CN113582983B - 1,3,4-oxadiazole thioether myricetin derivative, preparation method and application - Google Patents
1,3,4-oxadiazole thioether myricetin derivative, preparation method and application Download PDFInfo
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Abstract
The invention discloses a myricetin derivative containing 1,3,4-oxadiazole thioether, a preparation method and application thereof, wherein the structural general formula is as follows: r is substituted phenyl, aromatic heterocyclic group or substituted aromatic heterocyclic group; n is the number of carbons in the carbon chain of 2, 3,4,5 and 6 respectively. The substituted phenyl is an alkyl group containing C1-6, an alkoxy group containing C1-6, a nitro group, a halogen atom and a hydrogen atom at the ortho, meta and para positions on a benzene ring; the aromatic heterocyclic group is thienyl, furyl, pyrrolyl and pyridyl; the substituent on the substituted aromatic heterocycle is ortho-position, meta-position and para-position alkyl containing C1-6, alkoxy containing C1-6, nitryl, halogen atom and hydrogen atom. The compound synthesized by the invention has better control effects on tobacco mosaic virus, citrus canker pathogen, kiwi canker pathogen and rice bacterial blight.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a myricetin derivative containing 1,3,4-oxadiazole thioether, a preparation method of the myricetin derivative containing 1,3,4-oxadiazole thioether, and application of the myricetin derivative containing 1,3,4-oxadiazole thioether in the aspects of antiviral and antibacterial activity.
Background
Myricetin is a natural flavonoid compound and widely exists in plants. At present, the flavonoid myricetin has been found to have various biological activities, such as antibacterial, antiviral, antioxidant, antitumor, hypoglycemic activity and other biological activities. Because the plant source and the biological activity of the flavonoid myricetin have universality, most people pay attention to and research.
In 2015, xue et al (Xue, W.; song, B.A.; et al, eur.J.Med.chem.,2015,97,155-163.) reported a series of acylhydrazone-containing myricetin derivatives. The in vitro proliferation inhibition activity test of human breast cancer cell MDA-MB-231 is carried out on the synthesized compound by utilizing an MTT method, and the research result shows that: the myricetin acylhydrazone derivatives have good inhibition rate on human breast cancer cell MDA-MB-231.
A series of myricetin derivatives containing amide, thioether and 1,3,4-thiadiazole were synthesized in Rana et al (Ruan, X.H.; zhang, C.; et al. Molecules,2018,23,3132.) in 2018, preliminary testing results showed: the series of compounds have certain inhibiting effect on citrus canker pathogen, tobacco ralstonia solanacearum and rice bacterial leaf blight.
In 2020, tang et al (Tang, X.; zhang, C.; et al. New J. Chem.2020,44, 2374-2379.) synthesized a series of myricetin ferulate derivatives and tested the antiviral activity (TMV) of the synthesized compounds using the semi-leaf cumic method, and the results showed that: the EC50 value of protective activity of part of compounds on tobacco mosaic virus is 196.1, 425.3 and 386.7 mug/mL under the concentration of 500 mug/mL, which is better than that of a control medicament ningnanmycin (447.92 mug/mL).
The 1,3,4-oxadiazole belongs to one of important five-membered nitrogen heterocyclic compounds, and has wide application in the fields of medicines and organic synthesis. Since 1,3,4-oxadiazole backbone has a multifunctional building block, it has been extensively studied and developed in the course of bioactive recombination. Besides, the 1,3,4-oxadiazole derivative also shows various biological activities of resisting cancers, inhibiting bacteria, resisting viruses, resisting fungi, killing insects and the like.
Du et al (Du, Q.R.; li, D.D.; et al. Bioorg. Med. Chem.2013,21, 2286-2297.) synthesized a series of novel 1,3,4-oxadiazole thioether derivatives in 2013, and evaluated the in vitro antitumor activity of these compounds against 3 cancer cells by MTT method, and the results showed that the nitro substituent-containing compounds had strong in vitro antitumor activity, IC 50 The values are respectively 0.7 +/-0.2 mu M, 30.0 +/-1.2 mu M and 18.3 +/-1.4 mu M, which are superior to the control drugs of the triptolide 1.3 +/-0.2 mu M, 8.7 +/-1.7 mu M and 12.6 +/-2.1 mu M.
A series of 2-substituted methylthio-5- (4-amino-2-methylpyrimidin-5-yl) -1,3,4-oxadiazole derivatives were synthesized by active group splicing in 2015, wu et al (Wu, W.N.; chen, Q.; et al, bioorg.Med.Chem.Lett.2015,25, 2243-2246). The anti-TMV activity test is carried out on the synthesized compound, and the result shows that the compound has good antiviral activity, wherein the half-maximum effect concentration EC of the compound 50 246.48 ug/mL is better than the control drug ningnanmycin 301.83 ug/mL.
Wang et al (Wang, P.Y.; chen, L.; et al. J.Saudi chem.Soc.2017,21, 315-323.) synthesized a series of 1-aryl-4-hydroxy-1H-pyrrole-2 (5H) -one derivatives containing 1,3,4-oxadiazole group, and the antibacterial activity of the synthesized compounds was determined, and the results showed that the compounds have good antibacterial activity, and part of the compounds have EC (effective dose) against rice bacterial blight 50 The values are respectively 8.6 mug/mL and 7.3 mug/mL, which are superior to the control drug bismerthiazol (92.6 mug/mL).
