JP5572358B2 - A glyceryl ascorbyl acylated derivative or a salt thereof, a production method thereof, and a cosmetic. - Google Patents

Description

The present invention relates to an acylated derivative of glyceryl ascorbic acid or a salt thereof suitably used as a raw material for cosmetics. The present invention also relates to a method for producing the acylated derivative of glyceryl ascorbic acid or a salt thereof . The present invention further relates to a cosmetic comprising the glyceryl ascorbyl acylated derivative or a salt thereof.

  Ascorbic acid is a safe and useful substance, and is known as a compound having an antioxidant effect, a collagen production promoting effect, an excellent whitening effect, and the like. However, ascorbic acid is very unstable with respect to light, heat and oxidation, and its use in cosmetics, foods, pharmaceuticals and the like has been hindered. Therefore, various ascorbic acid derivatives or salts thereof have been proposed as those with improved temporal stability over ascorbic acid, such as blending into skin external preparations for whitening, blending as a moisturizer, collagen production promoter, etc. For the purpose, the formulation to cosmetics is proposed. (Patent Document 1, Patent Document 2)

  However, among the ascorbic acid derivatives of Patent Document 1, glyceryl ascorbic acid, which is particularly excellent in moisturizing effect, is water-soluble. Therefore, when applied to hydrophobic sites such as the skin and mucous membrane, the permeability becomes low, and the target tissue is reached. There was a problem that it was difficult to reach.

  In order to solve this problem, Patent Document 1 discloses a compound in which a long-chain alkyl group is ether-bonded to a glycerin skeleton, but only a simple ether bond of an alkyl group to a glyceryl group yields Glyceryl ascorbic acid is difficult to release in the body, and the moisturizing effect of glyceryl ascorbic acid in the skin cannot be expected. In addition, the manufacturing cost is high.

Patent Document 3 and Patent Document 4 disclose acylated derivatives of glycosyl-L-ascorbic acid, which are shown to be excellent for radical scavenging ability and anti-scurvy, but have no moisturizing effect. It is not disclosed, and it is difficult to expect a moisturizing effect that greatly contributes to improvement of skin flexibility and rough skin.

  Therefore, there is a demand for a glyceryl ascorbyl acylated derivative that has a moisturizing effect possessed by glyceryl ascorbic acid, has good permeability to the skin, and is excellent in whitening effect, collagen production promoting effect, etc. and can be produced at low cost. Yes.

WO2009 / 0253328 JP 2005-60239 A JP 11-286497 A Japanese Patent No. 4307784

  The present invention has an excellent function possessed by glyceryl ascorbic acid and is excellent in skin permeability, and further has a moisturizing effect, a feeling of use, an effect of preventing rough skin (an effect of improving rough skin), an anti-aging effect, an effect of preventing skin photoaging, It is an object to provide a novel glyceryl ascorbyl acylated derivative or a salt thereof excellent in collagen production promotion effect, whitening effect, Maillard reaction inhibition effect, wrinkle formation inhibition effect, antioxidant effect, blood circulation promotion effect, cell proliferation effect, etc. And Another object of the present invention is to provide a production method capable of easily and inexpensively producing this novel glyceryl ascorbic acid acylated derivative or a salt thereof. Another object of the present invention is to provide a cosmetic having an excellent function by incorporating the novel acylated ascorbic acid derivative or a salt thereof.

  As a result of intensive studies in view of the above circumstances, the present inventors have found that although glyceryl ascorbyl acylated derivatives are oil-soluble, they have high moisturizing properties in vivo. It has also been found that the acylated derivative of the present invention can be obtained by reacting glyceryl ascorbic acid with an acylating agent. These acylated derivatives of glyceryl ascorbic acid can be used as cosmetics, and can also be used as food additives, feeds and the like. The present invention has been completed based on these findings.

  That is, the present invention solves the above problems by providing an acylated derivative of glyceryl ascorbic acid. (Claim 1)

  The invention of claim 2 is such that hydrogen is bonded to oxygen at the 5-position of the ascorbic acid skeleton, and these glyceryl ascorbic acid acylated derivatives are easy to apply when used as cosmetics, and are sticky when applied. Excellent usability, such as lack of Claim 2 corresponds to this particularly preferable embodiment.

  The invention of claim 3 is one in which an acyl group is bonded to one of the hydroxyl groups of glyceryl ascorbic acid, and is excellent in solubility in water, and is blended in cosmetics such as lotion with high blending. It is also possible to do. Claim 3 corresponds to this particularly preferable aspect.

  In the invention of claim 4, only the hydroxyl group at the 6-position of the ascorbic acid skeleton of glyceryl ascorbic acid is substituted with an acyl group, and the cream or Improves the stability of emulsions such as emulsions. Claim 4 corresponds to this particularly preferable aspect.

  The invention of claim 5 is the one in which an acyl group is substituted at the 6-position of the ascorbic acid skeleton of 2-O-glyceryl ascorbic acid, and the acyl group is substituted at the 6-position of the ascorbic acid skeleton. Since glycerin is bonded to the 2-position of the acid skeleton, the stability over time, the emulsion stability, the absence of coloring over time, and the like are excellent. Further, a neutralized salt of the hydroxyl group at the 3-position can be prepared by a known method, and the solubility in water can be improved. The fifth aspect corresponds to this particularly preferable aspect.

  In addition, the present invention provides a method for easily producing a glyceryl ascorbic acid acylated derivative by providing a method for producing a glyceryl ascorbic acid acylated derivative, which comprises reacting glyceryl ascorbic acid with an acylating agent. Is a solution. (Claim 6)

  In addition, the present invention provides a cosmetic containing an acylated derivative of glyceryl ascorbic acid having excellent functions such as a moisturizing effect, a feeling of use, a rough skin preventing effect, an anti-aging effect, a collagen production promoting effect, and a whitening effect. Thus, a cosmetic having an excellent function is provided to solve the above problems. (Claim 7)

The glyceryl group referred to in the present invention represents HO—CH ₂ —CH (OH) —CH ₂ —, and glyceryl ascorbic acid is an oxygen of each hydroxyl group of ascorbic acid or a glyceryl group in plural oxygens. Combined. The glyceryl ascorbic acid acylated derivatives of the present invention include all glyceryl ascorbic acid acylated derivatives that impart hydrophobicity to glyceryl ascorbic acid. A desirable glyceryl ascorbic acid for the acylated derivative is 2-O-glyceryl ascorbic acid in which a glyceryl group of HO—CH ₂ —CH (OH) —CH ₂ — is bonded to oxygen of the hydroxyl group at the 2-position of ascorbic acid. It is.

