A polyhydroxybenzophenone compound and preparation method thereof

Abstract

The present invention relates to the field of organic synthesis, and specifically to a polyhydroxybenzophenone compound and a preparation method thereof. The structural formula of the polyhydroxybenzophenone compound is shown in the following formula (1): The polyhydroxybenzophenone compound has a diphenyl and polyhydroxy structure similar to flavonoids and resveratrol, can provide active hydrogen to inactivate free radicals, and has a good scavenging ability for DPPH free radicals at low concentrations. Moreover, the synthesis method is simple and the compound is essentially non-cytotoxic at low concentrations. The compound can provide reference and assistance for the research and development of new cosmetics and various antioxidants.

Description

Technical Field

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

[0002] The vast majority of natural antioxidants are polyphenols, which are benzene ring structures with several hydroxyl groups. Examples include flavonoids, quercetin, resveratrol, rosemary extract, and tea polyphenols. Among these, rosemary extract and tea polyphenols are among the most widely used. The main components of tea polyphenols are epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC), and epicatechin (EC). Tea polyphenols are rich in phenolic hydroxyl groups, which can provide active hydrogen to inactivate free radicals. The free radicals formed by oxidation are highly stable due to their catechol structure, making them hydrogen-donating free radical scavengers.

[0003] Polyhydroxybenzophenones are an important class of organic intermediates, widely used in plastics, resins, coatings, synthetic rubber, photosensitive materials, and cosmetics. Their applications are expanding, and market demand is rapidly increasing. Currently, research on polyhydroxybenzophenone compounds primarily focuses on their use as UV absorbers and photoinitiators. However, as pharmaceutical intermediates, research on their structural expansion and other properties is limited. Summary of the Invention

[0004] Purpose of the invention: In order to solve 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, hydroxy, 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 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, tris(dibenzylideneacetone)dipalladium, and an organic solvent were mixed and stirred under heating. After the reaction, the organic solvent was 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, 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 present invention provides a polyhydroxybenzophenone compound having a diphenyl and polyhydroxy structure similar to that of flavonoids and resveratrol, which can provide active hydrogen to inactivate free radicals and has good scavenging ability for DPPH free radicals at low concentrations. Moreover, the compound has a simple synthesis method and is essentially non-cytotoxic at low concentrations. The compound 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 DPPH free radical scavenging abilities of the polyhydroxybenzophenone compounds and 4,4'-dihydroxybenzophenone prepared in Example 1 of the present invention;

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

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

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

[0032] Unless otherwise specified, the following examples and comparative examples were conducted in parallel, using the same processing steps and parameters.

[0033] Example 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: Trimesoyl chloride (100 mmol, 26.5 g) was added to a flask, the entire system was evacuated to vacuum and nitrogen was introduced for at least three cycles. Under a nitrogen atmosphere, bromobenzene (800 mmol, 125.6 g) was added to the flask, and the flask was then placed in an ice bath and stirred for 15 min. Then, aluminum chloride (80 mmol, 10.7 g) was slowly added to the system in several portions. The mixture was stirred at room temperature for 12 h, and then the temperature was slowly raised to 90°C and maintained for 2 h. After cooling to room temperature, the reaction solution was poured into deionized water and washed with deionized water three times. Silica gel was added to the organic phase and the sample was mixed. RM1 was separated and purified by column chromatography using a 1:1 petroleum ether:dichloromethane eluent, with a yield of 88.3%;

[0039] S2: Under 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), tris(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 under nitrogen atmosphere for 8 h. After the reaction was completed, the solvent was removed by rotary evaporation and 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 (molecule 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] Example 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: Under 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), tris(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 under nitrogen atmosphere for 8 h. 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 (molecule C 63 H39 O9N3): Theoretical values ​​C, 77.05; N, 4.28; O, 14.66; H, 4.00; Found values ​​C, 77.21; N, 4.30; O, 14.58; H, 4.12.