In conclusion, myricetin and 1,3,4-oxadiazole thioether both have certain biological activity in the aspects of medicines and pesticides, but no report exists that an active group containing 1,3,4-oxadiazole thioether is introduced into myricetin to synthesize a myricetin derivative containing 1,3,4-oxadiazole thioether and carry out agricultural activity test.
Disclosure of Invention
The invention aims to overcome the defects and provide the myricetin derivative containing 1,3,4-oxadiazole thioether with better control effect on tobacco mosaic virus, citrus canker pathogen, kiwi canker pathogen and rice bacterial blight pathogen.
The invention also aims to provide a preparation method of the myricetin derivative containing 1,3,4-oxadiazole thioether.
The invention also aims to provide the application of the myricetin derivative containing 1,3,4-oxadiazole thioether in the aspects of tobacco mosaic virus resistance and plant pathogen inhibition.
In order to realize the purpose, the invention adopts the following technical scheme:
wherein: r is substituted phenyl, aromatic heterocyclic group or substituted aromatic heterocyclic group; n is the number of carbons in the carbon chain of 2-6.
The myricetin derivative containing 1,3,4-oxadiazole thioether is characterized in that: the substituted phenyl is alkyl containing C1-6, alkoxy containing C1-6, nitro, halogen atom or hydrogen atom at ortho-position, meta-position or para-position on the benzene ring.
The myricetin derivative containing 1,3,4-oxadiazole thioether is prepared by the following steps: the aryl heterocyclic group is thienyl, furyl, pyrrolyl or pyridyl, and the substituted aryl heterocyclic group is C1-6 alkyl, C1-6 alkoxy, nitro, halogen atom or hydrogen atom at ortho-position, meta-position or para-position of the aryl heterocyclic group.
The preparation method of the myricetin derivative containing 1,3,4-oxadiazole thioether comprises the following synthetic route:
(1) Taking myricitrin and methyl iodide as raw materials and crystalline potassium carbonate as a catalyst, and performing acidity regulation in preparation
Intermediate 1: 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin:
(2) Taking the intermediate 1 and dibromoalkanes with different chain lengths as raw materials, using potassium carbonate as a catalyst, and using N, N-Dimethylformamide (DMF) as a solvent to prepare an intermediate 2: 3-bromo-5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one:
(3) Using benzoic acid as raw material and H 2 SO 4 Methanol as a solvent for the catalyst to prepare intermediate 3: methyl benzoate:
(4) Intermediate 4 was prepared from intermediate 3 and hydrazine hydrate using methanol as solvent: benzoyl hydrazine:
(5) Using the intermediate 4, potassium hydroxide and carbon disulfide, using ethanol as a solvent, and adjusting the pH to 1-3 by using dilute hydrochloric acid to prepare an intermediate 5: 5-phenyl-1,3,4-oxadiazole-2-thiol:
(6) Preparing a target compound A by using the intermediate 2 and the intermediate 5, potassium carbonate as a catalyst and N, N-dimethylformamide as a solvent: myricetin derivative containing 1,3,4-oxadiazole thioether:
the invention relates to application of myricetin derivative containing 1,3,4-oxadiazole thioether in antiviral and antibacterial drugs.
The invention has the beneficial effects that: the technical scheme shows that: the invention introduces 1,3,4-oxadiazole thioether with activity into a myricetin structure, synthesizes a series of myricetin derivatives containing 1,3,4-oxadiazole thioether, and finds that the compound has good activity of resisting Tobacco Mosaic Virus (TMV) through tests on the antiviral and plant pathogen inhibition activity of the synthesized myricetin derivative containing 1,3,4-oxadiazole thioether, and the compound can be a potential plant virus resisting medicament.
Detailed Description
Example 1
5363 a process for the preparation of 5,7-dimethoxy-3- (3- ((5- (p-tolyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A1) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
into a 250mL round bottom flask were successively added 5.00g (10.77 mmol) of myricitrin and 19.34g (140 mmol) of crystalline K 2 CO 3 And 80mL of DMF, stirred at room temperature for 0.5-1h, then 7.50mL (120 mmol) of iodomethane was slowly added dropwise, stirred at room temperature for 48h, followed by tlc (methanol: ethyl acetate =1, V/V). After the reaction is stopped, filtering and precipitating, washing filter residues by dichloromethane, combining the filter residues, diluting the filter residues by 100mL of water, extracting the filter residues for three times by dichloromethane, combining organic layers, concentrating the organic layers under reduced pressure, then dissolving the concentrate in 100mL of absolute ethyl alcohol, heating to reflux, adding 10mL of concentrated hydrochloric acid under reflux after the solution is clarified, then separating out yellow solid, continuing the reaction for 2 hours, cooling to room temperature, and filtering to obtain a crude product, namely 3-hydroxy-3 ',4',5',5,7-pentamethoxyl myricetin (intermediate 1), wherein the yield is as follows: 62.3 percent.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
1.17g (3 mmol) of 3-hydroxy-3 ',4',5',5,7-pentamethoxyl myricetin (intermediate 1) and 1.66g K are sequentially added into a 100mL single-neck round-bottom flask 2 CO 3 (12 mmol) and 30mL of DMF were stirred at room temperature for 0.5-1h, 2.42g of 1, 3-dibromopropane (12 mmol) were added, the reaction was continued at this temperature for 12h, and the reaction was monitored by TLC (ethyl acetate). After the reaction was stopped, the reaction mixture was dispersed in 50mL of water, extracted with ethyl acetate (3X 25 mL), and the resulting ethyl acetate layer was washed with 1mol/L HCl and saturated NaHCO in that order 3 Saturated NaCl aqueous solution was washed 2 times, respectively, and the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography purification under reduced pressure (petroleum ether: ethyl acetate =2:1,v/V) gave a white solid (intermediate 2) in yield: 81.6 percent.