The acylation referred to in the present invention means introducing an acyl group R ⁶ —CO— into glyceryl ascorbic acid. Here, R ⁶ is preferably a linear or branched saturated or unsaturated alkyl group, usually a C 2-17 alkyl group, more preferably 4-15. Accordingly, the glyceryl ascorbic acid acylated derivative of the present invention is a general compound in which an acyl group is bonded to one or more hydroxyl groups in glyceryl ascorbic acid, preferably one hydroxyl group of the ascorbic acid skeleton in glyceryl ascorbic acid as described above. Represents.

  Specific examples of the acylated derivative of glyceryl ascorbic acid of the present invention can include the compounds shown below, but the scope of the present invention is not limited to those shown below.

In the following examples, the acyl group means formyl group, acetyl group, propionyl group, butanoyl group , pentanoyl group, hexanoyl group, heptanoyl group, octanoyl group, nonyl group, decanoyl group, undecanoyl group, dodecanoyl group, tetradecanoyl group Group, hexadecanoyl group, eicosanoyl group, hexadecenoyl group, octadecenoyl group, octadecatrienoyl group, icosatetraenoyl group, isooctanoyl group, isopalmitoyl group, isostearoyl group, 2-propylpentanoyl group, 2-butylhexanoyl group A noyl group, a 2-pentylheptanoyl group, and the like;

  2-O-glyceryl-6-O-acyl ascorbic acid, 2-O-glyceryl-5-O-acyl ascorbic acid, 2-O-glyceryl-3-O-acyl ascorbic acid, 2-O-acyl glyceryl ascorbic acid 3-O-glyceryl-6-O-acyl ascorbic acid, 3-O-glyceryl-5-O-acyl ascorbic acid, 3-O-glyceryl-2-O-acyl ascorbic acid, 3-O-acyl glyceryl ascorbine An acid etc. are mentioned as an acylated derivative of glyceryl ascorbic acid.

  The acylated derivatives of the present invention can be produced by various methods. For example, the acylated derivative of the present invention can be obtained by reacting glyceryl ascorbic acid with various acylating agents.

  Examples of acylating agents include carboxylic acid chlorides, carboxylic acid anhydrides, carboxylic acid esters, carboxylic acid amides, carboxylic acids, etc., and the acylating agents referred to in the present invention include, for example, acetic acid, propionic acid, butyric acid, isobutyric acid. , Valeric acid, isovaleric acid, trimethylacetic acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, pentadecylic acid, palmitic acid, palmitoyl acid, margaric acid, stearic acid, oleic acid, Carboxylic acid such as vaccenic acid, linoleic acid, linolenic acid, ricinoleic acid, arachidonic acid, petrothelic acid, eleostearic acid, licanoic acid, parinaric acid, talylic acid, cadreic acid, behenic acid, lignoceric acid, nervonic acid and melicic acid Acids and acid halides, carboxylic anhydrides and the like of these compounds A carboxylic acid ester and the like.

  The acylation reaction of the present invention can be carried out in various solvents. As a solvent, aprotic solvents such as water, lower alcohols such as methanol, ethanol and isopropanol, aprotic solvents such as dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF), pyridine, dioxane and tetrahydrofuran (THF) A solvent or a mixed solvent thereof can be used, and there is no particular limitation.

  The reaction temperature is not particularly limited, but is preferably 0 to 100 ° C. in order to speed up the reaction between glyceryl ascorbic acid and an acylating agent, and more preferably 20 to 60 ° C. in order to obtain regioselectivity in the reaction. It is. The pH of the reaction solvent is not particularly limited, but is preferably pH 8 to 11 in order to accelerate the progress of the reaction, preferably to prevent decomposition during the reaction of glyceryl ascorbic acid and an acylating agent under alkaline conditions. .

  Since ascorbic acids are easily oxidized, this reaction is preferably performed by substituting the inside of the reaction system with an inert gas such as argon, nitrogen, or helium. The glyceryl ascorbic acid acylated derivative of the present invention can be obtained without substitution with an inert gas. As the catalyst, alkali catalysts such as sodium hydroxide and sodium hydrogen carbonate, acid catalysts such as hydrochloric acid and sulfuric acid, and metal catalysts such as aluminum chloride can be used. It is also possible to use a phase transfer catalyst such as tetrabutylammonium bromide. In addition, the reaction can be performed using an enzyme such as lipase. When performing the reaction, the catalyst may be dissolved in a small amount of water and added so as to be sufficiently mixed. Moreover, the mixing method of raw materials, such as glyceryl ascorbic acid and an acylating agent, is not specifically limited, However, An acylating agent can also be dripped in a reaction system.

  Although there is no restriction | limiting in particular in the usage-amount of the acylating agent with respect to glyceryl ascorbic acid, 0.5-5 mol is preferable with respect to 1 mol of glyceryl ascorbic acid. The smaller the amount of acylating agent used relative to glyceryl ascorbic acid, the more obvious the regiospecificity of the addition reaction, that is, the selective addition of the ascorbic acid skeleton to the 6-position. Moreover, when adding only to 6th-position of an ascorbic acid frame | skeleton, the range of about 0.5-1.5 mol is preferable for the acylating agent to be used.

  When an acylating agent is to be added to both the 6-position of the ascorbic acid skeleton of glyceryl ascorbic acid and the 3-position of the glycerin skeleton, for example, the ascorbic acid skeleton under the above conditions (about 0.5 to 1.5 mol) After obtaining the adduct added only at the 6-position, purification was performed by the method described below, and only the adduct added to only one was taken out. Thereafter, an acylating agent was added to the adduct in an amount of 0.5 to 1 It can be obtained by a method of reacting about 5 moles. By changing the type of acylating agent used in the reaction before and after purification, a compound in which different acyl groups are added to both the 6-position of the ascorbic acid skeleton and the 3-position of the glycerin skeleton can be obtained.

