A polyhydroxybenzophenone derivative and its preparation method

Abstract

The present invention relates to the field of organic synthesis, and specifically to a polyhydroxybenzophenone derivative and a preparation method thereof. The structural formula of the polyhydroxybenzophenone derivative is shown in the following formula (1): The polyhydroxybenzophenone derivative 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. The hydroxyquinoline structure plays a positive role in improving the antioxidant activity. The polyhydroxybenzophenone derivative is simple to synthesize and has essentially no cytotoxicity at low concentrations. The polyhydroxybenzophenone derivative 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 derivative 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 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 each 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 has a structure of formula (2).

[0012] Furthermore, one of Ar1 and Ar2 has the 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: Phosphorus oxychloride was added dropwise to DMF under nitrogen protection at 0-5°C with stirring. After the addition was completed, the temperature was returned to room temperature. RM1 was added, and the mixture was heated for reaction and then cooled to room temperature. The reaction solution was poured into ice water. The organic phase was extracted with dichloromethane, concentrated under reduced pressure, and purified by column chromatography to obtain RM2.

[0024] S2: Under nitrogen protection, 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 heating reaction time is 15-30 hours.

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

[0027] The beneficial effects of the present invention are as follows: the present invention provides a polyhydroxybenzophenone derivative having a diphenyl and polyhydroxy structure similar to that of flavonoids and resveratrol, which can provide active hydrogen to inactivate free radicals and has a good scavenging ability for DPPH free radicals at low concentrations. The hydroxyquinoline structure plays a positive role in improving the antioxidant activity. Moreover, the present invention has a simple synthesis method and is basically non-cytotoxic at low concentrations. The present invention 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 derivatives prepared in Example 1 of the present invention and 4,4'-dihydroxybenzophenone;

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

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

[0031] Figure 4 This is a comparison chart of the DPPH radical scavenging abilities of the polyhydroxybenzophenone derivatives 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 derivative, the structural formula of which is as follows:

[0035]

[0036] The preparation method of the above-mentioned polyhydroxybenzophenone derivative is 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 added dropwise. After the addition was completed, the reaction solution was heated 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 nitrogen protection, 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 the eluent being dichloromethane:methanol = 1:1. 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 values ​​C, 76.58; N, 4.96; O, 14.17; H, 4.28; Found values ​​C, 76.50; N, 4.86; O, 14.22; H, 4.35.

[0040] Example 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 as follows:

[0044]

[0045] S1: Same as Example 1;

[0046] S2: Under nitrogen protection, 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 the eluent being dichloromethane:methanol = 1:1. 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 values ​​C, 78.82; N, 5.11; O, 11.67; H, 4.41; Found values ​​C, 78.93; N, 5.20; O, 11.54; H, 4.39.

[0047] Example 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 as follows:

[0051]

[0052] S1: Same as Example 1;

[0053] S2: Under nitrogen protection, 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; Found value C, 81.22; N, 5.40; O, 9.05; H, 4.49.

[0054] Example 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 as follows:

[0058]

[0059] S1: Same as Example 1;

[0060] S2: Under nitrogen protection, 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 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 derivatives and 4,4'-dihydroxybenzophenone prepared in Examples 1-4 were dissolved in DMSO, and 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 the dark 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, and place them in the dark at room temperature for 30 minutes. Then use a spectrophotometer to measure the absorbance at 517 nm 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 in the dark at room temperature for 30 minutes. Then use a spectrophotometer to measure the absorbance at 517 nm and record it as A0; 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;

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

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

[0067] A0 - absorbance value of the 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 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 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. 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 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 (without the addition of polyhydroxybenzophenone derivatives) was also set up.

[0070]

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

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

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

[0074] Table 1:

[0075]

[0076] As can be seen from Table 1 above, 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 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 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 hydroxyl; At least one of Ar1 and Ar2 is a structure of formula (2); At least two of R1 to R4 are hydroxyl groups.

2. The polyhydroxybenzophenone derivative according to claim 1, wherein One of Ar1 and Ar2 has the structure of formula (2), and the other is hydrogen.

3. The polyhydroxybenzophenone derivative according to claim 1, wherein Formula (1) is as follows: 。 4. The polyhydroxybenzophenone derivative according to claim 3, wherein The structure of formula (2) is as follows: 。 5. The polyhydroxybenzophenone derivative according to claim 4, wherein Any one of the following compounds: ； 。 6. A method for preparing a polyhydroxybenzophenone derivative according to claim 4 or 5, characterized in that: The details are as follows: ； S1: Phosphorus oxychloride was added dropwise to DMF under nitrogen protection at 0-5°C with stirring. After the addition was completed, the temperature was returned to room temperature. RM1 was added, and the mixture was heated for reaction and then cooled to room temperature. The reaction solution was poured into ice water. The organic phase was extracted with dichloromethane, concentrated under reduced pressure, and purified by column chromatography to obtain RM2. S2: Under nitrogen protection, 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.

7. The method for preparing a polyhydroxybenzophenone derivative according to claim 6, wherein: The temperature of the heating reaction in S1 is 70-90° C., and the heating reaction time is 15-30 h.

8. The method for preparing a polyhydroxybenzophenone derivative according to claim 6, wherein: The reflux reaction time in S2 is 24-72 hours.

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