(3) Preparation of methyl 4-methylbenzoate (intermediate 3):
2.72g (20 mmol) of 4-methylbenzoic acid and 12mL of methanol were sequentially added to a 50mL three-necked flask, and after stirring and dissolution, 1.2mL (22 mmol) of 98% concentrated sulfuric acid was slowly dropped into the system, and after completion of the dropping, the mixture was stirred under reflux for about 3 hours. After the reaction was complete, the solvent was removed under reduced pressure, then dispersed with 50mL of water, extracted with ethyl acetate (3X 25 mL), and the resulting ethyl acetate layer was successively washed with saturated aqueous NaCl solution and saturated NaHCO 3 After washing for 2 times, the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give an oil with a yield of 97%.
(4) Preparation of 4-methylbenzoyl hydrazine (intermediate 4):
in a 50mL three-necked flask, 3.00g (20 mmol) of methyl 4-methylbenzoate (intermediate 3), 1.94mL of 80% hydrazine hydrate and 20mL of methanol were sequentially added, and then the mixture was refluxed at 65 ℃ for 4h, followed by tlc (petroleum ether: ethyl acetate = 4. After the reaction was stopped, the solvent was removed under reduced pressure, and then dispersed with 50mL of water, extracted with ethyl acetate (3X 25 mL), and the organic layers were combined and washed with saturated aqueous NaCl solution and saturated NaHCO 3 After washing 2 times, the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give an oil in 89% yield.
(5) Preparation of 5-p-tolyl-1,3,4-oxadiazole-2-thiol (intermediate 5):
after 4-methylbenzoyl hydrazine (intermediate 4) 1.50g (10 mmol), potassium hydroxide 0.67g (12 mmol) and 20mL of ethanol were added to a 50mL three-necked flask in this order and stirred uniformly, carbon disulfide 0.9mL (15 mmol) was slowly added dropwise, and then the mixture was refluxed at 80 ℃ for 5h and the reaction was followed by TLC (petroleum ether: ethyl acetate = 1. After the reaction was stopped, the solvent was removed under reduced pressure, the residue was poured into 50mL of distilled water, followed by suction filtration, the pH of the filtrate was adjusted to 2, extraction was performed with ethyl acetate (3X 25 mL), the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give a white solid with a yield of 82%.
(6) Preparation of 5,7-dimethoxy-3- (3- ((5- (p-tolyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A1):
a50 mL three-necked flask was charged with 0.92g (1.8 mmol) of 5-p-tolyl-1,3,4-oxadiazole-2-thiol (intermediate 5), K 2 CO 3 0.30g (2.2 mmol) and 20mL DMF, stirring at room temperature for 10min, then 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2) is added and stirring is continued at 80 ℃ for 3H. The reaction was followed by TLC (petroleum ether: ethyl acetate = 1. When the reaction was completed, the reaction was stopped, the reaction solution was dispersed with 50mL of water, extracted with dichloromethane (3 × 25 mL), and the organic layers were combined, washed with saturated brine (3 × 30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate =1, 2, V/V) to obtain the objective compound A1, yield: and 64 percent.
Example 2
A method for preparing 3- (3- ((5- (4-fluorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A2) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl 4-fluorobenzoate (intermediate 3):
the process is carried out as in step (3) of example 1, except that R is 4-fluorobenzoic acid.
(4) Preparation of 4-fluorobenzoyl hydrazine (intermediate 4):
the procedure is as in step (4) of example 1, except that R is 4-fluorobenzoic acid.
(5) Preparation of 5- (4-fluorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the process is carried out as in step (5) of example 1, except that R is 4-fluorobenzoic acid.
(6) Preparation of 3- (3- ((5- (4-fluorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A2):
the process is carried out as in step (6) of example 1, except that R is 4-fluorobenzoic acid. Yield: and 69 percent.
Example 3
A method for preparing 3- (3- ((5- (4-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A3) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl 4-chlorobenzoate (intermediate 3):
the procedure is as in (3) of example 1, except that R is 4-chlorobenzoic acid.
(4) Preparation of 4-chlorobenzoyl hydrazine (intermediate 4):
the procedure is as in step (4) of example 1, except that R is 4-chlorobenzoic acid.