  The glyceryl ascorbyl acylated derivative or its salt produced as described above is used for column chromatography using silica gel, column chromatography using resin such as ion exchange resin, activated carbon treatment, extraction, distillation, crystallization, etc. It can be purified by means.

The glyceryl ascorbyl acylated derivative represented by the above general formula (I), wherein R ¹ or R ² is H, the hydrogen ion from which H is dissociated is replaced with a cation such as a metal ion or an ammonium ion And the salts are also included in the scope of the present invention. Examples of the salt include inorganic salts and organic salts. Examples of inorganic salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, and the like. Can include diethanolamine salts, triethanolamine salts, basic amino acid salts, and the like. The salt formation can be performed by a method similar to the formation of a known salt, such as a method of neutralizing an aqueous solution of an ascorbic acid derivative in which R ¹ or R ² is H with a basic substance.

  The ascorbic acid derivative of the present invention or a salt thereof is suitably used as a component of various cosmetics such as a skin external preparation and a hair cosmetic.

  As described above, the glyceryl ascorbyl acylated derivative of the present invention or a salt thereof has excellent effects such as whitening effect and collagen production promotion effect inherent in ascorbic acid and has a moisturizing effect, and can be stored for a long time. However, it is stable and has little discoloration, odor change, decreased activity, etc. Therefore, by including this glyceryl ascorbyl acylated derivative or a salt thereof as a component, it has an excellent whitening effect, collagen production promoting effect, moisturizing effect, etc., and also has an excellent stability over time, and a cosmetic for hair. Various cosmetics such as cosmetics can be obtained. It can also be used as food additives, feeds, pharmaceuticals, and the like.

  When the glyceryl ascorbyl acylated derivative of the present invention or a salt thereof is used as a humectant, the blending amount in various cosmetics is preferably 1 to 20% by weight, but in other applications, the range of the blending amount Varies depending on the use of the cosmetic, and is not particularly limited, but is usually preferably in the range of 0.01% to 20% by weight. In the case of less than 0.01% by weight, the effects of the ascorbic acid derivative of the present invention or a salt thereof such as a whitening effect cannot be sufficiently exhibited in many cases. On the other hand, when it exceeds 20% by weight, there are many cases where an effect commensurate with the blending amount cannot be expected, and there is a risk of breaking the agent system.

  In addition to this essential component, the cosmetics of the present invention usually include components such as oily raw materials, surfactants, moisturizers, polymer compounds, antioxidants, whitening agents, drugs, UV absorbers, A sequestering agent or the like can be appropriately blended. In addition, although the glyceryl ascorbyl acylated derivative of the present invention or a salt thereof exhibits an effect as a humectant, other humectant can be appropriately blended in the cosmetic of the present invention.

  Examples of the oily raw material include oils and fats such as olive oil, coconut oil, macadamia nut oil, tea seed oil, castor oil, and tri (caprin / capryl) glyceryl, jojoba oil, carnauba wax, candelilla wax, lanolin, beeswax and other waxes, Hydrocarbons such as liquid paraffin, paraffin, petrolatum, ceresin, microcrystalline wax, squalane, fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, isostearic acid, cetyl alcohol, stearyl alcohol, isostearyl Higher alcohols such as alcohol, isopropyl myristate, 2-octyldodecyl myristate, cetyl 2-ethylhexanoate, diisostearyl malate, tri-2-ethylhexanoin, etc., methylpolysiloxane Emissions, methylphenyl polysiloxanes, silicones such as decamethylcyclopentasiloxane or the like.

  Examples of surfactants include anionic surfactants such as higher fatty acid soaps, polyoxyethylene alkyl ether sulfates, acyl-N-methyl taurate salts, N-acyl amino acid salts, alkyl phosphate ester salts, and alkyltrimethyl chlorides. Cationic surfactants such as ammonium and dialkyldimethylammonium chloride, amphoteric surfactants such as alkyldimethylaminoacetic acid betaine, alkylamidoaminoacetic acid betaine, 2-alkyl-N-carboxy-N-hydroxyimidazolinium betaine, polyoxy Nonionic surfactants such as ethylene alkyl ether, polyethylene glycol fatty acid ester, polyhydric alcohol fatty acid ester, and polyether-modified silicone are listed.

  Examples of other humectants include glycerin, propylene glycol, maltitol, sorbitol, 1,3-butylene glycol, sodium lactate, polyethylene glycol, sodium pyrrolidone carboxylate, sodium hyaluronate, and the like.

  Examples of the polymer compound include carboxyvinyl polymer, sodium carboxymethyl cellulose, xanthan gum, polyvinyl alcohol, and polymer dimethylpolysiloxane.

  Examples of the antioxidant include vitamin E, tannin, BHT (butylhydroxytoluene) and the like.

  Examples of other whitening agents include ascorbine such as ellagic acid, chamomile extract, licorice extract, lucinol, rosemary extract, arbutin, tranexamic acid, 4-methoxysalicylic acid potassium salt, ascorbic acid, ascorbic acid glucoside, and ascorbic acid magnesium phosphate. An acid derivative etc. can be mentioned.

  Examples of other drugs include rough skin prevention agents and anti-inflammatory agents. Examples of the rough skin preventive agent or anti-inflammatory agent include dipotassium glycyrrhizinate, stearyl glycyrrhetinate, methyl salicylate, pyridoxine hydrochloride, allantoin, sea salt, persimmon extract, aloe extract, gardenia extract, chamomile extract, licorice extract, mukuroji extract, Kyounin extract, Ogon extract, strawberry tea extract, loquat extract, ginkgo biloba extract, hypericum extract, sorghum extract, safflower extract, spruce extract, salvia extract, birch extract, chimpi extract, tonin extract, gayo extract, altea extract, arnica extract, carrot extract, peony extract , Cucumber extract, gentian extract, cordyceps extract, duckweed extract, ginseng extract, ginseng extract, peach leaf Kiss, kumazasa extract, Yokuininekisu, horse chestnut extract, hawthorn extract, Coptis extract, litchi extract, Toukinsenkaekisu, peppermint extract, comfrey extract, Butcher bloom extract, mortar Beni mallow extract, YAG Rumaru Saw extract, Togenashiekisu, and the like. In addition, other agents such as hair-growth agents, acne agents, dandruff and itching agents, and odor-preventing agents can also be mentioned.

