Method for preparing bis-tocopherol azelate and application of bis-tocopherol azelate

Abstract

The invention discloses a method for preparing bis-tocopherol azelate and application of the bis-tocopherol azelate, and belongs to the technical field of compound synthesis. The invention provides a method for preparing bis-tocopherol azelate. The yield and purity of the bis-tocopherol azelate are improved. The prepared bis-tocopherol azelate overcomes the limitation that azelaic acid is poor in permeability, high in irritation and the like, the overall effect of the bis-tocopherol azelate can be possibly improved through the synergistic effect, and a better solution is provided for skin care and treatment.

Description

Technical Field

[0001] The present invention relates to a method for preparing ditocopheryl azelate and its application, belonging to the technical field of compound synthesis. Background Art

[0002] Azelaic acid is a naturally occurring dicarboxylic acid and is widely used in skin care, medicine and industrial applications. In the field of dermatology, azelaic acid is used to treat skin problems such as acne, rosacea and hyperpigmentation due to its anti-inflammatory, antibacterial and keratolytic effects. It can inhibit the growth of Propionibacterium acnes and reduce sebum oxidative damage, thereby improving inflammatory skin diseases. In addition, azelaic acid also has a certain whitening effect and can reduce the synthesis of melanin by inhibiting the activity of tyrosinase, so it is used in the treatment of hyperpigmentary skin diseases. In addition to skin care, azelaic acid is also used in the fields of plastics, lubricants and chemical synthesis. As a plasticizer or lubricant for polymer materials, it can improve the flexibility and stability of materials.

[0003] Although azelaic acid has good application value in many fields, it also has certain limitations and problems. First of all, due to its poor water solubility and oil solubility, its application in water-based systems is limited, resulting in greater difficulty in formulation design. In terms of skin application, the permeability of azelaic acid is limited, resulting in low bioavailability, and specific carrier or formulation technologies are required to improve its transdermal absorption efficiency. In addition, azelaic acid may cause skin irritation at high concentrations, especially for people with sensitive skin, which may cause adverse reactions such as redness and stinging. Therefore, its use concentration and compatibility method need to be controlled during formulation development. In industrial applications, the production cost of azelaic acid is relatively high, and the synthesis steps of some of its derivatives are relatively complex, which limits its further promotion and application.

[0004] In view of the limitations of azelaic acid, researchers have developed a variety of derivatives to improve its functional characteristics and application adaptability. Tocopherol, namely vitamin E, is a strong antioxidant that can neutralize free radicals and reduce oxidative stress damage. In the fields of cosmetics and pharmaceuticals, tocopherol is widely used in anti-aging and skin barrier repair.

[0005] Therefore, it has extremely high practical value and economic value to prepare azelaic acid compounds based on azelaic acid and tocopherol, further optimize its preparation process, improve production efficiency, and expand its application in the medical and industrial fields to better exert its comprehensive advantages. Summary of the Invention

[0006] To solve the above problems, the present invention provides a method for preparing ditocopheryl azelate, which improves the yield and purity of ditocopheryl azelate. The ditocopheryl azelate prepared by the present invention overcomes the limitations of poor permeability and high irritation of azelaic acid, and may also enhance its overall efficacy through synergistic effects, providing a better solution for skin care and treatment.

[0007] The first object of the present invention is to provide a method for synthesizing ditocopheryl azelate, comprising the steps of:

[0008] (1) Mix tocopherol, DCM and DMAP, and slowly add TEA to obtain mixture 1; mix sebacoyl chloride and DCM to obtain mixture 2, and slowly add mixture 2 to mixture 1 for reaction;

[0009] Among them, the molar ratio of tocopherol, sebacoyl chloride, TEA and DMAP is 1:0.2 - 5:0.5 - 10:0.01 - 3, and they are dissolved in DCM (the dosage ratio of tocopherol to DCM is 1 g:8 mL);

[0010] (2) After the reaction is completed, quench with water, stir and then extract with methanol and separate the layers; quench the lower layer liquid with water, stir and then extract with methanol and separate the layers; dry the lower layer liquid with anhydrous sodium sulfate, filter and concentrate to obtain a concentrate; dissolve the concentrate in a n - hexane - DCM solution, filter with thin - layer silica gel, wash with n - hexane, and concentrate and dry the filtrate to obtain ditocopheryl azelate.

