CN111205196B - Phenol AB ring structure compound and preparation method and application thereof - Google Patents

Phenol AB ring structure compound and preparation method and application thereof Download PDF

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CN111205196B
CN111205196B CN202010142202.5A CN202010142202A CN111205196B CN 111205196 B CN111205196 B CN 111205196B CN 202010142202 A CN202010142202 A CN 202010142202A CN 111205196 B CN111205196 B CN 111205196B
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phenol
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CN111205196A (en
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周俊
胡江苗
侯博
杨柳
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Kunming Institute of Botany of CAS
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Abstract

The invention provides a phenol AB ring structure compound and a preparation method and application thereof, belonging to the field of organic synthesis. The AB ring structure in the phenol AB ring structure compound provided by the invention has good activity of resisting influenza virus neuraminidase, and also has moderate inhibitory activity to Daphne-resistant H7N 9; the preparation method provided by the invention has simple flow and easy realization, the synthesis method is simpler than that of the positive drug duffy, the compound 1-1 can be completed only by 1 step, and the compound 3-5-10 can be synthesized by 4 steps.

Description

Phenol AB ring structure compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a phenol AB ring structure compound and a preparation method and application thereof.
Background
The polyphenol compounds have great medicinal value in the aspect of resisting influenza. 2,4, 6-trihydroxyacetophenone and 2, 4-dihydroxy methyl benzoate analogs are classified as polyphenols. Polyphenols not only have potential antioxidant properties and protect cells from oxidative damage, but have also recently been developed against influenza. For example, tea polyphenols have consistency in the experiment of influenza neuraminidase and influenza infected cells in vitro, and the bitter tea extract has good lung index inhibition rate on mice infected with H9N2 influenza virus strain; the research team of the Gaoyiping obtains basically consistent conclusion by verifying 12 separated polyphenol compounds and neuraminidase in influenza and a target compound through a cytopathic effect (CPE) method, and the target compound can better inhibit influenza viruses (screening [ J ] of anti-influenza virus activity of a benzenetriol compound in rhizoma dryopteris crassirhizomae, 2018,49(2): 305-312, Liuchang and the like), but the polyphenol compounds for resisting the influenza viruses in the prior art have the problems of few types and low activity.
Disclosure of Invention
In view of the above, the present invention aims to provide a phenol AB ring structure compound, and a preparation method and an application thereof. The phenol AB ring structure compound provided by the invention has anti-influenza virus activity.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a phenol AB ring structure compound, which has a structure shown in the following formula:
Figure GDA0002828834210000011
Figure GDA0002828834210000021
the invention also provides the phenol AB ring structure compound which has the structure shown in the formula I and R1The preparation method of 1-1,1-2 or 1-3, comprising the steps of:
carrying out condensation reaction on 2,4, 6-trihydroxyacetophenone and a compound 1 to obtain a compound R with a structure shown in formula I1Is a 1-1,1-2 or 1-3 phenol AB ring structure compound, wherein the compound 1 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid.
Preferably, the condensation reaction is carried out under conditions of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and 4-dimethylaminopyridine.
The invention also provides the phenol AB ring structure compound which has the structure shown in the formula I and R1The preparation method of 1-1,1-2 or 1-3, comprising the steps of:
performing acyl chlorination reaction on the compound 1, and then performing esterification reaction on the compound and 2,4, 6-trihydroxyacetophenone to obtain a compound R with a structure shown in formula I1Is a 1-1,1-2 or 1-3 phenol AB ring structure compound, wherein the compound 1 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid.
The invention also provides the phenol AB ring structure compound which has the structure shown in the formula I and R1The preparation method of 1-4 comprises the following steps:
performing acetylation, methyl oxidation, phenolic hydroxyl esterification and nitro reduction on the compound 4-1 in sequence to obtain the compound R with the structure shown in the formula I1A phenol AB ring structure compound of 1-4, wherein the structural formula of the compound 4-1 is as follows:
Figure GDA0002828834210000031
the invention also provides a preparation method of the phenol AB ring structure compound with the structure shown in the formula II, which comprises the following steps:
carrying out condensation reaction on 2, 4-dihydroxybenzoic acid and a compound 2 to obtain a phenol AB ring structure compound with a structure shown in a formula II, wherein the compound 2 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid, 3-methyl-4-aminobenzoic acid, 3, 4-diaminobenzoic acid or 3, 5-dinitrobenzoic acid.
The invention also provides a preparation method of the phenol AB ring structure compound with the structure shown in the formula II, which comprises the following steps:
and (2) performing acyl chlorination reaction on the compound 2, and then performing esterification reaction on the compound and 2, 4-dihydroxybenzoic acid to obtain a phenol AB ring structure compound with a structure shown in a formula II, wherein the compound 2 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid.
The invention also provides a preparation method of the phenol AB ring structure compound with the structure shown in the formula III, which comprises the following steps:
carrying out an ethyl ketone group introduction reaction on phloroglucinol to obtain a compound 3-1;
performing aldehyde group introduction reaction on the compound 3-1 to obtain a compound 3-2;
carrying out a hydroxylamination reaction on the compound 3-2 to obtain a compound 3-3;
carrying out amino introduction reaction on the compound 3-3 to obtain a compound 3-4;
carrying out esterification and amidation reactions on the compound 3-4 and different substrates to obtain a phenol AB ring structure compound with a structure shown in a formula III, wherein the structures of the compound 3-1, the compound 3-2, the compound 3-3, the compound 3-4 and the different substrates are shown as follows:
Figure GDA0002828834210000041
preferably, the aldehyde group introduction reaction is performed under phosphorus oxychloride conditions.
The invention also provides the application of the phenol AB ring structure compound in the technical scheme or the phenol AB ring structure compound prepared by the preparation method in the technical scheme in the preparation of anti-influenza virus drugs.
The invention provides a phenol AB ring structure compound, which has good activity of resisting influenza virus neuraminidase and has moderate inhibitory activity to Daphne drug-resistant H7N 9.
The preparation method provided by the invention has simple flow and easy realization, the synthesis method is simpler than that of the positive drug duffy, the compound 1-1 can be completed only by 1 step, and the compound 3-5-10 can be synthesized by 4 steps.
Detailed Description
The invention provides a phenol AB ring structure compound, which has a structure shown in the following formula:
Figure GDA0002828834210000051
Figure GDA0002828834210000061
the invention also provides the phenol AB ring structure compound which has the structure shown in the formula I and R1The preparation method of 1-1,1-2 or 1-3, comprising the steps of:
carrying out condensation reaction on 2,4, 6-trihydroxyacetophenone and a compound 1 to obtain a compound with a structure shown in formula I and R1Is a 1-1,1-2 or 1-3 phenol AB ring structure compound, wherein the compound 1 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid. In the present invention, the condensation reaction is preferably carried out under the conditions of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and 4-dimethylaminopyridine.
