Preparation method and application of vitamin C nicotinate
By reacting nicotinate with chlorinated reagent and vitamin C in the presence of catalyst and alkali, vitamin C nicotinate is formed, which solves the shortcomings of combining vitamin C and nicotinamide to form new compounds in the prior art, and realizes skin care products Significant whitening effect and stability improvement.
Patent Information
- Application Number
- CN202411400752.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-09
- Publication Date
- 2025-01-07
AI Technical Summary
In the prior art, vitamin C and nicotinamide have their own advantages and disadvantages as skin care ingredients, but they fail to effectively combine to produce new compounds, resulting in insufficient stability and whitening effects.
By reacting niacin salt with chlorinated reagent to form niacin chloride hydrochloride, and reacting with vitamin C in the presence of a catalyst and a base, it forms niacin acid esters. The specific organic solvents, catalysts and reaction conditions are used to improve the compound's Stability and biological activity.
Vitamin C niacin was successfully synthesized. Through clinical trials, it has good biological activity and whitening effects in moisturizing, brightening skin, anti-pigmentation and spot removal, significantly inhibiting melanin production and tyrosinase activity, and improving whitening effects.
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Figure CN119264118A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of preparation of active ingredients of skin care products in organic synthesis, and in particular to a method for synthesizing vitamin C nicotinate and its application. Background Art
[0002] Vitamin C, also called ascorbic acid because of its function of preventing and treating ascorbic acid, is a water-soluble vitamin with a molecular formula of C6H8O6 and a molecular weight of 176.12. It is a monoclinic crystal in the form of flakes or needles and is odorless.
[0003] Naturally occurring ascorbic acid is divided into L-type and D-type. Since D-type has no biological activity, L-type is mostly used in whitening products. It is stable in an acidic environment, but it can be oxidized and destroyed by oxygen, heat, light and alkaline substances in the air, especially in the presence of oxidases and metal ions. The two enol hydroxyl groups at the 2nd and 3rd carbon atoms in the molecule are easily dissociated to release H + , which is oxidized to form dehydrogenated vitamin C. Vitamin C and dehydrogenated vitamin C form a reversible redox system, which plays an important role in the human body. There are two whitening mechanisms of vitamins: reducing melanin and inhibiting melanin production. Tyrosine in melanocytes generates DOPA (DOPA) under the action of tyrosinase, and then oxidizes to dopaquinone. Vitamins can inhibit the activity of tyrosinase through their own antioxidant properties, and help reduce DOPA and dopaquinone, thereby reducing and inhibiting the production of melanin. L-ascorbic acid must be below a pH of 3.5 to enter the skin, and the maximum concentration for percutaneous absorption is 20%.
[0004] Niacinamide, also known as nicotinamide, is an amide compound of nicotinic acid. It belongs to the water-soluble B vitamins and is also known as vitamin B3, vitamin PP, etc. Its molecular formula is C6H6N2O, its molecular weight is 122.125, its appearance is white crystalline powder, odorless or almost odorless, and bitter. Its whitening mechanism is mainly through inhibiting the formation of melanin and its transfer from epidermal cells to the stratum corneum, effectively inhibiting the transfer of melanin to keratinocytes. When some melanin inevitably reaches the surface skin, nicotinamide can accelerate the renewal rate of skin cells and promote the shedding of melanin-containing cells. In addition, nicotinamide is a component of coenzyme I-NAD (nicotinamide adenine dinucleotide) and coenzyme II-NADP (nicotinamide adenine dinucleotide phosphate), which are essential in the production of ATP, and also plays an important role in DNA repair and maintaining skin dynamic balance. The latest research shows that niacinamide has beneficial effects in preventing photoimmunosuppression, photocarcinogenesis, preventing dermal collagen flow associated with photoaging, and reducing and improving the severity of acne. At the same time, niacinamide has a good effect on resisting skin aging, improving barrier function, anti-glycation, and reducing sebum production. Nicotinamide not only has a 35% to 68% inhibitory effect on the melanin transport system, but also accelerates the renewal rate of keratinocytes to accelerate melanin metabolism. Therefore, although niacinamide has only a low inhibitory effect on tyrosinase activity, it still has a very good whitening effect and is currently the most used chemical whitening agent.