[0011] In one embodiment, the molar ratio of tocopherol, sebacoyl chloride, TEA and DMAP in step (1) is 1:1 - 5:0.5 - 5:0.01 - 1;

[0012] Optionally, the molar ratio of tocopherol, sebacoyl chloride, TEA and DMAP in step (1) is 1:1 - 3:1 - 3:0.1 - 0.5.

[0013] In one embodiment, in step (1), mixture 2 is added to mixture 1 at a dropping rate of 2 - 50 L / h.

[0014] Optionally, in step (1), mixture 2 is added to mixture 1 at a dropping rate of 2 - 5 L / h.

[0015] In one embodiment, in step (1), the reaction is carried out at 30 - 70 °C for 3 - 6 h.

[0016] In one embodiment, in step (2), the ratio of n - hexane to DCM in the n - hexane - DCM solution is 10 - 20:1.

[0017] In one embodiment, in step (2), the filtration is carried out using thin - layer silica gel with 300 - 400 meshes.

[0018] The second object of the present invention is to provide the use of ditocopheryl azelate in the preparation of cosmetics, and the chemical structural formula of the ditocopheryl azelate is shown as Formula I

[0019]

[0020] The systematic nomenclature of the above chemical formula is 9-oxo-9-{[2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-chromen-6-yl]oxy}nonanoic acid 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-chromen-6-yl ester; 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-chromen-6-yl 9-oxo-9-{[2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-chromen-6-yl]oxy}nonanoate.

[0021] In one embodiment, the cosmetics include essence, essence water, spray, skin care foam, lotion, shampoo.

[0022] The third object of the present invention is to provide a kind of cosmetics which contains ditocopheryl azelate;

[0023] wherein, the chemical structural formula of the ditocopheryl azelate is shown as Formula I

[0024]

[0025] In one embodiment, the cosmetics include essence, essence water, spray, skin care foam, lotion, shampoo.

[0026] The fourth object of the present invention is to provide a method for improving the performance of azelaic acid, which is to prepare ditocopheryl azelate from azelaic acid and tocopherol;

[0027] wherein, the chemical structural formula of the ditocopheryl azelate is shown as Formula I

[0028]

[0029] Advantageous effects of the present invention

[0030] The present invention provides a method for preparing ditocopheryl azelate, which improves the yield and purity of ditocopheryl azelate. The ditocopheryl azelate prepared by the present invention overcomes the limitations of poor permeability and high irritation of azelaic acid, and may also enhance its overall efficacy through synergistic effects, providing a better solution for skin care and treatment. Specifically,

[0031] (1) The purity of the ditocopheryl azelate prepared in this application reaches more than 97.13%, and the highest can reach 97.95%;

[0032] (2) Compared with azelaic acid, the ditocopheryl azelate prepared in this application has lower irritation to cells. When the concentration reaches 250 μg / mL, there is no cytotoxicity (when the concentration of azelaic acid reaches 130 μg / mL, the cell viability is only 67.71%);

[0033] (3) The ditocopheryl azelate prepared in this application has a stronger inhibitory effect on cell lipogenesis than azelaic acid and tocopherol. When the concentration is 30 - 60 μg / mL, it is significantly superior to azelaic acid, tocopherol and isotretinoin;

[0034] (4) The ditocopheryl azelate prepared in this application has stronger antioxidant properties, and its IC 50 is only 10 μg / mL;

[0035] (5) The ditocopheryl azelate prepared in this application has a higher solubility (w / w) in dibutyl adipate, reaching 10%, which is significantly superior to 0.1% of azelaic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is the hydrogen spectrum of ditocopheryl azelate;

[0037] Figure 2 is the carbon spectrum of ditocopheryl azelate. DETAILED DESCRIPTION OF THE INVENTION

[0038] The following are the preferred embodiments of the present invention. It should be understood that the embodiments are for better explaining the present invention and are not used to limit the present invention.