In the specific embodiment of the present invention, it is preferable that 1.2 equivalents of p-aminobenzoic acid (4.28mmol,587.22mg), 1.5 equivalents of EDAC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) (5.35mmol,830.94mg), 0.15 equivalents of DMAP (4-dimethylaminopyridine) (535.24mol,65.39mg) are dissolved in dichloromethane and stirred at room temperature for 30min, then 1 equivalent of 2,4, 6-trihydroxyacetophenone is added and dissolved in (3.57mmol,600mg) to perform condensation reaction for 16 hours, after the condensation reaction is finished, TLC detection is performed, if no p-aminobenzoic acid is found by TLC detection, an appropriate amount of triethylamine can be added and stirred overnight, after the reaction is finished, the crude sample is purified by a silica gel column to obtain 1-1 white solid, and the eluent used for the silica gel column purification is a volume ratio of 3: 1, n-hexane and ethyl acetate.
In the specific embodiment of the present invention, preferably, 1.2 equivalents of 2-hydroxy-4-aminobenzoic acid (4.28mmol,655.72mg), 1.5 equivalents of EDAC (5.35mmol,830.94mg), 0.15 equivalents of DMAP (535.24mol,65.39mg) are dissolved in dichloromethane and stirred at room temperature for 30min, then 1 equivalent of 2,4, 6-trihydroxyacetophenone is added and dissolved in (3.57mmol,600mg), the reaction is carried out for 16 hours, after the condensation reaction is finished, TLC detection is carried out, if no 2-hydroxy-4-aminobenzoic acid is found by TLC detection, an appropriate amount of triethylamine can be added and stirred overnight, an equal volume of water is added, dichloromethane is extracted for 3 times, the organic layer is taken out and dried by spinning, and the crude sample is purified by a silica gel column to obtain 1-3 white solids, wherein the eluent used for silica gel column purification is a volume ratio of 3: 1, n-hexane and ethyl acetate.
The invention also provides the phenol AB ring structure compound which has the structure shown in the formula I and R1The preparation method of 1-1,1-2 or 1-3, comprising the steps of:
performing acyl chlorination reaction on the compound 1, and then performing esterification reaction on the compound and 2,4, 6-trihydroxyacetophenone to obtain a compound R with a structure shown in formula I1Is a 1-1,1-2 or 1-3 phenol AB ring structure compound, wherein the compound 1 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid.
In a specific embodiment of the invention, 3-methyl-4-aminobenzoic acid (500mg,3.13mmol) is preferably dissolved in dichloro, protected with nitrogen, and SOCl is added dropwise2Refluxing and reacting at 80 ℃ overnight, pumping out a reaction system by an oil pump, drying for 3h at 50 ℃ in vacuum to obtain a yellow solid for later use, dissolving 1 equivalent of 2,4, 6-trihydroxyacetophenone in boron trifluoride diethyl etherate (10mL), uniformly stirring, adding the solid for later use, stirring for 36h at room temperature, carrying out vacuum spin-drying on silica gel for sample mixing, and carrying out column chromatography to obtain a light yellow compound 1-2.
The invention also provides the phenol AB ring structure compound which has the structure shown in the formula I and R1The preparation method of 1-4 comprises the following steps:
the compound 4-1 is subjected to acetylation, methyl oxidation and phenolic hydroxyl in sequenceEsterification of the base and reduction of the nitro group to obtain the compound R with the structure shown in the formula I1A phenol AB ring structure compound of 1-4, wherein the structural formula of the compound 4-1 is as follows:
Figure GDA0002828834210000071
in the invention, the phenol AB ring structure compound has a structure shown in formula I and R1The preparation principle of 1-4 is shown as formula a, and the compound represented by 4-5 in the formula a is R1A phenol AB ring structure compound having a structure represented by formula I when 1-4:
Figure GDA0002828834210000081
in a specific embodiment of the invention, the phenol AB ring structure compound has a structure shown in formula I and R1The specific preparation steps for 1-4 are as follows:
synthesis of Compound 4-2: commercially available p-methyl o-aminonitrobenzene (4-1) (1.0g,6.57mmol) was dissolved in hot glacial acetic acid, acetic anhydride (745mg,7.89mmol) was slowly added dropwise, the mixture was stirred for 1h, the reaction liquid was rotary evaporated under reduced pressure and isolated on a silica gel column to give the title compound as a yellow solid in about 98% yield.
Synthesis of Compounds 4-3: 4-methyl-2-acetamidonitrobenzene (1.5g,5.41mmol) was added to KMnO4(1.11g,7.03mmol) in 30mL of aqueous solution, heating to 80 ℃ for reaction for 45min, filtering with diatomite while hot, washing with ethyl acetate, combining ethyl acetate layers, drying without magnesium sulfate, and concentrating under reduced pressure to obtain the yellow target product 3-acetamido-4-nitrobenzoic acid with the yield of 57%.
Synthesis of Compounds 4-4: esterification of compound 4-3 with the phenolic hydroxyl group provided a white solid (i.e., compound 4-4) in about 35% yield.
Synthesizing a compound 4-5, mixing 5mg of the compound 4-4 with 1.58mg of 10% Pd/C to 0.3mL of THF, adding 0.3mL of absolute ethanol, degassing and flushing with nitrogen for protection, inserting a hydrogen balloon, vigorously stirring at 40 ℃ for 3-4 h, checking whether the reaction is complete by using a dot plate, filtering 10% Pd/C after the reaction is complete, performing rotary drying under reduced pressure, and stirring with silica gel (chloroform: methanol is 20: 1 in volume ratio) to obtain a light yellow target product, wherein the yield is about 92%.
The invention also provides a preparation method of the phenol AB ring structure compound with the structure shown in the formula II, which comprises the following steps:
carrying out condensation reaction on 2, 4-dihydroxybenzoic acid and a compound 2 to obtain a phenol AB ring structure compound with a structure shown in a formula II, wherein the compound 2 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid, 3-methyl-4-aminobenzoic acid, 3, 4-diaminobenzoic acid or 3, 5-dinitrobenzoic acid.
The present invention is not particularly limited in terms of the specific manner of the condensation reaction, and a method known to those skilled in the art may be used. After the condensation reaction is completed, the TLC detection is preferably carried out, if no 2, 4-dihydroxy benzoic acid is detected by the TLC detection, a proper amount of triethylamine can be added for stirring overnight, equal volume of water is added, dichloromethane is used for extraction for 3 times, an organic layer is taken for spin drying, a crude sample is purified by a silica gel column, and an eluent used for purifying the silica gel column preferably has a volume ratio of 3: 1, n-hexane and ethyl acetate.
The invention also provides a preparation method of the phenol AB ring structure compound with the structure shown in the formula II, which comprises the following steps:
and (2) performing acyl chlorination reaction on the compound 2, and then performing esterification reaction on the compound and 2, 4-dihydroxybenzoic acid to obtain a phenol AB ring structure compound with a structure shown in a formula II, wherein the compound 2 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid. In a particular embodiment of the invention, it is preferred that the p-aminobenzoic acid is formed into p-aminobenzoyl chloride and the reaction product is drained off for use. Then 2,4, 6-trihydroxyacetophenone is dissolved in boron trifluoride ether, and p-aminobenzoyl chloride is added dropwise to the reaction liquid to obtain the target product.
