Diastereomeric forms of a vitamin c derivative, and preparation and use thereof
Through nucleophilic substitution reaction and catalytic nucleophilic ring-opening reaction, the complexity and cost problems in the preparation process of octyl 2-glyceryl ascorbic acid were solved, and efficient, green and environmentally friendly large-scale production and the preparation of high-purity diastereoisomers were achieved, which is suitable for antioxidant applications in cosmetics.
Patent Information
- Application Number
- CN202311639335.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-01
- Publication Date
- 2025-10-10
- Estimated Expiration
- 2043-12-01
AI Technical Summary
The existing technology for preparing octyl 2-glyceryl ascorbic acid (GO-VC) has problems such as complex process, low yield, many by-products, and inability to scale up production, resulting in high cost and difficulty in obtaining optically pure diastereomers.
By adopting nucleophilic substitution reaction and catalytic nucleophilic ring-opening reaction, using phase transfer catalyst and nitrogen heterocyclic carbene catalyst, two diastereomers of octyl 2-glyceryl ascorbic acid (R-GO-VC and S-GO-VC) were prepared through an efficient and simple synthetic process, which simplified the process flow and improved the yield.
Efficient, green and environmentally friendly large-scale production has been achieved, and high-purity octyl 2-glyceryl ascorbic acid diastereomers have been obtained, which are suitable for use in cosmetics and have significant antioxidant effects.
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Figure CN117658963B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the field of cosmetics, in particular, to a diastereoisomer of a vitamin C derivative and its preparation and application. BACKGROUND
[0002] Octyl 2-glyceryl ascorbate (GO-VC) has many excellent effects as a new active ingredient in the field of skin care. It is more stable than pure vitamin C (ascorbic acid), has a wider pH range for use, and is more flexible in formulation.
[0003] Octyl 2-glyceryl ascorbate (GO-VC) has been shown to help synthesize sphingolipids in the skin and is a powerful antioxidant. The stability of octyl 2-glyceryl ascorbate (GO-VC) is greatly improved compared to ascorbic acid, greatly expanding its use scenarios. However, due to process limitations, commercially available GOVC is generally a mixture of two diastereoisomers, and there is no optically pure product.
[0004] The traditional preparation method has the following problems:
[0005] 1. The route is long, and the general steps are: first, protecting the diol of ascorbic acid, then reacting with octanol derivative to connect octanol, then deprotecting, and then reacting with glycerol and salifying with lysine. From the above steps, it can be found that it often involves the problems of multiple use of protecting groups and multi-step reactions;
[0006] 2. Low yield, many by-products, poor atom economy, and complicated post-treatment in the key step;
[0007] 3. Cannot be produced on a large scale, and the cost is extremely high. SUMMARY
[0008] The present application aims to overcome the above-mentioned defects, and provides a method for synthesizing two diastereoisomers (R-GOVC) and (S-GOVC) of octyl 2-glyceryl ascorbate (GO-VC) independently from each other, from cheap and readily available ascorbic acid as raw material. The process is efficient and simple, with high yield, green and environmentally friendly, and suitable for large-scale industrial production.
[0009] The present application provides a diastereoisomer of a vitamin C derivative, characterized in that its structure is as shown below:
[0010]
[0011] In addition, the present application also provides a preparation method of a diastereoisomer of a vitamin C derivative, characterized in that it comprises the following steps:
[0012] S1. Synthesis of octyl ascorbic acid or its derivatives using ascorbic acid or its derivatives and octane derivatives as raw materials;
[0013] S2. reacting octyl ascorbic acid or a derivative thereof with (R)-dehydrated glycerol / (S)-dehydrated glycerol to obtain the target product.
[0014] Taking the above compound as an example,
[0015] S1. Synthesis of 3-O-octyl-L-ascorbic acid using ascorbic acid and octane derivatives as raw materials;
[0016] S2. reacting 3-O-octyl-L-ascorbic acid with (R)-dehydrated glycerol / (S)-dehydrated glycerol to obtain ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one / ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2S)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one;
[0017] The above-mentioned octane derivative refers to a compound that can undergo nucleophilic substitution with the -OH group of ascorbic acid, and is most preferably a halogenated octane.
[0018] Among them, the structure of 3-0-octyl-L-ascorbic acid is shown below:
[0019]
[0020] The structure of the above-mentioned ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one is shown below:
[0021]
[0022] The structure of the above-mentioned ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2S)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one is shown below:
[0023]
[0024] Furthermore, the above method for preparing a diastereomer of a vitamin C derivative is also characterized in that:
[0025] Step S1 is carried out under the action of a phase transfer catalyst and a base at a reaction temperature of 40-80°C.
