CN113582983A - Myricetin derivative of 1,3, 4-oxadiazole thioether, preparation method and application - Google Patents
Myricetin derivative of 1,3, 4-oxadiazole thioether, 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 alkyl containing C1-6, alkoxy containing C1-6, nitro, halogen atom and hydrogen atom at 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, nitro, halogen atom and hydrogen atom. The compound synthesized by the invention can treat tobacco mosaic virus, citrus canker pathogen and macaqueThe peach canker pathogen and the rice bacterial leaf blight pathogen have good control effects.
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, for example, 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 MTT method is utilized to carry out in-vitro proliferation inhibition activity test of human breast cancer cells MDA-MB-231 on the synthesized compound, and research results show that: the myricetin acylhydrazone derivatives have good inhibition rate on human breast cancer cells MDA-MB-231.
A series of amide, thioether and 1,3, 4-thiadiazole-containing myricetin derivatives 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-: the EC50 values of protective activity of part of compounds on tobacco mosaic virus are 196.1, 425.3 and 386.7 mu g/mL under the concentration of 500 mu g/mL, which is better than that of a control medicament ningnanmycin (447.92 mu g/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 the 1,3, 4-oxadiazole skeleton has a multifunctional structural block, it has been extensively studied and developed in the course of bioactive recombination. In addition, the 1,3, 4-oxadiazole derivative also shows various biological activities such as anticancer, bacteriostasis, antivirus, antifungal and insecticidal activities.
Du et al (Du, Q.R.; Li, D.D.; et al. Bioorg. Med. chem.2013,21, 2286-containing 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 and IC50The 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 in 2015 by Wu et al (Wu, W.N.; Chen, Q.; et al, Bioorg.Med.chem.Lett.2015,25, 2243-one 2246) by active group splicing. 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 compound50The concentration of 246.48 mug/mL is better than that of the control drug Ningnanmycin 301.83 mug/mL.
Wang et al (Wang, p.y.; Chen, L) 2017.(ii) a et al.J.Saudi chem.Soc.2017,21, 315-one 323) synthesizes a series of 1-aryl-4-hydroxy-1H-pyrrole-2 (5H) -one derivatives containing 1,3, 4-oxadiazole group, and antibacterial activity determination is carried out on the synthesized compounds, and the results show that the compounds have good antibacterial activity, and partial compounds have EC of rice bacterial blight50The values are respectively 8.6 mu g/mL and 7.3 mu g/mL, which are superior to the control drug bismerthiazol (92.6 mu g/mL).
In conclusion, myricetin and 1,3, 4-oxadiazole thioether both have certain biological activity in the aspects of medicines and pesticides, but reports 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 an agricultural activity test are not provided.
Disclosure of Invention
The invention aims to overcome the defects and provide the myricetin derivative containing the 1,3, 4-oxadiazole thioether, which has 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 further aims to provide application of the myricetin derivative containing 1,3, 4-oxadiazole thioether in resisting tobacco mosaic virus and inhibiting plant pathogenic bacteria.
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 prepared from the following raw materials: 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 from the following raw materials: the aromatic heterocyclic group is thienyl, furyl, pyrrolyl or pyridyl, and the substituted aromatic 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 aromatic heterocyclic group.
The preparation method of the myricetin derivative containing 1,3, 4-oxadiazole thioether of the invention 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
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 H2SO4Methanol 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: 1,3, 4-oxadiazole thioether-containing myricetin derivative:
the invention relates to application of myricetin derivatives containing 1,3, 4-oxadiazole thioether in antiviral and antibacterial drugs.
The invention has the beneficial effects that: the technical scheme shows that: according to the invention, 1,3, 4-oxadiazole thioether with activity is introduced into a myricetin structure, a series of myricetin derivatives containing 1,3, 4-oxadiazole thioether are synthesized, and the antiviral and phytogerm inhibiting activity test of the synthesized myricetin derivatives containing 1,3, 4-oxadiazole thioether shows that the compound has good activity of resisting Tobacco Mosaic Virus (TMV), and can be a potential anti-plant virus medicament.
