Retinol derivative and preparation method therefor
Patent Information
- Application Number
- PCT/CN2025/084264
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-03-22
- Publication Date
- 2026-10-01
Smart Images
Figure PCTCN2025084264-APPB-I100001 
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Abstract
Description
A retinol derivative and its preparation method Technical Field
[0001] This invention relates to a retinol derivative and its preparation method, belonging to the field of materials preparation technology. Background Technology
[0002] Retinol, also known as vitamin A, is an important skincare ingredient with benefits such as promoting skin cell renewal and anti-aging. However, retinol presents some challenges in cosmetic applications: its stability is poor, easily degrading under light and oxygen conditions, affecting product shelf life; additionally, retinol can cause skin irritation and discomfort. Therefore, finding a stable, gentle, and well-stabilized retinol derivative is crucial. Technical issues
[0003] In order to overcome the above-mentioned defects and deficiencies in the prior art, the present invention provides a retinol derivative and a method for preparing the same. Technical solutions
[0004] To solve the above technical problems:
[0005] The first objective of this invention is to provide a retinol derivative having the general structural formula as shown in (I):
[0006] (I).
[0007] Wherein, R is an alkyl or acyl group.
[0008] Furthermore, R can be a fatty acyl group or an aromatic acyl group.
[0009] Furthermore, R can be acetyl, propionyl, isobutyryl, butyryl, benzoyl, lauroyl, palmitoyl, cinnamoyl, or p-methoxycinnamoyl.
[0010] Furthermore, R can be methyl, ethyl, n-propyl, isopropyl, butyl, or tert-butyl.
[0011] The second objective of this invention is to provide a method for preparing retinol derivatives using the DCC condensation method, the specific process of which is as follows:
[0012] Retinol and 4-alkyloxycinnamic acid in a molar ratio of 1.0:1.0 to 1.0:1.5 are dissolved in an organic solvent;
[0013] The catalysts 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine were added.
[0014] Stir and react at 0~5℃ for 1~24 hours;
[0015] After the reaction was complete, the catalyst was removed by filtration, the filtrate was washed with saturated sodium bicarbonate solution and then dried with anhydrous sodium sulfate; the solvent was removed by rotary evaporation to obtain the crude product.
[0016] The crude product was purified by silica gel column chromatography to obtain retinol-4-alkyloxycinnamate.
[0017] A third objective of this invention is to provide another method for preparing retinol derivatives, using the acyl chloride method, the specific process of which is as follows:
[0018] 4-Alkyloxycinnamic acid was dissolved in an organic solvent, and thionyl chloride was added at 0°C. The mixture was stirred for 2 hours to obtain a 4-alkyloxycinnamicyl chloride solution.
[0019] Retinol is dissolved in an organic solvent, and triethylamine is added;
[0020] The above 4-alkanoyloxycinnamoyl chloride solution was slowly added to the retinol solution, and the mixture was stirred at 0-5°C for 1-12 hours. The molar ratio of retinol to 4-alkanoyloxycinnamoyl chloride was 1.0:1.0-1.0:1.5.
[0021] After the reaction is complete, wash with saturated sodium bicarbonate solution and then dry with anhydrous sodium sulfate.
[0022] The solvent was removed by rotary evaporation to obtain the crude product;
[0023] The crude product was purified by silica gel column chromatography to obtain retinol-4-alkyloxycinnamate.
[0024] A third objective of this invention is to provide another method for preparing retinol derivatives using an enzymatic method, the specific process of which is as follows:
[0025] Retinol and 4-alkoxycinnamic acid in a molar ratio of 1.0:1.0 to 1.0:1.5 are dissolved in a mixed solvent;
[0026] Add a catalyst to immobilize lipase;
[0027] The reaction was stirred for 12 to 48 hours at 40–50°C and pH 6.5–7.0.
[0028] After the reaction is complete, the catalyst is removed by filtration, and the solvent is removed from the filtrate by rotary evaporation to obtain the crude product.
[0029] The crude product was purified by silica gel column chromatography to obtain retinol-4-alkoxycinnamate.
[0030] Furthermore, the organic solvent is one of dichloromethane, trichloromethane, or tetrahydrofuran; the mixed solvent is a mixture of tetrahydrofuran and isooctane, or a mixture of toluene and n-hexane.
