Polyhydroxy benzophenone derivative and preparation method thereof

Abstract

The invention relates to the field of organic synthesis, in particular to a polyhydroxy benzophenone derivative and a preparation method thereof, the structural formula of the polyhydroxy benzophenone derivative is as shown in the following formula (1): # imgabs0 #, the # imgabs0 # has a diphenyl and polyhydroxy structure similar to flavonoid compounds and resveratrol, can provide reactive hydrogen to inactivate free radicals, has better scavenging capacity on. DPPH free radicals at low concentration, and can be used for preparing a novel compound. The structure of the hydroxyquinoline plays a positive role in improving the antioxidant activity, the synthesis mode is simple, no cytotoxicity exists basically at low concentration, and reference and help can be provided 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 derivative 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 derivative and a preparation method thereof.

[0005] The technical solutions adopted are as follows:

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

[0007]

[0008] wherein Ar1 and Ar2 are independently hydrogen, hydroxyl, carboxyl, amino, thiol, C1-C6 alkyl or any one of the structures of formula (2);

[0009]

[0010] R1-R4 are each independently hydrogen or hydroxy.

[0011] Furthermore, at least one of Ar1 and Ar2 is of the structure of formula (2).

[0012] Furthermore, one of Ar1 and Ar2 is a structure of formula (2), and the other is hydrogen.

[0013] Furthermore, at least two of R1-R4 are hydroxyl groups.

[0014] Furthermore, formula (1) is specifically as follows:

[0015]

[0016] Furthermore, the structure of formula (2) is as follows:

[0017]

[0018] Furthermore, the polyhydroxybenzophenone derivative is any one of the following compounds:

[0019]

[0020]

[0021] The present invention also provides a method for preparing a polyhydroxybenzophenone derivative, which is as follows:

[0022]

[0023] S1: Add phosphorus oxychloride dropwise into DMF under nitrogen protection at 0-5°C with stirring, return to room temperature after the addition, add RM1, heat for reaction and then cool to room temperature, pour the reaction solution into ice water, extract the organic phase with dichloromethane, concentrate under reduced pressure, and purify by column chromatography to obtain RM2;

[0024] S2: Under the protection of nitrogen, RM2, RM3 and acetic anhydride were mixed and heated to reflux for reaction. After the reaction was completed, the mixture was cooled to room temperature and poured into ice water. The organic phase was extracted with dichloromethane, concentrated under reduced pressure and purified by column chromatography to obtain TM.

[0025] Furthermore, the temperature of the heating reaction in S1 is 70-90° C., and the time of the heating reaction is 15-30 hours.

[0026] Furthermore, the reflux reaction time in S2 is 24-72h.

[0027] Beneficial effects of the invention: The invention provides a polyhydroxybenzophenone derivative, which has a diphenyl and polyhydroxy structure similar to flavonoids and resveratrol, can provide active hydrogen to inactivate free radicals, has a good scavenging ability for DPPH free radicals at low concentrations, and the structure of hydroxyquinoline plays a positive role in improving the antioxidant activity. Moreover, the synthesis method is simple, and it is basically non-cytotoxic at low concentrations, which can provide reference and help 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 derivative 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 derivatives 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 derivatives 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 derivatives 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 derivative, the structural formula of which is as follows:

[0035]

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

[0037]

[0038] S1: Under nitrogen protection, 0-5°C, and stirring, 10 ml of phosphorus oxychloride was added dropwise to 100 ml of DMF. After the addition was completed, the room temperature was restored. RM1 (4.56 g, 17.6 mmol) was dissolved in 40 ml of 1,2-dichloroethane and then added dropwise. After the addition was completed, the heating was turned on to raise the temperature of the reaction solution to 80°C. After the reaction was kept warm for 25 hours, it was naturally cooled to room temperature. The reaction solution was poured into 1000 g of ice water, and the organic phase was extracted with 1000 ml of dichloromethane. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. RM2 was purified by column chromatography. The eluent was petroleum ether: dichloromethane = 5:1. The yield was 56.3%. ESI-MS (m / z) (M + ): Theoretical value 375.43, measured value 375.88;

