CN115677803A - Preparation method of glucoside derivative containing quinazoline structure, preparation method of composition of glucoside derivative and application of composition in prevention and treatment of kiwifruit canker - Google Patents
Preparation method of glucoside derivative containing quinazoline structure, preparation method of composition of glucoside derivative and application of composition in prevention and treatment of kiwifruit canker Download PDFInfo
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- CN115677803A CN115677803A CN202211360657.XA CN202211360657A CN115677803A CN 115677803 A CN115677803 A CN 115677803A CN 202211360657 A CN202211360657 A CN 202211360657A CN 115677803 A CN115677803 A CN 115677803A
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- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of a glucoside derivative containing a quinazoline structure, a composition of the glucoside derivative and application of the composition in preventing and treating kiwifruit canker, wherein the general formula of the derivative is as follows:
Description
Technical Field
The invention relates to the technical field of chemistry, in particular to a preparation method of glucoside derivatives containing quinazoline structures and application of a composition of the glucoside derivatives in inhibiting kiwi canker, cucumber mosaic virus diseases and tobacco mosaic virus diseases.
Background
The kiwi fruit planting industry has a good development prospect, and is an important measure for increasing income and enriching farmer and driving the development of rural industry in terms of economic benefit, but because of the existence of Pseudomonas syringae kiwifruit pathogenic variants (PSA) which can cause kiwifruit canker, the kiwifruit can not grow healthily, and the development of the kiwifruit industry in China and all over the world is hindered. Because kiwifruit canker caused by PSA has the characteristics of rapid transmission, multiple transmission ways and difficult discovery of the transmission process, the plant generally has no symptoms in the early stage of plant infection, when canker diseases appear in a planting area, the disease condition can reach the degree of difficult control, the development trend of the disease condition is more and more difficult to control along with the continuous development of a protected area and the continuous cultivation of crops with high added values, besides, the plant diseases caused by bacteria and viruses cause the grain yield of the crops to be remarkably reduced, the diseases caused by the viruses or germs such as cucumber mosaic virus and tobacco mosaic virus cause huge economic loss to the agriculture, at present, the commonly used antibacterial agents on the market have the defects of poor field prevention effect and adverse sustainable development of the environment, and the drug resistance of the bacteria is enhanced continuously, so the research and development of the high-efficiency, low-toxicity and environment-friendly antiviral agent and antibacterial agent are inexorable.
Copper abietate is a high-efficiency spectrum bactericide, when the copper abietate is used, after the copper abietate is sprayed on plants, a medicine film can be formed on the surfaces of the plants, pathogenic bacteria falling on the medicine film can be effectively killed, in addition, the medicine film formed by the copper abietate has very similar adhesiveness, spreadability and permeability, the medicine effect is durable, and the high-efficiency spectrum bactericide has a good control effect on bacterial diseases and fungal diseases appearing on the plants.
Among heterocyclic compounds, nitrogen-containing heterocyclic compounds occupy an important position, are favored by many chemists due to unique biological activity, and are hot spots of domestic and foreign research due to good biological activity and environmental compatibility of quinazoline heterocycles. In recent years, compounds containing quinazoline heterocycles have been found to have superior activity against plant bacteria.
In 2007, the antibacterial activity screening and action mechanism preliminary study of xuguanfang bottom (xuguanfang, novel quinazoline compounds, [ D ]. University of Guizhou, 2007 ]) preliminarily screens dozens of quinazoline compounds synthesized by the indoor growth rate method, and the screening finds that the compounds containing quinazoline parent ring structure have good antifungal activity, the compound 6-fluoro-4-ethylthio quinazoline has the best antibacterial effect, and has good biological activity compared with nine-plant biological pathogenic fungi, namely, the biological activity of the compound has better biological activity compared with that of the plant pathogenic fungi, namely nine-plant pathogenic fungi, namely, the bacterial pathogens of wheat scab (G.zeae), pepper blight (F.oxysporum), apple rot (C.mandshurica), pinellia ternate fusarium solani (R.solani), rice sheath blight (T.cucumeris), potato late blight (P.infestans), rape core rot (S.sclerotium), cucumber gray mold (B.cinerea), apple anthracnose (C.gloeosporiosis), and even more than that of nine-plant pathogenic fungi.
In 2020, zhanggui Qiang et al (Zhanggui, qingguqing, yijunming, etc.. Synthesis and bacteriostatic activity of novel 2, 4-dichlorophenyl-containing 1,2, 4-triazole quinazoline derivatives [ J ] Synthesis chemistry, 2020 (6): 491-499.) synthesized 2, 4-dichlorophenyl-containing 1,2, 4-triazole 1,3, 4-thiadiazine quinazoline compounds, and turbidity method was adopted to test the inhibitory activity of target compounds on citrus canker pathogen (Xac), tobacco ralstonia solanacearum (Rs) and rice chlorothalonil (Xoo). The results show that some compounds have better bacteriostatic activity and the inhibitory rate of control agents comprising thiacetone and bisoxazole is equivalent to that of control agents comprising thiacetophenone and bismerthiazol.
