Polyhydroxy benzophenone compound and preparation method thereof

Abstract

The invention relates to the field of organic synthesis, in particular to a polyhydroxy benzophenone compound and a preparation method thereof, the structural formula of the polyhydroxy benzophenone compound is shown in the following formula (1): # imgabs0 #, the # imgabs0 # has a diphenyl and polyhydroxy structure similar to a flavonoid compound and resveratrol, can provide reactive hydrogen to inactivate free radicals, and can be used for preparing resveratrol. Compared with the prior art, the compound provided by the invention has the advantages that the compound has good scavenging capacity on. DPPH free radicals at low concentration, is simple in synthesis mode, basically has no cytotoxicity at low concentration, and can provide reference and help for research and development of novel cosmetics and various antioxidants.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, in particular to a polyhydroxybenzophenone compound and a preparation method thereof. Background Art

[0002] Most natural antioxidants are polyphenols, that is, they all have a benzene ring structure with several hydroxyl groups, such as flavonoids, quercetin, resveratrol, rosemary extract, tea polyphenols, etc. Among them, rosemary extract, tea polyphenols, etc. are the best used. The main components of tea polyphenols are epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC) and epicatechin (EC). Since tea polyphenols are rich in phenolic hydroxyl groups, they can provide active hydrogen to inactivate free radicals. The free radicals formed by oxidation have high stability due to the catechol structure. Therefore, tea polyphenols are hydrogen-supplying free radical scavengers.

[0003] Polyhydroxybenzophenone is an important organic intermediate, widely used in plastics, resins, coatings, synthetic rubber, photosensitive materials and cosmetics. Its application areas and scope are also expanding, and the market demand is also increasing rapidly. At present, the research on polyhydroxybenzophenone compounds is mainly focused on ultraviolet absorbers and photoinitiators, while as a pharmaceutical intermediate, there are few reports on the expansion of its structure and other properties. Summary of the invention

[0004] Purpose of the invention: In view of the above technical problems, the present invention provides a polyhydroxybenzophenone compound and a preparation method thereof.

[0005] The technical solutions adopted are as follows:

[0006] A polyhydroxybenzophenone compound, the structural formula of which is shown in the following formula (1):

[0007]

[0008] Wherein, Ar is a structure of formula (2):

[0009]

[0010] R1-R8 are each independently hydrogen, hydroxyl, carboxyl, amino, thiol or C1-C6 alkyl;

[0011] L1 is a single bond, phenylene or biphenylene;

[0012] L2 is a single bond or an ether bond.

[0013] Furthermore, R1-R8 contain at least one hydroxyl group.

[0014] Furthermore, R1-R8 contain at least two hydroxyl groups.

[0015] Furthermore, L1 is p-phenylene.

[0016] Furthermore, the above-mentioned polyhydroxybenzophenone compound is any one of the following compounds:

[0017]

[0018]

[0019] The present invention also provides a method for preparing a polyhydroxybenzophenone compound, which is as follows:

[0020]

[0021] Under a nitrogen atmosphere, RM1, RM2, tri-tert-butylphosphine tetrafluoroborate, sodium tert-butoxide, tri(dibenzylideneacetone)dipalladium and an organic solvent are mixed and stirred under heating to react. After the reaction is completed, the organic solvent is removed by rotary evaporation and purified by column chromatography to obtain the target product TM.

[0022] Furthermore, the molar ratio of RM1 to RM2 is 1:3-3.5.

[0023] Furthermore, the amounts of tri-tert-butylphosphine tetrafluoroborate, sodium tert-butoxide and tris(dibenzylideneacetone)dipalladium used are 0.5-1 times, 5-10 times and 0.01-0.1 times the amount of RM1 substance, respectively.

[0024] Furthermore, the organic solvent is dried toluene or dried xylene.

[0025] Furthermore, the reaction temperature is 100-110° C., and the reaction time is 5-10 h.