[0031] Furthermore, the organic solvent is 100 mL of dichloromethane, 50 mL of trichloromethane, or 100 mL of tetrahydrofuran.
[0032] Furthermore, the volume ratio of tetrahydrofuran to isooctane is 1:1, and the volume ratio of toluene to n-hexane is 1:2. Beneficial effects
[0033] This invention provides a retinol derivative and its preparation method. The method involves forming a stable chemical bond between the hydroxyl group of retinol and the functional group of 4-acetyloxycinnamate, a compound with UV absorption and soothing effects. This significantly improves the stability and reduces the irritation of retinol while maintaining its skin-care efficacy. Stability experiments show that the content of this derivative decreases by no more than 10% after 6 hours at 30°C and after 6 hours of sunlight exposure, while the content of traditional retinol acetate decreases by as much as 60% under the same conditions. This indicates that the derivative of this invention has a significantly improved stability. The cellular irritation of the retinol derivative was evaluated using the MTT assay. The results show that the MTT-50 value of retinol acetate is 12.37, while the MTT-50 value of the retinol-4-acetyloxycinnamate of this invention is as high as 95.63. This indicates that the derivative of this invention has a significantly improved cellular irritation and is gentler. Embodiments of the present invention
[0034] The present invention will be further described below with reference to specific embodiments. These embodiments are only used to more clearly illustrate the technical solutions of the present invention and should not be construed as limiting the scope of protection of the present invention.
[0035] The present invention will be further described below with reference to the embodiments.
[0036] Example 1: Synthesis of retinol-4-acetoxycinnamate by DCC condensation
[0037] 1. Dissolve retinol (0.1 mol) and 4-acetoxycinnamic acid (0.1 mol) in 100 mL of dichloromethane.
[0038] 2. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 0.12 mol) and 4-dimethylaminopyridine (DMAP, 0.01 mol) were added as catalysts.
[0039] 3. Stir and react at 0-5℃ for 6 hours.
[0040] 4. After the reaction is complete, filter to remove the catalyst, wash the filtrate with saturated sodium bicarbonate solution, and then dry it with anhydrous sodium sulfate.
[0041] 5. Remove the solvent using a rotary evaporator to obtain the crude product.
[0042] 6. The crude product was purified by silica gel column chromatography to obtain retinol-4-acetoxycinnamate, and mass spectrometry analysis showed that the mass-to-charge ratio m / z was 474.6.
[0043] Example 2: Synthesis of retinol-4-benzoyloxycinnamate by acyl chloride method
[0044] 1. Dissolve 0.1 mol of 4-benzoyloxycinnamic acid in 50 mL of chloroform.
[0045] 2. At 0°C, 0.12 mol of thionyl chloride was slowly added and the mixture was stirred for 2 hours to obtain 4-benzoyloxycinnamoyl chloride.
[0046] 3. Dissolve retinol (0.1 mol) in 50 mL of chloroform and add triethylamine (0.12 mol).
[0047] 4. Slowly add the above acyl chloride solution to the retinol solution and stir the mixture at 0-5°C for 12 hours.
[0048] 5. After the reaction is complete, wash with saturated sodium bicarbonate solution and then dry with anhydrous sodium sulfate.
[0049] 6. Remove the solvent using a rotary evaporator to obtain the crude product.
[0050] 7. The crude product was purified by silica gel column chromatography to obtain retinol-4-benzoyloxycinnamate; mass spectrometry analysis showed that the mass-to-charge ratio m / z = 536.7.
[0051] Example 3: Enzymatic synthesis of retinol-4-lauroyloxycinnamate
[0052] 1. Dissolve retinol (0.1 mol) and 4-lauroyloxycinnamic acid (0.1 mol) in a mixed solvent consisting of tetrahydrofuran and isooctane (volume ratio 1:1).
[0053] 2. Immobilized lipase (Novozym 435, 0.02 g) was added as a catalyst.
[0054] 3. Stir the reaction at 40℃ and pH 7.0 for 48 hours.
[0055] 4. After the reaction is complete, filter to remove the catalyst, and remove the solvent from the filtrate by rotary evaporation to obtain the crude product.
[0056] 5. The crude product was purified by silica gel column chromatography to obtain retinyl-4-lauroyloxycinnamate; mass spectrometry analysis showed a mass-to-charge ratio (m / z) of 614.9.