In conclusion, the quinazolinone derivatives show certain bactericidal activity. In order to create novel efficient antiviral agents and bactericides, the invention designs and synthesizes a series of glucoside derivative compounds containing quinazoline structures on the basis of earlier work, and expects to screen out high-activity antiviral drugs and antibacterial drugs.
Disclosure of Invention
The invention aims to provide a glucoside derivative containing a quinazoline structure and having bactericidal activity and antiviral activity and a preparation method of a composition thereof.
The invention also aims to provide the application of the inhibitor for the kiwifruit canker, the cucumber mosaic virus and the tobacco mosaic virus.
The technical scheme of the invention is as follows: a glucoside derivative containing a quinazoline structure has a general formula as shown in the following formula (I):
wherein: r1 is halogen, methyl, methoxy or disubstituted or trisubstituted by any combination of the substituent groups.
Preferably, R 1 Is 6-chloro, 3-chloro, 5-bromo, 5-methyl, 5-fluoro, 4-chloro, 3-methoxy, 3-methyl, 3, 4-dimethyl, 6-fluoro, 3-fluoro, 6-methoxy, 3-methyl-5-chloro,5-iodo, 4-fluoro, 4-methyl, 5-methoxy, 4-bromo or 6-methyl.
A preparation method of glycoside derivatives containing quinazoline structures comprises the following steps:
(1) Substituting benzoic acid according to molar ratio: feeding triethyl orthoacetate =1 by 20-50, heating and refluxing for 4-6H, and after the reaction is finished and the temperature is reduced to room temperature, filtering and collecting solid to obtain the substituted 2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Substitution of 2-methyl-4H-benzo [ d ] [1,3] oxazin-4-one in molar ratio: p-aminophenol or 3-aminophenol: glacial acetic acid = 1.1: 20-50, heating and refluxing for 4-6h, pouring the reaction system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. And after the temperature is reduced to room temperature, filtering and collecting solid to obtain the substituted 2-methyl-3-phenylquinazoline-4 (3H) -ketone.
(3) Substituting 2-methyl-3-phenylquinazolin-4 (3H) -one according to molar ratio: glycoside: dichloromethane =1:3: feeding 30 materials, heating to 35 ℃, extracting a reaction system by using a sodium hydroxide aqueous solution and a saturated sodium chloride solution after the reaction is finished, and purifying by column chromatography to obtain a target compound glucoside containing a 2-methyl-4-oxoquinazoline structure;
application of glucoside derivative containing quinazoline structure in preparing medicine and medicament for preventing and treating kiwifruit canker, cucumber mosaic virus disease and tobacco mosaic virus disease is provided.
A complex composition comprising a synthesized quinazoline structure-containing glycoside derivative, a23 ((2s, 3s,4r,5s, 6s) -2- (acetoxymethyl) -6- (3- (7-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester), and copper rosinate, wherein compound a23 has a compound of the following formula (2):
in the pesticide composition, the mass ratio of A23 to copper rosinate is 1; 1; 2:1. The composition is used for preventing and treating plant diseases, wherein the plant diseases are plant bacterial diseases. The plant bacterial disease is kiwifruit canker.
The invention has the beneficial effects that: the invention synthesizes the glucoside derivative containing the quinazoline structure and having the activity of resisting the kiwifruit canker pathogen. The invention has the advantages of easily obtained raw materials, simple process and mild reaction conditions. In addition, the compound A23 and copper abietate show a synergistic effect in the process of preventing and treating the kiwifruit canker germs, so that the production cost and the use cost can be further reduced, and the aim of reducing the effect and increasing the effect of the medicine is fulfilled.
The specific implementation mode is as follows:
example 1: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (5-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A1), comprising the following steps:
(1) Adding 2-amino-6-chlorobenzoic acid (10.0 mmol) into a 100mL three-neck flask by taking 50mL triethyl orthoacetate as a solvent, refluxing and reacting for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting a solid to obtain an intermediate 5-chloro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 5-chloro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 5-chloro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one.
(3) 5-chloro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution with. Times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (5-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy in a yield of 66.6% and a melting point of 219.2-220.1 ℃.
Example 2: synthesis of (2s, 3s,4r,5s, 6s) -2- (acetoxymethyl) -6- (4- (8-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A2) comprising the steps of:
(1) Adding 2-amino-3-chlorobenzoic acid (10.0 mmol) into a 100mL three-neck flask by taking 50mL triethyl orthoacetate as a solvent, refluxing and reacting for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting a solid to obtain an intermediate 8-chloro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating 8-chloro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by using glacial acetic acid 30mL as a solvent for refluxing for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 8-chloro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one.
(3) 8-chloro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in 30mL dichloromethane was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (8-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 52.6% and a melting point of 206.3-207.6 ℃.