[0026] Beneficial effects of the present invention:

[0027] The invention provides a polyhydroxybenzophenone compound, which has a diphenyl and polyhydroxy structure similar to flavonoid compounds and resveratrol, can provide active hydrogen to inactivate free radicals, has good scavenging ability for DPPH free radicals at low concentrations, has a simple synthesis method, is basically non-cytotoxic at low concentrations, and can provide reference and assistance for the research and development of new cosmetics and various antioxidants. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is a comparison chart of the scavenging ability of the polyhydroxybenzophenone compounds prepared in Example 1 of the present invention and 4,4'-dihydroxybenzophenone on DPPH free radicals;

[0029] Figure 2 This is a comparison chart of the scavenging ability of the polyhydroxybenzophenone compounds prepared in Example 2 of the present invention and 4,4'-dihydroxybenzophenone on DPPH free radicals;

[0030] Figure 3 This is a comparison chart of the scavenging ability of the polyhydroxybenzophenone compounds prepared in Example 3 of the present invention and 4,4'-dihydroxybenzophenone on DPPH free radicals;

[0031] Figure 4 This is a comparison chart of the scavenging abilities of the polyhydroxybenzophenone compounds prepared in Example 4 of the present invention and 4,4'-dihydroxybenzophenone on DPPH free radicals. DETAILED DESCRIPTION

[0032] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or the conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially. The techniques not mentioned in the present invention are all referenced to the prior art. Unless otherwise specified, the following examples and comparative examples are parallel experiments, using the same processing steps and parameters.

[0033] Embodiment 1:

[0034] This embodiment provides a polyhydroxybenzophenone compound, the structural formula of which is shown below:

[0035]

[0036] The preparation method of the above-mentioned polyhydroxybenzophenone compounds is as follows:

[0037]

[0038] S1: Add trimesoyl chloride (100 mmol, 26.5 g) into a flask, evacuate the entire system and introduce nitrogen for at least three cycles, add bromobenzene (800 mmol, 125.6 g) into the flask under a nitrogen atmosphere, then place the flask in an ice bath and stir for 15 min, then slowly add aluminum chloride (80 mmol, 10.7 g) into the system in several portions, stir the mixture at room temperature for 12 h, then slowly increase the temperature to 90°C and maintain for 2 h, after cooling to room temperature, pour the reaction solution into deionized water and wash it with deionized water for 3 times, add silica gel into the organic phase and mix the sample, separate and purify by column chromatography to obtain RM1, the eluent is 1:1 petroleum ether: dichloromethane, the yield is 88.3%;

[0039] S2: In a nitrogen atmosphere, RM1 (5 mmol, 3.14 g), RM2 3,7-dihydroxyphenoxazine (16.5 mmol, 3.55 g), tri-tert-butylphosphine tetrafluoroborate (2.5 mmol, 725.3 mg), sodium tert-butoxide (25 mmol, 2.4 g), tri(dibenzylideneacetone)dipalladium (0.5 mmol, 457.9 mg) and 100 ml of dry toluene solvent were added to a 250 ml round-bottom flask in sequence. The whole system was heated to 100 °C and stirred for 8 h under a nitrogen atmosphere. After the reaction was completed, the solvent was removed by rotary evaporation. The product TM was separated and purified by column chromatography. The eluent was petroleum ether: dichloromethane = 1:3. The yield was 59.4%. ESI-MS (m / z) (M + ): Theoretical value 1030.01, measured value 1030.25, elemental analysis results (molecular C 63 H 39 O 12 N3): Theoretical value C, 73.46; N, 4.08; O, 18.64; H, 3.82; Measured value C, 73.52; N, 4.77; O, 18.05; H, 3.46.

[0040] Embodiment 2:

[0041] This embodiment provides a polyhydroxybenzophenone compound, the structural formula of which is shown below:

[0042]

[0043] The preparation method of the above-mentioned polyhydroxybenzophenone compounds is as follows:

[0044] S1 is the same as in Example 1, and S2 is as follows:

[0045]

[0046] S2: In a nitrogen atmosphere, RM1 (5 mmol, 3.14 g), RM2 3-hydroxyphenoxazine (16.5 mmol, 3.28 g), tri-tert-butylphosphine tetrafluoroborate (2.5 mmol, 725.3 mg), sodium tert-butoxide (25 mmol, 2.4 g), tri(dibenzylideneacetone)dipalladium (0.5 mmol, 457.9 mg) and 100 ml of dry toluene solvent were added to a 250 ml round-bottom flask in sequence. The whole system was heated to 100 °C and stirred for 8 h under a nitrogen atmosphere. After the reaction was completed, the solvent was removed by rotary evaporation. The product TM was separated and purified by column chromatography. The eluent was petroleum ether: dichloromethane = 1:3. The yield was 58.2%. ESI-MS (m / z) (M + ): Theoretical value 982.02, measured value 982.15, elemental analysis results (molecular C 63 H39 O9N3): Theoretical value C, 77.05; N, 4.28; O, 14.66; H, 4.00; Measured value C, 77.21; N, 4.30; O, 14.58; H, 4.12.