[0039] S2: Under the protection of nitrogen, RM2 (1.01 g, 3.5 mmol), RM3 (0.73 g, 3.5 mmol) and 20 ml of acetic anhydride were mixed and heated to reflux for 48 h. After the reaction was completed, the mixture was cooled to room temperature and poured into 100 g of ice water. The organic phase was extracted with 100 ml of dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. TM was purified by column chromatography with dichloromethane:methanol = 1:1 as the eluent. The yield was 44.1%. ESI-MS (m / z) (M + ): Theoretical value 564.60, measured value 564.17, elemental analysis results (molecular C 36 H 24 O5N2): Theoretical value C, 76.58; N, 4.96; O, 14.17; H, 4.28; Measured value C, 76.50; N, 4.86; O, 14.22; H, 4.35.

[0040] Embodiment 2:

[0041] This embodiment provides a polyhydroxybenzophenone derivative, the structural formula of which is as follows:

[0042]

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

[0044]

[0045] S1: Same as Example 1;

[0046] S2: Under the protection of nitrogen, RM2 (1.01 g, 3.5 mmol), RM3 (0.67 g, 3.5 mmol) and 20 ml of acetic anhydride were mixed and heated to reflux for 48 h. After the reaction was completed, the mixture was cooled to room temperature and poured into 100 g of ice water. The organic phase was extracted with 100 ml of dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. TM was purified by column chromatography with dichloromethane:methanol = 1:1 as the eluent. The yield was 46.7%. ESI-MS (m / z) (M + ): Theoretical value 548.60, measured value 548.09, elemental analysis results (molecular C 36 H 24 O4N2): Theoretical value C, 78.82; N, 5.11; O, 11.67; H, 4.41; Measured value C, 78.93; N, 5.20; O, 11.54; H, 4.39.

[0047] Embodiment 3:

[0048] This embodiment provides a polyhydroxybenzophenone derivative, the structural formula of which is as follows:

[0049]

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

[0051]

[0052] S1: Same as Example 1;

[0053] S2: Under the protection of nitrogen, RM2 (1.01 g, 3.5 mmol), RM3 (0.61 g, 3.5 mmol) and 20 ml of acetic anhydride were mixed and heated to reflux for 48 h. After the reaction was completed, the mixture was cooled to room temperature and poured into 100 g of ice water. The organic phase was extracted with 100 ml of dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. TM was purified by column chromatography with the eluent being dichloromethane:methanol=1:1. The yield was 47.5%. ESI-MS (m / z) (M + ): Theoretical value 532.60, measured value 532.51, elemental analysis results (molecular C 36 H 24 O3N2): Theoretical value C, 81.19; N, 5.26; O, 9.01; H, 4.54; Measured value C, 81.22; N, 5.40; O, 9.05; H, 4.49.

[0054] Embodiment 4:

[0055] This embodiment provides a polyhydroxybenzophenone derivative, the structural formula of which is as follows:

[0056]

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

[0058]

[0059] S1: Same as Example 1;

[0060] S2: Under the protection of nitrogen, RM2 (1.01 g, 3.5 mmol), RM3 (0.61 g, 3.5 mmol) and 20 ml of acetic anhydride were mixed and heated to reflux for 48 h. After the reaction was completed, the mixture was cooled to room temperature and poured into 100 g of ice water. The organic phase was extracted with 100 ml of dichloromethane, dried over anhydrous sodium sulfate and concentrated under reduced pressure. TM was purified by column chromatography with the eluent being dichloromethane:methanol=1:1. The yield was 48.8%. ESI-MS (m / z) (M +): Theoretical value 532.60, measured value 532.46, elemental analysis results (molecular C 63 H 39 O 12 N3): Theoretical value C, 81.19; N, 5.26; O, 9.01; H, 4.54; Measured value C, 81.25; N, 5.28; O, 9.03; H, 4.50.