[0026] The phase transfer catalyst can be selected from any preparation having a phase transfer catalytic function, preferably an alkyl ammonium halide, most preferably tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride and the like.
[0027] The base can be selected from any one of an inorganic base and an organic base, and the most preferred base is triethylamine, cesium carbonate, potassium carbonate, or potassium hydroxide.
[0028] The above reaction is preferably carried out in a solvent such as DMSO, THF, or 1,4-dioxane.
[0029] Furthermore, the above method for preparing a diastereomer of a vitamin C derivative is also characterized in that:
[0030] The molar ratio of the ascorbic acid to the octane derivative is 1:1.05-1.2.
[0031] Furthermore, the above method for preparing a diastereomer of a vitamin C derivative is also characterized in that:
[0032] The molar ratio of the 3-0-octyl-L-ascorbic acid to (R) dehydroglycerol or (S) dehydroglycerol is 1:1-4.
[0033] Furthermore, the above method for preparing a diastereomer of a vitamin C derivative is also characterized in that:
[0034] Step S2 is carried out under the catalytic environment of nitrogen heterocyclic carbene at a reaction temperature of 60-100°C.
[0035] The above-mentioned nitrogen heterocyclic carbene catalyst is selected from alkyl-substituted tetrahydroimidazole derivatives or alkyl-substituted dihydroimidazole derivatives. If the above-mentioned substituent group is too small, the carbene reaction process will be unstable, and if the group is too large, the reaction will not proceed. It is preferably an alkyl group with 2-10 carbon atoms, which can be a linear or branched chain. The most preferred ones are: 1,3-di-tert-butylimidazole-2-ylidene, 1,3-bis(2-methylprop-2-yl)tetrahydro-1H-imidazole,
[0036] wait.
[0037] The above reaction is preferably carried out in a solvent such as DMSO or DMF.
[0038] The above reaction is also preferably carried out by adding a base, which can be selected from any one of an inorganic base and an organic base, and the most preferred base is potassium hydroxide, potassium carbonate, or triethylamine.
[0039] In addition, the present invention also provides the use of diastereomers of vitamin C derivatives as antioxidant preparations, characterized in that:
[0040] The diastereoisomer structure of the above vitamin C derivative is shown as follows:
[0041]
[0042] In addition, the present application also provides the use of the diastereoisomer of the vitamin C derivative in cosmetic / skin care products, characterized in that:
[0043] The diastereoisomer structure of the above vitamin C derivative is shown as follows:
[0044]
[0045] The above cosmetic / skin care product is a cosmetic / skin care product with antioxidant function.
[0046] Effects and advantages of the present application:
[0047] The first step of the synthesis method uses phase transfer catalyst in combination with inorganic base to carry out high-efficiency and high-selectivity nucleophilic substitution reaction to generate ether; the second step uses a new type of catalyst to activate the hydroxyl group of ascorbic acid, so that the reaction is more efficient and more specific, the product yield is high, the steps are few, and the purity is high, which is suitable for large-scale production. The obtained vitamin C derivative is used in cosmetics and skin care products, and has the characteristics of significant antioxidant effect. BRIEF DESCRIPTION OF DRAWINGS
[0048] Figure 1 . ABTS free radical scavenging rate column chart of sample R-GOVC at different concentrations;
[0049] Figure 2 . ABTS free radical scavenging rate column chart of sample S-GOVC at different concentrations;
[0050] Figure 3 . Superoxide anion scavenging rate column chart of sample R-GOVC at different concentrations;
[0051] Figure 4 . Superoxide anion scavenging rate column chart of sample S-GOVC at different concentrations; DETAILED DESCRIPTION
[0052] The present application can be implemented in various modifications and can have various embodiments, so that each specific embodiment is illustrated in the drawings and described. However, this is not intended to limit the present application to a specific embodiment, but should be understood to include all modifications, equivalents and even alternatives falling within the spirit and technical scope of the present application.