The invention also provides a preparation method of the phenol AB ring structure compound with the structure shown in the formula III, which comprises the following steps:
carrying out an ethyl ketone group introduction reaction on phloroglucinol to obtain a compound 3-1;
performing aldehyde group introduction reaction on the compound 3-1 to obtain a compound 3-2;
carrying out a hydroxylamination reaction on the compound 3-2 to obtain a compound 3-3;
carrying out amino introduction reaction on the compound 3-3 to obtain a compound 3-4;
carrying out esterification and amidation reactions on the compound 3-4 and different substrates to obtain a phenol AB ring structure compound with a structure shown in a formula III, wherein the structures of the compound 3-1, the compound 3-2, the compound 3-3, the compound 3-4 and the different substrates are shown as follows:
Figure GDA0002828834210000091
Figure GDA0002828834210000101
in the invention, the preparation principle of the phenol AB ring structure compound with the structure shown in the formula III is shown in the formula b:
Figure GDA0002828834210000102
in a specific embodiment of the invention, preferably phloroglucinol (15g,118.94mmol) is dissolved in boron trifluoride acetic acid solution (75mL), stirred at room temperature for 36h and then slowly poured into sodium acetate solution (1.5L,51g/L), stirred at room temperature for 24h and then filtered to give a yellow solid, an equal volume of ethyl acetate is added to the filtrate, extracted 3 times, dried over anhydrous sodium sulfate, the filtrates are combined and spun dry. Dissolving a solid by ethyl acetate, adding a subsequent filtrate part, pouring silica gel into the mixture, mixing the mixture with a sample, and carrying out column chromatography to obtain a target product 3-1, wherein an eluent used in the column chromatography is preferably a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1: 3; dissolving a compound 3-1(8g,47.58mmol) in ethyl acetate (5-8 mL), adding DMF (4.4mL,57.09mmol) and phosphorus oxychloride (13.07mL,142.7mmol), stirring the mixture at room temperature for 2h to obtain a large amount of white solid, slowly dripping water into the reaction system, extracting with ethyl acetate for three times, combining ethyl acetate layers, drying with anhydrous sodium sulfate, and separating by using a silica gel column to obtain a compound 3-2, wherein an eluent used for separating by using the silica gel column is preferably a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1: 1; dissolving 1 equivalent of compound 3-2(3.6g,18.35mmol) and 2.4 equivalents of hydroxylamine hydrochloride (3.06g,44.05mmol) in anhydrous methanol, separating with silica gel column, and stirring at room temperature overnight to obtain yellow target compound 3-3, wherein the eluent used for separating with silica gel column preferably has a volume ratio of 1: 3a mixed solvent of petroleum ether and acetone; dissolving 1 equivalent of compound 3-3(3.6g,18.35mmol) and 2.4 equivalents of hydroxylamine hydrochloride (3.06g,44.05mmol) in anhydrous methanol, separating with silica gel column, and stirring at room temperature overnight to obtain yellow target compound 3-4, wherein the eluent used for separating with silica gel column preferably has a volume ratio of 1: 3a mixed solvent of petroleum ether and acetone.
In a specific embodiment of the present invention, the preparation process of the compound 3-5-1 is preferably: mixing 1.2 equivalents of EDC & HCl and 1.2 equivalents of 2,4, 6-hydroxyacetophenone with amino group in dichloromethane at 0 deg.C, dissolving 1 equivalent of p-aminobenzoic acid, 1.1 equivalents of HOBt and 1.2 equivalents of triethylamine in dichloromethane, adding to the reaction system, stirring at room temperature for 2 hours, and detecting the reaction system by TCL. After the reaction is finished, 10% of citric acid is added, and then 10% of NaHCO is added3Washing with saturated salt water, and washing the organic layer with anhydrous MgSO4Drying, pressurizing and spin-drying the solvent, and separating by using a silica gel column to obtain the compound 3-5-1.
In a specific embodiment of the present invention, the preparation process of the compounds 3-5-10 is preferably: 2,4, 6-Trihydroxyl-3-acetylbenzaldehyde (18g,91.76mmmol) and amantadine hydrochloride (17.22g,91.76mmol) were dissolved in dichloromethane, 11.4g of anhydrous magnesium sulfate was added thereto, and triethylamine (14.03mL,100.94mmol) was added dropwise. Reacting for 4 hours at 40 ℃, detecting the reaction, if the reaction is not complete, adding triethylamine, and performing rotary drying under reduced pressure until the reaction is complete to obtain a red yellow solid. And (3) separating by using a silica gel column to obtain a target product compound 3-5-10, wherein the eluent used for separating by using the silica gel column is preferably a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10: 1.
The invention also provides the application of the phenol AB ring structure compound in the technical scheme or the phenol AB ring structure compound prepared by the preparation method in the technical scheme in the preparation of anti-influenza virus drugs.
In order to further illustrate the present invention, the following examples are given to describe the phenolic AB ring structure compounds provided in the present invention in detail, and the preparation method and application thereof, but they should not be construed as limiting the scope of the present invention.
Example 1
Preparation of Compounds 1-1: the compound can be prepared by 2 methods, wherein the first method is that the product can be obtained by one-step condensation by using common condensing agents (DMAP, EDAC); the second method is to adopt p-aminobenzoic acid to form p-aminobenzoyl chloride, amino does not generally participate in the reaction because of forming amino hydrochloride, then the reaction product is drained for standby, 2,4, 6-trihydroxyacetophenone is dissolved in boron trifluoride ethyl ether, the standby product is dripped into the reaction liquid, and the target product can be obtained.
1.2 equivalents of p-aminobenzoic acid (4.28mmol,587.22mg), 1.5 equivalents of EDAC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) (5.35mmol,830.94mg), 0.15 equivalents of DMAP (4-dimethylaminopyridine) (535.24mol,65.39mg) were dissolved in dichloromethane and stirred at room temperature for 30min, then 1 equivalent of 2,4, 6-trihydroxyacetophenone was added dissolved (3.57mmol,600mg) and reacted for 16 h. No substrate was detected by TLC, triethylamine was added and the mixture was stirred overnight, after the reaction was completed, the solvent was dried by spinning, and the crude product was purified by silica gel column (n-hexane: ethyl acetate 3: 1 by volume) to obtain 1-1 as a white solid with a reaction yield of about 15%.1H NMR(600MHz,DMSO,25℃):δ7,84(d,2H),6.68(d,2H),6.22(s,2H),4.63(s,2H),2.69(s,3H)；13C NMR(101MHz,DMSO,25℃)δ204.34,163.65,162.89,156.96,154.54,132.12,131.24,113.85,112.83,108.19,100.92,33.03.