  Examples of protein hydrolysates include protein hydrolysates such as milk protein, silk protein, wheat protein, rice protein, pea protein, collagen, keratin, soybean, sesame, conchiolin, marine collagen, and derivatives thereof. .

  Examples of amino acids or derivatives thereof include glycine, valine, leucine, isoleucine, serine, threonine, phenylalanine, arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid, cystine, cysteine, methionine, tryptophan, proline, histidine and the like. Examples include amino acids and their derivatives.

  Examples of the pH adjuster include lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, malic acid, potassium carbonate, sodium hydrogen carbonate, ammonium hydrogen carbonate and the like.

  Examples of the preservative include paraoxybenzoic acid alkyl ester, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, and phenoxyethanol.

  Examples of thickeners include gum arabic, gum tragacanth, cablo gum, guar gum, pectin, agar, quince seed, starch, alge colloid, xanthan gum, dextran, succinoglucan, collagen, gelatin, casein, albumin, carboxymethyl starch, methylcellulose , Ethyl cellulose, methyl hydroxypropyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, nitrocellulose, sodium cellulose sulfate, sodium carboxymethyl cellulose, sodium arginate, polyvinyl methyl ether, carboxyvinyl polymer, sodium polyacrylate, polyethylene acrylate, poly Acrylamide, cationic polymer, etc. It is below.

  Examples of the dye include tar dyes, natural dyes, inorganic pigments, and polymer powders. Examples of the fragrances include natural fragrances, synthetic fragrances, and blended fragrances.

  The agent system of the cosmetic of the present invention is arbitrary, and any of a solution system, a solubilization system, an emulsification system, a gel system, a powder dispersion system, a water-oil two-layer system, and the like can be used. It can be produced by blending the glyceryl ascorbyl acylated derivative represented by the above general formula (I) or a salt thereof and the above-mentioned optional blending components.

  The glyceryl ascorbyl acylated derivative represented by the general formula (I) or a salt thereof according to the present invention has excellent functions possessed by glyceryl ascorbic acid such as whitening effect and collagen production promoting effect, and has high permeability. It has a moisturizing effect, is stable even after long-term storage, and has little discoloration, odor change, decreased activity, etc. Therefore, by blending this compound into cosmetics such as external preparations for skin and hair cosmetics, it is possible to obtain cosmetics that are excellent in whitening effect, moisturizing effect and the like and stable even after long-term storage. The cosmetics of the present invention are excellent in use feeling, whitening effect, moisturizing effect, anti-aging effect, skin photo-aging preventing effect, Maillard reaction inhibitory effect, wrinkle formation inhibitory effect, antioxidant effect, blood circulation promoting effect, etc. Cosmetics that are stable even when stored (whitening cosmetics, moisturizing cosmetics, etc.).

  According to the production method of the present invention, the glyceryl ascorbic acid acylated derivative represented by the general formula (I) or a salt thereof can be produced simply by reacting glyceryl ascorbic acid with an acylating agent. The glyceryl ascorbyl acylated derivative or salt thereof of the present invention can be easily produced at a low cost.

  Next, specific modes for carrying out the present invention will be described by way of examples. However, the scope of the present invention is not limited by the following examples. Prior to the examples, production examples of glyceryl ascorbic acid used in the examples and comparative examples are shown as synthesis examples.

Synthesis Example 1 Synthesis of 2-O-glyceryl ascorbic acid In an argon atmosphere, L-ascorbic acid (10.0 g) and sodium hydrogen carbonate (9.54 g) were added to water, and the mixture was stirred at room temperature for 30 minutes to give glycidol (8 .41 g) was added. The mixture was heated to 60 ° C. and stirred for 5 hours. Methanol was added and filtered, the filtrate was concentrated under reduced pressure, and 19.0 g of the resulting residue was subjected to silica gel column chromatography. Elution was performed with chloroform / methanol / water = 6/4/1, and concentration was performed under reduced pressure to obtain 2-O-glyceryl ascorbic acid (1.21 g) represented by Chemical Formula 1.

The obtained product was subjected to ¹ H-NMR and ¹³ C-NMR measurements, and from this measurement result, it was confirmed that the product was 2-O-glyceryl ascorbic acid represented by the following structural formula. It was.

In addition, also in the Example shown below, about the obtained product, < ¹ > H-NMR and / or < ¹³ > C-NMR measurement is performed and the measurement result is shown.

In this formula, carbon atoms and hydrogen atoms bonded to each carbon atom are omitted. For example, positions 1 to 4 in this formula are carbon atoms, positions 6, 7, and 9 are CH ₂ groups, and positions 5 and 8 are CH groups. The same applies to the following equations.

The analysis results by NMR (nuclear magnetic resonance spectroscopy) were as follows.
¹ H-NMR (400 MHz, CD ₃ OD): δ ppm 3.61 (2H, m), 3.67 (2H, m), 3.90 (1H, m), 3.92 (1H, dt-like) ), 3.92 (1H, m), 4.07 / 4.09 (1H, dd), 4.86 (1H, d)
¹³ C-NMR (100 MHz, CD ₃ OD): δ ppm 63.3, 63.7, 70.4, 72.0, 74.6, 76.8, 122.2, 161.6, 172.9

Synthesis Example 2 Synthesis of 3-O-glyceryl ascorbic acid In an argon atmosphere, L-ascorbic acid (300 g) and sodium bicarbonate (42.9 g) were added to water, and the mixture was stirred at room temperature for 30 minutes, and then glycidol (126 g). Was added. Thereafter, the mixture was heated to 50 ° C. and stirred for 5 hours. Methanol was added and filtered, the filtrate was concentrated under reduced pressure, and 457 g of the resulting residue was subjected to silica gel column chromatography. Elution was performed with chloroform / methanol / water = 65/35/5, and concentration was performed under reduced pressure to obtain 3-O-glyceryl ascorbic acid (296 g) represented by Chemical Formula 2.