Example 3: synthesis of (2s, 3s,4r,5s, 6s) -2- (acetoxymethyl) -6- (4- (6-bromo-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A3) comprising the steps of:
(1) Adding 2-amino-5-bromobenzoic acid (10.0 mmol) into a 100mL three-neck flask by taking 50mL triethyl orthoacetate as a solvent, carrying out reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 6-bromo-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 6-bromo-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is brought to room temperature, the solid is collected by filtration to give 6-bromo-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one.
(3) 6-bromo-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution with. Times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-bromo-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 40.1% and a melting point of 198.1-199.3 ℃.
Example 4: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (2, 6-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A4), comprising the following steps:
(1) Adding 2-amino-5-methylbenzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting a solid to obtain an intermediate 2, 6-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 2, 6-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (4-hydroxyphenyl) -2, 6-dimethylquinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -2, 6-dimethylquinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in 30mL dichloromethane was heated to 35 deg.C and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a3 solution of saturated sodium chloride, and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (2, 6-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 20.8% and a melting point of 213.2 to 214.8 ℃.
Example 5: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A5), comprising the following steps:
(1) Adding 2-amino-5-fluoro-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 6-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 6-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is reduced to room temperature, the solid is collected by filtration to obtain 6-fluoro-3- (4-hydroxyphenyl) -2-methyl quinazolin-4 (3H) -one.
(3) 6-fluoro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution with. Times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy at a yield of 56.3% and a melting point of 204.5-204.9 ℃.
Example 6: synthesis of (2s, 3s,4r,5s, 6s) -2- (acetoxymethyl) -6- (4- (7-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A6) comprising the steps of:
(1) Adding 2-amino-4-chloro-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 7-chloro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 7-chloro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 7-chloro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one.
(3) 7-chloro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (7-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 54.2% and a melting point of 223.1 to 224.7 ℃.
Example 7: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (8-methoxy-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (Compound No. A7), comprising the following steps:
(1) Adding 2-amino-3-methoxy-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 8-methoxy-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 8-methoxy-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature has reached room temperature, the solid is collected by filtration to give 3- (4-hydroxyphenyl) -8-methoxy-2-methyl-quinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -8-methoxy-2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of 3 solution of sodium hydroxide and 20mL of 3 solution of saturated sodium chloride and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (8-methoxy-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in 28.8% yield and a melting point of 205.1-206.4 ℃.
Example 8: synthesis of (2s, 3s,4r,5s, 6s) -2- (acetoxymethyl) -6- (4- (2, 8-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy) (compound No. A8), comprising the steps of:
(1) Adding 2-amino-3-methyl-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 2, 8-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 2, 8-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (4-hydroxyphenyl) -2, 8-dimethylquinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -2, 8-dimethylquinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in 30mL dichloromethane was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (2, 8-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in 55.1% yield and a melting point of 193.3 to 194.8 ℃.
Example 9: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (2, 7, 8-trimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A9), comprising the following steps:
(1) Adding 2-amino-3, 4-dimethyl-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 2,7, 8-trimethyl-4H-benzo [ d ] [1,3] oxazin-4-one.
(2) Heating and refluxing 2,7, 8-trimethyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by using glacial acetic acid 30mL as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (4-hydroxyphenyl) -2,7, 8-trimethylquinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -2,7, 8-trimethylquinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol), dichloromethane 30mL as solvent, was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (2, 7, 8-trimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 56.6% and a melting point of 210.3 to 211.6 ℃.
Example 10: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (5-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A10), comprising the following steps:
(1) Adding 2-amino-6-fluoro-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 6-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 6-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is reduced to room temperature, the solid is collected by filtration to obtain 6-fluoro-3- (4-hydroxyphenyl) -2-methyl quinazolin-4 (3H) -one.
(3) 6-fluoro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of 3 solution of sodium hydroxide and 20mL of 3 solution of saturated sodium chloride, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (5-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in 48.0% yield and a melting point of 219.8-220.5 ℃.
Example 11: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (8-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (Compound No. A11), comprising the following steps:
(1) Adding 2-amino-3-fluoro-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 8-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating 8-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by using glacial acetic acid 30mL as a solvent for refluxing for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is reduced to room temperature, the solid is collected by filtration to obtain 8-fluoro-3- (4-hydroxyphenyl) -2-methyl quinazolin-4 (3H) -one.
(3) 8-fluoro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution with. Times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (8-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy in a yield of 54.0% and a melting point of 171.3-172.9 ℃.
Example 12: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (5-methoxy-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A12), comprising the following steps:
(1) Adding 2-amino-6-methoxy-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 5-methoxy-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 5-methoxy-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature has reached room temperature, the solid is collected by filtration to give 3- (4-hydroxyphenyl) -5-methoxy-2-methyl-quinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -5-methoxy-2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution with. Times.3, and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (5-methoxy-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 39.9% and a melting point of 241.2-242.8 ℃.
Example 13: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-chloro-2, 8-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A13), comprising the following steps:
(1) Adding 2-amino-3-methyl-5-chloro-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting a solid to obtain an intermediate 6-chloro-2, 8-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 6-chloro-2, 8-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 6-chloro-3- (4-hydroxyphenyl) -2, 8-dimethylquinazolin-4 (3H) -one.