Preparation of Compounds 1-2: dissolving 500mg,3.13mmol of substrate 3-methyl-4-aminobenzoic acid in dichloro, dropping SOCl under the protection of nitrogen2The reaction is performed under reflux at 80 ℃ overnight, an oil pump is used for draining a reaction system, the reaction system is dried under vacuum at 50 ℃ for 3 hours to obtain a yellow solid for later use, 1 equivalent of 2,4, 6-trihydroxyacetophenone is dissolved in boron trifluoride ether (10mL) and is uniformly stirred, the solid for later use is added, the mixture is stirred at room temperature for 36 hours, silica gel is dried under vacuum in a spinning mode and is stirred, and a light yellow compound 1-2 is obtained through column chromatography, wherein the yield is about 20%.1H NMR(400MHz,DMSO-d6,25℃)δ7.63(s,1H),7.61(d,1H),6.66(d,J＝8.2,1H),6.18(s,2H),5.98(s,2H),2.61(s,3H),2.08(s,3H).13C NMR(151MHz,MeOD,25℃)δ204.1,164.0,163.8,157.1,152.7,132.2,129.7,120.2,114.2,112.8,108.4,100.6,32.9,17.3.
Preparation of compounds 1-3: 1.2 equivalents of 2-hydroxy-4-aminobenzoic acid (4.28mmol,655.72mg), 1.5 equivalents of EDAC (5.35mmol,830.94mg), 0.15 equivalents of DMAP (535.24mol,65.39mg) were dissolved in dichloromethane and stirred at room temperature for 30min, then 1 equivalent of 2,4, 6-trihydroxyacetophenone was added to dissolve (3.57mmol,600mg) and reacted for 16 h, no product was detected by TLC, triethylamine was added and stirred overnight, an equal volume of water was added, dichloromethane was extracted 3 times, several layers were taken and spin dried, the crude was purified by silica gel column (n-hexane: ethyl acetate ═ 3: 1, volume ratio) to obtain 1-3 white solid with a reaction yield of about 13%.1H NMR(400MHz,DMSO-d6,25℃)δ12.21(s,2H),10.27(s,1H),7.61(d,J＝8.8,1H),6.36(s,2H),6.25(s,2H),6.18(dd,J＝8.8,2.2,1H),6.04(d,J＝2.1,1H),2.63(s,3H)；13C NMR(100MHz,DMSO-d6,25℃)δ204.4,166.7,163.4,162.8,156.9,156.1,132.0,108.5,107.1,101.0,98.6,98.5,40.1,40.0,39.9,39.7,39.5,39.3,39.1,38.9,33.0.
Example 2
Preparation of compound 2-1: see compound 1-1, except that 2,4, 6-trihydroxyacetophenone in example 1 was replaced with 2, 4-dihydroxybenzoic acid to give a white solid in about 51% yield.1H NMR(DMSO-d6,400MHz,25℃)δ10.69(s,1H),7.82(d,J＝8.7,1H),7.79-7.76(m,2H),6.86-6.85(d,J＝2.3,1H),6.81-6.79(dd,J＝8.7,2.3,1H),6.66-6.62(d,J＝8.7,2H),6.22(s,1H),3.88(s,3H)；13C NMR(DMSO-d6,101MHz,25℃)δ168.8,163.9,161.2,156.5,154.6,132.2,131.2,113.9,113.8,112.9,110.7,110.5,52.5.
Preparation of compound 2-2: see compound 1-2 methods, except that 2,4, 6-trihydroxyacetophenone in example 1 was replaced with 2, 4-dihydroxybenzoic acid, a white solid, in about 61% yield.1H NMR(DMSO-d6,400MHz,25℃)δ10.68(s,1H),7.82(d,J＝8.7Hz,1H),7.68(s,1H),7.66(d,J＝2.1Hz,1H),6.85(d,J＝2.2Hz,1H),6.80(dd,J＝8.7,2.3Hz,1H),6.66(dd,J＝8.7,2.3Hz,1H),5.98(br-s,2H),3.88(s,3H),2.10(s,3H)；13C NMR(DMSO-d6101 MHz,25℃)δ168.7,164.0,161.1,156.6,152.8,132.4,131.2,129.9,120.2,114.1,113.8,112.8,110.7,110.5,52.5,17.3.
Preparation of Compounds 2-3: see methods for Compounds 1-3, except that 2,4, 6-trihydroxyacetophenone in example 1 was replaced with 2, 4-dihydroxybenzoic acid as a white solid in about 32% yield.1H NMR(DMSO-d6,400MHz,25℃)δ10.27(s,1H),7.83(d,J＝8.7Hz,1H),7.64(d,J＝8.7Hz,1H),6.89(d,J＝2.3Hz,1H),6.83(dd,J＝8.7,2.3Hz,1H),6.36(s,2H),6.20(dd,J＝8.8,2.1Hz,1H),6.05(d,J＝2.1Hz,1H),3.89(s,3H)；13C NMR(DMSO-d6,101MHz,25℃)δ168.6,166.9,163.4,161.0,156.9,155.6,132.0,131.3,113.7,111.0,110.8,107.1,98.6,98.5,52.5.
Preparation of Compounds 2-4: see methods for Compounds 1-3, except that 2,4, 6-trihydroxyacetophenone in example 1 was replaced with 2, 4-dihydroxybenzoic acid, the ester condensation substrate was 3, 4-diaminobenzoic acid, a white solid, with a yield of about 15%.1H NMR(DMSO-d6,400MHz)δ10.67(s,1H),7.82(d,J＝8.6Hz,1H),7.26(m,2H),7.24(d,J＝1.8Hz,0H),7.24,7.23,6.83(d,J＝2.1Hz,1H),6.78(dt,J＝8.7,2.0Hz,1H),6.57(d,J＝7.9Hz,1H),5.53(br-s,2H),4.76(br-s,2H),3.89(s,3H)；13C NMR(DMSO-d6,100MHz)δ168.7,164.3,161.1,156.6,141.8,134.0,131.2,121.5,115.2,113.8,112.6,110.7,110.5,52.5.
Preparation of Compounds 2-5: see methods for Compounds 1-3, except that 2,4, 6-trihydroxyacetophenone in example 1 was replaced with 2, 4-dihydroxybenzoic acid, the ester condensation substrate was 3, 5-dinitrobenzoic acid, a yellow solid, and the yield was about 51%.1H NMR(CDCl3,400MHz,25℃)δ10.99(s,1H),9.30(s,1H),7.96(d,J＝8.7Hz,1H),6.93(d,J＝2.3Hz,1H),6.92,6.82(dd,J＝8.7,2.3Hz,1H),3.99(s,3H)；13C NMR(CDCl3,100MHz,25℃)δ170.0,163.1,160.6,155.4,149.0,133.0,131.7,130.1,123.3,112.7,111.3,110.6,52.7.