The analysis results by NMR (nuclear magnetic resonance spectroscopy) were as follows.
¹ H-NMR (600 MHz, CD ₃ OD):
δ ppm 3.59 (2H, m), 3.66 (2H, m), 3.89 (1H, m), 3.92 (1H, m), 4.45 / 4.49 (1H, dd) , 4.59 / 4.62 (1H, dd), 4.82 (1H, d)
¹³ C-NMR (150 MHz, CD ₃ OD):
δ ppm 63.4, 63.7, 70.56, 70.61, 71.79, 71.89, 73.4, 73.6, 76.9, 121.17, 121.24, 151.84 151.88, 173.04, 173.07

Example 1 Synthesis of 2-O-glyceryl-6-O-butanoyl ascorbic acid Under argon atmosphere, 5 mL of pyridine was added to 2-O-glyceryl ascorbic acid (50 mg), and n-butanoic anhydride (57 mg) was added. And stirring at 60 ° C. for 3 hours. Then, ethyl acetate was added and extracted with water. The extract was concentrated under reduced pressure, and 98 mg of the resulting residue was subjected to silica gel column chromatography. Purification is carried out by elution with a mixed solution of chloroform / methanol / water = 7/3 / 0.3, followed by concentration under reduced pressure, and 2-O-glyceryl-6-O- butanoylascorbic acid represented by Chemical formula 3 ( 43 mg) was obtained. Identification was performed by ¹ H-NMR and ¹³ C-NMR.

The analysis results by NMR (nuclear magnetic resonance spectroscopy) were as follows.
¹ H-NMR (400 MHz, CD ₃ OD):
δ ppm 0.95 (3H, t), 1.60 (2H, m), 2.34 (2H, m), 3.60 (2H, t), 3.90 (2H, m), 4.13 (3H, m), 4.79 (1H, d)
¹³ C-NMR (150 MHz, CD ₃ OD):
δ ppm 13.9, 19.3, 36.7, 63.7, 65.6, 67.9, 72.0, 74.65, 74.70, 77.19, 122.29, 122.32, 161.50, 161.54, 172.6, 174.9

Example 2 Synthesis of 2-O-glyceryl-6-O-octanoyl ascorbic acid Under argon atmosphere, 5 mL of pyridine was added to 2-O-glyceryl ascorbic acid (50 mg), and n-octanoic anhydride (97 mg) was added. And stirring at 60 ° C. for 3 hours. Then, ethyl acetate was added and extracted with water. The extract was concentrated under reduced pressure, and 134 mg of the resulting residue was subjected to silica gel column chromatography. Elution was carried out with a mixture of chloroform / methanol / water = 7/3 / 0.3, and the mixture was concentrated under reduced pressure to give 2-O-glyceryl-6-O-octanoylascorbic acid (67 0.0 mg) was obtained. Identification was performed by ¹ H-NMR and ¹³ C-NMR.

The analysis results by NMR (nuclear magnetic resonance spectroscopy) were as follows.
¹ H-NMR (400 MHz, CD ₃ OD):
δ ppm 0.89 (3H, t), 1.31 (8H, m), 1.60 (2H, m), 2.36 (2H, m), 3.60 (2H, t), 3.87 (1H, m), 3.94 (1H, m), 4.09 (2H, m), 4.17 (1H, m), 4.27 (1H, m), 4.79 (1H, d)
¹³ C-NMR (100 MHz, CD ₃ OD):
δ ppm 14.4, 23.6, 25.9, 30.0, 30.1, 32.8, 34.8, 63.8, 65.6, 67.9, 72.1, 74.70 , 74.70, 74.74, 77.2, 122.4, 161.3, 172.6, 175.4

Example 3 Synthesis of 2-O-glyceryl-6-O-hexadecanoyl ascorbic acid Under argon atmosphere, 5 mL of pyridine was added to 2-O-glyceryl ascorbic acid (50 mg), and n- hexadecanoic anhydride (176 mg) was added. In addition, the mixture was stirred at 60 ° C. for 3 hours. Then, water was added and extraction was performed with ethyl acetate . The extract was concentrated under reduced pressure, and 134 mg of the resulting residue was subjected to silica gel column chromatography. Elution was carried out with a mixture of chloroform / methanol / water = 7/3 / 0.3, followed by concentration under reduced pressure, and 2-O-glyceryl-6-O-hexadecanoyl ascorbic acid ( 65 mg) was obtained. Identification was performed by ¹ H-NMR and ¹³ C-NMR.

The analysis results by NMR (nuclear magnetic resonance spectroscopy) were as follows.
¹ H-NMR (400 MHz, CD ₃ OD):
δ ppm 0.95 (3H, t), 1.60 (2H, m), 2.34 (2H, m), 3.60 (2H, t), 3.90 (2H, m), 4.13 (3H, m), 4.79 (1H, d)
¹³ C-NMR (150 MHz, CD ₃ OD):
δ ppm 14.4, 23.7, 26.0, 30.2, 30.4, 30.5, 30.7, 33.0, 35.0, 63.7, 65.6, 67.8, 71.9, 74.7, 74.8, 77.3, 122.3, 161.6, 172.9, 175.1

Example 4 2-O-under argon atmosphere (3 '- - O octanoyl glyceryl) -6-O-octanoyl-ascorbic acid, the 2-O-glyceryl ascorbic acid (50 mg) in pyridine 5mL added, n- Octanoic anhydride (194 mg) was added, and the mixture was stirred at 60 ° C. for 3 hr. Then, water was added and extraction was performed with ethyl acetate. The extract was concentrated under reduced pressure, and 232 mg of the resulting residue was subjected to silica gel column chromatography. Chloroform / methanol / water = 7/3 / 0.3 eluting with mixture was purified, and concentration under reduced pressure, 2-O-represented by the formula 6 (3 '- O - octanoyl glyceryl) -6 -O-octanoyl ascorbic acid (83.0 mg) was obtained. Identification was performed by ¹ H-NMR and ¹³ C-NMR.