(5) Preparation of 5- (4-chlorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure is as in step (5) of example 1, except that R is 4-chlorobenzoic acid.
(6) Preparation of 3- (3- ((5- (4-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A3):
the procedure is as in step (6) of example 1, except that R is 4-chlorobenzoic acid. Yield: 59 percent.
Example 4
A method of preparing 5,7-dimethoxy-3- (3- ((5- (4-nitrophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A4) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl 4-nitrobenzoate (intermediate 3):
the procedure is as in step (3) of example 1, except that R is 4-nitrobenzoic acid.
(4) Preparation of 4-nitrobenzoyl hydrazide (intermediate 4):
the procedure is as in step (4) of example 1, except that R is 4-nitrobenzoic acid.
(5) Preparation of 5- (4-nitrophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure is as in example 1, step (5), except that the filtrate is adjusted to pH 1 and R is 4-nitrobenzoic acid.
(6) Preparation of 5,7-dimethoxy-3- (3- ((5- (4-nitrophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A4):
the procedure is as in step (6) of example 1, except that R is 4-nitrobenzoic acid. Yield: 44 percent. Example 5
5363 a process for the preparation of 5,7-dimethoxy-3- (3- ((5- (3-nitrophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A5) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl 3-nitrobenzoate (intermediate 3):
the procedure is as in step (3) of example 1, except that R is 3-nitrobenzoic acid.
(4) Preparation of 3-nitrobenzoyl hydrazide (intermediate 4):
the procedure is as in example 1, step (4), except that R is 3-nitrobenzoic acid.
(5) Preparation of 5- (3-nitrophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure is as in example 1, step (5), except that the filtrate is adjusted to pH 1 and R is 3-nitrobenzoic acid.
(6) Preparation of 5,7-dimethoxy-3- (3- ((5- (3-nitrophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A5):
the procedure is as in example 1, step (6), except that R is 3-nitrobenzoic acid. Yield: 50 percent.
Example 6
A method for preparing 3- (3- ((5- (3-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A6) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl 3-chlorobenzoate (intermediate 3):
the procedure is as in (3) of example 1, except that R is 3-chlorobenzoic acid.
(4) Preparation of 3-chlorobenzoyl hydrazine (intermediate 4):
the procedure is as in step (4) of example 1, except that R is 3-chlorobenzoic acid.
(5) Preparation of 5- (3-chlorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure is as in step (5) of example 1, except that R is 3-chlorobenzoic acid.
(6) Preparation of 3- (3- ((5- (3-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A6):
the procedure is as in (6) of example 1, except that R is 3-chlorobenzoic acid. Yield: 48 percent. Example 7
A method for preparing 3- (3- ((5- (2-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A7) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl 2-chlorobenzoate (intermediate 3):
the procedure is as in step (3) of example 1, except that R is 2-chlorobenzoic acid.
(4) Preparation of 2-chlorobenzoyl hydrazine (intermediate 4):
the procedure is as in step (4) of example 1, except that R is 2-chlorobenzoic acid.
(5) Preparation of 5- (2-chlorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure is as in step (5) of example 1, except that R is 2-chlorobenzoic acid.
(6) Preparation of 3- (3- ((5- (2-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A7):
the procedure is as in step (6) of example 1, except that R is 2-chlorobenzoic acid. Yield: and 55 percent.
Example 8
A method of preparing 3- (3- ((5- (2-bromophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A8) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl 2-bromobenzoate (intermediate 3):
the process is as in step (3) of example 1, except that R is 2-bromobenzoic acid.
(4) Preparation of 2-bromobenzoyl hydrazine (intermediate 4):
the process is as in step (4) of example 1, except that R is 2-bromobenzoic acid.
(5) Preparation of 5- (2-bromophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the process is as in step (5) of example 1, except that R is 2-bromobenzoic acid.
(6) Preparation of 3- (3- ((5- (2-bromophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A8):
the process is as in step (6) of example 1, except that R is 2-bromobenzoic acid. Yield: 59 percent.
Example 9
5363 a process for the preparation of 5,7-dimethoxy-3- (3- ((5- (2-methoxyphenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A9) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl 2-methoxybenzoate (intermediate 3):
the procedure is as in step (3) of example 1, except that R is 2-methoxybenzoic acid.
(4) Preparation of 2-methoxybenzoyl hydrazine (intermediate 4):
the procedure is as in step (4) of example 1, except that R is 2-methoxybenzoic acid.
(5) Preparation of 5- (2-methoxyphenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure is as in step (5) of example 1, except that the filtrate is adjusted to pH 3 and R is 2-methoxybenzoic acid.
(6) Preparation of 5,7-dimethoxy-3- (3- ((5- (2-methoxyphenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A9):
the procedure is as in step (6) of example 1, except that R is 2-methoxybenzoic acid. Yield: 62 percent. Example 10
5363 a process for the preparation of 5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -3- (3- ((5- (3,4,5-trimethoxyphenyl) -1,3,4-oxadiazol-2-yl) sulfanyl) propoxy) -4H-chromen-4-one (target compound a 10) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 3,4,5-trimethoxybenzoic acid methyl ester (intermediate 3):
the process is as in example 1, step (3), except that R is 3,4,5-trimethoxybenzoic acid.