[0047] Example 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: Under 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), tris(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 under nitrogen atmosphere for 8 h. After the reaction was completed, the solvent was removed by rotary evaporation and 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 values ​​C, 77.05; N, 4.28; O, 14.66; H, 4.00; Measured values ​​C, 77.14; N, 4.25; O, 14.80; H, 4.05.

[0054] Example 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: Under 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), tris(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 under nitrogen atmosphere for 8 h. After the reaction was completed, the solvent was removed by rotary evaporation and 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 (molecule C 63 H 39 O6N3): Theoretical values ​​C, 81.01; N, 4.50; O, 10.28; H, 4.21; Found values ​​C, 81.05; N, 4.44; O, 10.53; H, 4.19.

[0061] Performance testing:

[0062] ① Accurately weigh 19.72 mg of DPPH powder (M = 394.32 g / mol), dissolve it in anhydrous ethanol and dilute it to a 250 ml brown volumetric flask to obtain a 0.2 mmol / L DPPH ethanol solution (prepare it immediately before use and store it in the dark). The polyhydroxybenzophenone compounds and 4,4'-dihydroxybenzophenone prepared in Examples 1-4 were dissolved in DMSO. 3 ml of each sample solution and DPPH ethanol solution of different concentrations were added to the same stoppered test tube, shaken, and placed in a dark place at room temperature for 30 minutes. The absorbance was measured at 517 nm using a spectrophotometer and 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 3 ml of ·DPPH ethanol solution respectively and add them to the same stoppered test tube, shake well, and place it in the dark at room temperature for 30 minutes. Then use a spectrophotometer to measure the absorbance at 517 nm, recorded as A0, and calculate the scavenging rate of the sample on ·DPPH free radicals according to the following formula, and draw a curve based on the sample solution concentration and ·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, 100 U / ml penicillin, 100 mg / ml streptomycin, 1% non-essential amino acids, and 2 mmol / ml glutamate in a carbon dioxide incubator at 5% CO2, 37°C, and 95% humidity. When the cultured cells adhered to the wall and reached 90% confluence, they were digested with 0.25% trypsin to prepare a single-cell suspension, which was then 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 the culture was carried out in a 5% carbon dioxide incubator at 37°C for 24 h. After that, the polyhydroxybenzophenone compounds prepared in Examples 1-4 were added to each well according to Table 1 below and cultured for 24 h. Then, 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 removed, 150 μl of DMSO was added to each well, and after thorough shaking and mixing, the absorbance at 570 nm was measured using an automatic microplate reader. A control group (no polyhydroxybenzophenone compound was added) was also set up.

[0068]

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

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

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

[0072] Table 1:

[0073]

[0074]

[0075] As can be seen from Table 1 above, 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 they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. 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 various 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 the structure of formula (2): ; R1-R8 are each independently hydrogen or hydroxyl, and R1-R8 contain at least one hydroxyl group; L1 is a phenylene group; L2 is a single bond or an ether bond.

2. The polyhydroxybenzophenone compound according to claim 1, wherein R1-R8 contain at least two hydroxyl groups.

3. The polyhydroxybenzophenone compound according to claim 1, wherein Any one of the following compounds: 。 4. 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, tris(dibenzylideneacetone)dipalladium, and an organic solvent were mixed and stirred under heating. After the reaction, the organic solvent was removed by rotary evaporation and purified by column chromatography to obtain the target product TM.

5. The method for preparing the polyhydroxybenzophenone compound according to claim 4, wherein: The molar ratio of RM1 to RM2 is 1:3-3.

5.

6. The method for preparing a polyhydroxybenzophenone compound according to claim 4, wherein: 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 respectively.

7. The method for preparing the polyhydroxybenzophenone compound according to claim 4, wherein: The organic solvent is dried toluene or dried xylene.

8. The method for preparing a polyhydroxybenzophenone compound according to claim 4, wherein: The reaction temperature is 100-110°C and the reaction time is 5-10h.

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