The analysis results by NMR (nuclear magnetic resonance spectroscopy) were as follows.
¹ H-NMR (400 MHz, CD ₃ OD):
δ ppm 0.89 (6H, t), 1.30 (16H, brs), 1.59 (4H, m), (2H, m), 2.30 (4H, m), 3.98 (1H, m), 4.06 (2H, m), 4.15 (3H, m), 4.26 (1H, m), 4.76 (1H, d)
¹³ C-NMR (100 MHz, CD ₃ OD):
δ ppm 14.4, 23.5, 26.0, 30.0, 30.1, 32.7, 34.9, 65.4, 65.8, 67.9, 69.3, 74.0 , 77.1, 122.0, 161.5, 172.3, 174.8

Example 5 Synthesis of 2-O-glyceryl-6-O-dodecanoyl ascorbic acid Under argon atmosphere, 5 mL of pyridine was added to 2-O-glyceryl ascorbic acid (50 mg), and n-dodecanoic anhydride (138 mg) was added. And stirring at 60 ° C. for 3 hours. Then, ethyl acetate was added and extracted with water. The extract was concentrated under reduced pressure, and 134 mg of the resulting residue was subjected to silica gel column chromatography. Elution was performed with a mixed solution of chloroform / methanol / water = 7/3 / 0.3, followed by concentration under reduced pressure. 2-O-glyceryl-6-O-dodecanoyl ascorbic acid (73 mg) represented by Chemical formula 7 ) Identification was performed by ¹ H-NMR and ¹³ C-NMR.

Example 6 Synthesis of 2-O-glyceryl-6-O- (2- ethylhexanoyl ) ascorbic acid Under argon atmosphere, 5 mL of pyridine was added to 2-O-glycerylascorbic acid (50 mg), and 2-ethylhexanoic anhydride was added. (118 mg) was added, and the mixture was stirred at 60 ° C. for 3 hours. Then, ethyl acetate was added and extracted with water. The extract was concentrated under reduced pressure, and 134 mg of the resulting residue was subjected to silica gel column chromatography. Elution was carried out with a mixture of chloroform / methanol / water = 7/3 / 0.3, and the mixture was concentrated under reduced pressure. 2-O-glyceryl-6-O- (2- ethylhexanoyl ) represented by the formula 8 Ascorbic acid (55 mg) was obtained. Identification was performed by ¹ H-NMR and ¹³ C-NMR.

Test Example 1 [Melanin production inhibition test]
As a test of the whitening effect, the effect of B16 melanoma 4A5 cells on theophylline-induced melanin production was evaluated for the glyceryl ascorbyl acylated derivative of the present invention by the following procedure. In addition, as comparative products, melanin using arbutin, ascorbic acid, sodium ascorbate, magnesium ascorbate phosphate, glucoside ascorbate, and 3-O-glyceryl ascorbic acid and 2-O-glyceryl ascorbic acid produced in the synthesis example A production inhibition test was conducted.

(1) B16 mouse The melanoma 4A5 strain was seeded in a 48-well plate at a cell density of 2.0 × 10 ⁴ cells / well.
(2) After culture for 24 hours in Dulbecco's modified Eagle medium (manufactured by SIGMA, hereinafter abbreviated as D-MEM) containing 10% fetal bovine serum (manufactured by Invitrogen), 0.2 mM theophylline and a predetermined concentration The sample was replaced with D-MEM containing 10% fetal bovine serum containing the sample.
(3) After culturing for 3 days in the presence of the sample, the medium was removed using an aspirator, and distilled water was added and the cells were disrupted by ultrasonic waves.
(4) Thereafter, the amount of protein was quantified using a BCA protein assay kit (manufactured by PIERCE), and the amount of melanin produced was measured by the alkali solubilization method described later. Sodium hydroxide was added to the cell lysate so as to have a final concentration of 2N and dissolved by heating (60 ° C., 15 minutes), and then the absorbance at 450 nm was measured using a microplate reader. The amount of melanin was calculated from a calibration curve prepared using synthetic melanin (SIGMA) as a standard product. The amount of melanin per unit protein was calculated by dividing the amount of melanin by the amount of protein.
(5) The melanin production inhibition rate was calculated from the following equation.
Melanin production inhibition rate (%) = [1− (A−B) / (C−B)] × 100
[In the formula, A is the amount of melanin per unit protein at the time of sample addition (g / g), B is the amount of melanin per unit protein of the normal group (g / g), and C is the amount per unit protein of the control group. The amount of melanin (g / g) is shown. ]

  Normal was theophylline (−) and sample (−), and Control was theophylline (+) and sample (−).

The sample was applied at a concentration of 100 μM or less, and the whitening effect was expressed as follows based on the melanin production inhibition rate when measured , and the results are shown in Table 1. The measurement was performed at N = 4.
<30%: △
30 or more and less than 50% : ○
50% or more: ◎

  The results of Table 1 show that the glyceryl ascorbyl acylated derivative of the present invention is a known ascorbic acid derivative or a salt thereof, that is, sodium ascorbate, ascorbyl glucoside, magnesium ascorbate phosphate, 3-O-glyceryl ascorbic acid, It shows that it has a whitening effect superior to 2-O-glyceryl ascorbic acid.

Test Example 2 [Collagen production evaluation test]
The collagen production promoting effects of the glyceryl ascorbyl acylated derivatives of Examples 1 to 6 were evaluated by the following collagen production evaluation test method. As in Comparative Example 1, arbutin, ascorbic acid, sodium ascorbate, magnesium ascorbate phosphate, glucoside ascorbate, 3-O-glyceryl ascorbic acid and 2-O-glyceryl ascorbic acid were used as comparative products. It was.

After preparing normal human skin fibroblasts with D-MEM containing 10% (v / v) fetal bovine serum (manufactured by Invitrogen) to a cell density of 2.5 × 10 ⁴ cells / well, 96 wells The plate was preincubated for 24 hours. After removing the medium, a sample prepared with D-MEM containing 5% (v / v) fetal bovine serum to a concentration of 100 μM was added to each well, followed by culturing at 37 ° C. under 5% CO ₂ for 48 hours. . After completion of the culture, the amount of free collagen was measured using a Sircol collagen assay kit (manufactured by Biocolor). The measurement was performed at N = 4.

The sample was applied at a concentration of 100 μM, the amount of collagen produced when measured was compared with the Control group, and the results (% value when the Control group is 100%) are shown in Table 2 based on the following criteria.
<100%: ±
100-200%: +

  The results in Table 2 show that the glyceryl ascorbic acid acylated derivative of the present invention is as good as known ascorbic acid derivatives such as ascorbic acid, magnesium ascorbate phosphate, and glucoside ascorbate, which are very excellent as collagen production promoting substances. It shows that it has an effect of promoting collagen production.