(3) 6-chloro-3- (4-hydroxyphenyl) -2, 8-dimethylquinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in 30mL dichloromethane was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution with. Times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-chloro-2, 8-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 21.2% and a melting point of 195.8-196.3 ℃.
Example 14: synthesis of (2s, 3s,4r,5s, 6s) -2- (acetoxymethyl) -6- (4- (6-iodo-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. a 14) comprising the steps of:
(1) Adding 2-amino-5-iodo-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting a solid to obtain an intermediate 6-iodo-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 6-iodine-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is brought to room temperature, the solid is collected by filtration to give 3- (4-hydroxyphenyl) -6-iodo-2-methyl-quinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -6-iodo-2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol), dichloromethane 30mL as solvent, was heated to 35 deg.C and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of 3 solution of sodium hydroxide and 20mL of 3 solution of saturated sodium chloride and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-iodo-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in 35.6% yield and a melting point of 123.4-124.2 ℃.
Example 15: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (7-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A15), comprising the following steps:
(1) Adding 2-amino-4-fluoro-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 7-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 7-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is reduced to room temperature, the solid is collected by filtration to obtain 7-fluoro-3- (4-hydroxyphenyl) -2-methyl quinazolin-4 (3H) -one.
(3) 7-fluoro-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of 3 solution of sodium hydroxide and 20mL of 3 solution of saturated sodium chloride, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (7-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 33.0% and a melting point of 209.1-210.3 ℃.
Example 16: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (2, 7-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A16), comprising the following steps:
(1) Adding 2-amino-4-methyl-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 2, 7-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 2, 7-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by using glacial acetic acid 30mL as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (4-hydroxyphenyl) -2, 7-dimethylquinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -2, 7-dimethylquinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in 30mL dichloromethane was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution with. Times.3, and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (2, 7-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy at 26.7% yield and a melting point of 211.5-212.2 ℃.
Example 17: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-methoxy-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (Compound No. A17), comprising the following steps:
(1) Adding 2-amino-5-methoxy-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 6-methoxy-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 6-methoxy-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (3-hydroxyphenyl) -6-methoxy-2-methyl-quinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -6-methoxy-2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in 30mL dichloromethane was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-methoxy-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 34.2% and a melting point of 116.0 to 117.6 ℃.
Example 18: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-methoxy-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A18), comprising the following steps:
(1) Adding 2-amino-5-methoxy-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 6-methoxy-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 6-methoxy-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (4-hydroxyphenyl) -6-methoxy-2-methyl-quinazolin-4 (3H) -one.
(3) 3- (4-hydroxyphenyl) -6-methoxy-2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a3 solution of saturated sodium chloride, and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (6-methoxy-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 56.8% and a melting point of 196.6-197.3 ℃.
Example 19: synthesis of (2s, 3s,4r,5s, 6s) -2- (acetoxymethyl) -6- (4- (7-bromo-2-methyl-4-oxoquinazolin) -3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. a 19) comprising the steps of:
(1) Adding 2-amino-4-bromo-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 7-bromo-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 7-bromo-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and p-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is brought to room temperature, the solid is collected by filtration to give 7-bromo-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one.
(3) 7-bromo-3- (4-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol), dichloromethane 30mL as solvent, was heated to 35 deg.C and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (4- (7-bromo-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 45.1% and a melting point of 221.4-222.6 ℃.
Example 20: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (2, 7, 8-trimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy (compound number A20) comprising the steps of:
(1) Same as in step (1) of example 9
(2) Heating and refluxing 2,7, 8-trimethyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and 3-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (3-hydroxyphenyl) -2,7, 8-trimethylquinazolin-4 (3H) -one.
(3) 3- (3-hydroxyphenyl) -2,7, 8-trimethylquinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol), dichloromethane 30mL as solvent, was heated to 35 ℃ and the progress of the reaction was monitored by TLC follow-up until the reaction was complete. The reaction system was extracted with 20mL of 3 solution of sodium hydroxide and 20mL of 3 solution of saturated sodium chloride and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (2, 7, 8-trimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in 73.5% yield and a melting point of 238.2-239.5 ℃.
Example 21: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (6-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (Compound No. A21), comprising the following steps:
(1) Same as in step (1) of example 5
(2) Heating and refluxing 6-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and 3-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is reduced to room temperature, the solid is collected by filtration to obtain 6-fluoro-3- (3-hydroxyphenyl) -2-methyl quinazolin-4 (3H) -one.
(3) 6-fluoro-3- (3-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) and 30mL dichloromethane as solvent were heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution with X3, and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (6-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 69.8% and a melting point of 117.5-118.8 ℃.
Example 22: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (6-iodo-2-methyl-4-oxoquinazolin) -3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A22), comprising the following steps:
(1) Same as in step (1) of example 14
(2) Heating and refluxing 6-iodine-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and 3-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (3-hydroxyphenyl) -6-iodo-2-methyl-quinazolin-4 (3H) -one in 42.4% yield.
