5-methyl chromone derivative and synthetic method and application thereof
阅读说明：本技术 一种5-甲基色酮衍生物及其合成方法和应用 (5-methyl chromone derivative and synthetic method and application thereof ) 是由 王雪松 李友宾 曾婷婷 徐俊裕 王燕 谭银丰 于 2021-06-28 设计创作，主要内容包括：本发明提供一种5-甲基色酮衍生物及其合成方法和应用,所述其结构式如下所示：其中R-(1)为本发明以3,5-二羟基甲苯作为原料,通过一系列化学反应合成了化合物1-7和1-8,该化合物对PTIO自由基的清除活性较高,IC-(50)在11.97～13.50mM范围内,说明该化合物在制备PTIO清除剂等相关领域中具有良好的应用前景。(The invention provides a 5-methyl chromone derivative, a synthesis method and an application thereof, wherein the structural formula is as follows: wherein R is 1 Is composed of The invention takes 3, 5-dihydroxytoluene as raw material, compounds 1-7 and 1-8 are synthesized through a series of chemical reactions, the compound has higher scavenging activity to PTIO free radical, and IC 50 Within the range of 11.97-13.50 mM, the compound has good application prospect in the relevant fields of PTIO scavenger preparation and the like.)
1. A5-methyl chromone derivative is characterized in that the structural formula is shown as a formula (A):
wherein R is1Is composed of
2. The method of synthesizing 5-methylchromone derivatives of claim 1, comprising the steps of:
(1): taking compound 1-e-7 or compound 1-e-8, and reacting with itCompound 1-c is dissolved in dichloromethane, DMAP is added and EDC is added at 0 DEG C.Heating HCl to room temperature, and stirring for reaction; after the reaction is finished, extracting the reaction solution by using dichloromethane, taking an organic phase, drying, concentrating under reduced pressure, and separating and purifying a concentrate by using a silica gel column chromatography to obtain a compound 1-f-7 or a compound 1-f-8;
wherein, the compound 1-c is
The compound 1-e-7 is
The compound 1-e-8 is
The compound 1-f-7 is
The compound 1-f-8 is
(2): taking the compound 1-f-7 or the compound 1-f-8, dissolving the compound and sodium hydroxide in DMSO, and stirring for reaction; after the reaction is finished, extracting the reaction liquid by using ethyl acetate, collecting an organic phase, drying, concentrating under reduced pressure, and separating and purifying a concentrate by using a silica gel column chromatography to obtain a compound 1-g-7 or a compound 1-g-8;
wherein the compounds 1-g-7 are
Compounds 1-g-8 are
(3): dissolving 1-g-7 or 1-g-8 of the compound in 1, 4-dioxane, dropwise adding concentrated hydrochloric acid, heating to 45 ℃, and stirring for reaction; after the reaction is finished, carrying out reduced pressure concentration and washing to obtain a compound 1-7 or a compound 1-8;
wherein the compounds 1 to 7 areCompounds 1 to 8 are
3. The method of claim 2, wherein in step (1), the molar ratio of compound 1-c, compound 1-e-7 or compound 1-e-8, DMAP, EDC.HCl is 20:24:20: 40.
4. The method of claim 2, wherein in step (2), the compound 1-f-7 or the compound 1-f-8 is present in a molar ratio of 20: 48.
5. the synthesis method of claim 2, wherein in the step (1), the eluent for column chromatography is petroleum ether with a volume ratio of 6: 1: and (3) ethyl acetate.
6. The synthesis method of claim 2, wherein in the step (2), the eluent for column chromatography is petroleum ether with a volume ratio of 5: 1: and (3) ethyl acetate.
7. The method according to claim 2, wherein in step (3), the compound 1-g-7 or the compound 1-g-8 is in a molar ratio of concentrated hydrochloric acid of 20: 80.