Example 3
Preparation of compound 3-2: phloroglucinol (15g,118.94mmol) was dissolved in boron trifluoride acetic acid solution (75mL), stirred at room temperature for 36h and slowly poured into sodium acetate solution (1.5L,51g/L), stirred at room temperature for 24h and filtered to give a yellow solid, an equal volume of ethyl acetate was added to the filtrate, extracted 3 times, dried over anhydrous sodium sulfate, the filtrates combined and dried by spinning. The solids were dissolved in ethyl acetate plus the subsequent filtrate portion and poured over silica gel to stir the sample. Purification on a silica gel column (ethyl acetate: petroleum ether: 1:3 by volume) gave the desired product as a white powder in 71% yield.
Preparation of Compounds 3-3: 1 equivalent of the compound 3-2 substrate (3.6g,18.35mmol) and 2.4 equivalents of hydroxylamine hydrochloride (3.06g,44.05mmol) were dissolved in anhydrous methanol and subjected to silica gel column separation (petroleum ether: acetone ═ 1:3, volume ratio) and stirred at room temperature overnight to obtain the yellow target compound 3-3 in about 92% yield.1H NMR(CD3OD,400MHz,25℃)δ8.45(s,1H),5.88(s,1H),2.64(s,3H)；(-)-ESIMS m/z[M-H]-:210.
Preparation of Compounds 3-4: dissolving the compound 3-4(700mg,3.31mmol) with the bottom 1 equivalent in absolute ethyl alcohol, discharging air and protecting nitrogen, adding 10% Pd/C (726mg,331.46mmol) with 0.1 equivalent, adding 1 drop of concentrated hydrochloric acid, exhausting gas, introducing hydrogen, stirring vigorously, reacting at room temperature for 5 hours, heating to 40 ℃ if the reaction is not complete, continuing to react for 2 hours, after the reaction is finished, decompressing and drying by spinning, filtering with diatomite to obtain a light yellow target product with the yield of about 96%.1H NMR(MeOD,400MHz,25℃)δ6.03,4.05,2.60；13C NMR(MeOD,101MHz,25℃)δ204.9,166.1,164.6,164.4,105.2,99.4,94.7,33.0,32.7.
Preparation of 3-5-X analog of Compound (X represents the numbering).
Preparation of Compound 3-5-1: mixing 1.2 equivalents of EDC & HCl and 1.2 equivalents of 2,4, 6-hydroxyacetophenone with amino group in dichloromethane at 0 deg.C, dissolving 1 equivalent of p-aminobenzoic acid, 1.1 equivalents of HOBt and 1.2 equivalents of triethylamine in dichloromethane, adding to the reaction system, stirring at room temperature for 2 hours, and detecting the reaction system by TCL. After the reaction is finished, 10% of citric acid is added, and then 10% of NaHCO is added3Washing with saturated salt water, and washing the organic layer with anhydrous MgSO4Drying, pressurizing and spin-drying the solvent, and separating by using a silica gel column to obtain the white target compound with the yield of 32%.1HNMR(DMSO-d6,,400MHz,25℃)δ13.82(s,1H),11.72(s,1H),11.28(s,1H),8.84(t,J＝5.6Hz,1H),7.63(d,J＝8.4Hz,1H),6.51(d,J＝8.4Hz,1H),5.90(s,1H),5.75(br-s,2H),4.24(d,J＝5.6Hz,1H),2.57(s,3H).13C NMR(DMSO-d6,,101MHz,25℃)δ202.9,168.8,163.8,163.7,162.9,152.3,129.3,118.9,112.5,104.4,104.2,94.8,32.5,32.4.
Compound 3-5-2 was prepared in the same manner as compound 3-5-1 except that aminobenzoic acid was replaced with a substrate of the second structural formula among different substrates to give a white solid with a yield of about 25%.1H NMR(DMSO-d6,,400MHz,25℃)δ13.81(s,1H),11.73(s,1H),11.28(s,1H),8.83(t,J＝5.7Hz,1H),8.81,7.57,7.56(d,J＝2.1Hz,1H),7.51(dd,J＝8.4,2.2Hz,1H),6.55(d,J＝8.4Hz,1H),5.89(s,1H),5.48(s,1H),4.23(d,J＝5.6Hz,2H),2.57(s,3H),2.04(s,3H)；13C NMR(DMSO-d6,,101MHz,25℃)δ202.9,168.9,163.8,163.6,162.9,150.4,129.9,126.9,119.8,119.1,112.6,104.5,104.2,94.8,32.5,32.4,17.4.
Preparation of Compounds 3-5-3: the same procedure as that of Compound 3-5-1, except that aminobenzoic acid was replaced with a substrate of the third structural formula among different substrates, gave a white solid with a yield of about 30%.1H NMR(DMSO-d6,400MHz,25℃)δ7.53(d,J＝7.52Hz,1H),6.06-5.97(m,3H),5.69(s,2H),4.25(s,2H),2.55(s,3H).13C NMR(DMSO-d6,150MHz,25℃)δ216.86,169.13,161.28,153.82,149.78,132.64,129.64,122.45,105.59,103.95,103.39,102.98,99.45,32.38,31.81.
Preparation of Compounds 3-5-4: the compound was prepared with reference to 3-5-1, except that aminobenzoic acid was replaced with a substrate of the fourth structural formula among different substrates, and dichloromethane solvent was replaced with N, N-dimethylformamide. White solid, yield 31%.1H NMR(DMSO-d6,400MHz,25℃)δ14.02(s,1H),11.28(s,1H),10.93(s,1H),8.04(t,J＝5.3Hz,1H),6.32(s,1H),6.22(s,1H),4.13(d,J＝5.2Hz,2H),4.01(d,J＝2.3Hz,2H),3.84(t,J＝6.4Hz,1H),2.90(m,2H),2.54(s,3H)；13C NMR(DMSO-d6,100MHz,25℃)δ202.75,170.33,163.90,163.40,162.16,103.81,102.49,94.47,65.56,53.52,35.41,32.42,31.51.
Preparation of Compounds 3-5-5: the compound is prepared as described in 3-5-1, except that a substrate of the fifth formula among different substrates is used instead of aminobenzoic acid, amino, 4, 6-trihydroxyacetophenone, an acidic substrate and DMT-MM (4- (4,6-dimethoxy-1,3,5-triazin-2-yl) 4-methylorganophosphonium chloride) are dissolved in Tetrahydrofuran (THF), the reaction is terminated after 2h at room temperature, the reaction system is extracted with ethyl acetate, saturated saline, and finally the target product is isolated by a silica gel column (chloroform: methanol: 10:1, vol.%) with a brown yield of about 20%.1H NMR(DMSO-d6,400MHz,25℃)δ14.04(br s,1H),10.95(br s,1H),10.65(br s,1H),8.46(t,J＝4.9Hz,1H),7.15(s,2H),6.62(s,1H),6.00(s,1H),4.21(d,J＝4.8Hz,1H),3.77(s,3H),2.55(s,3H)；13C NMR(DMSO-d6,100MHz,25℃)δ202.7,168.2,164.4,163.4,162.5,162.0,149.6,143.3,109.4,103.8,102.3,94.2,61.8,48.6,32.5,31.1.