(3) 3- (3-hydroxyphenyl) -6-iodo-2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol), dichloromethane 30mL as solvent, was heated to 35 deg.C and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (6-iodo-2-methyl-4-oxoquinazolin) -3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy at 56.9% yield and 110.9-111.6 ℃ melting point.
Example 23: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (7-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A23), comprising the following steps:
(1) Same as in step (1) of example 6
(2) Heating and refluxing 7-chloro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and 3-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 7-chloro-3- (3-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one.
(3) 7-chloro-3- (3-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (7-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy at 74.4% yield and 105.3-106.7 ℃ melting point.
Example 24: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (8-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (Compound No. A24) comprising the following steps:
(1) Same as in step (1) of example 11
(2) Heating and refluxing 8-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and 3-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is reduced to room temperature, the solid is collected by filtration to obtain 8-fluoro-3- (3-hydroxyphenyl) -2-methyl quinazolin-4 (3H) -one.
(3) 8-fluoro-3- (3-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) and 30mL dichloromethane as solvent were heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution and purified by column chromatography to give a solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (8-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 45.0% and a melting point of 125.9-126.7 ℃.
Example 25: synthesis of (2s, 3s,4r,5s, 6s) -2- (acetoxymethyl) -6- (3- (5-fluoro-2-methyl-4-oxoquinazolin) -3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. a 25) comprising the steps of:
(1) Same as in step (1) of example 10
(2) Heating and refluxing 5-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and 3-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is reduced to room temperature, the solid is collected by filtration to obtain 5-fluoro-3- (3-hydroxyphenyl) -2-methyl quinazolin-4 (3H) -one.
(3) 5-fluoro-3- (3-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of 3 solution of sodium hydroxide and 20mL of 3 solution of saturated sodium chloride and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (5-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in 30.0% yield with a melting point of 112.9-113.5 ℃.
Example 26: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (2, 8-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (compound No. A26), comprising the following steps:
(1) Same as in step (1) of example 8
(2) Heating and refluxing 2, 8-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and 3-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (3-hydroxyphenyl) -2, 8-dimethylquinazolin-4 (3H) -one.
(3) 3- (3-hydroxyphenyl) -2, 8-dimethylquinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in 30mL dichloromethane was heated to 35 deg.C and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution, followed by purification by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (2, 8-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester in a yield of 52.1% and a melting point of 116.1-117.8 ℃.
Example 27: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (7-fluoro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (Compound No. A27), comprising the following steps:
(1) Same as in step (1) of example 15
(2) Heating and refluxing 7-fluoro-2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one (1.0 mmol) and 3-aminophenol (1.1 mmol) by taking 30mL of glacial acetic acid as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature is reduced to room temperature, the solid is collected by filtration to obtain 7-fluoro-3- (3-hydroxyphenyl) -2-methyl quinazolin-4 (3H) -one.
(3) 7-fluoro-3- (3-hydroxyphenyl) -2-methyl-quinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in dichloromethane 30mL was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (7-fluoro-2-methyl-4-oxoquinazolin) -3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy at 58.5% yield and 133.2-134.9 ℃ melting point.
Example 28: synthesis of (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (2, 5-dimethyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester (Compound No. A28), comprising the following steps:
(1) Adding 2-amino-6-methyl-benzoic acid (10.0 mmol) and triethyl orthoacetate 50mL serving as a solvent into a 100mL three-neck flask for reflux reaction for 4-5H, cooling to room temperature after the reaction is finished, and filtering and collecting solids to obtain an intermediate 2, 5-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-one.
(2) Heating and refluxing 2, 5-dimethyl-4H-benzo [ d ] [1,3] oxazine-4-ketone (1.0 mmol) and 3-aminophenol (1.1 mmol) by using glacial acetic acid 30mL as a solvent for 4-6H, tracking and monitoring the reaction process by TLC, pouring the system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring. After the temperature was brought to room temperature, the solid was collected by filtration to give 3- (3-hydroxyphenyl) -2, 5-dimethylquinazolin-4 (3H) -one.
(3) 3- (3-hydroxyphenyl) -2, 5-dimethylquinazolin-4 (3H) -one (1.0 mmol), acetyl bromide-alpha-D-glucose (3.0 mmol) in 30mL dichloromethane was heated to 35 ℃ and the progress of the reaction was monitored by TLC until the reaction was complete. The reaction system was extracted with 20mL of a.times.3 solution of sodium hydroxide and 20mL of a saturated sodium chloride solution times.3, and purified by column chromatography to give solid (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (2, 5-dimethyl-4-oxoquinazolin) -3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetoxy at 25.3% yield and a melting point of 142.1-143.8 ℃.
NMR spectra of glycoside derivatives having quinazoline Structure synthesized in examples A1 to A28 1 HNMR), carbon spectrum ( 13 CNMR) and High Resolution Mass Spectrometry (HRMS) data are shown in table 1.