(4) Preparation of 3,4,5-trimethoxybenzoyl hydrazine (intermediate 4):
the process is as in step (4) of example 1 except that R is 3,4,5-trimethoxybenzoic acid.
(5) Preparation of 5- (3,4,5-trimethoxyphenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure is as in example 1, step (5), except that the filtrate is adjusted to pH 3 and R is 3,4,5-trimethoxybenzoic acid.
(6) Preparation of 5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -3- (3- ((5- (3,4,5-trimethoxyphenyl) -1,3,4-oxadiazol-2-yl) sulfanyl) propoxy) -4H-chromen-4-one (target Compound A10):
the process is as in step (6) of example 1 except that R is 3,4,5-trimethoxybenzoic acid. Yield: 68 percent.
Example 11
5363 a process for the preparation of 5,7-dimethoxy-3- (3- (((5-phenyl-1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 11) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of methyl benzoate (intermediate 3):
the process is carried out as in step (3) of example 1, except that R is benzoic acid.
(4) Preparation of benzoyl hydrazine (intermediate 4):
the procedure is as in (4) in example 1, except that R is benzoic acid.
(5) Preparation of 5-phenyl-1,3,4-oxadiazole-2-thiol (intermediate 5):
the process is carried out as in step (5) of example 1 except that R is benzoic acid.
(6) Preparation of 5,7-dimethoxy-3- (3- (((5-phenyl-1,3,4-oxadiazol-2-yl) thio) propoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A11):
the process is carried out as in step (6) of example 1 except that R is benzoic acid. Yield: and 64 percent.
Example 12
A method for preparing 3- (3- ((5- (2,4-difluorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 12) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (3-bromopropoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1.
(3) Preparation of 2,4-difluorobenzoic acid methyl ester (intermediate 3):
the process is carried out as in example 1, step (3), except that R is 2,4-difluorobenzoic acid.
(4) Preparation of 2,4-difluorobenzoyl hydrazine (intermediate 4):
the process is carried out as in example 1, step (4), except that R is 2,4-difluorobenzoic acid.
(5) Preparation of 5- (2,4-difluorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the process is carried out as in step (5) of example 1 except that R is 2,4-difluorobenzoic acid.
(6) Preparation of 3- (3- ((5- (2,4-difluorophenyl) -1,3,4-oxadiazol-2-yl) thio) propoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 12):
the process is carried out as in step (6) of example 1 except that R is 2,4-difluorobenzoic acid. Yield: 48 percent. Example 13
5,7-dimethoxy-3- (4- ((5- (p-tolyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 13) preparation method comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 1. The difference is that 1,4-dibromobutane is used as the raw material.
(3) Preparation of methyl 4-methylbenzoate (intermediate 3):
as in step (3) of example 1.
(4) Preparation of 4-methylbenzoyl hydrazine (intermediate 4):
as in step (4) of example 1.
(5) Preparation of 5-p-tolyl-1,3,4-oxadiazole-2-thiol (intermediate 5):
as in step (5) of example 1.
(6) Preparation of 5,7-dimethoxy-3- (4- ((5- (p-tolyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A13):
as in step (6) of example 1. Yield: 61 percent.
Example 14
A method for preparing 3- (4- ((5- (4-fluorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 14) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in example 13, step (2).
(3) Preparation of methyl 4-fluorobenzoate (intermediate 3):
as in step (3) of example 2.
(4) Preparation of 4-fluorobenzoyl hydrazine (intermediate 4):
the procedure is as in step (4) of example 2.
(5) Preparation of 5- (4-fluorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
as in step (5) of example 2.
(6) Preparation of 3- (4- ((5- (4-fluorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 14):
as in step (6) of example 2. Yield: and 53 percent.
Example 15
A method for preparing 3- (4- ((5- (4-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 15) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 13.
(3) Preparation of methyl 4-chlorobenzoate (intermediate 3):
the procedure is as described in (3) of example 3.
(4) Preparation of 4-chlorobenzoyl hydrazine (intermediate 4):
the procedure was as in step (4) of example 3.
(5) Preparation of 5- (4-chlorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
as in step (5) of example 3.
(6) Preparation of 3- (4- ((5- (4-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 15):
as in step (6) of example 3. Yield: 60 percent.
Example 16
A method for preparing 5,7-dimethoxy-3- (4- ((5- (4-nitrophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 16) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in example 13, step (2).
(3) Preparation of methyl 4-nitrobenzoate (intermediate 3):
the procedure is as in step (3) of example 4.
(4) Preparation of 4-nitrobenzoyl hydrazide (intermediate 4):
the procedure was as in step (4) of example 4.
(5) Preparation of 5- (4-nitrophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
as in step (5) of example 4. Except that the filtrate was adjusted to PH 1.
(6) Preparation of 5,7-dimethoxy-3- (4- ((5- (4-nitrophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound A16):
as in step (6) of example 4. Yield: 65 percent.
Example 17
5363 a process for the preparation of 5,7-dimethoxy-3- (4- ((5- (3-nitrophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 17) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 13.