[0057] Example 4: Enzymatic synthesis of retinol-4-cinnamoyloxycinnamate
[0058] 1. Dissolve retinol (0.1 mol) and 4-cinnamoyloxycinnamic acid (0.1 mol) in a mixed solvent consisting of toluene and n-hexane (volume ratio 1:2).
[0059] 2. Immobilized lipase (Lipozyme TL IM, 0.03 g) was added as a catalyst.
[0060] 3. Stir the reaction at 50℃ and pH 6.5 for 36 hours.
[0061] 4. After the reaction is complete, filter to remove the catalyst, and remove the solvent from the filtrate by rotary evaporation to obtain the crude product.
[0062] 5. The crude product was purified by silica gel column chromatography to obtain retinol-4-cinnamoyloxycinnamate; mass spectrometry analysis showed that the mass-to-charge ratio m / z = 562.8.
[0063] Example 5: Synthesis of retinol-4-ethoxycinnamate by DCC condensation
[0064] 1. Dissolve retinol (0.1 mol) and 4-ethoxycinnamic acid (0.1 mol) in 100 mL of tetrahydrofuran.
[0065] 2. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 0.12 mol) and 4-dimethylaminopyridine (DMAP, 0.01 mol) were added as catalysts.
[0066] 3. Stir the reaction at 20°C for 30 hours.
[0067] 4. After the reaction is complete, filter to remove the catalyst, wash the filtrate with saturated sodium bicarbonate solution, and then dry it with anhydrous sodium sulfate.
[0068] 5. Remove the solvent using a rotary evaporator to obtain the crude product.
[0069] 6. The crude product was purified by silica gel column chromatography to obtain retinol-4-ethoxycinnamate, and mass spectrometry analysis showed that the mass-to-charge ratio m / z = 460.7.
[0070] Example 6: Preparation of retinol-4-acetoxycinnamate (R = acetyl group)
[0071] The preparation is carried out using the acyl chloride method, with the following specific steps:
[0072] Ingredients: retinol (1 mmol), 4-acetoxycinnamoyl chloride (1.2 mmol), anhydrous pyridine (3 mmol), dichloromethane (20 mL).
[0073] Reaction: Dissolve retinol in dichloromethane, cool to 0°C in an ice bath, add a mixture of acetyl chloride and pyridine dropwise, and stir for 4 hours.
[0074] Post-treatment: The reaction solution was washed with saturated NaHCO₃, the organic phase was dried (NaSO₄), and the solution was distilled under reduced pressure to give a white solid.
[0075] Yield: 85%, mass spectrometry analysis showed mass-to-charge ratio m / z: 474.6.
[0076] Example 7: Preparation of retinol-4-p-toluoxycinnamate
[0077] The preparation is carried out using the acyl chloride method, with the following specific steps:
[0078] Ingredients: Retinol (1 mmol), 4-p-toluamide cinnamoyl chloride (1.2 mmol), triethylamine (2 mmol), THF (20 mL).
[0079] Reaction: Retinol and triethylamine were dissolved in THF, and benzoyl chloride was slowly added dropwise while stirring at room temperature for 6 hours.
[0080] Post-processing: Filter the precipitate, concentrate the filtrate and purify by column chromatography (petroleum ether: ethyl acetate = 5:1).
[0081] Yield: 78%; mass spectrometry analysis showed a mass-to-charge ratio of m / z = 550.7.
[0082] Example 8: Preparation of retinol-4-p-methoxycinnamoyloxycinnamate (R = p-methoxycinnamoyl)
[0083] The preparation method using DCC is as follows:
[0084] Reaction: Retinol (1 mmol), 4-p-methoxycinnamoyloxycinnamic acid (1.2 mmol), and DCC (1.5 mmol) were added to dichloromethane (20 mL), activated for 30 minutes, and then retinol and DMAP (0.1 mmol) were added. The mixture was stirred at room temperature for 12 hours.
[0085] Post-processing: Filter with DCU, concentrate, and then purify with silica gel column (hexane:acetone = 4:1).
[0086] Yield: 70%; mass spectrometry analysis showed a mass-to-charge ratio of m / z = 592.8.