[0047] Embodiment 3:

[0048] This embodiment provides a polyhydroxybenzophenone compound, the structural formula of which is shown below:

[0049]

[0050] The preparation method of the above-mentioned polyhydroxybenzophenone compounds is as follows:

[0051] S1 is the same as in Example 1, and S2 is as follows:

[0052]

[0053] S2: In a nitrogen atmosphere, RM1 (5 mmol, 3.14 g), RM2 3,6-dihydroxycarbazole (16.5 mmol, 3.28 g), tri-tert-butylphosphine tetrafluoroborate (2.5 mmol, 725.3 mg), sodium tert-butoxide (25 mmol, 2.4 g), tri(dibenzylideneacetone)dipalladium (0.5 mmol, 457.9 mg) and 100 ml of dry toluene solvent were added to a 250 ml round-bottom flask in sequence. The whole system was heated to 100 °C and stirred for 8 h under a nitrogen atmosphere. After the reaction was completed, the solvent was removed by rotary evaporation. The product TM was separated and purified by column chromatography. The eluent was petroleum ether: dichloromethane = 1:3. The yield was 52.7%. ESI-MS (m / z) (M + ): Theoretical value 982.02, measured value 982.34, elemental analysis results (molecular C 63 H 39 O9N3): Theoretical value C, 77.05; N, 4.28; O, 14.66; H, 4.00; Measured value C, 77.14; N, 4.25; O, 14.80; H, 4.05.

[0054] Embodiment 4:

[0055] This embodiment provides a polyhydroxybenzophenone compound, the structural formula of which is shown below:

[0056]

[0057] The preparation method of the above-mentioned polyhydroxybenzophenone compounds is as follows:

[0058] S1 is the same as in Example 1, and S2 is as follows:

[0059]

[0060] S2: In a nitrogen atmosphere, RM1 (5 mmol, 3.14 g), RM2 3-hydroxycarbazole (16.5 mmol, 3.02 g), tri-tert-butylphosphine tetrafluoroborate (2.5 mmol, 725.3 mg), sodium tert-butoxide (25 mmol, 2.4 g), tri(dibenzylideneacetone)dipalladium (0.5 mmol, 457.9 mg) and 100 ml of dry toluene solvent were added to a 250 ml round-bottom flask in sequence. The whole system was heated to 100 °C and stirred for 8 h under a nitrogen atmosphere. After the reaction was completed, the solvent was removed by rotary evaporation. The product TM was separated and purified by column chromatography. The eluent was petroleum ether: dichloromethane = 1:3. The yield was 53.9%. ESI-MS (m / z) (M + ): Theoretical value 934.02, measured value 934.10, elemental analysis results (molecular C 63 H 39 O6N3): Theoretical value C, 81.01; N, 4.50; O, 10.28; H, 4.21; Measured value C, 81.05; N, 4.44; O, 10.53; H, 4.19.

[0061] Performance Testing:

[0062] ① Accurately weigh 19.72 mg · DPPH powder (M = 394.32 g / mol), dissolve it in anhydrous ethanol and make up to volume in a 250 ml brown volumetric flask to obtain a 0.2 mmol / L · DPPH ethanol solution (prepared before use, stored in the dark), take the polyhydroxybenzophenone compounds and 4,4'-dihydroxybenzophenone prepared in Example 1-4 as samples and dissolve them in DMSO, take 3 ml of each sample solution and · DPPH ethanol solution of different concentrations and add them to the same stoppered test tube, shake well, place it in a dark place at room temperature for 30 minutes, and measure the absorbance at 517 nm with a spectrophotometer, which is recorded as A i , take 3 ml of each sample solution and anhydrous ethanol of different concentrations and add them to the same stoppered test tube, shake well, place in the dark at room temperature for 30 minutes, and measure the absorbance at 517 nm with a spectrophotometer and record it as A j , take 3 ml of DMSO and ·DPPH ethanol solution respectively and add them to the same stoppered test tube, shake well, place in the dark at room temperature for 30 minutes, measure the absorbance at 517 nm with a spectrophotometer, record it as A0, calculate the scavenging rate of the sample for ·DPPH free radicals according to the following formula, and draw a curve of sample solution concentration versus ·DPPH scavenging rate.