Detailed Description
Example 1
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 (10.77mmol) of myricitrin and 19.34g (140mmol) of crystalline K2CO3And 80mL of DMF, and after stirring at room temperature for 0.5-1h, 7.50mL (120mmol) of iodomethane was slowly added dropwise, and the mixture was stirred at room temperature for 48h, followed by TLC (methanol: ethyl acetate ═ 1:4, V/V). After the reaction is stopped, the precipitate is filtered, the filter residue is washed by dichloromethane, the filtrate is combined, diluted by 100mL of water and extracted by dichloromethane for three times,combining organic layers, concentrating under reduced pressure, then dissolving the concentrate in 100mL of absolute ethanol, heating to reflux, adding 10mL of concentrated hydrochloric acid under reflux after the solution is clarified, then precipitating yellow solid, continuing to react for 2h, 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 (3mmol) of 3-hydroxy-3 ', 4 ', 5 ', 5, 7-pentamethoxy myricetin (intermediate 1) and 1.66g K are sequentially added into a 100mL single-neck round-bottom flask2CO3(12mmol) and 30mL of DMF, stirring at room temperature for 0.5-1h, adding 2.42g of 1, 3-dibromopropane (12mmol), continuing the reaction at this temperature for 12h, and monitoring the reaction by TLC (ethyl acetate). After the reaction was stopped, the reaction mixture was dispersed in 50mL of water, extracted with ethyl acetate (3X 25mL), and the resulting ethyl acetate layer was washed with 1mol/L HCl and saturated NaHCO in that order3After washing with saturated aqueous NaCl solution 2 times, 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 was performed (petroleum ether: ethyl acetate 2:1, V/V) to obtain a white solid (intermediate 2), yield: 81.6 percent.
(3) Preparation of methyl 4-methylbenzoate (intermediate 3):
2.72g (20mmol) of 4-methylbenzoic acid and 12mL of methanol were sequentially added to a 50mL three-necked flask, and after stirring and dissolution, 1.2mL (22mmol) 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 25mL), and the resulting ethyl acetate layer was successively washed with saturated aqueous NaCl solution and saturated NaHCO3After 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 in 97% yield.
(4) Preparation of 4-methylbenzoyl hydrazine (intermediate 4):
in a 50mL three-necked flask, methyl 4-methylbenzoate (intermediate 3)3.00g (20mmol), 80% hydrazine hydrate 1.94mL and 20mL of methanol were sequentially added, and then mixedThe solution was refluxed at 65 ℃ for 4h and the reaction was followed by TLC (petroleum ether: ethyl acetate 4:1, V/V). After the reaction was stopped, the solvent was removed under reduced pressure, and then dispersed with 50mL of water, extracted with ethyl acetate (3X 25mL), and the organic layers were combined and washed with saturated aqueous NaCl solution and saturated NaHCO3After 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 in 89% yield.
(5) Preparation of 5-p-tolyl-1, 3, 4-oxadiazole-2-thiol (intermediate 5):
after 4-methylbenzoyl hydrazine (intermediate 4) (1.50 g (10 mmol)), potassium hydroxide (0.67 g (12mmol) and ethanol (20 mL) were added to a 50mL three-necked flask in this order and stirred uniformly, carbon disulfide (0.9 mL (15mmol) was slowly added dropwise, and the mixture was refluxed at 80 ℃ for 5 hours and followed by TLC (petroleum ether: ethyl acetate ═ 1:2, V/V). 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 25mL), 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 (1.8mmol) of 5-p-tolyl-1, 3, 4-oxadiazole-2-thiol (intermediate 5) and K2CO30.30g (2.2mmol) and 20mL DMF, stirring at room temperature for 10min, adding 3- (3-bromopropoxy) -5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -4H-chromen-4-one (intermediate 2), and stirring at 80 deg.C for 3H. The reaction was followed by TLC (petroleum ether: ethyl acetate 1:2, V/V). When the reaction was completed, the reaction was stopped, the reaction solution was dispersed in 50mL of water, extracted with dichloromethane (3 × 25mL), the organic layers were combined, washed with saturated brine (3 × 30mL), 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 (title 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 process for the 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) 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 step (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 process for the 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) 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
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 step (4) of example 1, 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 step (6) of example 1, except that R is 3-nitrobenzoic acid. Yield: 50 percent.