[0053] First part, preparation of new compound and condition screening
[0054] This embodiment provides a new compound, the structure of which is shown below:
[0055]
[0056] The compound is obtained via the following reaction formula:
[0057]
[0058] In the above reaction process S1, the molar ratio of ascorbic acid to the octane derivative is 1:1.05-1.2. S1 is carried out in the presence of a phase transfer catalyst and a base at a reaction temperature of 40-80°C. The phase transfer catalyst can be selected from any agent having phase transfer catalytic properties, preferably an alkyl ammonium halide, most preferably tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, etc., and the amount used is 1-1.2 times the molar amount of ascorbic acid. The base can be selected from any inorganic base or organic base, most preferably triethylamine, cesium carbonate, potassium carbonate, or potassium hydroxide, and the amount used is 1-1.5 times the molar amount of ascorbic acid. The above reaction is preferably carried out in a solvent such as DMSO, THF, 1,4-dioxane, etc.
[0059] In the above reaction process S2, the molar ratio of the above-mentioned 3-0-octyl-L-ascorbic acid 126100-57-0 and (R)-anhydroglycerol or (S)-anhydroglycerol is 1:1-4. S2 is carried out in the presence of a nitrogen heterocyclic carbene catalyst at a reaction temperature of 60-100°C. The above-mentioned nitrogen heterocyclic carbene catalyst is selected from alkyl- or aromatic-substituted tetrahydroimidazole derivatives or alkyl- or aromatic-substituted dihydroimidazole derivatives, and the amount used is 0.001-0.05 times the molar amount of 3-0-octyl-L-ascorbic acid. Preferred examples include 1,3-di-tert-butylimidazole-2-ylidene and 1,3-bis(2-methylprop-2-yl)tetrahydro-1H-imidazole. The above reaction is preferably carried out in a solvent such as DMSO or DMF. The above reaction is also preferably carried out by adding a base, which can be selected from any one of an inorganic base or an organic base. The most preferred base is potassium hydroxide, potassium carbonate, or triethylamine, and the amount used is 1.2-2 times the molar amount of 3-O-octyl-L-ascorbic acid.
[0060] The following are examples of optimal conditions, optional conditions, and comparative conditions:
[0061] Example 1: (Optimal Conditions)
[0062] (1) Add 176 g (1 mol) of ascorbic acid, 202.6 g (1.05 mol) of bromooctane, 369 g (1 mol) of tetrabutylammonium iodide, 390 g (1.2 mol) of cesium carbonate, and 2 L of 1,4-dioxane to a 5 L reactor in sequence, heat to 60°C, and stir for 120 minutes. Remove the solvent under reduced pressure, add 2 L of water, and extract with 4 L of dichloromethane. Spin dry to obtain 306.3 g of 3-0-octyl-L-ascorbic acid, with a yield of 93.3% and a purity of 92%. The spectrum is consistent with that reported in the literature. [Beifuss, Uwe; et al Tetrahedron (2000), 56 (3), 357-361] [Beifuss, Uwe; et al Synlett (1999), (1), 147-149]
[0063] (2) 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 3 and 500 g of DMF were added to a 5 L reactor and stirred to dissolve. 88.8 g (1.2 mol) of (R)-dehydrated glycerol and 3.6 g (0.02 mol) of 1,3-di-tert-butylimidazole-2-ylidene were added as a catalyst. 84.1 g (1.5 mol) of potassium hydroxide were added. The temperature was raised to 80° C. and stirred at this temperature for 6 hours. 500 g of water and 600 g of ethyl acetate were added, and after standing for stratification, the upper ethyl acetate phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give 329.8 g of the product ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one) with a yield of 91% and a purity of 94%.
[0064] MS=363.58[M+H] +
[0065] 1 H NMR(500MHz,Chloroform-d)δ4.76(d,J=7.0Hz,1H),4.35(dd,J=12.5,6.9Hz,1H),4.29(dd, J=12.4,6.9Hz,1H),4.18–4.07(m,2H),4.05(q,J=7.0Hz,1H),3.85–3.72(m,2H),3.71(dd,J =12.2,6.6Hz,1H),3.68(d,J=6.9Hz,1H),3.68–3.62(m,1H),1.67(pd,J=7.1,1.7Hz,2H),1. 46–1.37(m,1H),1.40–1.34(m,1H),1.37–1.25(m,7H),1.29–1.22(m,1H),0.94–0.83(m,3H).