8. The synthesis method according to claim 2, wherein the stirring reaction time in step (1) and step (2) is 6 h.
9. The synthesis method according to claim 2, wherein in the step (3), the stirring reaction time is 3 h.
10. Use of a 5-methylchromone derivative according to claim 1 for the preparation of PTIO radical scavengers.
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a 5-methyl chromone derivative, and a synthesis method and application thereof.
Background
Chromones are oxygen-containing heterocyclic compounds with a benzo gamma-pyran ring, which are part of a family of flavonoids and widely exist in the plant world. Chromone and the structure of the derivatives thereof are indispensable structural characteristics of various natural products and medicines. The heterocyclic compounds show various pharmacological effects, and the structural change provides diversity, so that the heterocyclic compounds can be used for searching new therapeutic drugs.
The researches suggest that the aloe chromone substances are natural substances with development potential, and the biological activity of the aloe chromone substances mainly has the aspects of tyrosinase inhibition, antioxidation, anti-inflammation, antibiosis and the like. At present, the research on aloe chromone is less, and the reports on 5-methyl chromone compounds are less, but the activities of resisting oxidation and inhibiting tyrosinase are not negligible. The applicant discloses 5-methyl chromone and a preparation method and application thereof (application number 2020111667917) in early research, and synthesizes an aloe chromone compound which has good inhibitory activity on tyrosinase. But its scavenging ability for DPPH radicals is weak. In addition, the applicant has synthesized a series of 5-methyl chromone derivatives, and found that the scavenging activity of most compounds on PTIO free radicals is not high generally.
Disclosure of Invention
In view of the shortcomings of the prior art, the present invention aims to solve the above problems and provide a 5-methyl chromone derivative, a synthesis method and applications thereof.
The scheme of the invention comprises the following contents:
a5-methyl chromone derivative has a structural formula shown in formula (A):
wherein R is1Is composed of
The invention also provides a synthesis method of the 5-methyl chromone derivative, which comprises the following steps:
(1) dissolving compound 1-e-7 or compound 1-e-8 and compound 1-c in dichloromethaneDMAP (4-dimethylaminopyridine) was added and EDC was added at 0 deg.C.HCl (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride), warmed to room temperature and stirred for reaction; after the reaction is finished, extracting the reaction solution by using dichloromethane, taking an organic phase, drying, concentrating under reduced pressure, and separating and purifying a concentrate by using a silica gel column chromatography to obtain a compound 1-f-7 or a compound 1-f-8;
wherein, the compound 1-c is
The compound 1-e-7 is
The compound 1-e-8 is
The compound 1-f-7 is
The compound 1-f-8 is
(2) Taking the compound 1-f-7 or the compound 1-f-8, dissolving the compound and sodium hydroxide in DMSO (dimethyl sulfoxide), and stirring for reaction; after the reaction is finished, extracting the reaction liquid by using ethyl acetate, collecting an organic phase, drying, concentrating under reduced pressure, and separating and purifying a concentrate by using a silica gel column chromatography to obtain a compound 1-g-7 or a compound 1-g-8;
wherein the compounds 1-g-7 are
Compounds 1-g-8 are
(3) Dissolving 1-g-7 or 1-g-8 of the compound in 1, 4-dioxane, dropwise adding concentrated hydrochloric acid, heating to 45 ℃, and stirring for reaction; after the reaction is finished, carrying out reduced pressure concentration and washing to obtain a compound 1-7 or a compound 1-8;
wherein the compounds 1 to 7 areCompounds 1 to 8 are
Preferably, in step (1), the compound 1-c, the compound 1-e-7 or the compound 1-e-8, DMAP and EDC.HCl are in a molar ratio of 20:24:20: 40.
Preferably, in the step (2), the compound 1-f-7 or the compound 1-f-8 has a molar ratio of sodium hydroxide of 20: 48.
preferably, in the step (1), the eluent for column chromatography is petroleum ether with a volume ratio of 6: 1: and (3) ethyl acetate.
Preferably, in the step (2), the eluent for column chromatography is petroleum ether with a volume ratio of 5: 1: and (3) ethyl acetate.
