Azelaic acid-pterostilbene ester and application thereof

Abstract

Disclosed are an azelaic acid-pterostilbene ester and an application thereof, belonging to the technical field of compound synthesis. Pterostilbene is reacted with azelaic acid to obtain a new compound. The prepared azelaic acid-pterostilbene ester not only helps overcome limitations of azelaic acid such as poor permeability and high irritation, but can also improve the overall efficacy thereof by means of a synergistic effect, thereby providing a better solution for skin care and treatment.

Description

Azelaic acid-pterostilbene ester and its application Technical Field

[0001] This invention relates to an azelaic acid-pterostilbene ester and its applications, belonging to the field of compound synthesis technology. Background Technology

[0002] Azelaic acid is a naturally occurring saturated dicarboxylic acid widely used in cosmetics, pharmaceuticals, and industry. Its importance in dermatology is particularly prominent due to its antibacterial, anti-inflammatory, and keratinization-inhibiting properties, making it widely used to treat skin conditions such as acne, rosacea, and pigmentation. Azelaic acid can inhibit the growth of microorganisms such as Propionibacterium acnes and Staphylococcus aureus, while also reducing melanin production by intervening in tyrosinase activity, thus exerting a whitening and spot-fading effect. Azelaic acid can also regulate sebum secretion and improve abnormal follicular keratinization, making it a gentle yet highly effective skincare ingredient, especially suitable for people with sensitive skin.

[0003] Despite its broad pharmacological activity and clinical applications, azelaic acid still faces certain limitations and drawbacks in practical use. Firstly, its poor lipid solubility results in low skin penetration, affecting bioavailability. For topical applications, enhancing transdermal absorption often requires the use of penetration enhancers or specialized formulation technologies such as microemulsions and nanocarriers. However, these methods may increase formulation complexity and potentially lead to skin irritation or other safety issues. Secondly, azelaic acid is relatively irritating; some users may experience dry skin, mild stinging, or erythema initially, limiting its application at high concentrations. Regarding efficacy, while azelaic acid effectively inhibits inflammation and melanin deposition, its effects are relatively mild, and significant results may take a considerable amount of time to materialize when used alone. Therefore, it is typically used in combination with other drugs or active ingredients to enhance its therapeutic effects.

[0004] Pterostilbene is a natural polyphenolic compound derived from plants of the genus Pterostilbene. While structurally similar to resveratrol, it exhibits superior bioavailability and stability due to the presence of two methoxy groups in its molecular structure. Pterostilbene possesses multiple beneficial effects, including antioxidant, anti-inflammatory, antibacterial, and skin-whitening properties, demonstrating broad application potential in skin care and drug development. Studies have shown that pterostilbene can alleviate skin damage by inhibiting oxidative stress and the release of inflammatory factors. It also possesses certain tyrosinase inhibitory activity, making it suitable for fading pigmentation and improving uneven skin tone. Its strong hydrophobicity allows it to easily penetrate the skin barrier, enhancing its permeability and bioavailability in topical applications.

[0005] Therefore, the preparation of a new compound based on pterostilbene and azelaic acid to overcome the existing defects of azelaic acid and further enhance its efficacy is expected to expand the application scope of azelaic acid and bring new breakthroughs to the fields of cosmetics and drug development. Summary of the Invention

[0006] To address the aforementioned issues, this invention combines pterostilbene with azelaic acid to form a novel compound. The azelaic acid compound prepared by this invention not only helps overcome the limitations of azelaic acid, such as poor permeability and high irritation, but may also enhance its overall efficacy through synergistic effects, providing a superior solution for skin care and treatment.

[0007] The first objective of this invention is to provide an azelaic acid-pterostilbene ester, with the structural formula shown in Formula I or Formula II:

[0008] Among them, the compound shown in Formula I is mono-pterostilbene azelaate; the compound shown in Formula II is di-pterostilbene azelaate;

[0009] The compound shown in Formula I is systematically named 9-({4-[(1E)-2-(3,5-dimethoxyphenyl)vinyl]phenyl}oxy)-9-oxononanoic acid; 9-({4-[(1E)-2-(3,5-dimethoxyphenyl)vinyl]phenyl}oxy)-9-oxononanoic acid;

[0010] The compound shown in Formula II is systematically named 9-({4-[(1E)-2-(3,5-dimethoxyphenyl)vinyl]phenyl}oxy)-9-oxononanoate-4-[(1E)-2-(3,5-dimethoxyphenyl)vinyl]phenyl; 4-[(1E)-2-(3,5-dimethoxyphenyl)vinyl]phenyl9-({4-[(1E)-2-(3,5-dimethoxyphenyl)vinyl]phenyl}oxy)-9-oxononanoate.