(3) Preparation of methyl 3-nitrobenzoate (intermediate 3):
the procedure was as in (3) of example 5.
(4) Preparation of 3-nitrobenzoyl hydrazide (intermediate 4):
the procedure was as in step (4) of example 5.
(5) Preparation of 5- (3-nitrophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure is as in (5) of example 5. Except that the filtrate was adjusted to PH 1.
(6) Preparation of 5,7-dimethoxy-3- (4- ((5- (3-nitrophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A17):
as in step (6) of example 5. Yield: 49 percent.
Example 18
A method for preparing 3- (4- ((5- (3-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 18) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 13.
(3) Preparation of methyl 3-chlorobenzoate (intermediate 3):
as in step (3) of example 6.
(4) Preparation of 3-chlorobenzoyl hydrazine (intermediate 4):
as in step (4) of example 6.
(5) Preparation of 5- (3-chlorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
as in step (5) of example 6.
(6) Preparation of 3- (4- ((5- (3-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A18):
as in step (6) of example 6. Yield: and 69 percent.
Example 19
A method for preparing 3- (4- ((5- (2-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 19) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 13.
(3) Preparation of methyl 2-chlorobenzoate (intermediate 3):
the procedure is as described in (3) of example 7.
(4) Preparation of 2-chlorobenzoyl hydrazine (intermediate 4):
the procedure is as described in (4) of example 7.
(5) Preparation of 5- (2-chlorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure was as in step (5) of example 7.
(6) Preparation of 3- (4- ((5- (2-chlorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 19):
as in step (6) of example 7. Yield: 60 percent.
Example 20
A method for preparing 3- (4- ((5- (2-bromophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 20) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 13.
(3) Preparation of methyl 2-bromobenzoate (intermediate 3):
the procedure is as in step (3) of example 8.
(4) Preparation of 2-bromobenzoyl hydrazine (intermediate 4):
the procedure is as described in (4) of example 8.
(5) Preparation of 5- (2-bromophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
the procedure was as in step (5) of example 8.
(6) Preparation of 3- (4- ((5- (2-bromophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 20):
as in step (6) of example 8. Yield: 48 percent.
Example 21
5363 a process for the preparation of 5,7-dimethoxy-3- (4- ((5- (2-methoxyphenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 21) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 13.
(3) Preparation of methyl 2-methoxybenzoate (intermediate 3):
as in step (3) of example 9.
(4) Preparation of 2-methoxybenzoyl hydrazine (intermediate 4):
the procedure is as described in (4) of example 9.
(5) Preparation of 5- (2-methoxyphenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
as in step (5) of example 9. Except that the filtrate was adjusted to PH 3.
(6) Preparation of 5,7-dimethoxy-3- (4- ((5- (2-methoxyphenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A21):
as in step (6) of example 9. Yield: and 63 percent.
Example 22
5363 a process for the preparation of 5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -3- (4- ((5- (3,4,5-trimethoxyphenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -4H-chromen-4-one (target compound a 22) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in example 13, step (2).
(3) Preparation of methyl 3,4,5-trimethoxybenzoate (intermediate 3):
as in step (3) of example 10.
(4) Preparation of 3,4,5-trimethoxybenzoyl hydrazine (intermediate 4):
as in example 10, step (4).
(5) Preparation of 5- (3,4,5-trimethoxyphenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
as in step (5) of example 10. Except that the filtrate was adjusted to PH 3.
(6) Preparation of 5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -3- (4- ((5- (3,4,5-trimethoxyphenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -4H-chromen-4-one (target Compound A22):
as in step (6) of example 10. Yield: 65 percent.
Example 23
A method for preparing 5,7-dimethoxy-3- (4- ((5-phenyl-1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 23) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 13.
(3) Preparation of methyl benzoate (intermediate 3):
as in step (3) of example 11.
(4) Preparation of benzoyl hydrazine (intermediate 4):
as in step (4) of example 11.
(5) Preparation of 5-phenyl-1,3,4-oxadiazole-2-thiol (intermediate 5):
as in example 11, step (5).
(6) Preparation of 5,7-dimethoxy-3- (4- ((5-phenyl-1,3,4-oxadiazol-2-yl) thio) butoxy) -2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target Compound A23):
as in step (6) of example 11. Yield: and 64 percent.
Example 24
A method of preparing 3- (4- ((5- (2,4-difluorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 24) comprising the steps of:
(1) Preparation of 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin (intermediate 1):
as in step (1) of example 1.
(2) Preparation of 3- (4-bromobutoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2):
as in step (2) of example 13.
(3) Preparation of 2,4-difluorobenzoic acid methyl ester (intermediate 3):
as in example 12, step (3).
(4) Preparation of 2,4-difluorobenzoyl hydrazine (intermediate 4):
as in step (4) of example 12.
(5) Preparation of 5- (2,4-difluorophenyl) -1,3,4-oxadiazole-2-thiol (intermediate 5):
as in step (5) of example 12.
(6) Preparation of 3- (4- ((5- (2,4-difluorophenyl) -1,3,4-oxadiazol-2-yl) thio) butoxy) -5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one (target compound a 24):
as in step (6) of example 12. Yield: 62 percent.