[0061] Performance Test:

[0062] ① Accurately weigh 19.72 mg · 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 before use and store it in the dark); use the polyhydroxybenzophenone derivatives 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, 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, place in the dark at room temperature for 30 minutes, and measure the absorbance at 517 nm using a spectrophotometer, recorded 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 (%) - scavenging ability of DPPH free radical;

[0065] A i -Absorbance value of the solution with added sample;

[0066] A j -Absorbance value of blank reagent;

[0067] A0-absorbance value of solution without sample added.

[0068] Test results see Figure 1-4 ,Depend on Figure 1-4 It can be seen that the polyhydroxybenzophenone derivatives prepared in the present invention have a strong effect of scavenging DPPH free radicals and are better than 4,4'-dihydroxybenzophenone.

[0069] ② HepG2 cells were cultured in DMEM medium containing 10% inactivated 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 cells adhered to the wall and the fusion reached 90%, the cells were digested with 0.25% trypsin to prepare a single cell suspension, which was diluted with DMEM medium containing 10% 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. Then, the polyhydroxybenzophenone derivatives prepared in Examples 1-4 were added to each well according to Table 1 and cultured 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 derivatives) was set up.

[0070]

[0071] Where: G (%)-cell destruction rate;

[0072] B i -The absorbance value of the solution in the experimental group with added samples;

[0073] B0-absorbance value of the control solution without sample.

[0074] Table 1:

[0075]

[0076] It can be seen from Table 1 above that the polyhydroxybenzophenone derivatives of the present invention have low cytotoxicity and are substantially non-cytotoxic at low concentrations.

[0077] 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 derivative, characterized in that: Its structural formula is shown in the following formula (1): wherein Ar1 and Ar2 are independently hydrogen, hydroxyl, carboxyl, amino, thiol, C1-C6 alkyl or any one of the structures of formula (2); R1-R4 are each independently hydrogen or hydroxy.

2. The polyhydroxybenzophenone derivative according to claim 1, characterized in that At least one of Ar1 and Ar2 has the structure of formula (2).

3. The polyhydroxybenzophenone derivative according to claim 2, characterized in that One of Ar1 and Ar2 is a structure of formula (2), and the other is hydrogen.

4. The polyhydroxybenzophenone derivative according to claim 3, characterized in that At least two of R1 to R4 are hydroxyl groups.

5. The polyhydroxybenzophenone derivative according to claim 4, characterized in that Formula (1) is as follows:

6. The polyhydroxybenzophenone derivative according to claim 5, characterized in that The structure of formula (2) is as follows:

7. The polyhydroxybenzophenone derivative according to claim 6, characterized in that Any one of the following compounds:

8. A method for preparing a polyhydroxybenzophenone derivative as claimed in claim 6 or 7, characterized in that: The details are as follows: S1: Add phosphorus oxychloride dropwise into DMF under nitrogen protection at 0-5°C with stirring, return to room temperature after the addition, add RM1, heat for reaction and then cool to room temperature, pour the reaction solution into ice water, extract the organic phase with dichloromethane, concentrate under reduced pressure, and purify by column chromatography to obtain RM2; S2: Under the protection of nitrogen, RM2, RM3 and acetic anhydride were mixed and heated to reflux for reaction. After the reaction was completed, the mixture was cooled to room temperature and poured into ice water. The organic phase was extracted with dichloromethane, concentrated under reduced pressure and purified by column chromatography to obtain TM.

9. The method for preparing a polyhydroxybenzophenone derivative according to claim 8, characterized in that: The temperature of the heating reaction in S1 is 70-90°C, and the heating reaction time is 15-30h.

10. The method for preparing a polyhydroxybenzophenone derivative according to claim 8, characterized in that: The reflux reaction time in S2 is 24-72h.

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