[0066] (3) 3-O-octyl-L-ascorbic acid (500 g) prepared in Example 3 and DMF (500 g) were added to a 5 L reactor and stirred to dissolve. 88.8 g (1.2 mol) of (S)-dehydrated glycerol were added, 3.6 g (0.02 mol) of 1,3-di-tert-butylimidazole-2-yl was added as a catalyst, and 84.1 g (1.5 mol) of potassium hydroxide was added. The temperature was raised to 80° C. and stirred at this temperature for 6 hours. 500 g of water and 600 g of ethyl acetate were added, and after standing for decomposition, the upper ethyl acetate phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give 326.1 g of the product ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2S)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one) with a yield of 90% and a purity of 95%. MS = 363.58 [M+H] +
[0067] Example 2 (First step condition screening) (Phase transfer catalyst is different)
[0068] To a 5L reactor, 176g (1 mol) of ascorbic acid, 202.6g (1.05 mol) of bromooctane, 322g (1 mol) of tetrabutylammonium bromide, 390g (1.2 mol) of cesium carbonate, and 2L of 1,4-dioxane were added in sequence. The temperature was raised to 60°C and stirred for 120 minutes. The solvent was removed under reduced pressure, and 2L of water and 4L of dichloromethane were added for extraction. The mixture was then spin-dried to obtain 206g of 3-0-octyl-L-ascorbic acid, with a yield of 62.8% and a purity of 80%. The spectrum was consistent with that reported in the literature.
[0069] Example 3 (First step condition screening) (Phase transfer catalyst is different)
[0070] To a 5L reactor, 176g (1 mol) of ascorbic acid, 202.6g (1.05 mol) of bromooctane, 322g (1 mol) of tetrabutylammonium chloride, 390g (1.2 mol) of cesium carbonate, and 2L of 1,4-dioxane were added in sequence. The temperature was raised to 60°C and stirred for 120 minutes. The solvent was removed under reduced pressure, and 2L of water and 4L of dichloromethane were added for extraction. The product was then spin-dried to obtain 200g of 3-0-octyl-L-ascorbic acid, with a yield of 62.0% and a purity of 77%. The spectrum was consistent with that reported in the literature.
[0071] Example 4 (first step condition screening) (different bases)
[0072] To a 5L reactor, 176g (1 mol) of ascorbic acid, 202.6g (1.05 mol) of bromooctane, 369g (1 mol) of tetrabutylammonium iodide, 165.9g (1.2 mol) of potassium carbonate, and 2L of 1,4-dioxane were added in sequence. The temperature was raised to 60°C and stirred for 120 minutes. The solvent was removed under reduced pressure, and 2L of water and 4L of dichloromethane were added for extraction. The mixture was then spin-dried to obtain 262.2g of 3-0-octyl-L-ascorbic acid, with a yield of 79.9% and a purity of 92%. The spectrum was consistent with that reported in the literature.
[0073] Example 5 (First step condition screening) (different bases)
[0074] In a 5L reactor, 176g (1mol) of ascorbic acid, 202.6g (1.05mol) of bromooctane, 369g (1mol) of tetrabutylammonium iodide, 67.9g (1.2mol) of potassium hydroxide, and 2L of 1,4-dioxane were added in sequence, and the temperature was raised to 60°C and stirred for 120 minutes. The solvent was removed under reduced pressure, 2L of water and 4L of dichloromethane were added for extraction, and the mixture was dried to obtain 62.9g of 3-0-octyl-L-ascorbic acid, with a yield of 19.1% and a purity of 62%.
[0075] Example 6 (First step condition screening) (different bases)
[0076] To a 5L reactor, 176g (1 mol) of ascorbic acid, 202.6g (1.05 mol) of bromooctane, 369g (1 mol) of tetrabutylammonium iodide, 121g (1.2 mol) of triethylamine, and 2L of 1,4-dioxane were added in sequence. The temperature was raised to 60°C and stirred for 120 minutes. The solvent was removed under reduced pressure, and 2L of water and 4L of dichloromethane were added for extraction. TLC monitoring revealed no product.
[0077] Example 7: (First step condition screening) (different solvents)
[0078] To a 5L reactor, 176 g (1 mol) of ascorbic acid, 202.6 g (1.05 mol) of bromooctane, 369 g (1 mol) of tetrabutylammonium iodide, 390 g (1.2 mol) of cesium carbonate, and 2 L of DMSO were added in sequence. The temperature was raised to 60°C and stirred for 120 minutes. The solvent was removed under reduced pressure, and 2 L of water and 4 L of dichloromethane were added for extraction. TLC monitoring revealed that no product was obtained.
[0079] Example 8: (First step condition screening) (different solvents)
[0080] In a 5L reactor, ascorbic acid 176 g (1 mol), bromooctane 202.6 g (1.05 mol), tetrabutylammonium iodide 369 g (1 mol), cesium carbonate 390 g (1.2 mol), THF 2 L, was added successively and stirred at 60 °C for 120 min. The solvent was removed under reduced pressure, water 2 L was added, and dichloromethane 4 L was used to extract, and spin dry to get 3-0-octyl-L-ascorbic acid 63 g, yield 19.5%; purity 72%.