TABLE 1 spectroscopic data for the Compounds of examples A1 to A28
Example 29: inhibitory activity of target compound on kiwifruit canker pathogen
(1) Test method
The bactericidal activity of the compounds was determined by nephelometry (yangl.; et., 2017). Test compounds were prepared at a concentration of 100. Mu.g/mL. Preparing NB culture medium (3.0 g beef extract, 5.0g peptone, 1.0g yeast powder, 10.0g glucose, 1000mL distilled water, pH 7.0-7.2), respectively using inoculation ring to divide a small piece of culture medium containing tobacco ralstonia solanacearum and konjak soft rot pathogen into two NB culture medium, plugging the small piece of culture medium, and carrying out shaking culture at 28 ℃,180rpm and constant temperature shaking table until the logarithmic phase of growth (OD = 0.6-0.8) for standby. The test tube was incubated at 28. + -. 1 ℃ with 40. Mu.L of the bacterial solution, 4mL of water-Tween (1% Tween 20), 1mL of the prepared compound solution, and shaken continuously at 180rpm for 1-3 days. Bacterial growth was monitored by measuring optical density at 600nm (OD 600), but with the same concentration of solvent and 0.1% Tween20 as a blank and bismerthiazol as a control agent, repeated three times per treatment. The inhibition rate of the agent against bacteria was calculated by the following formula:
I＝(Ctur-Ttur)/Ctur×100％
where I is the inhibition, ctur represents the corrected turbidity value for bacterial growth in non-drug treated tubes (blank), ttur represents the corrected turbidity value for bacterial growth in compound treated tubes.
(2) Biological test results
TABLE 2 inhibitory Activity of the target Compounds on Actinidia canker at 100. Mu.g/mL
The in vitro growth rate method is adopted, the antibacterial activity of the target compound is tested by taking bismerthiazol as a control medicament at the concentration of 100 mu g/mL, and the biological activity test result in a table 2 shows that the glucoside derivative containing a quinazoline structure has better inhibitory activity on kiwifruit canker, wherein the activity of A23 is the best, and the inhibition rate is 90.8%, which is better than that of the control medicament bismerthiazol. Example 30: target compound anti-cucumber mosaic virus therapeutic, passivation and protective activity
(1) Test method
A. Purification of viruses
Selecting and inoculating the upper leaves of a plant of a CMV system infected host heart-leaf tobacco (Nicotiana luteinosa L.) for more than 3 weeks by a Gooding method (Gooding; equivalent.1967), homogenizing in a phosphate buffer solution, filtering by a double-layer gauze, centrifuging at 1000rpm, treating by polyethylene glycol for 2 times, centrifuging again, and suspending precipitates by the phosphate buffer solution to obtain a crude extract of the CMV. The entire 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.
Virus concentration (mg/mL) = (A260. Times. Dilution factor)/E0.1% 1cm260nm
Where E represents the extinction coefficient, i.e., the value of the optical absorption (optical density) at an optical path length of lcm for a suspension having a concentration of 0.1% (1 mg/mL) at a wavelength of 260 nm. E0.1% of TMV 1cm260nm is 3.1.
B. Active therapeutic effect of agents on CMV infestation: selecting heart-leaf tobacco with consistent growth vigor, dipping virus juice with a writing brush, inoculating the whole leaf with the virus, and washing with clear water after inoculation. After the leaves are dry, the right half leaf is coated with the medicament, and the left half leaf is coated with the solvent with the corresponding dose for comparison. Then performing moisture-preserving culture in a light incubator, controlling the temperature to be 23 +/-1 ℃, and observing and recording the number of dead spots generated after lighting 10000Lux for 3-4 d. 3 plants are set for each medicament treatment, and each plant has 3 to 4 leaves. The inhibition rate was calculated by repeating the above method 3 times per dose according to the following formula.
C. In vivo protection of CMV infection by Agents
In vivo protection of CMV infection by the agent: selecting heart-leaf tobacco with consistent growth, firstly coating a medicament on the right half leaf by using a writing brush, coating a solvent with a corresponding dose on the left half leaf as a contrast, dipping a pen in virus juice after the leaves are dry, inoculating the virus on the whole leaf, and washing with clear water after inoculation. Then, the culture was performed in a light incubator with a humidity maintained at 23. + -. 1 ℃ under 10000Lux light for 3-4 days, and the number of the dead spots was observed and recorded. 3 plants are set for each medicament treatment, and each plant has 3 to 4 leaves. The inhibition rate was calculated according to the following formula, with 3 repetitions per dose in accordance with the above method.
D. In vivo inactivation of CMV infection by Agents
In-vivo inactivation of CMV-infestation by the agent selected from heart-leaf tobacco of the same growth, uniformly spreading carborundum over the whole leaves, inactivating the compound by mixing it with an equal volume of viral juice for 30 minutes, manually rubbing it with a rowpen, inoculating it on the right-half lobe of Portulaca oleracea L, spreading carborundum, inoculating it with a corresponding amount of solvent, mixing it with viral juice, inoculating it on the left-half lobe of Portulaca oleracea L, spreading carborundum, observing and recording the number of dead spots after 3-4 days. 3 plants are set for each medicament treatment, and each plant has 3 to 4 leaves. The inhibition rate was calculated by repeating the above method 3 times per dose according to the following formula.