[0039] Raw materials used in the examples:

[0040] Azelaic acid was purchased from Shandong Aigelin Pharmaceutical Co., Ltd.;

[0041] Thionyl chloride was purchased from Shanghai Baisun Biological Technology Co., Ltd.;

[0042] Tocopherol was purchased from Zhejiang Weishi Biological Technology Co., Ltd.;

[0043] DMF (N,N-dimethylformamide) was purchased from Shanghai Chutai Chemical Technology Co., Ltd.;

[0044] DCM (Dichloromethane) was purchased from Shanghai Chutai Chemical Technology Co., Ltd.;

[0045] DMAP (4-Dimethylaminopyridine) was purchased from Jiangsu Haosheng Chemical Co., Ltd.;

[0046] TEA (Triethylamine) was purchased from Shanghai Chutai Chemical Technology Co., Ltd.

[0047] Testing method:

[0048] High performance liquid chromatography, 1H NMR, 13C NMR.

[0049] Example 1: A method for preparing ditocopheryl azelate

[0050] 1. Preparation of azelaoyl chloride

[0051] Add azelaic acid, toluene, and DMF into the reaction flask according to the ratio in Table 1, stir at room temperature for 30 min; slowly add thionyl chloride, react at 50 °C for 6 h; after the reaction is completed, concentrate the system as much as possible to dryness, and seal to obtain azelaoyl chloride.

[0052] Table 1

[0053] substrate MW feed amount eq azelaic acid 188.22 g / mol 200g 1.0 eq thionyl chloride 118.97 g / mol 568.81g 4.5 eq toluene 600g 3 w / w DMF 6g 0.03 w / w

[0054] 2. Preparation of ditocopheryl azelate

[0055] Add tocopherol, DCM (6 vol), and DMAP according to the ratio in Table 2, start stirring, control the temperature below 5 °C and add TEA to obtain mixture 1; prepare a mixture of azelaoyl chloride and DCM (2 vol) according to Table 2 to obtain mixture 2; slowly add mixture 2 dropwise to mixture 1 within 10 min, and after dropping, raise the temperature to 30 - 35 °C and react for 7 h (monitor by TLC, quenching with methanol: PE:EA = 10:1 as the developing agent, and observing the color reaction with phosphomolybdic acid);

[0056] After the reaction is completed, quench with 5 w / w (1000 g) of water, stir for 30 min, then add 1 w / w (200 g) of methanol, extract and separate the layers; wash the lower layer with 5 w / w (1000 g) of water and 2 w / w (200 g) of methanol for the second time, separate the layers, dry the lower layer with anhydrous sodium sulfate, filter, and concentrate; dissolve the concentrate in 4 w / w (800 g) of n-hexane - DCM with a volume ratio of 15:1, filter through a thin layer of silica gel with a mesh size of 300 - 400, wash with n-hexane, concentrate and dry the filtrate, and remove the solvent by pumping with an oil pump. 221 g of ditocopheryl azelate (m / z = 1013.85) with a purity of 97.95% was obtained.

[0057] Table 2

[0058] substrate MW feed amount eq tocopherol 430.69 g / mol 200g 1.0 eq azelaoyl chloride 225.11 g / mol 188.16g 1.8 eq TEA 101.19 g / mol 94g 2.0 eq DMAP 122.17 g / mol 11.35g 0.2 eq DCM 1200 mL + 400 mL 6 vol + 2 vol

[0059] Example 2: A method for preparing ditocopheryl azelate

[0060] On the basis of Example 1, step 2 is changed to:

[0061] Add tocopherol, DCM (6 vol), and DMAP in the proportions shown in Table 2, start stirring, add TEA while controlling the temperature below 10 °C to obtain mixture 1; prepare a mixture of azeloyl chloride and DCM (2 vol) to obtain mixture 2; slowly add mixture 2 dropwise to mixture 1 within 10 minutes, and after dropping, raise the temperature to 25 - 30 °C and react for 8 hours (monitor by TLC with methanol quenching: PE:EA = 10:1 as the developing solvent, and simultaneously observe the color development with phosphomolybdic acid);