[0081] Example 9: (first step condition screening) (temperature different)
[0082] In a 5L reactor, ascorbic acid 176 g (1 mol), bromooctane 202.6 g (1.05 mol), tetrabutylammonium iodide 369 g (1 mol), cesium carbonate 390 g (1.2 mol), 1,4 dioxane 2 L, was added successively and stirred at 40 °C for 120 min. The solvent was removed under reduced pressure, water 2 L was added, and dichloromethane 4 L was used to extract, and TLC monitoring found that no product was obtained.
[0083] Example 10: (first step condition screening) (temperature different)
[0084] In a 5L reactor, ascorbic acid 176 g (1 mol), bromooctane 202.6 g (1.05 mol), tetrabutylammonium iodide 369 g (1 mol), cesium carbonate 390 g (1.2 mol), 1,4 dioxane 2 L, was added successively and stirred at 80 °C for 120 min. The solvent was removed under reduced pressure, water 2 L was added, and dichloromethane 4 L was used to extract, and spin dry to get 3-0-octyl-L-ascorbic acid 300.3 g, yield 92%; purity 89%, the spectrum was consistent with the reported literature.
[0085] Example 11: (first step condition screening) (substrate equivalent different)
[0086] In a 5L reactor, ascorbic acid 176 g (1 mol), bromooctane 231.5 g (1.2 mol), tetrabutylammonium iodide 369 g (1 mol), cesium carbonate 390 g (1.2 mol), 1,4 dioxane 2 L, was added successively and stirred at 60 °C for 120 min. The solvent was removed under reduced pressure, water 2 L was added, and dichloromethane 4 L was used to extract, and spin dry to get 3-0-octyl-L-ascorbic acid 306 g, yield 93.1%; purity 88%.
[0087] Example 12: (second step condition screening) (catalyst different)
[0088] To a 5 L reactor, 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 1 and 500 g of THF were added, stirred and dissolved, 88.8 g (1.2 mol) of (R) dehydrated glycerol were added, 3.6 g (0.02 mol) of 1,3-bis(2-methylprop-2-yl)tetrahydro-1H-imidazole as a catalyst were added, and 84.1 g (1.5 mol) of potassium hydroxide were added. The temperature was raised to 80° C. and stirred at this temperature for 6 hours. 500 g of water and 600 g of ethyl acetate were added, and after standing for stratification, the upper ethyl acetate phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to give 229.7 g of the product ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one) with a yield of 63% and a purity of 84%.
[0089] Example 13: (Second step condition screening) (Different catalysts)
[0090] To a 5 L reactor, 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 1 and 500 g of THF were added and stirred to dissolve. 88.8 g (1.2 mol) of (R)-anhydroglycerol was added, along with 8.4 g (0.02 mol) of 1,3-bis[4-methyl-2,6-di(prop-2-yl)phenyl]-2,3-dihydro-1H-imidazole as a catalyst, and 84.1 g (1.5 mol) of potassium hydroxide. The reaction mixture was heated to 80° C. and stirred at this temperature for 6 hours. TLC monitoring revealed no product.
[0091] Example 14: (Second step condition screening) (Different catalysts)
[0092] To a 5 L reactor, 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 1 and 500 g of THF were added and dissolved by stirring. 88.8 g (1.2 mol) of (R)-anhydroglycerol was added, along with 8.4 g (0.02 mol) of 1,3-bis[4-methyl-2,6-di(prop-2-yl)phenyl]tetrahydro-1H-imidazole as a catalyst, and 84.1 g (1.5 mol) of potassium hydroxide. The mixture was heated to 80° C. and stirred at this temperature for 6 hours. TLC monitoring revealed no product.
[0093] Example 15 (Second step condition screening) (different solvents)
[0094] 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 1 and 500 g of DMSO were added to a 5 L reactor and stirred to dissolve. 88.8 g (1.2 mol) of (R) dehydrated glycerol, 3.6 g (0.02 mol) of 1,3-di-tert-butylimidazole-2-ylidene as a catalyst, and 84.1 g (1.5 mol) of potassium hydroxide were added. The temperature was raised to 80° C. and stirred at this temperature for 6 hours. 500 g of water and 600 g of ethyl acetate were added. After standing and stratification, the upper ethyl acetate phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 240.8 g of the product ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one) with a yield of 66% and a purity of 90%.