[0011] A second objective of this invention is to provide a method for preparing the above-mentioned azelaic acid-pterostilbene ester, characterized in that the preparation of monopterostilbene ester includes the following steps:

[0012] (1) Mix pterostilbene, azelaic anhydride and DMAP in a molar ratio of 1:0.1 to 10:0.01 to 2, dissolve in THF, heat and reflux; cool down, remove solvent and dry, reconstitute with EA, wash and dry to obtain solids;

[0013] (2) Dissolve the solids in methanol, filter and concentrate; redissolve in EA, add PE to pulp, filter and dry to obtain pterostilbene azelaate;

[0014] The preparation of bis-pterostilbene azelaate includes the following steps:

[0015] (1) Pterostilbene, DCM and DMAP are mixed, and TEA is slowly added to obtain mixture 1; azelaic chloride and DCM are mixed to obtain mixture 2, and mixture 2 is slowly added to mixture 1 to react; wherein, the molar ratio of pterostilbene, azelaic chloride, TEA and DMAP is 1:0.1~5:0.2~10:0.01~3;

[0016] (2) After the reaction is complete, water is added to quench the liquid, and after stirring, methanol is added for extraction and separation. The lower liquid is added to quench the liquid, and after stirring, methanol is added for extraction and separation. The lower liquid is dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a concentrate. The concentrate is added to methanol and stirred until a solid precipitates. After filtration and drying, bis-pterostilbene azelaic acid ester is obtained.

[0017] In one embodiment, pterostilbene, azelaic anhydride, and DMAP are mixed and dissolved in THF (the ratio of pterostilbene to THF is 1g:14mL).

[0018] In one embodiment, in step (1) of preparing pterostilbene azelaic acid ester, the heating and reflux are performed at 50–95°C for 1–8 hours.

[0019] In one embodiment, in step (2) of preparing pterostilbene azelaic acid ester, the washing is performed by washing 2 to 10 times with dilute acid water.

[0020] In one embodiment, in step (1) of preparing bis-pterostilbene azelaate, the reaction is carried out at 5-80°C for 1-12 hours.

[0021] In one embodiment, in step (1) of preparing pterostilbene azelaate, the TEA is added at a rate of 1 to 30 L / h; the mixture 2 is added at a rate of 2 to 50 L / h.

[0022] In one embodiment, in step (1) of preparing pterostilbene azelaate, the TEA is added at a rate of 1-3 L / h; the mixture 2 is added at a rate of 2-5 L / h.

[0023] A third objective of this invention is to provide the application of azelaic acid-pterostilbene ester in the preparation of cosmetics.

[0024] In one embodiment, the cosmetic includes, but is not limited to, serums, essences, sprays, skin foams, lotions, and shampoos.

[0025] A fourth object of the present invention is to provide a cosmetic product, characterized in that the cosmetic product contains the azelaic acid-pterostilbene esterified product as described in claim 1.

[0026] In one embodiment, the aforementioned cosmetics include, but are not limited to, serums, essences, sprays, skin foams, lotions, and shampoos.

[0027] The fifth objective of this invention is to provide a method for improving the properties of azelaic acid, characterized in that azelaic acid and pterostilbene are used to prepare an azelaic acid-pterostilbene ester.

[0028] The structural formula of the azelaic acid-pterostilbene ester is shown in Formula I or Formula II:

[0029] Among them, the compound shown in Formula I is mono-pterostilbene azelaate; the compound shown in Formula II is di-pterostilbene azelaate.

[0030] Beneficial effects of the present invention

[0031] This invention combines pterostilbene with azelaic acid to form a novel compound. The azelaic acid compound prepared by this invention not only helps overcome the limitations of azelaic acid, such as poor permeability and high irritation, but may also enhance its overall efficacy through synergistic effects, providing a better solution for skin care and treatment. Specifically,

[0032] (1) The purity of the mono-pterostilbene azelaate prepared in this application reaches 96.91% or higher, and can reach up to 97.84%; the purity of the di-pterostilbene azelaate reaches 97.96% or higher, and can reach up to 99.01%.

[0033] (2) The mono- and di-pterostilbene azelaate prepared in this application have lower cell irritation and no cytotoxicity when the concentration reaches 250 μg / mL, which is significantly better than azelaic acid (when the concentration reaches 130 μg / mL, the cell activity is only 67.71%).

[0034] (3) When the concentration of the mono- and di-pterostilbene esters prepared in this application is 30 μg / mL, the lipid droplet inhibition rates are 33.5% and 37.5%, respectively; when the concentration is 60 μg / mL, the lipid droplet inhibition rates are 53.25% and 58.5%, respectively, which are significantly better than those of azelaic acid and isotretinoin.