[0062] After the reaction is completed, quench with 5 w / w (1000 g) of water, stir for 30 minutes, then add 1 w / w (200 g) of methanol, extract and separate the layers; extract and wash the lower layer again with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol for the second time, dry the lower layer with anhydrous sodium sulfate after separation, filter, and concentrate; dissolve the concentrate in a solvent with a ratio of n - hexane:DCM = 20:1 at 4 w / w (800 g), filter through a thin - layer silica gel with a mesh size of 300 - 400, wash with n - hexane, concentrate and dry the filtrate, and remove the solvent by pumping vacuum with an oil pump. Obtain 217 g of ditocopheryl azelate with a purity of 97.46%.

[0063] Example 3: A method for preparing ditocopheryl azelate

[0064] On the basis of Example 1, step 2 is changed to:

[0065] Add tocopherol, DCM (6 vol), and DMAP in the proportions shown in Table 2, start stirring, add TEA while controlling the temperature below 10 °C to obtain mixture 1; prepare a mixture of azeloyl chloride and DCM (2 vol) to obtain mixture 2; slowly add mixture 2 dropwise to mixture 1 within 10 minutes, and after dropping, raise the temperature to 35 - 40 °C and react for 5 - 6 hours (monitor by TLC with methanol quenching: PE:EA = 10:1 as the developing solvent, and simultaneously observe the color development with phosphomolybdic acid);

[0066] After the reaction was completed, the reaction was quenched by adding 5 w / w (1000 g) of water. After stirring for 30 minutes, 1 w / w (200 g) of methanol was added, and after extraction, the layers were separated; the lower layer was washed again with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol for the second time. After separation, the lower layer was dried over anhydrous sodium sulfate, filtered, and concentrated; 4 w / w (800 g) of a solvent with a ratio of n-hexane:DCM = 20:1 was added to the concentrate for dissolution, and it was filtered through a thin layer of silica gel with a mesh size of 300 - 400, rinsed with n-hexane, the filtrate was concentrated and dried, and the solvent was removed by pumping vacuum with an oil pump. 187 g of ditocopheryl azelate was obtained with a purity of 97.13%.

[0067] Example 4: A method for preparing ditocopheryl azelate

[0068] On the basis of Example 1, step 2 was changed to:

[0069] Tocopherol, DCM (6 vol), and DMAP were added in the proportions shown in Table 2, and stirring was started. TEA was added while controlling the temperature below 5 °C to obtain mixture 1; a mixture of azelaoyl chloride and DCM (2 vol) was prepared to obtain mixture 2; mixture 2 was added dropwise to mixture 1 at a uniform rate over 30 seconds, and after dropping, the temperature was raised to 25 - 35 °C and the reaction was carried out for 5 - 6 hours (monitoring by TLC with methanol quenching: using PE:EA = 10:1 as the developing solvent and observing the color development with phosphomolybdic acid at the same time);

[0070] After the reaction was completed, the reaction was quenched by adding 5 w / w (1000 g) of water. After stirring for 30 minutes, 1 w / w (200 g) of methanol was added, and after extraction, the layers were separated; the lower layer was washed again with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol for the second time. After separation, the lower layer was dried over anhydrous sodium sulfate, filtered, and concentrated; 4 w / w (800 g) of a solvent with a ratio of n-hexane:DCM = 20:1 was added to the concentrate for dissolution, and it was filtered through a thin layer of silica gel with a mesh size of 300 - 400, rinsed with n-hexane, the filtrate was concentrated and dried, and the solvent was removed by pumping vacuum with an oil pump. 178 g of ditocopheryl azelate was obtained with a purity of 96.96%.