[0095] Example 16 (Second step condition screening) (different solvents)
[0096] To a 5 L reactor, 328.4 g (1 mol) of 3-O-octyl-L-ascorbic acid prepared in Example 1 and 500 g of water were added and stirred to dissolve. 88.8 g (1.2 mol) of (R)-anhydroglycerol and 3.6 g (0.02 mol) of 1,3-di-tert-butylimidazole-2-ylidene as a catalyst were added. 84.1 g (1.5 mol) of potassium hydroxide were also added. The temperature was raised to 80° C. and stirred at this temperature for 6 hours. TLC monitoring revealed no product.
[0097] Example 17: (Second step condition screening) (different temperatures)
[0098] 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 3 and 500 g of DMF were added to a 5 L reactor and stirred to dissolve. 88.8 g (1.2 mol) of (R) dehydrated glycerol, 3.6 g (0.02 mol) of 1,3-di-tert-butylimidazole-2-ylidene as a catalyst, and 84.1 g (1.5 mol) of potassium hydroxide were added. The temperature was raised to 60° C. and stirred at this temperature for 6 hours. 500 g of water and 600 g of ethyl acetate were added. After standing and stratification, the upper ethyl acetate phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 105.8 g of the product ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one) with a yield of 29% and a purity of 74%.
[0099] Example 18: (Second step condition screening) (different temperatures)
[0100] To a 5 L reactor, 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 3 and 500 g of DMF were added and dissolved by stirring. 88.8 g (1.2 mol) of (R)-anhydroglycerol was added, 3.6 g (0.02 mol) of 1,3-di-tert-butylimidazole-2-ylidene was added as a catalyst, and 84.1 g (1.5 mol) of potassium hydroxide was added. The temperature was raised to 100° C. and stirred at this temperature for 6 hours. 500 g of water and 600 g of ethyl acetate were added, and after standing for decomposition, the upper ethyl acetate phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 323.8 g of the product ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one) with a yield of 90% and a purity of 84%.
[0101] Example 19: (Second step condition screening) (different bases)
[0102] 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 3 and 500 g of DMF were added to a 5 L reactor and stirred to dissolve. 88.8 g (1.2 mol) of (R) dehydrated glycerol were added, 3.6 g (0.02 mol) of 1,3-di-tert-butyl imidazole-2-ylidene was added as a catalyst, and 207 g (1.5 mol) of potassium carbonate was added. The temperature was raised to 80° C. and stirred at this temperature for 6 hours. 500 g of water and 600 g of ethyl acetate were added. After standing and stratification, the upper ethyl acetate phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 129 g of the product ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one) with a yield of 35.7% and a purity of 91%.
[0103] Example 20: (Second step condition screening) (different bases)
[0104] 328.4 g (1 mol) of 3-0-octyl-L-ascorbic acid prepared in Example 3 and 500 g of DMF were added to a 5 L reactor and stirred to dissolve. 88.8 g (1.2 mol) of (R) dehydrated glycerol were added, 3.6 g (0.02 mol) of 1,3-di-tert-butyl imidazole-2-ylidene was added as a catalyst, and 151 g (1.5 mol) of triethylamine was added. The temperature was raised to 80° C. and stirred at this temperature for 6 hours. 500 g of water and 600 g of ethyl acetate were added. After standing and stratification, the upper ethyl acetate phase was taken, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 30 g of the product ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one) with a yield of 8.3% and a purity of 81%.
[0105] Part II: Performance test experiment:
[0106] 1. Test Purpose
[0107] This test is divided into two parts. The first part detects the ability of the sample to scavenge ABTS free radicals, and the second part detects the ability of the sample to scavenge superoxide anions. The comprehensive test results are used to evaluate the antioxidant effect of the sample.
[0108] 2. ABTS free radical scavenging test
[0109] 1. Test Method
[0110] 1.1 In vitro ABTS free radical scavenging assay
[0111] Prepare the sample into a test solution of corresponding concentration, prepare the reaction system in a 96-well plate according to the reagent addition amounts in Table 1, mix well, set up 3 replicate wells for each concentration and 1 background control well.
[0112] Table 1 ABTS free radical scavenging test reaction system settings
[0113]
[0114] After incubation at room temperature for 2-6 minutes, the absorbance OD value was read at 734 nm, and the scavenging rate of the sample on ABTS free radicals was calculated according to the following formula.