Preparation of Compounds 3-5-6: see 3-5-1 for the preparation of this compound, except that aminobenzoic acid was replaced with a substrate of the sixth formula from among the different substrates and the dichloromethane solvent was replaced with N, N-dimethylformamide as a white solid in 25% yield.1H NMR(DMSO-d6,400MHz,25℃)δ13.95(s,1H),12.88(s,1H),11.11(s,1H),10.68(s.1H),8.25(t,J＝5.0Hz,1H),5.99(s,1H),4.07(d,J＝5.0Hz,2H),3.16(s,1H),2.55(s,3H),2.02(s,2H)；13C NMR(DMSO-d6,100MHz，25℃)δ202.8,186.9,168.9,164.1,163.3,162.1,134.7,117.3,103.9,102.8,94.3,48.6,32.5,32.1,31.6,11.3；
Preparation of Compounds 3-5-7: see 3-5-1 for the preparation of this compound, except that aminobenzoic acid was replaced with a substrate of the seventh structural formula from among different substrates to give a white solid in 44% yield.1H NMR(DMSO-d6,400MHz,25℃)δ13.79(s,1H),11.37(s,1H),10.85(s,1H),8.37(t,J＝5.4Hz,1H),6.85(s,2H),6.21(s,1H),5.96(s,1H),4.08(d,J＝5.3Hz,2H),3.28(s,2H),2.56(s,3H)；13C NMR(DMSO-d6,150MHz,25℃)δ202.8,170.9,168.2,163.8,163.4,162.4,145.8,104.0,103.5,102.5,94.5,38.0,32.5,31.7.
Preparation of Compounds 3-5-8: see 3-5-1 for the preparation of this compound, except that aminobenzoic acid was replaced with a substrate of the eighth structural formula from among the different substrates and the dichloromethane solvent was replaced with N, N-dimethylformamide as a yellow solid in 25% yield.1H NMR(DMSO-d6,400MHz,25℃)δ8.19(s,1H),5.99(s,1H),4.61,4.59(d,J＝9.0Hz,1H),4.54(s),4.34(d,J＝9.0Hz,1H),4.10(t,J＝4.8Hz,2H),4.09,3.99-3.27(s,2H),2.98(m,2H),2.54(s,3H)；13C NMR(DMSO-d6,150MHz,25℃)δ202.5,170.6,164.3,164.1,162.8,153.6,103.9,102.6,94.5,61.3,49.8,48.6,35.0,32.4,31.9,14.5.
Preparation of Compounds 3-5-9: see 3-5-1 for the preparation of this compound, except that aminobenzoic acid was replaced with a substrate of the ninth formula from among different substrates to give a yellow solid in 17% yield.1H NMR(DMSO-d6,400MHz,25℃)δ14.02(br-s,1H),11.05(br-s,1H),10.69(br-s,1H),8.26(s,1H),,8.00(t,J＝4.9Hz,1H),,6.02(s,1H),4.29(m,1H),4.14(d,J＝4.8Hz,2H),3.91(m,2H),3.62,3.60(dd,J＝11.2,8.5Hz,1H),2.56(s,3H)；13C NMR(DMSO-d6,100MHz)δ202.8,173.4,170.3,164.2,163.3,162.1,103.9,102.4,94.2,56.0,32.4,32.3,31.7.
Preparation of Compounds 3-5-10: dissolving 2,4, 6-trihydroxy-3-acetylbenzaldehyde (18g,91.76mmmol) and amantadine hydrochloride (17.22g,91.76mmol) in dichlorineTo methane, 11.4g of anhydrous magnesium sulfate was added, and triethylamine (14.03mL,100.94mmol) was added dropwise. Reacting for 4 hours at 40 ℃, detecting the reaction, if the reaction is not complete, adding triethylamine, and performing rotary drying under reduced pressure until the reaction is complete to obtain a red yellow solid. The desired product was isolated via silica gel column (petroleum ether: ethyl acetate 10:1 by volume) in about 80% yield.1HNMR(Acetone-d6,400MHz,25℃)δ13.61(br s,1H),9.85(br s,1H),8.24,8.23(s,1H),5.30(s,1H),2.46(s,3H),1.89(p,J＝2.2Hz,3H),1.84(d,J＝2.9Hz,6H),1.62(d,J＝3.1Hz,6H)；13C NMR(Acetone-d6,150MHz,25℃)δ203.3,182.3,178.4,167.4,153.1,108.7,101.8,90.4,55.2,43.1,43.1,36.4,31.4；(-)-ESIMS m/z[M-H]-:328.
Preparation of Compound 4-2: commercially available p-methyl o-aminonitrobenzene (1.0g,6.57mmol) was dissolved in hot glacial acetic acid, acetic anhydride (745mg,7.89mmol) was slowly added dropwise, the mixture was stirred for 1h, the reaction liquid was rotary evaporated under reduced pressure and isolated on a silica gel column to give the title compound as a yellow solid in about 98% yield.1H NMR(CDCl3,400MHz,25℃)δ10.16(br s,),8.57(d,1H),7.97(s,1H),7.43(s,1H),2.36(s,3H),2.25(s,3H)；13C NMR(CDCl3,100MHz,25℃)δ169.2,136.9,136.4,133.7,132.4,125.5,122.3,25.6,20.6.
Preparation of Compounds 4-3: 4-methyl-2-acetamidonitrobenzene (1.5g,5.41mmol) was added to KMnO4(1.11g,7.03mmol) is added into 30mL of aqueous solution, the temperature is raised to 80 ℃ for reaction for about 45min, the mixture is filtered by using kieselguhr while the mixture is hot, washed by ethyl acetate, combined with an ethyl acetate layer, dried without magnesium sulfate and concentrated under reduced pressure to obtain a yellow target product, namely 3-acetamido-4-nitrobenzoic acid, and the yield is 57%.1H NMR(DMSO-d6,400MHz,25℃)δ10.52(s,1H),8.36(d,1H),8.35,8.17(dt,J＝8.5,1.5Hz,2H),7.82(d,J＝8.5Hz,2H),2.10(s,3H)；13C NMR(DMSO-d6,100MHz,25℃)δ168.8,165.3,141.2,135.1,134.3,126.8,126.0,124.6,23.7.
Preparation of Compounds 4-4: see compound 1-1 procedure, white solid, yield about 35%.