[0071] Example 5: A method for preparing ditocopheryl azelate

[0072] On the basis of Example 1, step 2 was changed to:

[0073] Tocopherol, DCM (6 vol), and DMAP were added in the proportions shown in Table 2, and stirring was started. TEA was added while controlling the temperature below 5 °C to obtain mixture 1; a mixture of azelaoyl chloride and DCM (2 vol) was prepared to obtain mixture 2; mixture 2 was added dropwise to mixture 1, and after dropping, the temperature was raised to 25 - 35 °C and the reaction was carried out for 5 - 6 hours (monitoring by TLC with methanol quenching: using PE:EA = 10:1 as the developing solvent and observing the color development with phosphomolybdic acid at the same time);

[0074] After the reaction was completed, 5 w / w (1000 g) of water was added for quenching. After stirring for 30 minutes, 1 w / w (200 g) of methanol was added, and after extraction, the liquid was separated; the lower layer was washed again with 5 w / w (1000 g) of water and 1 w / w (200 g) of methanol for the second time. After liquid separation, the lower layer was dried over anhydrous sodium sulfate, filtered, and concentrated; 4 w / w (800 g) of a solvent with a ratio of n-hexane:DCM = 10:1 was added to the concentrate for dissolution, and it was filtered through a thin-layer silica gel with a mesh size of 300 - 400, rinsed with n-hexane, and the filtrate was concentrated and dried, and the solvent was removed by pumping vacuum with an oil pump. 221 g of ditocopheryl azelate was obtained. There were a small amount of impurities on the TLC plate, and the purity was 95.43%.

[0075] Example 6: A method for preparing ditocopheryl azelate

[0076] On the basis of Example 1, step 2 was changed to:

[0077] Tocopherol, DCM (6 vol), and DMAP were added in the proportions shown in Table 2, and stirring was started. TEA was added while controlling the temperature below 5 °C to obtain mixture 1; a mixture of azeloyl chloride and DCM (2 vol) was prepared to obtain mixture 2; mixture 2 was added dropwise to mixture 1, and after dropping, the temperature was raised to 25 - 35 °C and the reaction was carried out for 5 - 6 hours (quenched with methanol when spotting on the TLC plate: PE:EA = 10:1 was used as the developing agent, and at the same time, the color development situation of phosphomolybdic acid was observed);

[0078] After the reaction was completed, 5 w / w (1000 g) of water was added for quenching, and after stirring for 30 minutes, the liquid was separated; the lower layer was washed again with 5 w / w (1000 g) of water for the second time. After liquid separation, the lower layer was dried over anhydrous sodium sulfate, filtered, and concentrated; 4 w / w (800 g) of a solvent with a ratio of n-hexane:DCM = 20:1 was added to the concentrate for dissolution, and it was filtered through a thin-layer silica gel with a mesh size of 300 - 400, rinsed with n-hexane, and the filtrate was concentrated and dried, and the solvent was removed by pumping vacuum with an oil pump. 205 g of ditocopheryl azelate was obtained. There were a small amount of impurities on the TLC plate, and the purity was 95.17%. Comparative Example 1: Preparation of azelaic acid compounds using other substances

[0079] On the basis of Example 1, p-methoxyphenol was used to replace tocopherol, and the remaining steps were the same as those in Example 1 to prepare azelaic acid - p-methoxyphenol diester.

[0080] Example 7: Performance detection of ditocopheryl azelate

[0081] The ditocopheryl azelate prepared in Examples 1 - 6 and the azelaic acid - p-methoxyphenol diester prepared in Comparative Example 1 were taken, and the performance detection results are as follows:

[0082] 1. Structural data

[0083] (1) 1H NMR

[0084] The hydrogen spectrum of ditocopheryl azelate is as Figure 1 shown below:

[0085] 1 H NMR(400MHz,Chloroform-d)δ2.59(q,J=7.1,6.6Hz,8H),2.08(s,6H),2.01(s,6H),1.96(s,6H),1.82(d,J=6.8Hz,4H),1.76(dd,J=14.2,7.1Hz,4H),1.59–1.44(m,8H),1.39(m,4H),1.32–1.20(m,19H),1.10(m,8H),0.85(m,24H).

