathogen (X.oryzae) strains into each test tube, wrapping the strains in newspapers, carrying out shaking culture in a constant temperature shaking table at 30 ℃ and 180rpm for 24-48 h, measuring the OD value of the in-vitro solution during the period to track the growth state of bacteria, and taking 200 mu L of the solution in the test tube to measure the OD value and record after the culture is finished;
F. the calculation formula of the inhibition rate of the compound on bacteria is as follows,
corrected OD value-bacteria-containing medium OD value-sterile medium OD value
(2) Results of biological Activity test
TABLE 5 inhibition of two bacteria at set concentrations of target compound
The inhibition activity of the target compound on citrus canker pathogen and rice fusarium solani was tested by the turbidity method with the commercial agents comprising benziothiazolinone and bismerthiazol as positive controls at test concentrations of 100 μ g/mL and 50 μ g/mL (see table 5). The test results show that: most of target compounds have good inhibitory activity on citrus canker pathogen and rice fusarium solani. The inhibition rate of most target compounds on citrus canker pathogen and rice fusarium solani is better than that of control medicaments comprising benziothiazolinone (66.67%) and bismerthiazol (70.53%). Compound I at a concentration of 100. mu.g/mL1、I3And I12Has 94.87, 77.03 and 78.77 percent of inhibition rate on citrus canker pathogen and is better than bismerthiazol (70.53 percent), and the concentration of the drug is 50 mu g/mL1、I2、I3、I5、I9、I11And I12The inhibition rate of the citrus canker pathogen is higher than that of a control medicament by 48.97 percent and is respectively 70.45, 52.03, 63.13, 60.54, 63.89 and 69.51 percent. The compound has higher inhibition rate on rice leaf blight bacteria when the concentration of the medicament is 100 mu g/mL, wherein the compound I2、I9And I16The inhibition ratio of (2) is more than 80%. Far better than bismerthiazol (54.38%).
The compounds have good inhibition effect on TMV and plant pathogenic bacteria (citrus canker pathogenic bacteria and rice leaf blight pathogenic bacteria), wherein part of the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives have excellent inhibition activity on plant viruses and plant pathogenic bacteria, can be used as potential plant virus resistant medicines, and have good application prospect.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are within the scope of the present invention without departing from the technical spirit of the present invention.
Claims (6)
1. 1, 4-pentadiene-3-ketoxime ether derivative containing quinazoline is characterized in that: the general formula is as follows:
wherein R is1Is phenyl, substituted phenyl or substituted aromatic heterocyclic radical; r2Is phenyl, substituted phenyl or substituted aromatic heterocyclic radical; r3Is more than one hydrogen atom, methoxyl, nitryl, methyl, trifluoromethyl or halogen atom contained in the 5, 6,7 or 8 position of the quinazoline; the substituted phenyl is characterized in that the ortho-position, the meta-position, the para-position or the two positions on the benzene ring contain more than one methoxyl group, nitryl group, methyl group, trifluoromethyl group or halogen atom; the substituted aromatic heterocyclic group is furyl, pyridyl, thienyl, pyrrolyl, thiazolyl, 2-chloropyridyl or 2-chlorothiazolyl.
2. The process for producing a quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative according to claim 1, wherein: preparing the quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivatives by using 4-chloroquinazoline containing substituent groups and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials:
3. the process for producing a quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative according to claim 2, wherein: the preparation method of the 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or the 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime comprises the following steps:
(1) preparing 2- (hydroxyphenyl) -3-butene-2-one or 4- (hydroxyphenyl) -3-butene-2-one from acetone, salicylaldehyde or 4-hydroxybenzaldehyde under alkaline conditions:
(2) preparing 1-substituted aryl-5- (4-hydroxyphenyl) -1, 4-pentadiene-3-ketone or 1-substituted aryl-5- (2-hydroxyphenyl) -1, 4-pentadiene-3-ketone under alkaline conditions by using substituted aromatic aldehyde, 2- (hydroxyphenyl) -3-buten-2-ketone or 4- (hydroxyphenyl) -3-buten-2-ketone as raw materials:
(3) preparing 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadien-3-one or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadien-3-one by using substituted benzyl chloride, 1-substituted aryl-5- (4-hydroxyphenyl) -1,4-pentadien-3-one as raw materials:
preparing 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime by taking hydroxylamine hydrochloride and 1- (4- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketone or 1- (2- (substituted benzyloxy) phenyl) -5-substituted aryl-1, 4-pentadiene-3-ketoxime as raw materials:
4. the process for producing a quinazoline-containing 1, 4-pentadiene-3-ketoxime ether derivative according to claim 2, wherein: the preparation method of the 4-chloroquinazoline containing the substituent comprises the following steps: with quinazolinone and thionyl chloride containing substituentsPreparing 4-chloroquinazoline containing substituent groups by using raw materials:
5. the quinazoline-containing 1, 4-pentadien-3-ketoxime ether derivative as claimed in claim 1, which is used for preparing anti-plant virus pesticide for Cucumber Mosaic Virus (CMV) and Tobacco Mosaic Virus (TMV).
6. A quinazoline-containing 1, 4-pentadien-3-ketoxime ether derivative as claimed in claim 1 for use in the preparation of agricultural fungicides for citrus canker and rice bacterial blight.
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| CN107056687A (en) * | 2016-11-23 | 2017-08-18 | 贵州大学 | The ketoxime ester compound of 1,4 pentadiene 3, Preparation method and use containing pyridine groups |
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