[0035] (4) The mono- and di-pterostilbene esters prepared in this application exhibit excellent antioxidant properties against DPPH free radicals, IC50, and 2,5-dimethylphenol esters. 50 The concentrations were 14 μg / mL and 9.4 μg / mL, respectively.

[0036] (5) The mono-pterostilbene azelaate prepared in this application has a solubility (w / w) of 5% in dibutyl adipate; the di-pterostilbene azelaate has a solubility of 10% in dibutyl adipate, both of which are significantly better than azelaic acid. Attached Figure Description

[0037] Figure 1 shows the 1H NMR spectrum of pterostilbene ester;

[0038] Figure 2 shows the carbon spectrum of pterostilbene ester;

[0039] Figure 3 shows the 1H NMR spectrum of azelaic acid-santalinic acid monoester;

[0040] Figure 4 shows the carbon spectrum of azelaic acid-santalinic acid monoester. Detailed Implementation

[0041] The preferred embodiments of the present invention are described below. It should be understood that the embodiments are for better explanation of the present invention and are not intended to limit the present invention.

[0042] Raw materials used in the examples:

[0043] Azelaic acid was purchased from Shandong Aigelin Pharmaceutical Co., Ltd.

[0044] Acetic anhydride was purchased from Shanghai Chutai Chemical Technology Co., Ltd.

[0045] Astragalus membranaceus was purchased from Hangzhou Yihe Biomedical Technology Co., Ltd.

[0046] Thionyl chloride was purchased from Shanghai Baishun Biotechnology Co., Ltd.

[0047] DMF (N,N-dimethylformamide) was purchased from Shanghai Chutai Chemical Technology Co., Ltd.

[0048] DCM (dichloromethane) was purchased from Shanghai Chutai Chemical Technology Co., Ltd.

[0049] DMAP (4-dimethylaminopyridine) was purchased from Jiangsu Haosheng Chemical Co., Ltd.

[0050] TEA (triethylamine) was purchased from Shanghai Chutai Chemical Technology Co., Ltd.

[0051] Test method:

[0052] High performance liquid chromatography, hydrogen nuclear magnetic resonance (HMR) spectroscopy, and carbon nuclear magnetic resonance (CMR) spectroscopy.

[0053] Example 1: Preparation of azelaic acid-pterostilbene ester

[0054] 1. Preparation of azelaic anhydride

[0055] The preparation of azelaic anhydride involves the following steps:

[0056] Azelaic acid (100g) and acetic anhydride (300mL) were added to a three-necked flask and stirred to react. The temperature was slowly raised to 150℃ and refluxed for 3 hours.

[0057] After the reaction was complete, the mixture was cooled and transferred to a single-necked flask. It was concentrated under reduced pressure in an 80°C water bath until it reached a viscous state. Toluene was added in three portions (150 mL × 3), and the water was removed by vacuum distillation. 50 mL of toluene was added to dissolve the product, and it was stirred with 150 mL of n-hexane for 1–3 hours. The mixture was then filtered and dried under vacuum to obtain 100 g of solid product. 100 g of solid product was dissolved in 100 mL of toluene and stirred with 400 mL of methyl tert-butyl ether for 1–3 hours. The mixture was then filtered and dried under vacuum to obtain 90 g of pure azelaic anhydride.

[0058] 2. Preparation of pterostilbene azelaic acid ester

[0059] Pterostilbene, azelaic anhydride, DMAP, and THF (tetrahydrofuran) were added sequentially to a three-necked flask according to the proportions in Table 1. The mixture was heated to 85°C and refluxed for 1–2 hours. After the reaction was complete, the solvent was evaporated by cooling. The mixture was dissolved in 20 mL of EA (ethyl acetate), washed five times with dilute hydrochloric acid water (pH 3.5), and the organic phase was dried and concentrated to obtain a solid.

[0060] The solid was dissolved in 75 mL of anhydrous methanol, the precipitated solid impurities were filtered off, the mixture was adsorbed by activated carbon and then filtered again, and concentrated. EA was added and completely dissolved, the mixture was pulped with PE (petroleum ether), filtered and dried, and the process was repeated twice to obtain pterostilbene azelaic acid ester (m / z 427.38), with a yield of 3.71 g and a purity of 97.84% as determined by liquid chromatography.

[0061] Table 1 Raw material addition amount

[0062] Example 2: Preparation of azelaic acid-pterostilbene ester

[0063] Based on Example 1, step 2 is modified as follows:

[0064] Pterostilbene, azelaic acid, DMAP, and THF were added sequentially to a three-necked flask according to the proportions in Table 1. The mixture was heated to 90°C and refluxed for 3–4 hours. After the reaction was complete, the solvent was evaporated by cooling. 20 mL of EA was added to dissolve the solvent. The mixture was washed three times with dilute hydrochloric acid water (pH 3.5). The organic phase was dried and concentrated.