[0005] Vitamin C and niacinamide are both active ingredients in common skin care products on the market, and each has its own advantages and disadvantages. Vitamin C can effectively reduce melanin and inhibit melanin production, but it is not stable enough in the air; niacinamide has a very good whitening effect, but it has only a low tyrosinase activity inhibition. There are currently no reports on the combination of vitamin C and niacinamide to generate new compounds, so it is necessary to establish a synthesis scheme to combine the two to form a new compound and confirm its specific biological activity through clinical trials. Summary of the invention
[0006] In order to overcome the above technical defects, the present invention provides a combination of the two: vitamin C nicotinate, the chemical structure of which is as follows:
[0007]
[0008] The present invention also provides a method for preparing the above vitamin C nicotinate, which has not been reported in the literature. The reaction equation is as follows:
[0009]
[0010] Its preparation comprises the following steps:
[0011] S1, nicotinic acid hydrochloride reacts with a chlorination reagent in an organic solvent to obtain nicotinyl chloride hydrochloride;
[0012] S2. Nicotinoyl chloride hydrochloride reacts with vitamin C in the presence of a catalyst and a base to generate vitamin C nicotinate.
[0013] In a preferred embodiment of the present invention, the organic solvent in step S1 is selected from one or more of dichloromethane, tetrahydrofuran or DMF. Dichloromethane is most preferably used as the solvent, and a few drops of DMF are added to increase the solubility.
[0014] In a preferred embodiment of the present invention, the chlorination reagent in step S1 is selected from thionyl chloride or oxalyl chloride, preferably oxalyl chloride.
[0015] In a preferred embodiment of the present invention, the reaction temperature of step S1 is selected from -10°C to 50°C, and most preferably, the material is first added at 0°C, and after the addition, the ice bath is removed and the reaction is carried out at 20-30°C; the reaction time is 0.2 to 24h.
[0016] In a preferred embodiment of the present invention, in step S2, the catalyst is selected from 4-dimethylaminopyridine or pyridine.
[0017] In a preferred embodiment of the present invention, in step S2, the base is selected from triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide or sodium hydroxide; preferably selected from N,N-diisopropylethylamine.
[0018] In a preferred embodiment of the present invention, the molar ratio of nicotinoyl chloride hydrochloride, vitamin C and alkali in step S2 is 1:1-2:1.5-2.5.
[0019] In a preferred embodiment of the present invention, the reaction temperature of step S2 is selected from -10°C to 30°C.
[0020] The present invention also provides the use of the vitamin C nicotinate in moisturizing, skin lightening, anti-pigmentation and spot removal.
[0021] Advantageous Effects of the Invention
[0022] The present invention successfully synthesized the compound vitamin C nicotinate for the first time and conducted a series of clinical trials on it, which showed that it has good biological activity and has good effects in moisturizing, lightening, anti-pigmentation and spot removal. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 This is a graph showing the inhibition of melanin production by vitamin C nicotinate (in human cells);
[0024] Figure 2 This is a graph showing the inhibition of intracellular tyrosinase activity by vitamin C nicotinate;
[0025] Figure 3 This is a clinical in vivo study of the effect of vitamin C nicotinate on melanin in volunteers;
[0026] Figure 4 This is a clinical in vivo study of the effect of vitamin C nicotinate on ultraviolet-induced pigmentation;
[0027] Figure 5 This is a diagram of a clinical in vivo study of vitamin C nicotinate on volunteers with pigmentation. DETAILED DESCRIPTION
[0028] The present invention is further described below by means of specific embodiments, but the protection scope of the present invention is not limited thereto.
[0029] Example 1
[0030] Nicotinoic acid hydrochloride (15.95 g, 100 mmol) was added to a three-necked flask containing 150 mL of dichloromethane. The internal temperature was lowered to 0°C in an ice-salt bath while stirring. Then, thionyl chloride (14.28 g, 120 mmol) was slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled not to be higher than 5°C during the addition process. After the addition was completed, the reaction was carried out at room temperature for 12 h. The solvent was spin-dried to obtain 13.88 g of nicotinoyl chloride hydrochloride with a yield of 78%.
[0031] Example 2
[0032] Nicotinoic acid hydrochloride (15.95 g, 100 mmol) was added to a three-necked flask containing 150 mL of tetrahydrofuran. The internal temperature was lowered to 0°C in an ice-salt bath while stirring. Then, thionyl chloride (14.28 g, 120 mmol) was slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled not to be higher than 5°C during the addition process. After the addition was completed, the reaction was carried out at room temperature for 12 h. The solvent was spin-dried to obtain 14.42 g of nicotinoyl chloride hydrochloride, with a yield of 81%.