[0086] (2) 13C NMR

[0087] The carbon-13 nuclear magnetic resonance results of ditocopheryl azelate are as Figure 2 shown below:

[0088] 13 C NMR(101MHz,Chloroform-d)δ172.38,149.39,140.52,126.72,124.94,123.06,117.40,75.08,39.44,37.61,37.52,37.47,37.42,37.35,34.17,32.85,32.77,31.12,29.23,29.04,28.05,25.17,24.89,24.52,22.80,22.71,21.11,20.67,19.82,19.76,19.73,19.70,19.67,13.06,12.21,11.91.

[0089] 2. Performance data

[0090] (1) Irritation to cells

[0091] To detect the effect of the compound on cell viability, the steps include:

[0092] 1) Cell seeding:

[0093] Seed SZ95 cells into a 96-well plate at an inoculation density of 1×10 4 cells / well and incubate overnight in an incubator (37 °C, 5% CO2).

[0094] 2) Experimental grouping:

[0095] The experimental setup included a blank control group, a positive control group (10% DMSO), and a sample group. In the sample group, each sample was set at 8 concentration gradients, with 3 replicate wells for each concentration gradient.

[0096] 3) Administration of drugs:

[0097] When the cell seeding rate in the 96-well plate reached 40% - 60%, drugs were administered. In the control group, 200 μL of culture medium containing 10% PBS was added to each well; in the positive control group, 200 μL of culture medium containing 10% DMSO was added to each well; in the sample group, 200 μL of culture medium containing the sample at the concentrations shown in Table 3 was added to each well; in the zero-adjustment group, no cells were inoculated, and only 200 μL of cell culture medium was added. After drug administration, the 96-well plate was placed in an incubator for culture.

[0098] 4) Viability detection:

[0099] After the cells were incubated for 24 h, the supernatant was discarded, and MTT working solution (0.5 mg / mL) was added. Incubation was carried out at 37 °C in the dark for 4 h. After incubation, the supernatant was discarded, 100 μL of DMSO was added to each well, and the OD value was read at 490 nm. The calculation of cell viability was as follows:

[0100]

[0101] Table 3 Drug administration concentrations and detection results

[0102]

[0103] The results are shown in Table 3, indicating that ditocopheryl azelate has low irritation to cells and is superior to azelaic acid and other azelaic acid compounds.

[0104] (2) Inhibitory effect on cell adipogenesis

[0105] 1) Cell seeding: Cells were seeded into a 24-well plate at an inoculation density of 1×10 5 cells / well and incubated overnight in an incubator (37 °C, 5% CO2).

[0106] 2) Preparation of solutions: Working solutions of the test substances at different concentrations were prepared according to the experimental design table shown in Table 4.

[0107] 3) Administration of drugs: According to Table 4, when the cell seeding rate in the 24-well plate reached 40% - 60%, grouped drug administration was carried out, with 3 replicate wells for each group, and the cells were continued to be cultured in the incubator for 24 h.

[0108] 4) Staining: The culture medium was discarded, the cells were rinsed with PBS, fixed, stained with Nile red for 15 min, rinsed, and photographed with a fluorescence microscope.

[0109] 5) Analysis results: The fluorescence intensity was quantitatively analyzed using Image Pro Plus software.

[0110] As shown in Table 4, tocopherol itself does not have a lipid droplet inhibitory effect, while ditocopheryl azelate has a significantly better lipid droplet inhibitory effect than azelaic acid and other azelaic acid compounds.

[0111] Table 4 Administration concentrations and detection results

[0112]

[0113] (3) Antioxidant performance detection

[0114] Prepare DPPH solution: Weigh 7.9 mg of DPPH with an electronic analytical balance, dissolve it with absolute ethanol, and make up the volume to 200 mL in a volumetric flask. The concentration is 0.1 mmol / L. Shake well and keep it away from light for later use.

[0115] A0 is 3 mL of DPPH solution + 3 mL of absolute ethanol;

[0116] Aj is 3 mL of DPPH solution + 3 mL of sample solution;

[0117] Ai is 3 mL of sample solution + 3 mL of absolute ethanol.

[0118] Shake well vigorously. After standing the sample at 37 °C for 10 min, add it to a cuvette for absorbance measurement. Measure the absorbance values of the samples represented by Ao, Aj, and Ai. The scavenging rate is calculated according to the formula:

[0119] SA(%) = 1 - (A i - A j ) / A0 × 100%.