[0065] Dissolve in 80 mL of anhydrous methanol, filter out the precipitated solid impurities, adsorb using activated carbon and then filter again, concentrate; add EA to dissolve completely, slurry using PE, filter and dry, repeat twice to obtain the product, yield 3.2 g, purity 97.73%.

[0066] Example 3: Preparation of azelaic acid-pterostilbene ester

[0067] Based on Example 1, step 2 is modified as follows:

[0068] Pterostilbene, azelaic acid, DMAP, and THF were added sequentially to a three-necked flask according to the proportions in Table 1. The mixture was heated to 80°C and refluxed for 5 hours. After the reaction was complete, the solvent was evaporated by cooling. 15 mL of EA was added to dissolve the solvent. The mixture was washed three times with dilute hydrochloric acid water (pH 3.5). The organic phase was dried and concentrated.

[0069] Dissolve in 75 mL of anhydrous methanol, filter out the precipitated solid impurities, adsorb using activated carbon and then filter again, concentrate; add EA to dissolve completely, slurry using PE, filter and dry, repeat twice to obtain the product, yield 3.9 g, purity 97.04%.

[0070] Example 4: Preparation of azelaic acid-pterostilbene ester

[0071] Based on Example 1, step 2 is modified as follows:

[0072] Pterostilbene, azelaic acid, DMAP, and THF were added sequentially to a three-necked flask according to the proportions in Table 1. The mixture was heated to 70°C and refluxed until the reaction was complete. The solvent was then evaporated by rotary evaporation, and 20 mL of EA was added to dissolve the solvent. The mixture was washed three times with dilute hydrochloric acid water (pH 3.5), and the organic phase was dried and concentrated.

[0073] Dissolve in 75 mL of anhydrous methanol, filter out the precipitated solid impurities, adsorb using activated carbon and then filter again, concentrate; add EA to dissolve completely, slurry using PE, filter and dry, repeat twice to obtain the product, yield 2.7 g, purity 96.91%.

[0074] Example 5: Preparation of azelaic acid-pterostilbene ester

[0075] Based on Example 1, step 2 is modified as follows:

[0076] Pterostilbene, azelaic acid, DMAP, and THF were added sequentially to a three-necked flask according to the proportions in Table 1. The mixture was heated to 80°C and refluxed for 3–4 hours. After the reaction was complete, the solvent was evaporated by cooling. 20 mL of EA was added to dissolve the solvent. The mixture was washed three times with dilute hydrochloric acid water (pH 3.5). The organic phase was then dried and concentrated.

[0077] Dissolve in 75 mL of anhydrous ethanol, filter out the precipitated solid impurities, adsorb using activated carbon and then filter again, concentrate; add EA and dissolve completely, pulp using PE, filter and dry, repeat twice to obtain the product, yield 3.6 g, purity 97.80%.

[0078] Example 6: Preparation of azelaic acid-pterostilbene ester

[0079] Based on Example 1, step 2 is modified as follows:

[0080] Pterostilbene, azelaic acid, DMAP, and THF were added sequentially to a three-necked flask according to the proportions in Table 1. The mixture was heated to 80°C and refluxed for 3–4 hours. After the reaction was complete, the solvent was evaporated by cooling. 20 mL of EA was added to dissolve the solvent. The mixture was washed once with dilute hydrochloric acid water (pH 3.5). The organic phase was dried and concentrated.

[0081] Add 80 mL of MeOH to dissolve, filter out the precipitated solid impurities, adsorb using activated carbon and then filter again, concentrate; add EA to dissolve completely, use PE to slurry, filter and dry, repeat twice to obtain the product, the yield is 4.0 g, the purity is 95.66%, and a small amount of impurities are found in TLC.

[0082] Comparative Example 1: Preparation of azelaic acid compound using other substances

[0083] (1) Based on Example 1, phenol was used to replace pterostilbene, and the remaining steps were the same as in Example 1 to prepare azelaic acid-phenol monoester.

[0084] (2) Based on Example 1, p-methoxyphenol was used to replace pterostilbene, and the remaining steps were the same as in Example 1 to prepare azelaic acid-p-methoxyphenol monoester.

[0085] Example 7: Properties of Pterostilbene Azelaic Acid Ester

[0086] The results of testing the mono-pterostilbene esters prepared in Examples 1-6 and the azelaic acid-phenol monoester and azelaic acid-p-methylphenol monoester prepared in Comparative Example 1 are as follows:

[0087] 1. Structural data

[0088] (1) 1H NMR

[0089] The 1H NMR spectrum of pterostilbene ester is shown in Figure 1, as detailed below:

[0090] 1 H NMR (600MHz, DMSO-d6) δ11.99(s,1H),7.66–7.61(m,2H),7.29(d,J=16.4Hz,1H),7.16(d,J=16.4Hz,1H),7.13–7.10(m,2H),6.79(d ,J=2.3Hz,2H),6.43(t,J=2.3Hz,1H),3.78(s,6H),2.57(t,J=7.4Hz,2H),2.24–2.19(m,2H),1.64(m,2H),1.51(m,2H),1.31(m,6H).