[0115] ABTS free radical scavenging rate (%) = {1-(T1-T2) / (C1-C2)}*100%
[0116] Where: C1——absorbance value of ABTS system in solvent control group;
[0117] C2——Absorbance value of solvent control group without ABTS system;
[0118] T1——the sample group has the absorbance value of ABTS system;
[0119] T2——absorbance value of the sample group without ABTS system;
[0120] 1.2 Statistical analysis of results
[0121] Graphs were generated using GraphPad Prism, and the results are expressed as mean ± SD. Comparisons between groups were analyzed using the t-test. All statistical analyses were two-tailed. P < 0.05 was considered a significant difference, and P < 0.01 was considered a highly significant difference.
[0122] 2. Test results
[0123] 2.1 ABTS free radical scavenging rate of sample R-GOVC
[0124] The test was carried out according to the ABTS free radical scavenging rate operation steps. The free radical scavenging rates of the sample R-GOVC at various concentrations are shown in Table 2. The changes in free radical scavenging rates at different concentrations are shown in Figure 1 :
[0125] Table 2 Summary of ABTS free radical scavenging rates of sample R-GOVC at different concentrations
[0126]
[0127] Note: When the t-test method was used for statistical analysis, the significance was indicated by *, P-value < 0.05 was indicated by *, and P-value < 0.01 was indicated by ** compared with the control group.
[0128] Compared with the control group, the sample R-GOVC at concentrations of 0.01%, 0.1%, 1%, 2% and 4% could significantly inhibit ABTS free radicals, with free radical scavenging rates of 56.36%, 68.41%, 75.52%, 86.54% and 96.73%, respectively.
[0129] 2.2 ABTS radical scavenging rate of sample S-GOVC
[0130] The test was carried out according to the ABTS free radical scavenging rate operation steps. The free radical scavenging rates of the sample S-GOVC at various concentrations are shown in Table 3. The changes in free radical scavenging rates at different concentrations are shown in Figure 2 :
[0131] Table 3 Summary of ABTS free radical scavenging rates of sample S-GOVC at different concentrations
[0132]
[0133] Note: When the t-test method was used for statistical analysis, the significance was indicated by *, P-value < 0.05 was indicated by *, and P-value < 0.01 was indicated by ** compared with the control group.
[0134] Compared with the control group, the sample S-GOVC at concentrations of 0.01%, 0.1%, 1%, 2% and 4% could significantly inhibit ABTS free radicals, with free radical scavenging rates of 76.27%, 89.39%, 96.52%, 97.11% and 97.70%, respectively.
[0135] 3. Superoxide Anion Clearance Test
[0136] 1. Test Method
[0137] 1.1 In vitro superoxide anion scavenging assay
[0138] Prepare the sample into the test solution of the corresponding concentration. According to the kit instructions, prepare the reaction system according to the amount of each reagent added in Table 4, mix well, and replace the sample with distilled water or sample solvent as a negative control or solvent control. Set up 3 replicate wells for each concentration and 1 background control well.
[0139] Table 4 Superoxide anion scavenging test reaction system settings
[0140]
[0141] 1.2 Results Settlement
[0142] Superoxide anion clearance rate (%) = {1-(T1-T2) / (C1-C2)}*100%
[0143] Where: C1——absorbance value of the solvent control group with superoxide anion system;
[0144] C2——absorbance value of the solvent control group without superoxide anion system;
[0145] T1——absorbance value of the sample group with superoxide anion system;
[0146] T2——absorbance value of the sample group without superoxide anion system;
[0147] 1.3 Statistical analysis of results
[0148] Graphs were generated using GraphPad Prism, and the results are expressed as mean ± SD. Comparisons between groups were analyzed using the t-test. All statistical analyses were two-tailed. P < 0.05 was considered a significant difference, and P < 0.01 was considered a highly significant difference.
[0149] 2. Test results
[0150] 2.1 Superoxide anion clearance rate of sample R-GOVC
[0151] The test was carried out according to the superoxide anion scavenging rate operation steps. The free radical scavenging rates of the sample R-GOVC at various concentrations are shown in Table 5. The trend of free radical scavenging rates at different concentrations is shown in Figure 3 :
[0152] Table 5 Summary of superoxide anion clearance rates of sample R-GOVC at different concentrations
[0153]
[0154] Note: When the t-test method was used for statistical analysis, the significance was indicated by *, P-value < 0.05 was indicated by *, and P-value < 0.01 was indicated by ** compared with the control group.