Synthesis of Compound 4-5, 5mg of Compound 4-4 was mixed with 1.58mg of 10Adding 0.3mL of absolute ethyl alcohol into 0.3mL of THF from% Pd/C, degassing and flushing with nitrogen for protection, then inserting a hydrogen balloon, vigorously stirring at 40 ℃ for 3-4 h, detecting whether the reaction is complete by using a dot plate, filtering 10% Pd/C after the reaction is complete, performing reduced pressure spin-drying, and stirring the product with silica gel (chloroform: methanol is 20: 1 in volume ratio) to obtain a light yellow target product with the yield of about 92%.1H NMR(DMSO-d6,400MHz,25℃)δ12.22(br s,2H),10.62(s,1H),8.51(d,J＝2.1Hz,1H),8.33(dd,J＝8.5,2.1Hz,1H),7.91(d,J＝8.6Hz,1H),6.35(s,2H),2.65(s,3H),2.13(s,3H)；13C NMR(DMSO-d6,100MHz,25℃)δ204.4,168.9,162.8,161.8,155.8,141.2,136.0,134.8,126.7,108.8,100.8,33.0,23.7.
In vitro cell inhibition assay
The above compounds were formulated at 10mM initial concentration and 25uM final concentration for single concentration prescreening.
Cells and viruses
Cell: MDCK cell virus: A/California/7/2009(H1N1) pdm09-like viruses, abbreviated as H1N 1; anhui strain H5N1 modified strain of avian influenza, abbreviated as H5N 1; A/Hong Kong/4801/2014(H3N2) -like virus, abbreviated as H3N 2; B/Brisbane/60/2008-like virus BV, referred to as BV for short; B/Phuket/3073/2013-like virus BY, abbreviated BV. The source of the involved virus strains is provided by the national flu center.
Reagent
Cell culture fluid (100 mL): fetal bovine serum (FBS,10 mL); glutamine (2 mL); double antibody (1 mL); NaHCO 23(3mL)；DMOM/F12(84mL)；
Virus culture (100 mL): Tosyl-L-phenylallyl-chloromethane (TPCK,2 mL); bovine serum albumin (BSA,1 mL); glutamine (2 mL); double antibody (1 mL); sodium bicarbonate (NaHCO)3,2 mL); DMOM/F12(92mL) medium;
dimethyl sulfoxide (DMSO) and tetramethyl azone (MTT).
Experimental methods
Sample preparation: dissolving DMSO, adding appropriate amount of virus culture solution or cell culture solution, and diluting, wherein the final content of DMSO is controlled below one thousandth.
MDCK cytotoxicity test (MTT): MDCK cells in 96-well culture plate single-layer culture at 37 deg.C and 5% CO2After 24 hours of incubation, the cells were observed for morphology, the supernatant was aspirated off and the different samples prepared above were added individually, 6 wells for each sample. At 37 ℃ with 5% CO2The incubator was incubated for 24 hours, and the cell morphology was observed. Adding 10. mu.L of MTT per well at 37 ℃ and 5% CO2And culturing in an incubator for 1-4 hours. Absorbing waste liquid, adding DMSO (dimethylsulfoxide) in a volume of 100 mu L per hole, detecting by an enzyme-linked immunosorbent assay (ELISA), and calculating half-cell toxicity TC caused by the drug50。
Influenza virus inhibition experiments: MDCK cells are cultured in 96-well culture plates in a monolayer way at 37 ℃ and 5% CO2Culturing for 24 hr, removing supernatant, washing cells with diluent, adding 100 μ L of washing solution into each well, removing washing solution, adding 50 μ L of 15TCI virus solution, 37 deg.C, and 5% CO2Adsorbing for 2 hours, absorbing the virus, adding liquid medicines with different concentrations, and repeating the holes with 4 concentrations. At 37 ℃ with 5% CO2After 72 hours of incubation, CPE (lesions) was observed and 50. mu.L of chicken blood (containing only blood cells) per well was added. And (3) setting a cell control group, a virus control group, a positive control group and an experimental sample group, observing CPE (CPE), inhibiting lesion by more than 50%, and calculating half effective inhibition concentration of IC50 and a therapeutic index TI value.
Experiment on chick embryo
Adding medicinal liquid with different concentrations into 15TCID50The virus solution is composed into a 100 mu L reaction system, and the reaction system is 5 percent CO at 37 DEG C2The cells were cultured for 2 hours. Culturing one week old chick embryo in a constant temperature incubator at 38 deg.C for 2 hr, taking out, placing each chick embryo with upward gas chamber, marking, sterilizing with iodine tincture, perforating, adding co-cultured medicine and virus solution into chick embryo with concentration of 4 chick embryos per 100 μ L by use of 1mL syringe. Immediately sealing the small hole (preventing infection) with liquid paraffin, placing in a constant-temperature incubator at 38 ℃ for culturing for 72 hours, taking out, knocking open the air chamber, observing CPE (pathological change), sucking 50 mu L of supernatant out of each hole, adding 50 mu L of chicken blood containing blood cells into a round-bottom 96-hole plate (special plate for observing CPE (pathological change)) to observe the blood cell sedimentation condition, inhibiting the pathological change by more than 50%, and calculating IC50Half effective inhibitory concentration, therapeutic index TI value and half inhibitory rate IC50The calculation method is as follows: will notThe same concentration gradient was converted to LOG base LOG LOG10, and each + was expressed as percent inhibition, with 100% inhibition for all 4 wells and 25% inhibition for each + well, and the values were used to calculate IC50。
Table 1 shows the solubility of the compounds and the primary screening test for the cell inhibition of the H3N2 influenza virus strain at a final concentration of 25. mu.M, and Table 2 shows the cell inhibition IC of the compounds against the H1N1, H5N1, BY and BV strains50As a result of the experiment, it was found that Compound 1-1 was resistant to the virus strain H1N1 (IC)50＝0.2μM)，H5N1(IC50＝10.53μM)，BV(IC50＝1.9μM)，BY(IC505.6 μ M) exhibited good inhibitory effect, which was best compared to the inhibitory activity of H1N1, at 200 nM. The inhibitory activities of the compounds 3-5-7 to H1N1 and H5N1 are better to be 64.4nM and 31nM respectively, the inhibitory activity to BY is worse to be 7.4 mu M, no obvious inhibitory activity to BV virus strain is found, and the compounds can be obtained to have stronger inhibitory activity to A-type influenza. Compounds 3-5-10 all exhibited good inhibitory activity at several tens of nM levels against the strain studied, 32.0nM, 7.8nM, 64.4nM and 47.9nM, respectively. The two positive drugs are rimantadine and duffy respectively, the rimantadine has no obvious inhibition effect on B type influenza virus, the BV virus has no activity basically at the level of 107 mu M, the inhibition level of single digit appears on H1N1 and H5N1 of A type influenza, the inhibition effect on the duffy of the positive drugs is all at the level of several nM to dozens of nM, and the inhibition effect on the cells of BY anti-influenza virus is 216.0nM which is slightly weaker. It is known that compound 1-1 is a broad-spectrum anti-influenza compound, and compound 3-5-10 is a compound having the best inhibitory effect on influenza a, and has better inhibitory activity than amantadine.