[0091] (2) 13C NMR

[0092] The carbon-13 NMR results of pterostilbene ester mono-pterostilbene ester are shown in Figure 2, as detailed below:

[0093] 13 C NMR (101MHz, DMSO-d6) δ175.03,172.32,161.17,150.43,139.50,135.12,129.09,128. 48,127.97,122.61,104.99,100.43,55.71,34.14,33.96,28.91,28.77,24.95,24.80.

[0094] Example 8: Preparation of azelaic acid-pterostilbene ester

[0095] 1. Preparation of azelaic chloride

[0096] Azelaic acid, toluene, and DMF were added to the reaction flask according to the proportions in Table 2, and stirred at room temperature for 30 min. Thionyl chloride was slowly added, and the reaction was carried out at 60℃ for 3 hours. After the reaction was completed, the system was concentrated to dryness as much as possible and packaged to obtain azelaic chloride.

[0097] Table 2 Dosage and Proportioning

[0098] 2. Preparation of bis-Pterostilbene azelaic acid ester

[0099] Add pterostilbene, DCM (6 vol), and DMAP to the reaction flask according to the proportions in Table 3, stir, and add TEA dropwise at a constant rate over 10 minutes at 5°C to obtain mixture 1; prepare a mixture of azeloyl chloride and DCM (2 vol) to obtain mixture 2; add mixture 2 dropwise to mixture 1 at a constant rate over 10 minutes, and after the addition is complete, raise the temperature to 20-25°C and react for 4-5 hours (quench with methanol for TLC; use pure DCM as the developing solvent, and observe the color development of phosphomolybdic acid at the same time);

[0100] After the reaction was completed, 5 w / w (1000 g) of water was added to quench the reaction. After stirring for 30 minutes, 1 w / w (200 g) of methanol was added, and the mixture was extracted and separated. The lower layer was washed a second time with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol. After separation, the lower layer was dried with anhydrous sodium sulfate, filtered, and concentrated. 2 w / w (400 g) of methanol was added to the concentrate, and the mixture was stirred at room temperature (15-25 °C) until a solid precipitated. The solid was filtered and dried to obtain 246 g of the product (i.e., bis-pterostilbene azelaic acid ester, m / z 665.50), with a purity of 99.01%.

[0101] Table 3 Dosage and Proportioning

[0102] Example 9: Preparation of azelaic acid-pterostilbene ester

[0103] Based on Example 8, step 2 is modified as follows:

[0104] Add pterostilbene, DCM (6 vol), and DMAP to the reaction flask according to the proportions in Table 3, stir, and add TEA at a constant rate over 10 minutes at 10°C to obtain mixture 1; prepare a mixture of azeloyl chloride and DCM (2 vol) to obtain mixture 2; add mixture 2 dropwise to mixture 1 at a constant rate over 10 minutes, and after the addition is complete, raise the temperature to 35-40°C and react for 5-6 hours (quench with methanol for TLC; use pure DCM as the developing solvent, and observe the color development of phosphomolybdic acid at the same time);

[0105] After the reaction was completed, 5 w / w (1000 g) of water was added to quench the reaction. After stirring for 15 minutes, 1 w / w (200 g) of methanol was added, and the mixture was extracted and separated. The lower layer was washed a second time with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol. After separation, the lower layer was dried with anhydrous sodium sulfate, filtered, and concentrated. 2 w / w (400 g) of methanol was added to the concentrate, and the mixture was stirred at room temperature (15-25°C) until a solid precipitated. The solid was filtered and dried to obtain 230 g of product with a purity of 98.92%.

[0106] Example 10: Preparation of azelaic acid-pterostilbene ester

[0107] Based on Example 8, step 2 is modified as follows:

[0108] Add pterostilbene, DCM (6 vol), and DMAP to the reaction flask according to the proportions in Table 3, stir, and add TEA at a constant rate over 10 minutes at 10°C to obtain mixture 1; prepare a mixture of azeloyl chloride and DCM (2 vol) to obtain mixture 2; add mixture 2 dropwise to mixture 1 at a constant rate over 10 minutes, and after the addition is complete, raise the temperature to 25-35°C and react for 7 hours (quench with methanol for TLC; use pure DCM as the developing solvent, and observe the color development of phosphomolybdic acid at the same time);

[0109] After the reaction was completed, 5 w / w (1000 g) of water was added to quench the reaction. After stirring for 15 minutes, 1 w / w (200 g) of methanol was added, and the mixture was extracted and separated. The lower layer was washed a second time with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol. After separation, the lower layer was dried with anhydrous sodium sulfate, filtered, and concentrated. 2 w / w (400 g) of methanol was added to the concentrate, and the mixture was stirred at room temperature (15-25°C) until a solid precipitated. The solid was filtered and dried to obtain 248 g of product with a purity of 98.61%.