[0033] Example 3
[0034] Nicotinoic acid hydrochloride (15.95 g, 100 mmol) was added to a three-necked flask containing 150 mL of DMF, and the internal temperature was lowered to 0°C in an ice-salt bath while stirring. Then, thionyl chloride (14.28 g, 120 mmol) was slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled not to be higher than 5°C during the addition process. After the addition was completed, the reaction was carried out at room temperature for 12 hours, and the solvent was spin-dried (when the solvent was spin-dried, the required temperature was higher and it took a long time to remove the high-boiling-point DMF) to obtain 17.27 g of the product nicotinoyl chloride hydrochloride with a yield of 97%.
[0035] Example 4
[0036] Nicotinoic acid hydrochloride (15.95 g, 100 mmol) was added to a three-necked flask containing 150 mL of dichloromethane, and three drops of DMF were added to increase the solubility. The internal temperature was lowered to 0°C in an ice-salt bath under stirring, and then thionyl chloride (14.28 g, 120 mmol) was slowly added using a constant pressure dropping funnel. The temperature was controlled not to be higher than 5°C during the addition process. After the addition was completed, the reaction was carried out at room temperature for 12 hours, and the solvent was dried (the solvent dichloromethane was first fully dried, and then toluene was added to azeotropize it with a small amount of DMF to remove DMF) to obtain 16.91 g of the product nicotinoyl chloride hydrochloride with a yield of 95%.
[0037] Example 5
[0038] Nicotinoic acid hydrochloride (15.95 g, 100 mmol) was added to a three-necked flask containing 150 mL of dichloromethane, and 2-3 drops of DMF were added to increase the solubility. The internal temperature was lowered to 0°C in an ice-salt bath while stirring. Then, oxalyl chloride (15.24 g, 120 mmol) was slowly added using a constant pressure dropping funnel. The temperature was controlled not to be higher than 5°C during the addition process. After the addition, the reaction was carried out at room temperature for 2 h. The solvent was dried (the dichloromethane solvent was first fully dried, and then toluene was added to azeotropize it with a small amount of DMF to remove DMF) to obtain 17.62 g of the product nicotinoyl chloride hydrochloride with a yield of 99%. 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.73(d,1H),8.05(d,1H),7.45(t,1H).
[0039] Example 6
[0040] Vitamin C (21.12 g, 120 mmol) was added to a three-necked flask containing 200 mL of tetrahydrofuran, and the internal temperature was lowered to -5°C in an ice-salt bath while stirring. Then, triethylamine (10.10 g, 100 mmol) and pyridine (0.40 g, 5 mmol) were slowly added to the reaction system in sequence. Finally, nicotinoyl chloride hydrochloride (17.80 g, 100 mmol) was slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled to be stable at about -5°C during the addition process. After the addition was completed, the reaction was continued at -5°C for 6 h. Water was added to quench the reaction, the solvent tetrahydrofuran was spun off, and then the pH was adjusted to weak acidity with saturated ammonium chloride. The crude product of vitamin C nicotinate was obtained by suction filtration, and the product vitamin C nicotinate was obtained by recrystallization with ethyl acetate / petroleum ether = 2 / 1. 16.30 g of the product was obtained, with a yield of 58%.
[0041] Example 7
[0042] Vitamin C (21.12 g, 120 mmol) was added to a three-necked flask containing 200 mL of tetrahydrofuran, and the internal temperature was lowered to -5°C in an ice-salt bath while stirring. Potassium tert-butoxide (11.20 g, 100 mmol) and pyridine (0.40 g, 5 mmol) were then slowly added to the reaction system in sequence. Nicotinoyl chloride hydrochloride (17.80 g, 100 mmol) was finally slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled to be stable at about -5°C during the addition process. After the addition was completed, the reaction was continued at -5°C for 6 h. Water was added to quench the reaction, the solvent tetrahydrofuran was spun off, and then the pH was adjusted to weak acidity with saturated ammonium chloride. The crude product of vitamin C nicotinate was obtained by suction filtration, and the product vitamin C nicotinate was obtained by recrystallization with ethyl acetate / petroleum ether = 2 / 1. 11.52 g of the product was obtained, with a yield of 41%.
[0043] Example 8
[0044] Vitamin C (21.12 g, 120 mmol) was added to a three-necked flask containing 200 mL of tetrahydrofuran, and stirred. The internal temperature was lowered to -5°C in an ice-salt bath. Then, sodium hydroxide (4.00 g, 100 mmol) and pyridine (0.40 g, 5 mmol) were slowly added to the reaction system in sequence. Finally, nicotinoyl chloride hydrochloride (17.80 g, 100 mmol) was slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled to be stable at about -5°C during the addition process. After the addition was completed, the reaction was continued at -5°C for 6 h. Water was added to quench the reaction, the solvent tetrahydrofuran was spun off, and then the pH was adjusted to weak acidity with saturated ammonium chloride. The crude product of vitamin C nicotinate was obtained by suction filtration, and the product vitamin C nicotinate was obtained by recrystallization with ethyl acetate / petroleum ether = 2 / 1. 4.22 g of the product was obtained, with a yield of 15%.