Y＝(C-A)/C×100％
Wherein: y is the inhibition rate of the compound on the tobacco mosaic virus; c is the number of the control group (left half leaf) dry spots, and A is the number of the control group (right half leaf) dry spots.
(2) Biological test results
TABLE 3 curative, protective and inactivating activity of target compound on cucumber mosaic virus
The anti-TMV activity of the target compound is tested by adopting a half-leaf withered spot method and taking ningnanmycin as a contrast medicament, and the determination result of the biological activity in the table 3 shows that the glucoside derivative containing a quinazoline structure has medium to excellent inhibitory activity on CMV, wherein A23 is superior to the ningnanmycin serving as the contrast medicament in the aspects of treatment, protection and passivation.
Example 31: therapeutic, inactivating and protective activity of target compound against tobacco mosaic virus
(1) Test method
A. Purification of viruses
Inoculating for more than 3 weeks by using a Gooding method (Gooding; equivalent.1967), infecting upper leaves of a host heart-leaf tobacco (Nicotiana luteosa L.) plant with a TMV system, homogenizing in a phosphate buffer, filtering with double-layer gauze, centrifuging at 1000rpm, treating with polyethylene glycol for 2 times, centrifuging, and suspending precipitates with the phosphate buffer to obtain a crude extract of the TMV. The entire 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.
Virus concentration (mg/mL) = (A260. Times. Dilution factor)/E0.1% 1cm260nm
Wherein E represents the extinction coefficient, i.e. the value of the optical absorption (optical density) at an optical path length lcm for a suspension with a concentration of 0.1% (1 mg/mL) at a wavelength of 260 nm. E0.1% of TMV 1cm260nm is 3.1.
B. Active therapeutic effect of agents on TMV infection: selecting heart-leaf tobacco with consistent growth vigor, dipping virus juice with a writing brush, inoculating the whole leaf with virus, and washing with clear water after inoculation. After the leaves are dry, the right half leaf is coated with the medicament, and the left half leaf is coated with the solvent with the corresponding dose for comparison. Then performing moisture-preserving culture in a light incubator, controlling the temperature to be 23 +/-1 ℃, and observing and recording the number of dead spots generated after lighting 10000Lux for 3-4 d. 3 plants are set for each medicament treatment, and each plant has 3 to 4 leaves. The inhibition rate was calculated according to the following formula, with 3 repetitions per dose in accordance with the above method.
C. In vivo protection of agents against TMV infection
In vivo protection of agents against TMV infection: selecting heart-leaf tobacco with consistent growth, firstly coating a medicament on the right half leaf by using a writing brush, coating a solvent with a corresponding dose on the left half leaf as a contrast, dipping a pen in virus juice after the leaves are dry, inoculating the virus on the whole leaf, and washing with clear water after inoculation. Then, the culture was performed in a light incubator with a humidity maintained at 23. + -. 1 ℃ under 10000Lux light for 3-4 days, and the number of the dead spots was observed and recorded. 3 plants are set for each medicament treatment, and each plant has 3 to 4 leaves. The inhibition rate was calculated according to the following formula, with 3 repetitions per dose in accordance with the above method.
D. In vivo inactivation of TMV infection by agents
Selecting heart leaf tobacco with consistent growth, uniformly spreading carborundum on the whole leaf, mixing and passivating the compound and virus juice with the same volume for 30 minutes, manually rubbing and inoculating the compound and the virus juice to the right half leaf of summer purslane with carborundum, mixing and inoculating a solvent with a corresponding dose and the virus juice to the left half leaf of summer purslane with carborundum, and observing and recording the number of generated withered spots after 3-4 days. 3 plants are set for each medicament treatment, and each plant has 3 to 4 leaves. The inhibition rate was calculated according to the following formula, with 3 repetitions per dose in accordance with the above method.
Y＝(C-A)/C×100％
Wherein: y is the inhibition rate of the compound on the tobacco mosaic virus; c is the number of the control group (left half leaf) dry spots, and A is the number of the control group (right half leaf) dry spots.
(2) Biological test results
TABLE 4 therapeutic, protective, inactivating activity of target compounds against tobacco mosaic virus
The anti-TMV activity of the target compound is tested by adopting a half-leaf spot method and taking ningnanmycin as a control medicament, and the determination result of the biological activity in the table 4 shows that the glucoside derivative containing the quinazoline structure has moderate to excellent inhibitory activity on TMV, wherein A23 is superior to the ningnanmycin of the control medicament in the aspects of treatment, protection and passivation.
Example 32: preparation of the composition of the object Compound A23
The following partial preparations were prepared by adjusting the concentrations of commercially available preparations. The following examples are further illustrative of the present invention, but the present invention is not limited to the proportions, type of formulation and use in the examples. In the following examples, a compound composition is prepared from the target compound a23 and the copper rosinate wettable powder, and the ratio of the target compound a23 to the copper rosinate in each composition is calculated according to the mass ratio. The following formulations of the target compound a23 and copper rosinate were prepared as required.