[0110] Example 11: Preparation of azelaic acid-pterostilbene ester

[0111] Based on Example 8, step 2 is modified as follows:

[0112] Add pterostilbene, DCM (6 vol), and DMAP to the reaction flask according to the proportions in Table 3, stir, and add TEA at a constant rate over 30 seconds at 10℃ to obtain mixture 1; prepare a mixture of azeloyl chloride and DCM (2 vol) to obtain mixture 2; add mixture 2 dropwise to mixture 1 at a constant rate over 10 minutes, and after the addition is complete, raise the temperature to 25-35℃ and react for 5-6 hours (quench with methanol for TLC; use pure DCM as the developing solvent, and observe the color development of phosphomolybdic acid at the same time);

[0113] After the reaction was completed, 5 w / w (1000 g) of water was added to quench the reaction. After stirring for 30 minutes, 1 w / w (200 g) of methanol was added, and the mixture was extracted and separated. The lower layer was washed a second time with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol. After separation, the lower layer was dried with anhydrous sodium sulfate, filtered, and concentrated. 2 w / w (400 g) of methanol was added to the concentrate, and the mixture was stirred at room temperature (15-25°C) until a solid precipitated. The solid was filtered and dried to obtain 233 g of product with a purity of 98.35%.

[0114] Example 12: Preparation of azelaic acid-pterostilbene ester

[0115] Based on Example 8, step 2 is modified as follows:

[0116] Add pterostilbene, DCM (6 vol), and DMAP to the reaction flask according to the proportions in Table 3, stir, and add TEA at a constant rate over 10 minutes at 10°C to obtain mixture 1; prepare a mixture of azeloyl chloride and DCM (2 vol) to obtain mixture 2; add mixture 2 dropwise to mixture 1 at a constant rate over 30 seconds, and after the addition is complete, raise the temperature to 25-35°C and react for 5-6 hours (quench with methanol for TLC; use pure DCM as the developing solvent, and observe the color development of phosphomolybdic acid at the same time);

[0117] After the reaction was completed, 5 w / w (1000 g) of water was added to quench the reaction. After stirring for 30 minutes, 1 w / w (200 g) of methanol was added, and the mixture was extracted and separated. The lower layer was washed a second time with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol. After separation, the lower layer was dried with anhydrous sodium sulfate, filtered, and concentrated. 2 w / w (400 g) of methanol was added to the concentrate, and the mixture was stirred at room temperature (15-25°C) until a solid precipitated. The solid was filtered and dried to obtain 221 g of product with a purity of 97.96%.

[0118] Example 13: Preparation of azelaic acid-pterostilbene ester

[0119] Based on Example 8, step 2 is modified as follows:

[0120] Add pterostilbene, DCM (6 vol), and DMAP to the reaction flask according to the proportions in Table 3, stir, and add TEA dropwise at a constant rate over 10 minutes at 10°C to obtain mixture 1; prepare a mixture of azeloyl chloride and DCM (2 vol) to obtain mixture 2, and add mixture 2 dropwise to mixture 1 at a constant rate over 10 minutes. After the addition is complete, raise the temperature to 25-35°C and react for 5-6 hours (quench with methanol for TLC; use pure DCM as the developing solvent, and observe the color development of phosphomolybdic acid at the same time);

[0121] After the reaction was completed, 5 w / w (1000 g) of water was added to quench the reaction. After stirring for 15 minutes, 1 w / w (200 g) of methanol was added, and the mixture was extracted and separated. The lower layer was washed a second time with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol. After separation, the lower layer was dried with anhydrous sodium sulfate, filtered, and concentrated. 1 w / w (200 g) of methanol was added to the concentrate, and the mixture was stirred at room temperature (15-25°C) until a solid precipitated. The product was filtered and dried to obtain 253 g of product. TLC showed that impurities were present, and the purity was 96.82%.

[0122] Comparative Example 2: Preparation of azelaic acid compounds using other substances

[0123] (1) Based on Example 8, phenol was used to replace pterostilbene, and the remaining steps were the same as in Example 1 to prepare azelaic acid-phenol diester.

[0124] (2) Based on Example 8, p-methoxyphenol was used to replace pterostilbene, and the remaining steps were the same as in Example 1 to prepare azelaic acid-methoxyphenol diester.