[0087] Example 9: Preparation of retinyl-4-lauroyloxycinnamate (R = lauroyl group)
[0088] Prepared using an enzymatic method, the steps are as follows:
[0089] Ingredients: retinol (1 mmol), 4-lauroyloxycinnamic acid (1.5 mmol), lipase (Novozym 435, 10% w / w), tert-butanol (15 mL).
[0090] Reaction: Stir at 50℃ for 24 hours, then add molecular sieves to absorb water.
[0091] Post-processing: filter enzyme, vacuum distillation, and recrystallize the product with diethyl ether.
[0092] Yield: 65%, and mass spectrometry analysis showed a mass-to-charge ratio of m / z = 614.91.
[0093] Example 10: Preparation of retinyl-4-palmitoyloxycinnamate (R = palmitoyl)
[0094] The preparation method is enzymatic, and the specific steps are as follows:
[0095] Ingredients: retinol (1 mmol), 4-palmitoyloxycinnamic acid (1.2 mmol), Candida antarcticis lipase (CALB, 5% w / w), n-hexane (10 mL).
[0096] Reaction: Stirred at 40°C for 18 hours, and the reaction progress was monitored by TLC.
[0097] Post-processing: filter enzyme, concentrate and freeze-dry to obtain a waxy solid.
[0098] Yield: 68%, and mass spectrometry analysis showed a mass-to-charge ratio of m / z = 671.0.
[0099] Example 11: Preparation of retinol-4-isobutyryloxycinnamate (R = isobutyryl)
[0100] The preparation method using DCC is as follows:
[0101] Ingredients: Retinol (1 mmol), 4-isobutyryloxycinnamoyl chloride (1.2 mmol), DCC (1.5 mmol), DMAP (0.1 mmol), THF (20 mL).
[0102] Reaction: Isobutyric acid and DCC were activated in THF for 30 minutes, then retinol and DMAP were added, and the mixture was stirred at room temperature for 8 hours.
[0103] Post-processing: Filtration, concentration of the filtrate and purification by preparative HPLC (C18 column, methanol:water = 85:15).
[0104] Yield: 75%, mass spectrometry analysis showed mass-to-charge ratio m / z = 502.7.
[0105] Example 12: Preparation of retinol-4-cinnamoyloxycinnamate (R = cinnamoyl group)
[0106] The preparation is carried out using the acyl chloride method, with the following specific steps:
[0107] Ingredients: Retinol (1 mmol), 4-cinnamoyloxycinnamoyl chloride (1.2 mmol), pyridine (2 mmol), dichloromethane (20 mL).
[0108] Reaction: Cinnamyl chloride was slowly added dropwise to the retinol solution at 0°C, and the temperature was raised to 25°C and stirred for 5 hours.
[0109] Post-treatment: Wash with water until neutral, dry and then perform column chromatography (dichloromethane:methanol = 20:1).
[0110] Yield: 72%, mass spectrometry analysis showed a mass-to-charge ratio m / z = 562.8.
[0111] Example 13: Preparation of retinol-4-tert-butoxycinnamate (R = tert-butyl)
[0112] The preparation method using DCC is as follows:
[0113] Ingredients: Retinol (1 mmol), tert-butoxycinnamic acid (1.2 mmol), DCC (1.5 mmol), DMAP (0.1 mmol), DMF (15 mL).
[0114] Reaction: After activating the carboxylic acid, add retinol and stir at 50°C for 10 hours.
[0115] Post-processing: filtration, dialysis to remove DMF, and lyophilization to obtain powder.
[0116] Yield: 60%, mass spectrometry analysis showed mass-to-charge ratio m / z = 488.7.
[0117] Test Example 1: Thermal Stability Test
[0118] 1. The retinol derivatives prepared in Examples 1-13 above were placed in constant temperature ovens at 10°C, 20°C, and 30°C, respectively, with retinol acetate as a comparative example.
[0119] 2. Take out the sample every 24 hours and determine its content using high performance liquid chromatography.
[0120] 3. After 7 days, the changes in the content of the two compounds were compared, and the results are shown in Table 1.
[0121] Table 1
[0122]
[0123] As shown in Table 1, the retinol derivatives of Examples 1-13 decreased by approximately 1% after 7 days at 10°C. The decrease rate in Example 1 was only 0.5%, while retinol acetate decreased by 5.0%, approximately 10 times that of this application. The decrease rates of the comparative examples at 20°C and 30°C were also approximately 10 times that of this application: retinol-4-acetoxycinnamate decreased by 2.6% after 7 days at 20°C, while retinol acetate decreased by 21.5%. Retinol-4-cinnamoyloxycinnamate decreased by 8.9% after 3 days at 30°C, while retinol acetate decreased by 76.2%.