Test Example 3 [Stability test]
Using 2-O-glyceryl-6-O-octanoylascorbic acid of Example 2, the stability was evaluated in the following manner for odor and coloring when stored at 50 ° C. for 4 weeks. As comparative products, magnesium ascorbate phosphate, ascorbic acid, and 3-O-glyceryl ascorbic acid were used.

  A 2% aqueous solution of each test sample was adjusted to pH 7 with dilute sodium hydroxide aqueous solution or dilute hydrochloric acid aqueous solution, sealed in a 50 mL screw tube, and stored at 50 ° C. for 4 weeks. Immediately after the preparation of the test sample, 2 weeks and 4 weeks after storage, the odor and the coloring degree of the solution were evaluated by 10 panelists based on the following criteria. The results are shown in Table 3.

odor:
3: Almost odorless 2: Slight odor is felt 1: Coloring with strong odor:
3: Little change compared to immediately after preparation 2: Colored compared to immediately after preparation 1: Strongly colored compared to immediately after preparation

The evaluation results of odor and coloring were classified as follows.
○: Total score of 10 people is 25 or more Δ: Total score of 10 people is 16-24
×: Total score of 10 people is 15 or less

  As shown in Table 3, it was confirmed that the glyceryl ascorbyl acylated derivative of the present invention is excellent in stability in terms of odor and coloring.

Test Example 4 [Emulsification stability test]
2-O-glyceryl -6-O-hexadecanoyl-ascorbic acid of Example 3, ascorbic acid as a comparative example, emulsion composition of the formulation shown in Table 4 by using ascorbic acid magnesium phosphate and 2-O-glyceryl ascorbic acid Each product was prepared. Each preparation was sealed in a 50 mL screw tube and stored at 50 ° C. for 1 week. The appearance of the emulsified composition after 1 week was evaluated by 10 panelists according to the following evaluation criteria.

Evaluation criteria 3: Separation of two layers of water layer and oil layer is not observed 2: Aqueous layer is slightly raised 1: Separation of water layer and oil layer into two layers is observed Based on this evaluation result, Classified. The results are shown in Table 4.
○: Total score of 10 people is 25 or more Δ: Total score of 10 people is 16-24
×: Total score of 10 people is 15 or less

The remainder means an amount necessary for the total amount to be 100 parts by weight. The same applies to the remainder in the table below.

  As shown in Table 4, it was confirmed that the glyceryl ascorbyl acylated derivative of the present invention was excellent in terms of emulsion stability.

Test Example 5 [Skin permeability test]
The permeability of the glyceryl ascorbyl acylated derivatives of Examples 1 to 5 to the skin was tested by the following method. As comparative products, sodium ascorbate, magnesium ascorbate phosphate, glucoside ascorbate, 3-O-glyceryl ascorbic acid, 2-O-glyceryl ascorbic acid and 3-O-cetyl ascorbic acid were used.

  3 g of each test sample is dissolved in 100 mL of water, adjusted to pH 7 with dilute aqueous sodium hydroxide or dilute hydrochloric acid, respectively, a 2 cm × 2 cm filter paper is placed on the forearm, and 0.5 mL of the prepared sample is attached thereto. , Covered with nylon and fixed. After 8 hours, the portion of the forearm with the sample was washed and subjected to tape stripping 15 times. Samples were extracted from each tape with a mixed solvent of water / acetone = 1/1, and the extract was analyzed at a detection wavelength of 254 nm using HPLC (high performance liquid chromatography) to examine the degree of penetration of the sample into the skin. . The permeability of the sample to the skin was determined according to the following evaluation criteria. The results are shown in Table 5.

(Criteria)
○: Sample was detected until tape stripping 10 to 15 times Δ: Sample was detected until tape stripping 3 to 9 times ×: Sample was detected or not detected until tape stripping 1 to 2 times

Test Example 6 [Moisturizing test]
In vitro and in vivo moisture retention tests of the glyceryl ascorbyl acylated derivatives of Examples 1 to 5 were performed as follows. As comparative products, sodium ascorbate, magnesium ascorbate phosphate, glucoside ascorbate, 3-O-glyceryl ascorbic acid, 2-O-glyceryl ascorbic acid and 3-O-cetyl ascorbic acid were used.

1. In vitro moisturizing test Each sample was dried, and the dried sample was placed at the bottom of a weighing bottle (diameter 3.6 cm, height 1.8 cm excluding the lid) at about 0.4 g (this weight is designated as W ₀ ). ) And stretched to a uniform thickness. The sample contained in the weighing bottle was allowed to stand in an environment of 25 ° C. and 65% RH in a thermo-hygrostat (ENVIROS KCL-1000, EYELA). The weight was measured periodically, fully absorbed and waited for the weight gain to reach equilibrium (about 48 hours). Thereafter, the mixture was transferred to an environment of 25 ° C. and 20% RH (in a sealed container filled with a saturated CH ₃ COOK aqueous solution at the bottom), and the weight after 24 hours (this weight is defined as W ₁ ) is calculated from the formula (W ₁ − Based on W ₀ ) / W ₀ , the amount of water retained per gram of the dried sample was calculated. The moisture retention effect was determined based on the following determination criteria from the moisture content thus calculated, and the results are shown in Table 6.

(Criteria)
○: 35 mg or more Δ: 15 mg or more and less than 35 mg ×: less than 15 mg

2. In vivo moisturizing test 5 g of each test sample was dissolved in 100 mL of water, adjusted to pH 7 with dilute sodium hydroxide aqueous solution or dilute hydrochloric acid aqueous solution, and a 1 cm × 1 cm filter paper was placed on the forearm, and the prepared sample was 0 3 mL was attached and covered with nylon and fixed. Thereafter, after 3 hours and 8 hours, the corneum water content of the part to which the sample was attached was determined to be CORNEOMETER.
Measurement was performed using CM825 (manufactured by Integral). The test was performed with 10 test subjects, and the evaluation was performed according to the following evaluation criteria.