TABLE 1 Compound lytic Properties and Primary screening experiment for cellular inhibition of the H3N2 influenza Virus strain at a final concentration of 25. mu.M
Figure GDA0002828834210000201
Figure GDA0002828834210000211
Cell inhibition IC of the Compounds of Table 2 against H1N1, H5N1, BY and BV strains50Experiment of
Figure GDA0002828834210000212
Note: in tables 1 and 2, positive references amantadine abbreviation (AMA), tamiflu abbreviation (OSV).
The invention is based on 3 sprout compounds of cell inhibition experiments, and finds that the compound in the formula I has better anti-H3N 2 activity than the compound in the formula III, and basically shows one more inhibitory activity, wherein the compound 1-1,1-2 shows 4+ at 25 mu M final concentration, while the compound in the formula II shows 3+, which indicates that the skeleton activity of the compound in the formula I is stronger than that of the skeleton activity of the compound in the formula II, the activity of the obtained ethanone is larger than that of carboxyl protected by methyl, both are electron-withdrawing groups, and the steric hindrance possibly depending on the ethanone is smaller, so that the activity of the compound in the formula I is larger than that of the compound in the formula II on the whole. The activity of the formula I is mainly determined by the activity of para-amino, and one more hydrogen bond donor hydroxyl (1-3) or hydrophobic group (1-2) is not obviously improved, so that the activity result is basically maintained. Compared with the compounds 1-4, the compound has one more acetamido electron withdrawing group at the ortho position, and the activity is not improved, although the structural modification is similar to the acetamido group on the structure of a positive drug (tamiflu, zanamivir) reported previously, the possible reason for the activity not being improved is that two benzene rings increase steric hindrance.
From the synthetic angle of the compounds, the compound 1-1 has higher yield than other compounds of the formula I, and is a good seedling-end compound. In view of the results of the cellular activities of the compounds of formula I and II, the compounds of formula I were selected as the subject, wherein compound 1-1 was produced in higher yields than the same type of compound.
The compound of the formula III is subjected to amide condensation through 5 steps of reaction to obtain 12 compounds, an in vitro influenza cell inhibition primary screening experiment shows that the compounds 3-5-7 have 3+ inhibition activity, the compounds are obtained by performing amide condensation on thiazole and 2,4, 6-trihydroxyacetophenone with amino, the thiazole compound (disclosed in CN 108774193A) also shows good in vitro cell inhibition activity on inhibiting influenza viruses, and the combination of two molecular fragments with anti-influenza viruses shows good inhibition activity is reasonable.
The compound 3-5-10 has an inhibition activity of 4+, the structure is that rimantadine and trihydroxyacetophenone with amino form oxime, rimantadine is a commonly used medicine for inhibiting an influenza virus M2 ion channel, the treatment effect of the inhibition medicine is greatly reduced by mutation of amino acid S31N on the M2 ion channel in recent years, and the occurrence of drug-resistant strains also accounts for about 70-80% of the proportion of virus strains, so that the development of a new amantadine analogue for resisting novel influenza is urgent, the active site of the trihydroxyacetophenone is mainly neuraminidase combined with the M2 ion channel to inhibit rimantadine, the structural modification can be a miao-head molecule with a double-target-point inhibition effect, and the cell inhibition experiment of the molecule presents a good preliminary screening result.
The foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be construed as the protection scope of the present invention.

Claims (10)

1. A phenol AB ring structure compound having a structure represented by the following formula:
Figure FDA0002828834200000011
2. the method for preparing a phenol AB ring structure compound according to claim 1, wherein when said phenol AB ring structure compound has a structure represented by formula I and R is11-1,1-2 or 1-3, comprising the steps of:
carrying out condensation reaction on 2,4, 6-trihydroxyacetophenone and a compound 1 to obtain a compound R with a structure shown in formula I1Is a 1-1,1-2 or 1-3 phenol AB ring structure compound, wherein the compound 1 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid.
3. The production method according to claim 2, wherein the condensation reaction is carried out under conditions of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) and 4-dimethylaminopyridine.
4. The method for preparing a phenol AB ring structure compound according to claim 1, wherein when said phenol AB ring structure compound has a structure represented by formula I and R is11-1,1-2 or 1-3, comprising the steps of:
performing acyl chlorination reaction on the compound 1, and then performing esterification reaction on the compound and 2,4, 6-trihydroxyacetophenone to obtain a compound R with a structure shown in formula I1Is a phenol AB ring structure compound of 1-1,1-2 and 1-3, wherein the compound 1 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid.
5. The method for preparing a phenol AB ring structure compound according to claim 1, wherein when said phenol AB ring structure compound has a structure represented by formula I and R is11-4, comprising the following steps:
performing acetylation, methyl oxidation, phenolic hydroxyl esterification and nitro reduction on the compound 4-1 in sequence to obtain the compound R with the structure shown in the formula I1A phenol AB ring structure compound of 1-4, wherein the structural formula of the compound 4-1 is as follows:
Figure FDA0002828834200000021
6. the method for producing a phenol type AB ring structure compound according to claim 1, which comprises the following steps when the phenol type AB ring structure compound has a structure represented by the formula II:
carrying out condensation reaction on 2, 4-dihydroxybenzoic acid and a compound 2 to obtain a phenol AB ring structure compound with a structure shown in a formula II, wherein the compound 2 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid, 3-methyl-4-aminobenzoic acid and 3, 4-diaminobenzoic acid.
7. The method for producing a phenol type AB ring structure compound according to claim 1, which comprises the following steps when the phenol type AB ring structure compound has a structure represented by the formula II:
and (2) performing acyl chlorination reaction on the compound 2, and then performing esterification reaction on the compound and 2, 4-dihydroxybenzoic acid to obtain a phenol AB ring structure compound with a structure shown in a formula II, wherein the compound 2 is p-aminobenzoic acid, 2-hydroxy-4-aminobenzoic acid or 3-methyl-4-aminobenzoic acid.
8. The method for producing a phenol type AB ring structure compound according to claim 1, which comprises the following steps when the phenol type AB ring structure compound has a structure represented by the formula III:
carrying out an ethyl ketone group introduction reaction on phloroglucinol to obtain a compound 3-1;
performing aldehyde group introduction reaction on the compound 3-1 to obtain a compound 3-2;
carrying out a hydroxylamination reaction on the compound 3-2 to obtain a compound 3-3;
carrying out amino introduction reaction on the compound 3-3 to obtain a compound 3-4;
carrying out esterification and amidation reactions on the compound 3-4 and different substrates to obtain a phenol AB ring structure compound with a structure shown in a formula III, wherein the structures of the compound 3-1, the compound 3-2, the compound 3-3, the compound 3-4 and the different substrates are shown as follows:
Figure FDA0002828834200000031
9. the production method according to claim 8, wherein the aldehyde group-introducing reaction is carried out under phosphorus oxychloride conditions.
10. Use of the phenol AB ring structure compound as defined in claim 1 or the phenol AB ring structure compound prepared by the preparation method as defined in any one of claims 2 to 9 in the preparation of anti-influenza virus drugs.
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