Example 6
A process for the 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) 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 step (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 step (6) of example 1, except that R is 3-chlorobenzoic acid. Yield: 48 percent. Example 7
A process for the 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) 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 for 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
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 a 9):
the procedure is as in step (6) of example 1, except that R is 2-methoxybenzoic acid. Yield: 62 percent. Example 10
A method for producing 5, 7-dimethoxy-2- (3,4, 5-trimethoxyphenyl) -3- (3- ((5- (3,4, 5-trimethoxyphenyl) -1,3, 4-oxadiazol-2-yl) thio) propoxy) -4H-chromen-4-one (target compound a10), 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 3,4, 5-trimethoxybenzoate (intermediate 3):
the process is carried out as in step (3) of example 1 except that R is 3,4, 5-trimethoxybenzoic acid.
(4) Preparation of 3,4, 5-trimethoxy benzoyl hydrazine (intermediate 4):
the process is carried out 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) thio) propoxy) -4H-chromen-4-one (target Compound A10):
the process is carried out as in step (6) of example 1 except that R is 3,4, 5-trimethoxybenzoic acid. Yield: 68 percent.
Example 11
A method for preparing 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) 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 process is carried out as in step (4) of 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 a 11):
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 a12) 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, 4-difluorobenzoate (intermediate 3):
the process is as in step (3) of example 1, except that R is 2, 4-difluorobenzoic acid.
(4) Preparation of 2, 4-difluorobenzoyl hydrazine (intermediate 4):
the process is carried out as in step (4) of example 1, 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
A process for the 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) 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 (title 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 a14) 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-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 (title compound A14):
as in step (6) of example 2. Yield: 53 percent.
Example 15
A process for the 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 a15) 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):
as in step (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 (title compound A15):
as in step (6) of example 3. Yield: 60 percent.
Example 16
A process for the 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) 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-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
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 a17) 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 was as in step (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 process for the 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) 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 (title compound A18):
as in step (6) of example 6. Yield: and 69 percent.
Example 19
A process for the 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 a19) 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 in step (3) of example 7.
(4) Preparation of 2-chlorobenzoyl hydrazine (intermediate 4):
the procedure was as in step (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 (title compound A19):
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 a20) 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 was as in step (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 (title compound A20):
as in step (6) of example 8. Yield: 48 percent.
Example 21
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 a21) 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):
as in step (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 (title compound A21):
as in step (6) of example 9. Yield: and 63 percent.
Example 22
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 a22) 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 3,4, 5-trimethoxybenzoate (intermediate 3):
as in step (3) of example 10.
(4) Preparation of 3,4, 5-trimethoxy benzoyl hydrazine (intermediate 4):
as in step (4) of example 10.
(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 process for the 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) 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 step (5) of example 11.
(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 for 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 a24) 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, 4-difluorobenzoate (intermediate 3):
as in step (3) of example 12.
(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 (1H NMR), carbon spectrum (13C NMR) and fluorine Spectroscopy (19F 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, adding 40 μ L NB liquid culture medium containing Citrus canker, Actinidia chinensis canker and Padina oryzae into the test tube, and placing at 28 deg.COC. Shaking and culturing for 24-48h at constant temperature of 180 r/min. Measuring OD of sterilized NB liquid medium at 595nm wavelength in spectrophotometer595The OD of the bacterial suspension was measured simultaneously at each concentration595The value is obtained.