Preferably, in step (3), compound 1-g-7 or compound 1-g-8, the molar ratio of concentrated hydrochloric acid is 20: 80.
Preferably, in the step (1) and the step (2), the stirring reaction time is 6 h.
Preferably, in step (3), the reaction time is 3 h.
On the other hand, the invention also provides application of the 5-methyl chromone derivative in preparing PTIO free radical scavengers.
The invention has the following beneficial effects:
the invention takes 3, 5-dihydroxytoluene as raw material, compounds 1-7 and 1-8 are synthesized through a series of chemical reactions, the compound has higher scavenging activity to PTIO free radical, and IC50Within the range of 11.94-13.50 mM, the compound has a good application prospect in the related fields of PTIO scavenger preparation and the like.
The invention also discloses a synthesis method of the compounds 1-7 and 1-8, which has the advantages of high yield (more than 90%), relatively simple synthesis line, easy operation and higher safety.
Drawings
FIG. 1: of compounds 1 to 71H-NMR chart;
FIG. 2: of compounds 1 to 713C-NMR chart;
FIG. 3: of Compounds 1 to 81H-NMR chart;
FIG. 4: of compounds 1 to 713C-NMR chart;
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
Example 1: synthesis of Compounds 1-7
Synthesis path:
compound 1-c (20mmol,5.080g) and compound 1-e-7(24mmol,3.024g) were dissolved in 70mL of dichloromethane, DMAP (20mmol,2.440g) was added, EDC.HCl (40mmol,7.640g) was added at 0 deg.C, allowed to warm to room temperature naturally, and the reaction was stirred magnetically for 6 h. After the reaction is finished, dichloromethane is used for extracting the reaction liquid for 3 times, an organic phase is taken, dried by anhydrous sodium sulfate, decompressed and concentrated, and a concentrated substance is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: 6:1, v/v) to obtain a colorless oily liquid product 1-f-7.
Compound 1-f-7(20mmol,7.240g) and sodium hydroxide (48mmol,1.920g) were dissolved in 40mL of DMSO and reacted for 6h with magnetic stirring at room temperature. After the reaction is finished, the reaction liquid is extracted by water and ethyl acetate for 3 times, an organic phase is collected, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by a silica gel column chromatography (petroleum ether: ethyl acetate is 5:1, v/v) to obtain a colorless oily liquid product 1-g-7.
The compound 1-g-7(20mmol,7.240g) is dissolved in 40mL of 1, 4-dioxane, then the catalyst concentrated hydrochloric acid (80mmol,2.920g) is added dropwise, the mixture is heated to 45 ℃ in an oil bath, and the reaction is carried out for 3h by magnetic stirring. After the reaction is finished, the mixture is decompressed and concentrated, and the white solid is washed by dichloromethane to obtain white powder products 1-7.
Compounds 1-7: a white solid powder of a mixture of a white solid,1H NMR(400MHz,D6)δ6.66(s,1H),6.61(s,1H),5.95(s,1H),5.72(s,2H),2.76-2.70(m,1H),2.64(s,3H),2.51-1.95(m,5H),1.69-1.63(m,1H)；13C NMR(100MHz,D6)δ178.51,169.66,161.07,159.20,141.46,126.78,125.27,116.59,114.45,108.51,100.63,37.29,28.35,25.59,24.27,22.45。
EXAMPLE 2 Synthesis of Compounds 1-8
Synthesis path:
compound 1-c (20mmol,5.080g) and compound 1-e-8(24mmol,3.312g) were dissolved in 70mL of dichloromethane, DMAP (20mmol,2.44 g) was added, EDC.HCl (40mmol,7.640g) was added at 0 deg.C, allowed to warm to room temperature naturally, and the reaction was stirred magnetically for 6 h. After the reaction is finished, dichloromethane is used for extracting the reaction liquid for 3 times, an organic phase is taken, dried by anhydrous sodium sulfate, decompressed and concentrated, and the concentrated product is separated and purified by column chromatography (petroleum ether: ethyl acetate: 6:1, v/v) to obtain a colorless oily liquid product 1-f-8.