The physicochemical properties of the synthesized myricetin derivative containing 1,3,4-oxadiazole thioether are shown in table 1, and the nuclear magnetic resonance hydrogen spectrum ( 1 H NMR), carbon spectrum ( 13 C NMR) and fluorine spectra ( 19 F NMR) data are shown in table 2.
TABLE 1 physicochemical Properties of the target Compounds obtained in examples 1 to 24
TABLE 2 nuclear magnetic resonance spectroscopy data for the target compounds
Test example 1: anti-plant bacterial activity test:
(1) Test method
The in-vitro inhibitory activity of the target compound on citrus canker pathogen, kiwi canker pathogen and rice bacterial blight pathogen is tested by adopting a turbidity method at the concentrations of 100 and 50 mu g/mL, and the control agents in the experiment are bismerthiazol and thiediazole copper. Culturing citrus canker pathogen, kiwi canker pathogen and rice bacterial leaf blight pathogen on NA solid culture medium, and culturing in 28 deg.C constant temperature bacterial incubator until single colony grows out. Selecting a proper amount of central yellow single colony, placing the single colony in an NB liquid culture medium, and carrying out shake culture in a constant-temperature shaking table at 28 ℃ and 180r/min until the single colony reaches the logarithmic growth phase for later use. Mixing the compound and control agent at concentrations of 100 and 50 μ g/mL, adding 1mL into a test tube containing 4mL NB liquid culture medium, and measuring 40 μ L of the mixture containing Sclerotinia citrea, actinidia chinensis planch and rice white leafAdding NB liquid culture medium of Bacillus subtilis into test tube at 28 deg.C O C. Shaking and culturing for 24-48h at constant temperature of 180 r/min. Measuring OD of sterilized NB liquid medium at 595nm wavelength in spectrophotometer 595 Value, bacterial suspension OD of each concentration was measured simultaneously 595 The value is obtained.
Correcting OD 595 Value = bacteria-containing medium OD 595 Sterile Medium OD 595
Inhibition ratio (%) = (control medium bacterial liquid OD after correction) 595 Correction of the drug-containing Medium OD 595 ) Corrected OD value of control medium liquid is multiplied by 100%.
(2) Results of bioactivity test of plant pathogen resistance
TABLE 3 bacteriostatic activity (% inhibition) of examples 1-24 a
a On average three replicates were used. b Bismerthiazol and copper thielavide (20% wettable powder) were used as positive controls
The inhibition activity of the target compound on citrus canker pathogen, kiwi canker pathogen and rice bacterial leaf blight pathogen was tested by the turbidity method with commercial agents of bismerthiazol and thiediazole copper as positive controls at a test concentration of 100 and 50 μ g/mL (see table 3). The results show that: all the compounds have certain inhibitory activity on citrus canker pathogen, kiwi canker pathogen and rice bacterial blight. Wherein when the concentration is 100 mu g/mL, the inhibition rate of the compound A12 on citrus canker pathogenic bacteria (Xac) exceeds that of bismerthiazol (54.3%) and thiacetone (48.1%); for kiwifruit canker pathogen, the inhibition rates of compound A12 (65.7%), A15 (54.4%), A16 (70.1%) and A24 (73.3%) at 100 μ g/mL exceed those of bismerthiazol (53.4%), copper thielavide (47.5%); for rice bacterial blight, the inhibition rates of the compound A6 (73.4%), A8 (84.4%) and A13 (63.2%) at 100. Mu.g/mL exceeded that of bismerthiazol (60.1%) and thiediazole copper (51.3%).
Test example 2: anti-tobacco mosaic virus activity test:
A. purification of viruses
The method comprises the steps of selecting and inoculating a host Nicotiana tabacum.L plant upper leaf infected by a TMV system for more than 3 weeks by adopting a Zhou Xue flat method (Zhou, X.P.; xu, Z.X.; xu, J.; li, D.B.J.south Chin.agric.Univ.1995,16,74-79.), homogenizing in a phosphate buffer solution, filtering by using double-layer gauze, centrifuging at 8000r, treating by using polyethylene glycol for 2 times, centrifuging again, and suspending precipitates by using the phosphate buffer solution to obtain a refined liquid of the TMV. The whole experiment was carried out at 4 ℃. And measuring the absorbance value of the wavelength of 260nm by using an ultraviolet spectrophotometer, and calculating the virus concentration according to a formula.
Virus concentration (mg/mL) = (A260 Xdilution factor)/E0.1% 1cm260nm
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% (1 mg/mL) at an optical path length of 1 cm. E0.1% of TMV 1cm260nm is 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 -3 mg/mL) whole leaf virus, air-dried naturally and washed with clear water. After the leaves are dry, the left half leaves are lightly coated with the medicament by using a writing brush, the right half She Tushi is used as a contrast with the solvent with the concentration corresponding to the solvent, the number of the dead spots is recorded after 6-7d, and the inhibition rate is calculated according to the following formula.