[0120] As shown in Table 5, the results show that the antioxidant property of ditocopheryl azelate is significantly better than that of tocopherol and other azelaic acid compounds.

[0121] Table 5 Antioxidant property detection results

[0122]

[0123]

[0124] (4) Solubility detection

[0125] The solubility (w / w) of the compound was detected. The results show that azelaic acid can only dissolve 0.1% in dibutyl adipate, while the solubility of ditocopheryl azelate in dibutyl adipate reaches 10%.

[0126] Example 8: Application of ditocopheryl azelate in the preparation of products

[0127] 1. Take the ditocopheryl azelate prepared in Example 1 and prepare a cosmetic, the ingredients of which are shown in Table 6.

[0128] Table 6 Cosmetic Ingredients

[0129] component percentage water 62.1 glycerol 5 PHCG 0.8 xanthan gum 0.1 PEG-100, glyceryl stearate 3 cetearyl alcohol 2 Cetiol B (dibutyl adipate) 22 ditetrahexyldecyl dicarboxylate 5

[0130] 2. Prepare a cosmetic using equal amounts of azelaic acid and tocopherol

[0131] Replace the ditocopheryl azelate in 1 with azelaic acid and tocopherol to prepare a cosmetic, and test the stability of the cosmetic (test whether the cosmetic precipitates or changes color at 40 °C within 60 days). The results are shown in Table 7.

[0132] Table 7 Stability Test

[0133]

[0134] Although the present invention has been disclosed above with preferred embodiments, it is not intended to limit the present invention. Anyone familiar with this technology can make various modifications and decorations without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be defined by the claims.

Claims

1. A method for synthesizing ditocopheryl azelate, characterized in that, Comprising the steps of: (1) Mix tocopherol, DCM, and DMAP, and slowly add TEA to obtain mixture 1; mix sebacoyl chloride and DCM to obtain mixture 2, and slowly add mixture 2 to mixture 1 for reaction; Among them, the molar ratio of tocopherol, sebacoyl chloride, TEA, and DMAP is 1: 0.2 - 5: 0.5 - 10: 0.01 - 3; (2) After the reaction is completed, quench with water, stir and then extract with methanol and separate the layers; quench the lower layer liquid with water, stir and then extract with methanol and separate the layers; dry the lower layer liquid with anhydrous sodium sulfate, filter, and concentrate to obtain a concentrate; dissolve the concentrate in a n-hexane-DCM solution, filter through thin-layer silica gel, wash with n-hexane, and take the filtrate to concentrate and dry to obtain ditocopheryl sebacate.

2. The method according to claim 1, wherein In step (1), mixture 2 is added to mixture 1 at a dropping rate of 2 - 50 L / h.

3. The method according to claim 1, characterized in that, In step (1), the reaction is carried out at 30 - 70 °C for 3 - 6 h.

4. The method according to claim 1, characterized in that, In step (2), the ratio of n-hexane to DCM in the n-hexane-DCM solution is 10 - 20:

1.

5. The method according to claim 1, wherein In step (2), the filtration is carried out using thin-layer silica gel with 300 - 400 mesh.

6. Use of ditocopheryl azelate in the preparation of cosmetics, characterized in that, The chemical structural formula of the ditocopheryl sebacate is as shown in Formula I 7. The application according to claim 6, wherein The cosmetic includes essence, essence water, spray, skin care foam, lotion, shampoo.

8. A cosmetic, characterized in that, The cosmetic contains ditocopheryl sebacate; Among them, the chemical structural formula of the ditocopheryl sebacate is as shown in Formula I 9. The cosmetic according to claim 8, characterized in that, The cosmetic includes essence, essence water, spray, skin care foam, lotion, shampoo.

10. A method for improving the performance of azelaic acid, characterized in that, Prepare ditocopheryl sebacate from sebacic acid and tocopherol; Among them, the chemical structural formula of the ditocopheryl sebacate is as shown in Formula I

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