Composition 1: a23: 1, 1
Composition 2: a23: copper rosinate wettable powder =1
Composition 3: a23: copper rosinate wettable powder =2
Example 33: activities of the composition of the target compound A23 to resisting kiwifruit canker
The combination of the object compound a23 and copper rosinate was subjected to the activity test against kiwifruit canker pathogen according to the bacteriostatic activity test method mentioned in example 29.
TABLE 5 inhibitory Activity of drugs against Actinidia canker
The activity of the composition against the kiwifruit canker germs is tested by adopting an in vitro growth rate method at a concentration of 100 mug/mL, and the determination result of the biological activity in Table 5 shows that the activity of the compound composition against the kiwifruit canker germs is improved compared with that of a compound before compound, and the inhibition activity of the composition 3 (A23: copper abietate wettable powder = 2) against the kiwifruit canker germs reaches 100.0 percent. Therefore, the compound composition of the A23 and the copper abietate has a synergistic effect on the kiwifruit canker.
Claims (10)
1. A glucoside derivative containing a quinazoline structure is characterized in that: the general formula of the derivative is as follows:
wherein: r1 is halogen, methyl, methoxy or the disubstituted or trisubstituted of any combination of the substituent groups.
2. The glycoside derivative with quinazoline structure according to claim 1, wherein: r 1 Is 6-chloro, 3-chloro, 5-bromo, 5-methyl, 5-fluoro, 4-chloro, 3-methoxy, 3-methyl, 3, 4-dimethyl, 6-fluoro, 3-fluoro, 6-methoxy, 3-methyl-5-chloro, 5-iodo, 4-fluoro, 4-methyl, 5-methoxy, 4-bromo or 6-methyl.
3. A method for preparing glycoside derivatives having quinazoline structure according to claim 1 or 2, characterized in that: the method comprises the following steps:
4. the method for preparing glycoside derivative with quinazoline structure according to claim 3, characterized in that: the synthesis steps and the process conditions are as follows: substituting benzoic acid according to molar ratio: feeding triethyl orthoacetate =1 by 20-50, heating and refluxing for 4-6H, after the reaction is finished and the temperature is reduced to room temperature, filtering and collecting solid to obtain substituted 2-methyl-4H-benzo [ d ] [1,3] oxazine-4-one; substitution of 2-methyl-4H-benzo [ d ] [1,3] oxazin-4-one in molar ratio: p-aminophenol or 3-aminophenol: glacial acetic acid =1:1 to 1.2: feeding 20-50 materials, heating and refluxing for 4-6h, pouring a reaction system into ice water with a magnetic stirrer after the reaction is finished, and fully stirring; after the temperature is reduced to room temperature, filtering and collecting solid to obtain substituted 2-methyl-3-phenylquinazoline-4 (3H) -ketone; the molar ratio of the substituted 2-methyl-3-phenyl quinazoline-4 (3H) -ketone: glycoside: dichloromethane =1:3: and (3) feeding 30, heating to 35 ℃, extracting the reaction system with a sodium hydroxide aqueous solution and a saturated sodium chloride solution after the reaction is finished, and purifying by column chromatography to obtain the glucoside target compound containing the quinazoline structure.
5. The use of a glycoside derivative containing a quinazoline structure according to claim 1 or 2 in the preparation of medicaments and medicaments for preventing and treating kiwifruit canker, cucumber mosaic virus disease and tobacco mosaic virus disease.
6. A compound pesticide composition is characterized in that: the composition comprising the derivative of claim 1 and copper rosinate.
7. The composition of claim 6, wherein: the mass ratio of the derivative to the ethylicin is 1.
8. Use of a composition according to claim 6 for the preparation of a medicament for the control of bacterial diseases in plants.
9. The composition of claim 6, wherein: the derivative is as follows: (2S, 3S,4R,5S, 6S) -2- (acetoxymethyl) -6- (3- (7-chloro-2-methyl-4-oxoquinazolin-3 (4H) -yl) phenoxy) tetrahydro-2H-pyran-3, 4, 5-triacetic acid triester.
10. The pesticidal composition according to claim 8, characterized in that: the plant bacterial disease is kiwifruit canker.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4731106A (en) * | 1984-11-24 | 1988-03-15 | Schering Agrochemicals Limited | Fungicidal azole compounds |
| CN114573516A (en) * | 2020-11-30 | 2022-06-03 | 山东先达农化股份有限公司 | Triketone-quinazolinone compound, preparation method and application thereof, and herbicide |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4731106A (en) * | 1984-11-24 | 1988-03-15 | Schering Agrochemicals Limited | Fungicidal azole compounds |
| CN114573516A (en) * | 2020-11-30 | 2022-06-03 | 山东先达农化股份有限公司 | Triketone-quinazolinone compound, preparation method and application thereof, and herbicide |
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