[0063]

[0064] Where: Y (%) - DPPH free radical scavenging ability; A i -Absorbance value of the solution with added sample;

[0065] A j - the absorbance value of blank reagent; A0- the absorbance value of solution without adding sample.

[0066] Test results see Figure 1-4 ,Depend on Figure 1-4 It can be seen that the polyhydroxybenzophenone compounds prepared in the present invention have a strong effect of scavenging DPPH free radicals and are better than 4,4'-dihydroxybenzophenone.

[0067] ② HepG2 liver cancer cells were cultured in DMEM medium containing 10% inactivated newborn calf serum, 100U / ml penicillin, 100mg / ml streptomycin, 1% non-essential amino acids and 2mmol / ml glutamate in a carbon dioxide incubator at 5% CO2, 37°C and 95% humidity. When the cultured cells adhered to the wall and the fusion reached 90%, the cultured cells were digested with 0.25% trypsin to prepare a single cell suspension, which was diluted with DMEM medium containing 10% newborn calf serum to adjust the cell density to 1×10 4 / ml, 200 μl per well was inoculated into a 96-well culture plate, and cultured in a 5% carbon dioxide incubator at 37°C for 24 h. After adding the polyhydroxybenzophenone compounds prepared in Examples 1-4 according to Table 1 below to each well and culturing for 24 h, 20 μl of 5 mg / mL MTT was added to each well of each group, and the culture was continued in a carbon dioxide incubator for 2 h. The culture plate was taken out, 150 μl of DMSO was added to each well, and after sufficient oscillation and mixing, the absorbance at 570 nm was measured using an automatic microplate reader. A control group (without the addition of polyhydroxybenzophenone compounds) was also set up.

[0068]

[0069] Where: G (%)-cell destruction rate;

[0070] B i -The absorbance value of the solution in the experimental group with added samples;

[0071] B0-absorbance value of the control solution without sample.

[0072] Table 1:

[0073]

[0074]

[0075] It can be seen from Table 1 above that the polyhydroxybenzophenone compounds of the present invention have low cytotoxicity and are substantially non-cytotoxic at low concentrations.

[0076] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A polyhydroxybenzophenone compound, characterized in that: Its structural formula is shown in the following formula (1): Wherein, Ar is a structure of formula (2): R1-R8 are each independently hydrogen, hydroxyl, carboxyl, amino, thiol or C1-C6 alkyl; L1 is a single bond, phenylene or biphenylene; L2 is a single bond or an ether bond.

2. The polyhydroxybenzophenone compound according to claim 1, characterized in that: R1-R8 contain at least one hydroxyl group.

3. The polyhydroxybenzophenone compound according to claim 1, characterized in that: R1-R8 contain at least two hydroxyl groups.

4. The polyhydroxybenzophenone compound according to claim 1, characterized in that: L1 is p-phenylene.

5. The polyhydroxybenzophenone compound according to claim 1, characterized in that: Any one of the following compounds:

6. A method for preparing a polyhydroxybenzophenone compound as claimed in claim 1, characterized in that: The details are as follows: Under a nitrogen atmosphere, RM1, RM2, tri-tert-butylphosphine tetrafluoroborate, sodium tert-butoxide, tri(dibenzylideneacetone)dipalladium and an organic solvent are mixed and stirred under heating to react. After the reaction is completed, the organic solvent is removed by rotary evaporation and purified by column chromatography to obtain the target product TM.

7. The method for preparing a polyhydroxybenzophenone compound according to claim 6, characterized in that: The molar ratio of RM1 to RM2 is 1:3-3.

5.

8. The method for preparing a polyhydroxybenzophenone compound according to claim 6, characterized in that: The amounts of tri-tert-butylphosphine tetrafluoroborate, sodium tert-butoxide and tris(dibenzylideneacetone)dipalladium used are 0.5-1 times, 5-10 times and 0.01-0.1 times the amount of RM1 substance, respectively.

9. The method for preparing a polyhydroxybenzophenone compound according to claim 6, characterized in that: The organic solvent is dried toluene or dried xylene.

10. The method for preparing a polyhydroxybenzophenone compound according to claim 6, characterized in that: The reaction temperature is 100-110°C and the reaction time is 5-10h.

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