Compound 1-f-8(20mmol,7.480g) and sodium hydroxide (48mmol,1.920g) were dissolved in 40mL of DMSO and reacted for 6h with magnetic stirring at room temperature. After the reaction is finished, the reaction liquid is extracted by water and ethyl acetate for 3 times, an organic phase is collected, dried by anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by a concentrated column chromatography (petroleum ether: ethyl acetate: 5:1, v/v) to obtain a colorless oily liquid product 1-g-8.
The compound 1-g-8(20mmol,7.240g) is dissolved in 40mL of 1, 4-dioxane, then the catalyst concentrated hydrochloric acid (80mmol,2.920g) is added dropwise, the mixture is heated to 45 ℃ in an oil bath, and the reaction is carried out for 3h by magnetic stirring. After the reaction is finished, the mixture is decompressed and concentrated, and the white solid is washed by dichloromethane to obtain white powder products 1-8.
Compounds 1-8: a white solid powder of a mixture of a white solid,1H NMR(400MHz,D6)δ6.65(s,1H),6.60(s,1H),6.23(s,1H),5.86(s,1H),5.75(s,2H),3.29-3.23(m,2H),2.92(s,1H),2.61(s,3H),2.05-2.01(m,1H),1.40(s,2H),1.20-1.16(m,1H)；13C NMR(100MHz,D6)δ178.26,168.96,161.09,159.09,141.38,137.74,132.20,116.56,114.34,109.39,100.61,49.35,46.10,42.30,41.48,29.68,22.44。
example 3PTIO free radical scavenging experiment
3.1 Experimental materials and instruments
PTIO, Tokyo chemical industry Co., Ltd;
absolute ethanol, west longa science ltd;
fluorescent microplate readers, Molecular Devices;
microplate constant temperature incubator, wuxinwxin instruments ltd;
96-well plates, Costar;
pipette, Thermo;
microplate incubator, Wuxi Wagner instruments Co., Ltd.
3.2 Experimental methods
(1) Preparation of PTIO test liquid
Dissolving PTIO solid 10mg in 20mL of absolute ethanol to make the concentration of the PTIO solid 0.5mg/mL, performing ultrasonic treatment for 5min, and sufficiently shaking until the absorbance is between 0.2 and 0.6.
(2) Preparation of sample solution
The sample was dissolved in absolute ethanol at a concentration of 4mg/mL and was diluted in 5 concentrations (4mg/mL, 2mg/mL, 1mg/mL, 0.5mg/mL, 0.25mg/mL) in a gradient.
(3) Method of operation
After adding 100uL of sample and PTIO solution into each well of a 96-well plate and mixing uniformly (repeating for 3 times), reacting for 2h at 37 ℃, and measuring absorbance at 557nm by using an enzyme-linked immunosorbent assay. The clearance was calculated according to the following formula. Drawing a standard curve by taking the concentration of the sample as an abscissa and the clearance rate of free radicals as an ordinate, and then calculating the IC of the standard curve50。
Clearance%1-A2)/A3]*100％
A1Absorbance of sample with PTIO
A2Absorbance of sample with ethanol
A3PTIO and BAbsorbance of alcohol
3.3 results of the experiment
In vitro PTIO free radical scavenging Activity of the Compounds of Table 1
PTIO is a free radical with oxygen atom as the center, and has maximum absorption at 557nm, and the decrease of the absorbance level indicates the increase of the antioxidant activity. PTIO free radical scavenging experiment results show that the 2-C site of the lead compound aloreferring is substituted by cyclic olefin, the activity is obviously increased, and IC50The value is 11.97 to 13.50 mM. It was demonstrated that the difference in the 2-C position groups has a certain influence on the scavenging of PTIO free radicals.
Note: compounds 1 to 16 described in Table 1 are
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
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