[0045] Example 9
[0046] Vitamin C (21.12 g, 120 mmol) was added to a three-necked flask containing 200 mL of tetrahydrofuran, and the internal temperature was lowered to -5°C in an ice-salt bath while stirring. Then, N,N-diisopropylethylamine (12.90 g, 100 mmol) and pyridine (0.40 g, 5 mmol) were slowly added to the reaction system in sequence. Finally, nicotinoyl chloride hydrochloride (17.80 g, 100 mmol) was slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled to be stable at about -5°C during the addition process. After the addition was completed, the reaction was continued at -5°C for 6 h. Water was added to quench the reaction, the solvent tetrahydrofuran was spun off, and then the pH was adjusted to weak acidity with saturated ammonium chloride. The crude product of vitamin C nicotinate was obtained by suction filtration, and the product vitamin C nicotinate was obtained by recrystallization with ethyl acetate / petroleum ether = 2 / 1. 17.42 g of the product was obtained, with a yield of 62%.
[0047] Example 10
[0048] Vitamin C (21.12 g, 120 mmol) was added to a three-necked flask containing 200 mL of tetrahydrofuran, and the internal temperature was lowered to -5°C in an ice-salt bath while stirring. Then, N,N-diisopropylethylamine (12.90 g, 100 mmol) and 4-dimethylaminopyridine (0.61 g, 5 mmol) were slowly added to the reaction system in sequence. Finally, nicotinoyl chloride hydrochloride (17.80 g, 100 mmol) was slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled to be stable at about -5°C during the addition process. After the addition was completed, the reaction was continued at -5°C for 2 h. Water was added to quench the reaction, the solvent tetrahydrofuran was spun off, and then the pH was adjusted to weak acidity with saturated ammonium chloride. The crude product of vitamin C nicotinate was obtained by suction filtration, and the product was recrystallized with ethyl acetate: petroleum ether = 2:1 to obtain 20.79 g of the product with a yield of 74%.
[0049] Embodiment 11
[0050] Vitamin C (21.12 g, 120 mmol) was added to a three-necked flask containing 200 mL of tetrahydrofuran, and the internal temperature was lowered to -5°C in an ice-salt bath while stirring. Then, N,N-diisopropylethylamine (25.8 g, 200 mmol) and 4-dimethylaminopyridine (0.61 g, 5 mmol) were slowly added to the reaction system in sequence. Finally, nicotinoyl chloride hydrochloride (17.80 g, 100 mmol) was slowly added dropwise using a constant pressure dropping funnel. The temperature was controlled to be stable at about -5°C during the addition process. After the addition was completed, the reaction was continued at -5°C for 2 h, and water was added to quench the reaction. The solvent tetrahydrofuran was spun off, and then the pH was adjusted to weak acidity with saturated ammonium chloride. The crude product of vitamin C nicotinate was obtained by suction filtration, and the product was recrystallized with ethyl acetate / petroleum ether = 2 / 1 to obtain 22.76 g of the product with a yield of 81%. 1 H NMR(400MHz,DMSO-d6)δ16.23(s,1H),10.61(s,1H),9.05(s,1H),8.81(d,1H),8.26( d,1H),7.53(t,6H),4.53(t,1H),5.66(s,1H),4.80-4.84(m,2H),4.22-4.43(dd,2H).
[0051] Although vitamin C nicotinate has a relatively large molecular weight and structure, its conversion efficiency advantage gives it a potential advantage in whitening effect. However, to judge its whitening effect, it is more inclined to rely on clinical data because in vitro studies are more diverse. Studies have shown that vitamin C nicotinate performs well in reducing skin dullness and spots caused by ultraviolet B (UVB), and clinical data clearly show that after using vitamin C nicotinate, the spot lightening effect is significant. Examples 12 to 16 are examples of clinical trials.
[0052] Example 12
[0053] Various concentrations of vitamin C nicotinate were added to cultured human melanoma (HM-3-KO). After four days of culture, the amount of melanin produced was measured by observing the color tone of each cell cluster. Figure 1 As shown, the greater the concentration of vitamin C nicotinate, the more significant its inhibitory effect on the production of human melanin. When the concentration is 0.2%, the amount of melanin produced decreases by 7 times compared to when no vitamin C nicotinate is added, which effectively inhibits the production of melanin.