Correcting OD595Value-bacteria-containing Medium OD595Sterile Medium OD595
Inhibition ratio (%) (control medium OD after correction)595Corrected drug-containing Medium OD595) Corrected OD value of control medium liquid is multiplied by 100%.
(2) Test results of biological activity against plant pathogens
TABLE 3 bacteriostatic activity (% inhibition) of examples 1-24a
aThree replicates were averaged.bBismerthiazol 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 pathogen. Wherein when the concentration is 100 mug/mL, the inhibition rate of the compound A12 on citrus canker pathogen (Xac) exceeds that of bismerthiazol (54.3%) and thiacetone (48.1%); for the kiwifruit canker pathogen, the inhibition rates of the compound A12 (65.7%), A15 (54.4%), A16 (70.1%) and A24 (73.3%) at 100 mu g/mL are all higher than those of bismerthiazol (53.4%) and thiediazole copper (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 thiabendazole (51.3%).
Test example 2: anti-tobacco mosaic virus activity test:
A. purification of viruses
A Zhoxueping method (Zhou, X.P.; Xu, Z.X.; Xu, J.; Li, D.B.J.south Chin.Agric.Univ.1995,16,74-79.) is adopted, and the upper leaves of the host Nicotiana tabacum.L plant are selected and inoculated for more than 3 weeks, a TMV system infects the upper leaves of the host Nicotiana tabacum.L plant, the upper leaves are homogenized in a phosphate buffer solution, the upper leaves are filtered by a double-layer gauze, the upper leaves are centrifuged at 8000r, the upper leaves are treated by 2 times of polyethylene glycol, the upper leaves are centrifuged, and the precipitate is suspended by the phosphate buffer solution to obtain a refined extraction liquid of the TMV. The whole experiment was carried out at 4 ℃. And measuring the absorbance value of the 260nm wavelength by using an ultraviolet spectrophotometer, and calculating the virus concentration according to a formula.
Concentration of virus (mg/mL) ═ 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% (1mg/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-3mg/mL) whole leaf virus, air-dried naturally and washed with clear water. After the leaves are dry, lightly applying the medicament on the left half leaf by using a writing brush, applying a solvent with the concentration corresponding to the solvent on the right half leaf as a control, recording the number of the dead spots after 6-7 days, and calculating the inhibition rate according to the following formula.
C. In vivo protection of agents against TMV infection
In vivo protection of agents against TMV infection: selecting the heart-leaf tobacco with consistent growth and 5-6 leaf stage, topping, lightly applying the medicament on the left half leaf with a writing brush, and applying the solvent with the concentration corresponding to the solvent on the right half leaf as a control. Spreading emery powder to the whole leaf after 24 hr, and dipping virus juice (6 × 10) with a row pen-3mg/mL) of the whole leaf was inoculated with the virus, washed with clear water, and after 6-7 days, the number of dead spots was recorded, and the inhibition rate was calculated according to the following formula.
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, each plant has 5-6 leaves, then the plants are put into 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 scorched spots is observed and recorded after 6-7d, and the inhibition rate is calculated according to the following formula.
Inhibition rate (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 Virusa
aAverage three replicates;bningnanmycin was used as a positive control.
The therapeutic activity, protective activity and inactivating activity of the target compound A1-A24 against Tobacco Mosaic Virus (TMV) were tested at a test concentration of 500. mu.g/mL using the semileaf cumic method with the commercial agent ningnanmycin as a control (see Table 4). The test results show that: most of the target compounds have certain therapeutic, protective and inactivating activity against TMV. The target compounds A9, A13 and A15 have good therapeutic effect on TMV, and the inhibition rates of the target compounds A9, A13 and A15 are 69.6%, 61.4% and 58.0% respectively, and exceed that of ningnanmycin (55.1%); target compounds A9 and A13 have better protection effect on TMV, and the inhibition rates 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 passivation effect on TMV, and the inhibition rates are 80.1%, 79.9% and 78.6%, which are close to Ningnanmycin (85.1%).