C. In vivo protection of agents against TMV infection
In vivo protection of agents against TMV infection: the heart-leaf tobacco with the same growth vigor and the 5-6 leaf period is selected to be topped, the left half leaf is lightly coated with the medicament by using a writing brush, and the right half She Tushi is used as a solvent with the concentration corresponding to the solvent to be used as a comparison. Spreading emery powder to the whole leaf after 24 hr, and dipping virus juice (6 × 10) with a row pen -3 mg/mL), washing with clear water, recording the number of dead spots after 6-7 days, and calculating the inhibition rate according to the following formula.
D. In vivo inactivation of TMV infection by agents
Mixing the medicament and virus juice with the same volume, inactivating for 30min, dipping the mixed solution of the medicament and virus with a row pen, manually rubbing and inoculating on the left half of the leaf scattered with carborundum, and supporting the lower part of the leaf with a flat wood plate. Sterile water is mixed with the viral juice to inoculate the right half leaf. 3 plants are set for each medicament treatment, 5-6 leaves are set for each plant, then the plants are put in a light incubator for moisture preservation and culture, the temperature is controlled to be 23 +/-1 ℃, after the light is 10000Lux, the number of the generated withered spots is observed and recorded, and the inhibition rate is calculated according to the following formula.
Inhibition = (average number of dead spots in half leaf without drug application-number of dead spots in half leaf with drug application)/average number of dead spots in half leaf without drug application × 100%
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.
Results of biological activity test for resisting tobacco mosaic virus
TABLE 4 examples 1-24 therapeutic, protective and inactivating activity against tobacco mosaic Virus a
a Average three replicates; b ningnanmycin was used as a positive control.
The therapeutic activity, protective activity and inactivating activity of the target compounds A1-A24 against Tobacco Mosaic Virus (TMV) were tested by the semi-leaf cumic plaque assay with the commercial drug Ningnanmycin as a control at a test concentration of 500. Mu.g/mL (see Table 4). The test results show that: most of the target compounds have certain therapeutic, protective and inactivating activity against TMV. Wherein, the target compounds A9, A13 and A15 have better therapeutic action on TMV, and the inhibition rates are 69.6, 61.4 and 58.0 percent respectively, which exceed that of ningnanmycin (55.1 percent); target compounds A9 and A13 have better protection effect on TMV, and the inhibition rates of the target compounds are 66.2 percent and 63.6 percent respectively, which are superior to ningnanmycin (57.7 percent); the target compounds A17, A19 and A21 have certain inactivation effect on TMV, and the inhibition rates are 80.1, 79.9 and 78.6 percent and are close to Ningnanmycin (85.1 percent).
The experimental activity data show that the myricetin derivative containing 1,3,4-oxadiazole thioether has a certain inhibition effect on plant viruses (TMV) and plant germs (citrus canker, kiwi canker and rice bacterial blight), wherein part of target compounds show excellent activity on resisting the plant viruses and inhibiting the plant germs, can be used as potential plant virus resisting and bacteriostatic medicaments, and have good application prospects.
In summary, the present invention is only a preferred embodiment, and is not limited to any form, and any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention are within the scope of the technical solution of the present invention without departing from the technical solution of the present invention.
Claims (3)
1. A myricetin derivative containing 1,3,4-oxadiazole thioether is characterized in that: the general structural formula is as follows:
wherein: r is phenyl or substituted phenyl; n is the number of carbon in the carbon chain is 3-4; the substituted phenyl is alkyl containing 1 to 6 carbon atoms, alkoxy containing 1 to 6 carbon atoms, nitryl, halogen atoms or hydrogen atoms at the ortho-position, meta-position or para-position on a benzene ring.
2. The process of claim 1, wherein the preparation of the myricetin derivative containing 1,3,4-oxadiazole thioether is as follows: the method comprises the following specific steps:
(1) Taking myricitrin and methyl iodide as raw materials, taking crystallized potassium carbonate as a catalyst, and preparing an intermediate 1: 3-hydroxy-3 ',4',5',5,7-pentamethoxy myricetin:
(2) Taking the intermediate 1 and dibromoalkanes with different chain lengths as raw materials, using potassium carbonate as a catalyst, and using N, N-Dimethylformamide (DMF) as a solvent to prepare an intermediate 2: 3-bromo-5,7-dimethoxy-2- (3,4,5-trimethoxyphenyl) -4H-chromen-4-one:
(3) Using benzoic acid as raw material and H 2 SO 4 Methanol as a solvent for the catalyst to prepare intermediate 3: methyl benzoate:
(4) Intermediate 4 was prepared from intermediate 3 and hydrazine hydrate using methanol as solvent: benzoyl hydrazine:
(5) Using the intermediate 4, potassium hydroxide and carbon disulfide, using ethanol as a solvent, and adjusting the pH to 1-3 by using dilute hydrochloric acid to prepare an intermediate 5: 5-phenyl-1,3,4-oxadiazole-2-thiol:
(6) Preparing a target compound A by using the intermediate 2 and the intermediate 5, potassium carbonate as a catalyst and N, N-dimethylformamide as a solvent: myricetin derivative containing 1,3,4-oxadiazole thioether:
3. the use of the myricetin derivative containing 1,3,4-oxadiazole thioether as claimed in claim 1 or 2 in the field of antiviral and antibacterial drugs in plants.
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