[0054] Embodiment 13
[0055] Different concentrations of vitamin C nicotinate were added to mouse melanoma cells (B16-4A5). After 72 hours of culture, the cells were dissolved and extracted, and then L-dopa was added to the extract. After 60 hours at 37°C, the amount of dopachrome formed due to tyrosine activity was evaluated by measuring its absorbance at 540 nm, as shown in Figure 2. Figure 2 As shown, vitamin C nicotinate at a concentration of 0.02% or more inhibited the activity of intracellular tyrosine.
[0056] Embodiment 14
[0057] A clinical in vivo study was conducted on volunteers (30 volunteers, test period 3 weeks)
[0058] Test method: First, use a solar simulator to test the minimum erythema dose of each volunteer. Specifically, 6 doses of UV rays were used to irradiate the inside of the right arm. The minimum erythema dose was tested 24 hours after irradiation. Second, 1.5 doses of UV rays were used to irradiate the inside of the left upper arm of each volunteer to generate melanin. After irradiation, the sample was used. During the test period, the sample was applied twice a day, and there was a certain change in the sample application area of each volunteer ( Figure 3 ).
[0059] Embodiment 15
[0060] An in vivo clinical study on the skin lightening and anti-pigmentation effects of vitamin C nicotinate was conducted on volunteers (30 volunteers, test period: 56 days, concentration 2%). Figure 4 As shown, after 56 days, there was a very significant reduction in UV-induced pigmentation.
[0061] Example 16
[0062] An in vivo clinical study on the efficacy of vitamin C nicotinate in removing pigmentation was conducted on volunteers (30 volunteers with pigmentation, test period: 16 weeks, concentration 10%). Figure 5 As shown, after 16 weeks, the volunteers' pigmentation spots were significantly reduced.
[0063] Through comparative experiments: for synthesizing the compound nicotinyl chloride hydrochloride, Example 5 is the best solution; for synthesizing the compound vitamin C nicotinate, Example 11 is the best solution.
[0064] Vitamin C nicotinate is equivalent to the complete esterification reaction of niacinamide and vitamin C. It is a vitamin C derivative, more stable than vitamin C, can better penetrate sebum into the epidermis and dermis, can be quickly absorbed by the skin, and then converted into vitamin C to play a whitening effect, with a conversion rate of up to 84%. In addition, vitamin C nicotinate can better inhibit the increase of active oxygen in cells after UVB irradiation and enhance cell tolerance. These characteristics greatly improve the effective utilization rate of vitamin C nicotinate and its commercial value in the cosmetics industry.
[0065] The above content is a detailed description of the preparation and application of the present invention in combination with specific preferred embodiments, but it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, without departing from the preparation ideas and application directions of the present invention, several simple deductions or substitutions can be made, which should be regarded as belonging to the protection scope of the present invention.
Claims
1. Vitamin C nicotinate, characterized in that The structural formula is as follows:
2. The method for preparing vitamin C nicotinate according to claim 1, characterized in that: The steps include: S1, nicotinic acid hydrochloride reacts with a chlorination reagent in an organic solvent to obtain nicotinyl chloride hydrochloride; S2. Nicotinoyl chloride hydrochloride reacts with vitamin C in the presence of a catalyst and a base to generate vitamin C nicotinate.
3. The method for preparing vitamin C nicotinate according to claim 2, characterized in that: In step S1, the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran or DMF.
4. The method for preparing vitamin C nicotinate according to claim 2, characterized in that: In step S1, the chlorination agent is selected from thionyl chloride or oxalyl chloride, preferably oxalyl chloride.
5. The method for preparing vitamin C nicotinate according to claim 2, characterized in that: In step S1, the reaction temperature is selected from -10°C to 50°C, and the reaction time is 0.2 to 24 hours.
6. The method for preparing vitamin C nicotinate according to claim 2, characterized in that: In step S2, the catalyst is selected from 4-dimethylaminopyridine or pyridine.
7. The method for preparing vitamin C nicotinate according to claim 2, characterized in that: In step S2, the base is selected from triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide or sodium hydroxide; preferably selected from N,N-diisopropylethylamine.
8. The method for preparing vitamin C nicotinate according to claim 2, characterized in that: In step S2, the molar ratio of nicotinoyl chloride hydrochloride, vitamin C and alkali is 1:1-2:1.5-2.
5.
9. The method for preparing vitamin C nicotinate according to claim 2, characterized in that: In step S2, the reaction temperature is selected from -10°C to 30°C.
10. Use of the vitamin C nicotinate according to claim 1 in moisturizing, skin lightening, anti-pigmentation and spot removal.