[0155] Compared with the control group, the sample R-GOVC at the concentration of 0.01%, 0.1%, 1%, 2%, and 4% can significantly inhibit the superoxide anion, with the clearance rates being 14.24%, 43.83%, 48.50%, 59.68%, and 66.25%, respectively. 2.2 Superoxide anion clearance rate of sample S-GOVC
[0156] The test was carried out according to the superoxide anion scavenging rate operation steps. The free radical scavenging rates of the sample S-GOVC at various concentrations are shown in Table 6. The trend of free radical scavenging rates at different concentrations is shown in Figure 4 :
[0157] Table 6 Summary of superoxide anion clearance rates of sample S-GOVC at different concentrations
[0158]
[0159]
[0160] Note: When the t-test method was used for statistical analysis, the significance was indicated by *, P-value < 0.05 was indicated by *, and P-value < 0.01 was indicated by ** compared with the control group.
[0161] Compared with the control group, the sample S-GOVC at concentrations of 0.01%, 0.1%, 1%, 2% and 4% could significantly inhibit superoxide anions, with clearance rates of 33.54%, 56.73%, 63.43%, 85.63% and 93.75%, respectively.
[0162] IV. Conclusion
[0163] 1. Compared with the control group, sample R-GOVC can significantly inhibit ABTS free radicals and superoxide anions at 0.01%, 0.1%, 1%, 2%, 4% concentrations. It shows that sample R-GOVC has antioxidant effect at the corresponding concentration.
[0164] 2. Compared with the control group, sample S-GOVC can significantly inhibit ABTS free radicals and superoxide anions at 0.01%, 0.1%, 1%, 2%, 4% concentrations. It shows that sample S-GOVC has antioxidant effect at the corresponding concentration.
[0165] 3. At 0.01%, 0.1%, 1%, 2%, 4% concentrations, the clearance rate of sample S-GOVC on ABTS free radicals and superoxide anions is higher than that of sample R-GOVC. It shows that the antioxidant effect of sample S-GOVC is stronger than that of sample R-GOVC at the corresponding concentration.
[0166] Although the above is described centering on the embodiments, this is only an example and does not limit the present application, and it is clear for those skilled in the art that various modifications and applications not exemplified above can be made within the scope of the essential characteristics of the embodiments. For example, each constituent element specifically shown in the embodiments can be modified and implemented. Moreover, various differences related to such modifications and applications should be interpreted as included in the scope of the present application defined in the appended claims.
Claims
1. A method for preparing diastereomers of vitamin C derivatives, characterized in that: The following steps are included: S1. Synthesis of 3-O-octyl-L-ascorbic acid using ascorbic acid and octane derivatives as raw materials; S2. reacting 3-O-octyl-L-ascorbic acid with (R)-dehydrated glycerol / (S)-dehydrated glycerol to obtain ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one / ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2S)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one; The structure of 3-0-octyl-L-ascorbic acid is shown below: The structure of the ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one is shown below: The structure of the ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2S)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one is shown below: Step S1 is carried out under the action of a phase transfer catalyst and a base at a reaction temperature of 60-80°C; The phase transfer catalyst is selected from alkyl ammonium halides; the base is selected from cesium carbonate and potassium carbonate; The reaction solvent of step S1 is selected from 1,4-dioxane; Step S2 is carried out under the catalytic environment of 1,3-di-tert-butylimidazole-2-ylidene or 1,3-bis(2-methylprop-2-yl)tetrahydro-1H-imidazole at a reaction temperature of 80-100° C.; The reaction solvent of step S2 is selected from DMF and DMSO; Potassium hydroxide is also added to the reaction in step S2.
2. The method for preparing diastereomers of a vitamin C derivative according to claim 1, wherein: The molar ratio of the ascorbic acid to the octane derivative is 1:1.05-1.
2.
3. The method for preparing a diastereomer of a vitamin C derivative according to claim 1, wherein: The molar ratio of the 3-0-octyl-L-ascorbic acid to (R) dehydrated glycerol or (S) dehydrated glycerol is 1:1-4.
4. A method for preparing a diastereomer of a vitamin C derivative according to any one of claims 1 to 3, characterized in that: The ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one / ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2S)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one is used to prepare an antioxidant preparation.
5. The method for preparing a diastereomer of a vitamin C derivative according to any one of claims 1 to 3, characterized in that: The ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one / ((5R)-5-[(1S)-1,2-dihydroxyethyl]-3-{[(2S)-2,3-dihydroxypropyl]oxy}-4-(octyloxy)-2,5-dihydrofuran-2-one is used to prepare cosmetics / skin care products.
6. The method for preparing diastereomers of a vitamin C derivative according to claim 5, wherein: The cosmetics / skin care products are cosmetics / skin care products with antioxidant function.