The experimental activity data show that the myricetin derivative containing the 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 better 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 (6)
1. A myricetin derivative containing 1,3, 4-oxadiazole thioether is characterized in that: the general structural formula is as follows:
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.
2. The myricetin derivative containing 1,3, 4-oxadiazole thioether as claimed in claim 1, wherein: 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 a benzene ring.
3. The myricetin derivative containing 1,3, 4-oxadiazole thioether as claimed in claim 1, wherein: the aromatic heterocyclic group is thienyl, furyl, pyrrolyl or pyridyl.
4. The myricetin derivative containing 1,3, 4-oxadiazole thioether as claimed in claim 1, wherein: the substituted aromatic heterocyclic group is an alkyl group containing C1-6, an alkoxy group containing C1-6, a nitro group, a halogen atom or a hydrogen atom at the ortho position, the meta position or the para position of the aromatic heterocyclic group.
5. The process for preparing myricetin derivative containing 1,3, 4-oxadiazole thioether as claimed in claim 1, wherein: 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 H2SO4Methanol 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: 1,3, 4-oxadiazole thioether-containing myricetin derivative:
6. the use of myricetin derivative containing 1,3, 4-oxadiazole thioether as claimed in claims 1-5 in antiviral and antibacterial drugs.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674216A (en) * | 2016-12-21 | 2017-05-17 | 贵州大学 | Myricetin derivative containing thiadiazole thioether structure and preparation method thereof |
| CN107602548A (en) * | 2017-09-14 | 2018-01-19 | 贵州大学 | A kind of myricetin derivative, the Preparation method and use of amide containing thioether thiadiazoles |
| CN109438433A (en) * | 2018-10-22 | 2019-03-08 | 贵州大学 | A kind of myricetin derivative, the preparation method and the usage of amide containing oxadiazoles |
| CN109438427A (en) * | 2018-12-04 | 2019-03-08 | 贵州大学 | A kind of triazole schiff bases myricetin derivative, the preparation method and the usage of Sulfide-containing Hindered |
| CN111961039A (en) * | 2020-08-28 | 2020-11-20 | 贵州大学 | Myricetin derivative containing substituted pyrimidine, preparation method and application thereof |
| CN112300141A (en) * | 2020-10-12 | 2021-02-02 | 贵州大学 | Quinazoline-containing myricetin derivative, and preparation method and application thereof |
-
2021
- 2021-07-13 CN CN202110793881.7A patent/CN113582983B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674216A (en) * | 2016-12-21 | 2017-05-17 | 贵州大学 | Myricetin derivative containing thiadiazole thioether structure and preparation method thereof |
| CN107602548A (en) * | 2017-09-14 | 2018-01-19 | 贵州大学 | A kind of myricetin derivative, the Preparation method and use of amide containing thioether thiadiazoles |
| CN109438433A (en) * | 2018-10-22 | 2019-03-08 | 贵州大学 | A kind of myricetin derivative, the preparation method and the usage of amide containing oxadiazoles |
| CN109438427A (en) * | 2018-12-04 | 2019-03-08 | 贵州大学 | A kind of triazole schiff bases myricetin derivative, the preparation method and the usage of Sulfide-containing Hindered |
| CN111961039A (en) * | 2020-08-28 | 2020-11-20 | 贵州大学 | Myricetin derivative containing substituted pyrimidine, preparation method and application thereof |
| CN112300141A (en) * | 2020-10-12 | 2021-02-02 | 贵州大学 | Quinazoline-containing myricetin derivative, and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| XINMIN ZHONG等: "Synthesis and biological activity of myricetin derivatives containing 1,3,4-thiadiazole scaffold", 《CHEMISTRY CENTRAL JOURNAL》 * |
| 李普: "含氮杂环杨梅素衍生物的合成及生物活性研究", 《中国优秀硕士学位论文全文数据库》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213406A (en) * | 2022-01-10 | 2022-03-22 | 贵州大学 | Myricetin derivative of 1,3, 4-oxadiazole thioether sulfonate, preparation method and application |
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