Evaluation criteria 3: The amount of keratin moisture increased by 15% or more than before sample application 2: The amount of horny water increased by more than 0 and less than 15% than before sample application 1: The amount of horny water changed before and after sample application Based on the evaluation results that were absent or decreased, the classification was as follows. The results are shown in Table 6.
○: Total score of 10 people is 25 or more Δ: Total score of 10 people is 16-24
×: Total score of 10 people is 15 or less

As shown in Table 5, the glyceryl ascorbic acid acylated derivative of the present invention is superior in moisture retention when applied to the skin, as compared with the comparative product ascorbic acid and its derivatives. Moreover, compared with glyceryl ascorbic acid, the amount of stratum corneum increases in a short time . The glyceryl ascorbic acid acylated derivative of the present invention is imparted with hydrophobicity to glyceryl ascorbic acid and has excellent permeability to the skin. Furthermore, excellent solubility in oil, superior in permeability to the skin, compared to 3-O-cetyl ascorbic acid shows a high moisturizing effect in tests in in vivo. Similar to glyceryl ascorbic acid having moisturizing properties in vitro , a moisturizing effect derived from a glyceryl group is obtained.

Example 6 Cream (1) to (5) oil phase raw materials and compositions (6) to (10) water phase raw materials of the compositions shown in Table 6 were each heated to 70 ° C and dissolved, An oil phase and an aqueous phase were prepared respectively. Thereafter, the oil phase was added to the aqueous phase, preliminarily emulsified, and uniformly emulsified with a homomixer, and then cooled to room temperature with good stirring, whereby a cream excellent in moisturizing effect and whitening effect could be prepared. . In addition, in the table | surface after Table 7, a compounding quantity represents a mass part.

Example 7 Emulsion (1) to (9) oil phase part raw materials and (10) to (13) aqueous phase part raw materials of the composition shown in Table 8 were each heated to 70 ° C and dissolved, An oil phase and an aqueous phase were prepared respectively. Then, after preliminarily emulsifying by adding the oil phase to the aqueous phase, uniformly emulsifying with a homomixer, and cooling to room temperature with good stirring, an emulsion having excellent moisturizing and whitening effects could be prepared. .

Example 8 Emulsion The raw materials for the oil phase parts (4) to (10) and the aqueous phase parts (1) to (3) and (11) to (12) having the compositions shown in Table 9 were each 70 ° C. And dissolved in an oil phase and an aqueous phase, respectively. Thereafter, the oil phase was added to the aqueous phase, preliminarily emulsified, and uniformly emulsified with a homomixer, and then cooled to room temperature with good stirring, whereby a cream excellent in moisturizing effect and whitening effect could be prepared. .

Example 9 Cream (1) to (3) oil phase raw materials and compositions (4) to (10) water phase raw materials of the composition shown in Table 10 were each heated to 70 ° C. and dissolved. After preparing the oil phase and the water phase, respectively, preliminarily emulsify by adding the oil phase to the water phase, uniformly emulsify with a homomixer, and then cool to room temperature while stirring well, so that the moisturizing effect and whitening effect are excellent. A cream could be prepared.

Example 10 Cream The oil phase parts (1) to (5) and the water phase parts (6) to (10) having the compositions shown in Table 11 are heated and dissolved at 70 ° C., respectively. The oil phase was added to the water phase and pre-emulsified, and then emulsified with a homomixer, and then cooled to room temperature with good stirring, whereby a cream excellent in moisturizing effect and whitening effect could be prepared.

Example 11 Lotion A lotion excellent in moisturizing effect and whitening effect could be prepared by mixing the raw materials of (1) to (6) having the composition shown in Table 12 with good stirring.

Claims (8)

The acylated derivative of glyceryl ascorbic acid represented by the following general formula (I) or a salt thereof.
[Wherein, R ¹ and R ² are a hydrogen atom, R ⁵ —O—CH ₂ —CH (OH) —CH ₂ —, or a group represented by R ⁶ —CO— (R ⁵ represents hydrogen An atom or a group represented by R ⁶ —CO—, wherein R ⁶ represents a hydrogen atom, an alkyl group having 1 to 22 carbon atoms or an alkenyl group having 2 to 22 carbon atoms), R ³ and R ⁴ are A group represented by R ⁵ — (R ⁵ is the same as above). However, at least one of R ¹ and R ² is a group represented by R ⁵ —O—CH ₂ —CH (OH) —CH ₂ —, and when R ³ and R ⁴ are both hydrogen atoms, ^At least one of ¹ and R ² is a group represented by R ⁶ —CO—O—CH ₂ —CH (OH) —CH ₂ —, or ^one of R ¹ and R ² is HO—CH _2. A group represented by —CH (OH) —CH ₂ — and the other is a group represented by R ⁶ —CO— (R ⁶ is as defined above). ] The glyceryl ascorbic acid acylated derivative according to claim 1, wherein R ³ in the general formula (I) is a hydrogen atom, and R ⁴ is a hydrogen atom or a group represented by R ⁶ —CO—, or a derivative thereof. salt. The glyceryl ascorbyl acylated derivative according to claim 1, which has an R ⁶ -CO- group in only one of R ¹ , R ² and R ^{4 in} the general formula (I). Its salt. In the general formula (I), at least one of R ¹ and R ² is a group represented by R ⁵ —O—CH ₂ —CH (OH) —CH ₂ —, and R ⁵ is a hydrogen atom. The glyceryl ascorbic acid acylated derivative or a salt thereof according to claim 2, wherein R ⁴ is R ⁶ -CO-. In the general formula (I), R ¹ is a group represented by R ⁵ —O—CH ₂ —CH (OH) —CH ₂ —, R ⁵ is a hydrogen atom, and R ² is hydrogen. The glyceryl ascorbic acid acylated derivative or salt thereof according to claim 4, which is an atom. R in the general formula (I) ¹ Is R ⁵ -O-CH ₂ -CH (OH) -CH ₂ A group represented by-and R ⁵ Is R ⁶ A group represented by -CO-, R ² And R ³ Is a hydrogen atom and R ⁴ Is R ⁶ The glyceryl ascorbyl acylated derivative or a salt thereof according to claim 1, which is a group represented by -CO-. A cosmetic comprising the glyceryl ascorbyl acylated derivative according to any one of claims 1 to 6, or a salt thereof. A whitening cosmetic comprising the glyceryl ascorbyl acylated derivative or a salt thereof according to any one of claims 1 to 6.