[0124] Experimental Example 2: Comparison of Light Stability
[0125] 1. The retinol derivatives prepared in Examples 1-13 above were placed under sunlight irradiation, with retinol acetate as a comparative example.
[0126] 2. After 6 hours of irradiation, the content was determined by high performance liquid chromatography. The results are shown in Table 2.
[0127] Table 2
[0128]
[0129] The results showed that the content of retinol derivatives decreased by 15% after 6 hours of sunlight exposure, while that of retinol acetate decreased by 50%.
[0130] The present invention has been disclosed above with reference to preferred embodiments, but it is not intended to limit the present invention. All technical solutions obtained by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the present invention.
Claims
1. A retinol derivative, characterized in that: It has a general structural formula such as (I): （I）； Wherein, R is an alkyl or acyl group.
2. The retinol derivative according to claim 1, characterized in that: R represents fatty acyl or aromatic acyl.
3. The retinol derivative according to claim 2, characterized in that: R can be acetyl, propionyl, isobutyryl, butyryl, benzoyl, lauroyl, palmitoyl, cinnamoyl, or p-methoxycinnamoyl.
4. The retinol derivative according to claim 1, characterized in that: R is methyl, ethyl, n-propyl, isopropyl, butyl, or tert-butyl.
5. A method for preparing a retinol derivative, characterized in that: The DCC reduction method was used for preparation, and the specific process is as follows: Retinol and 4-alkyloxycinnamic acid in a molar ratio of 1.0:1.0 to 1.0:1.5 are dissolved in an organic solvent; The catalysts 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and 4-dimethylaminopyridine were added. Stir and react at 0~5℃ for 1~24 hours; After the reaction was complete, the catalyst was removed by filtration, the filtrate was washed with saturated sodium bicarbonate solution and then dried with anhydrous sodium sulfate; the solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain retinol-4-alkyloxycinnamate.
6. A method for preparing a retinol derivative, characterized in that: The preparation is carried out using the acyl chloride method, and the specific process is as follows: 4-Alkyloxycinnamic acid was dissolved in an organic solvent, and thionyl chloride was added at 0°C. The mixture was stirred for 2 hours to obtain a 4-alkyloxycinnamicyl chloride solution. Retinol is dissolved in an organic solvent, and triethylamine is added; The above 4-alkanoyloxycinnamoyl chloride solution was slowly added to the retinol solution, and the mixture was stirred at 0-5°C for 1-12 hours. The molar ratio of retinol to 4-alkanoyloxycinnamoyl chloride was 1.0:1.0-1.0:1.
5. After the reaction is complete, wash with saturated sodium bicarbonate solution and then dry with anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain the crude product; The crude product was purified by silica gel column chromatography to obtain retinol-4-alkyloxycinnamate.
7. A method for preparing a retinol derivative, characterized in that: The preparation is carried out using an enzymatic method, and the specific process is as follows: Retinol and 4-alkoxycinnamic acid in a molar ratio of 1.0:1.0 to 1.0:1.5 are dissolved in a mixed solvent; Add a catalyst to immobilize lipase; The reaction was stirred for 12 to 48 hours at 40–50°C and pH 6.5–7.
0. After the reaction is complete, the catalyst is removed by filtration, and the solvent is removed from the filtrate by rotary evaporation to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain retinol-4-alkoxycinnamate.
8. The method for preparing the retinol derivative according to any one of claims 5-7, characterized in that: The organic solvent is one of dichloromethane, trichloromethane, or tetrahydrofuran; the mixed solvent is a mixture of tetrahydrofuran and isooctane, or a mixture of toluene and n-hexane.
9. The method for preparing the retinol derivative according to claim 8, characterized in that: The organic solvent is 100 mL of dichloromethane, 50 mL of trichloromethane, or 100 mL of tetrahydrofuran.
10. The method for preparing the retinol derivative according to claim 8, characterized in that: The volume ratio of tetrahydrofuran to isooctane is 1:1, and the volume ratio of toluene to n-hexane is 1:2.