[0125] Example 14: Properties of Pterostilbene Azelaic Acid Ester

[0126] The detection results of the mono-pterostilbene azelaate prepared in Examples 1-7, the di-pterostilbene azelaate prepared in Examples 8-13, the azelaic acid-phenol monoester and azelaic acid-p-methoxyphenol monoester prepared in Comparative Example 1, and the azelaic acid-phenol diester and azelaic acid-p-methoxyphenol diester prepared in Comparative Example 2 are as follows:

[0127] 1. Structural data

[0128] (1) 1H NMR

[0129] The 1H NMR spectrum of pterostilbene azelaate is shown in Figure 3, as detailed below:

[0130] 1 H NMR(400MHz,Chloroform-d)δ7.51(d,J=8.5Hz,4H),7.12–6.90(m,8H),6.66(d,J=2.3Hz, 4H), 6.40 (t, J = 2.3Hz, 2H), 3.83 (s, 12H), 2.58 (t, J = 7.5Hz, 4H), 1.79 (m, 4H), 1.46 (m, 6H).

[0131] (2) 13C NMR

[0132] The carbon-13 NMR results of pterostilbene azelate are shown in Figure 4, as detailed below:

[0133] 13 C NMR (101MHz, DMSO-d6) δ175.03,172.32,161.17,150.43,139.50,135.12,129.09,128. 48,127.97,122.61,104.99,100.43,55.71,34.14,33.96,28.91,28.77,24.95,24.80.

[0134] 2. Performance Data

[0135] (1) Irritation to cells

[0136] The steps for detecting the effect of compounds on cell activity include:

[0137] 1) Cell seeding:

[0138] Press 1×10 4 SZ95 cells were seeded into 96-well plates at a seeding density of cells / well and incubated overnight in an incubator (37°C, 5% CO2).

[0139] 2) Experimental Groups:

[0140] The experiment included a blank control group, a positive control group (10% DMSO), and a sample group. In the sample group, each sample was set up with 8 concentration gradients, and 3 replicate wells were set up for each concentration gradient.

[0141] 3) Administration:

[0142] When the cell seeding rate in the 96-well plate reached 40%–60%, the drug was administered. For the control group, 200 μL of culture medium containing 10% PBS was added to each well; for the positive control group, 200 μL of culture medium containing 10% DMSO was added to each well; for the sample group, 200 μL of culture medium containing the concentrations of the samples shown in Table 4 was added to each well; for the zeroing group, no cells were seeded, only 200 μL of cell culture medium was added. After drug administration, the 96-well plate was placed in an incubator for culture.

[0143] 4) Vitality test:

[0144] After 24 hours of cell incubation, the supernatant was discarded, and MTT working solution (0.5 mg / mL) was added. The cells were incubated at 37°C in the dark for 4 hours. After incubation, the supernatant was discarded, and 100 μL LDMSO was added to each well. The OD value was read at 490 nm. Cell viability was calculated as follows:

[0145] The results are shown in Table 4. The results indicate that mono- and di-pterostilbene azelaate have low irritant activity to cells and are significantly better than azelaic acid and other azelaic acid compounds.

[0146] Table 4. Dosage Concentration and Detection Results

[0147] (2) Inhibition of cell adipogenesis

[0148] 1) Cell seeding: at 1×10 5 Cells were seeded at a density of cells / well into 24-well plates and incubated overnight in an incubator (37°C, 5% CO2).

[0149] 2) Solution preparation: Prepare working solutions of different concentrations of the test substance according to the experimental design table shown in Table 5.

[0150] 3) Drug administration: According to Table 5, when the cell deposition rate in the 24-well plate reaches 40% to 60%, the cells are administered to groups, with 3 replicates per group, and the cells are incubated for another 24 hours.

[0151] 4) Staining: Discard the culture medium, rinse the cells with PBS, fix them, add Nile Red for 15 min, rinse and take pictures with a fluorescence microscope.

[0152] 5) Analysis results: The fluorescence intensity was quantitatively analyzed using Image Pro Plus software.

[0153] The results are shown in Table 5. The results indicate that mono- and di-pterostilbene azelaate have excellent lipid droplet inhibition effects, which are significantly better than those of azelaic acid and other azelaic acid compounds.

[0154] Table 5. Compound concentrations and lipid droplet inhibition results

[0155] (3) Antioxidant performance testing

[0156] Preparation of DPPH solution: Weigh 7.9 mg of DPPH using an electronic analytical balance, dissolve it in anhydrous ethanol, and dilute to 200 mL in a volumetric flask to a concentration of 0.1 mmol / L. Shake well, protect from light, and set aside.

[0157] A0 is 3 mL DPPH solution + 3 mL anhydrous ethanol;

[0158] Aj is 3 mL DPPH solution + 3 mL sample solution;

[0159] Ai is 3 mL of sample solution + 3 mL of anhydrous ethanol.

[0160] Shake vigorously to mix well. After standing at 37℃ for 10 minutes, add the sample to a cuvette for absorbance measurement. Measure the absorbance values ​​of Ao, Aj, and Ai, representing the sample. The clearance rate is calculated using the formula: SA(%)=1-(A i -A j ) / A0×100%.

[0161] The results are shown in Table 6. The results indicate that mono- and di-pterostilbene azelaate have excellent antioxidant effects, which are significantly better than those of azelaic acid and other azelaic acid compounds.

[0162] Table 6. Results of Antioxidant Tests

[0163] (4) Solubility test

[0164] The solubility (w / w) of the compounds was tested, and the results showed that azelaic acid was only 0.1% soluble in dibutyl adipate, while mono-pterostilbene azelaate was 5% soluble in dibutyl adipate, and di-pterostilbene azelaate was 10% soluble in dibutyl adipate.

[0165] Example 15: Application of azelaic acid compounds in product preparation

[0166] 1. Using the mono-pterostilbene azelaate prepared in Example 1 and the di-pterostilbene azelaate prepared in Example 8, cosmetics were prepared. The components are shown in Table 7.

[0167] Table 7 Cosmetic Ingredients

[0168] 2. Prepare cosmetics using equal amounts of azelaic acid and pterostilbene.

[0169] Cosmetics were prepared by replacing the mono- and di-pterostilbene azelaate esters in step 1 with azelaic acid and pterostilbene azelaate esters. The stability of the cosmetics was tested (the cosmetics were tested for precipitation and discoloration at 40℃ for 60 days). The results are shown in Table 8.

[0170] Table 8 Stability Testing

[0171] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Anyone skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. An azelaic acid-pterostilbene ester, characterized in that, The structural formula is shown in Formula I or Formula II: Among them, the compound shown in Formula I is mono-pterostilbene azelaate; the compound shown in Formula II is di-pterostilbene azelaate.

2. A method for preparing the azelaic acid-pterostilbene ester of claim 1, characterized in that, The preparation of pterostilbene azelaic acid ester includes the following steps: (1) Mix pterostilbene, azelaic anhydride and DMAP in a molar ratio of 1:0.1-10:0.01-2, dissolve in THF, heat and reflux; cool down, remove solvent and dry, reconstitute with EA, wash and dry to obtain solids; (2) Dissolve the solids in methanol, filter and concentrate; redissolve in EA, add PE to pulp, filter and dry to obtain pterostilbene azelaate; The preparation of bis-pterostilbene azelaate includes the following steps: (1) Pterostilbene, DCM and DMAP are mixed and TEA is slowly added to obtain mixture 1; azelaic chloride and DCM are mixed to obtain mixture 2, and mixture 2 is slowly added to mixture 1 to react; The molar ratio of pterostilbene, azelaic chloride, TEA and DMAP is 1:0.1-5:0.2-10:0.01-3. (2) After the reaction is complete, water is added to quench the liquid, and after stirring, methanol is added for extraction and separation. The lower liquid is added to quench the liquid, and after stirring, methanol is added for extraction and separation. The lower liquid is dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a concentrate. The concentrate is added to methanol and stirred until a solid precipitates. After filtration and drying, bis-pterostilbene azelaic acid ester is obtained.

3. The method according to claim 2, characterized in that, In step (1) of preparing pterostilbene azelaate, the heating and reflux are performed at 50-95°C for 1-8 hours.

4. The method according to claim 2, characterized in that, In step (2) of preparing pterostilbene azelaate, the washing process involves washing with dilute acid water 2 to 10 times.

5. The method according to claim 2, characterized in that, In step (1) of preparing bis-pterostilbene diacetate, the reaction is carried out at 5-80℃ for 1-12 hours.

6. The method according to claim 2, characterized in that, In step (1) of preparing bis-Pterostilbene azelaate, the TEA was added at a rate of 1-30 L / h; the mixture 2 was added at a rate of 2-50 L / h.

7. The use of the azelaic acid-pterostilbene esterified compound according to claim 1 in the preparation of cosmetics.

8. The application according to claim 7, characterized in that, The aforementioned cosmetics include, but are not limited to, serums, essences, sprays, skin foams, lotions, and shampoos.

9. A cosmetic product, characterized in that, The cosmetic contains the azelaic acid-pterostilbene esterified as described in claim 1.

10. A method for improving the properties of azelaic acid, characterized in that, Azelaic acid-pterostil ester was prepared by reacting azelaic acid and pterostilbene. The structural formula of the azelaic acid-pterostilbene ester is shown in Formula I or Formula II: Among them, the compound shown in Formula I is mono-pterostilbene azelaate; the compound shown in Formula II is di-pterostilbene azelaate.

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